Heteroaryl Rings in Peptide Macrocycles | Chemical Reviews

Review Cite This: Chem. Rev. XXXX, XXX, XXX−XXX

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Heteroaryl Rings in Peptide Macrocycles Ivan V. Smolyar,† Andrei K. Yudin,*,‡ and Valentine G. Nenajdenko*,† †

Department of Chemistry, Moscow State University, Leninskije Gory, 199991 Moscow, Russia Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S 3H6, Canada

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‡

ABSTRACT: This Review is devoted to the chemistry of macrocyclic peptides having heterocyclic fragments in their structure. These motifs are present in many natural products and synthetic macrocycles designed against a particular biochemical target. Thiazole and oxazole are particularly common constituents of naturally occurring macrocyclic peptide molecules. This frequency of occurrence is because the thiazole and oxazole rings originate from cysteine, serine, and threonine residues. Whereas other heteroaryl groups are found less frequently, they offer many insightful lessons that range from conformational control to receptor/ligand interactions. Many options to develop new and improved technologies to prepare natural products have appeared in recent years, and the synthetic community has been pursuing synthetic macrocycles that have no precedent in nature. This Review attempts to summarize progress in this area.

CONTENTS 1. Introduction 2. Pyrroles in Macrocyclic Peptide Scaffolds 3. Indoles in Macrocyclic Peptide Scaffolds 3.1. Cross-Linking to Position 1 of the Indole of Tryptophan 3.2. Cross-Linking to Position 2 of the Indole of Tryptophan 3.3. Cross-Linking to Position 6 of the Indole of Tryptophan 3.4. Cross-Linking to Position 7 of the Indole of Tryptophan 3.5. Other Methods 4. Carbazoles in Macrocyclic Peptide Scaffolds 5. Furans in Macrocyclic Peptide Scaffolds 5.1. Incorporation of Furan by Positions 2 and 5 5.2. Incorporation of Furan by Positions 2 and 4 5.3. Incorporation of Furan by Positions 2 and3 6. Thiophenes in Macrocyclic Peptide Scaffolds 7. Imidazoles Macrocyclic Peptide Scaffolds 7.1. Natural Imidazole-Containing Macrocycles 7.1.1. Aciculitins 7.1.2. Theonellamides 7.2. Artificial Imidazole-Containing Macrocycles 7.2.1. Incorporation of Imidazole by Positions 2 and 4 7.2.2. Incorporation of Imidazole by Positions 4 and 5 7.2.3. Incorporation of Imidazole by Positions 1 and 5 7.2.4. Incorporation of Imidazole by Positions 1 and 4 8. Oxazoles in Macrocyclic Peptide Scaffolds 8.1. Natural Oxazole-Containing Macrocycles © XXXX American Chemical Society

8.1.1. Discobahamins A and B 8.1.2. Keramamides B−E and M−N 8.1.3. Nazumazoles A−F 8.1.4. Orbiculamide A 8.1.5. Telomestatin 8.1.6. Wewakazoles 8.2. Artificial Oxazole-Incorporating Macrocycles 8.2.1. Incorporation of Oxazole by Positions 2 and 4 8.2.2. Incorporation of Oxazole by Positions 4 and 5 9. Thiazoles in Macrocyclic Peptide Scaffolds 9.1. Natural Thiazole-Containing Macrocycles 9.1.1. Aerucyclamides 9.1.2. Aeruginazole A 9.1.3. Antalid 9.1.4. Argyrins 9.1.5. Ascidiacyclamide 9.1.6. Balgacyclamides 9.1.7. Bistratamides, Didmolamides, and Related Synthetic Macrocycles 9.1.8. Calyxamides 9.1.9. Ceratospongamide 9.1.10. Cyclodidemnamides 9.1.11. Danamides D and F and Sanguinamide A 9.1.12. Dolastatin and Homodolastatin 9.1.13. Guineamides 9.1.14. Haligramides and Waiakeamide 9.1.15. Hectochlorin

B E G G O V AC AC AD AD AD AG AH AH AL AL AL AL AM AM AQ AR AR AS AS

AS AS AT AT AT AW AZ AZ BA BA BD BD BE BF BG BN BQ BQ BU BU BV BX BY CB CB CB

Special Issue: Macrocycles Received: January 3, 2019

A

DOI: 10.1021/acs.chemrev.8b00789 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews 9.1.16. Hoiamides 9.1.17. Jamaicensamide A 9.1.18. Keramamides F−H, J, and K 9.1.19. Kororamide 9.1.20. Largazole 9.1.21. Largazole Analogues 9.1.22. Lissoclinamides 9.1.23. Lyngbyabellins 9.1.24. Marthiapeptide A 9.1.25. Mayotamides 9.1.26. Mollamide C 9.1.27. Microcyclamide GL616 9.1.28. Obyanamide 9.1.29. Oriamide and Cyclotheonellazoles 9.1.30. Patellamides 9.1.31. Scleritodermin A 9.1.32. Tawicyclamides 9.1.33. Trichamide 9.1.34. Ulicyclamide 9.1.35. Ulithiacyclamides 9.1.36. Ulongamides 9.2. Other Thiazole-Containing Macrocycles 10. Triazoles in Macrocyclic Peptide Scaffolds 10.1. General Considerations: Monomers and Dimers: Extreme Cases of Click-Macrocyclization 10.2. Other Peptidomimetic Fragments 10.3. Double-Click Stapling 10.4. MCR and CuAAC 10.5. Flow Chemistry 10.6. Diversity-Oriented Synthesis 10.7. Biotechnology 10.8. Stabilization of Peptide Secondary Structure 10.9. Disulfide Mimetics 10.10. Analogues of Natural Products 10.11. De Novo Design 11. Oxa - and Thiadiazoles in Macrocyclic Peptide Scaffolds 12. Tetrazoles in Macrocyclic Peptide Scaffolds 13. Pyridines in Macrocyclic Peptide Scaffolds 13.1. Pyridine Largazole Analogues 13.2. DMP 757 Analogue 13.3. Bipicolyl Fragments in Cyclic Peptides 13.4. Other Methods 14. Pyrimidines and Purines in Macrocyclic Peptide Scaffolds 15. Triazines and Tetrazines in Macrocyclic Peptide Scaffolds 15.1. Triazine 15.2. s-Tetrazine 16. Thiazolyl Peptides 16.1. Group 1 (Type II, Series a Compounds) 16.2. Group 2 (Type II, Series b Compounds) 16.2.1. Thiostrepton 16.2.2. Siomycin A 16.3. Group 3 (Type II, Series c Compounds) 16.4. Group 4 (Type III, Series d Compounds) 16.4.1. GE2270 16.4.2. Amythiamicins 16.5. Group 5 (Type III, Series d Compounds) 16.5.1. Micrococcin P1 16.5.2. Thiocillin I

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CC CC CD CF CF CR DD DF DG DG DH DH DH DI DI DK DM DM DM DM DN DP DP

16.6. Group 6 (Type III, Series d Compounds) 16.6.1. Baringolin 16.7. Group 7 (Type III, Series d Compounds) 16.8. Group 8 (Type III, Series d Compounds) 16.8.1. Promothiocin 16.9. Group 9 (Type III, Series d Compounds) 16.10. Group 10 (Type I, Series e Compounds) 16.10.1. Nosiheptide 17. Macrocycles with Multiple Different Heteroarenes 17.1. Macrocycles Related to Bistratamides and Lissoclinamides 17.2. Macrocycles Related to Telomestatin and Marthiapeptide A 17.3. Celogentin C and Moroidin 18. Conclusions Author Information Corresponding Authors ORCID Notes Biographies Acknowledgments References

FQ FQ FS FS FS FT FU FU

DP DS DU DU DV DX DY

1. INTRODUCTION Peptides and proteins play a key role in all biological systems. Despite the fact that peptides and proteins are the basis of all

FW FW FW FX GG GK GK GK GK GK GK GK

EA EB EC EF EG EK EL EL EN EN ES ES ES ES EU EU EW EX EX FB FF FF FG FJ FN FN FO

Figure 1. Scope of aromatic heterocycles in natural and synthetic macrocyclic peptides.

living organisms, the pharmacological application of peptides is somewhat limited, and members of this large family of molecules have significant limitations as medicines. Peptides usually do not correspond to Lipinski’s “rule of five”1,2 and Veber’s rules3 used to qualitatively evaluate the “drug-likeness” of a molecule. Indeed, a relatively short sequence of ten amino B


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Scheme 1. Synthesis of Pyrrole-Containing Macrocyclic Peptides 16−18

the “middle space”. Many natural macrocyclic scaffolds include indole and imidazole fragments (originated from transformations of Trp and His side chains), oxa- and thiazole rings (metabolism of Ser and Cys fragments), and highly (three- or four-) substituted pyridine (biosynthesized in several thiopeptides via a hetero-Diels−Alder reaction). Synthetic peptide macrocycles include furan, thiophene, pyrrole, carbazole, 1,2,3-triazole, tetrazole oxadiazole, thiadiazole, pyrimidine, purine, and s-triazine moieties as well as all of the above-mentioned naturally occurring heterocycles (Figure 1). The introduction of heteroaryl grafts in peptide scaffolds also extends the usual synthetic toolset for assembling macrocyclic architectures. Whereas homodetic peptides are usually accessed via numerous macrolactamization protocols, the incorporation of a heteroaromatic fragment allows the use of intra- and intermolecular SNAr reactions, cross-coupling, as well as click chemistry and multicomponent reactions (MCRs), which allow tandem macrocyclization and the installation of a heterocycle in the peptide scaffold.10−12 Heterocycle-bearing macrocycles are conformationally (and therefore topologically) more restricted than their all-amide counterparts, and if these predefined conformations correspond to the structure of the target receptor, then the former can become not only exceptionally active but also selective for different receptor subtypes.13−15 Many candidates for peptide drugs are macrocycles that have not only high affinity but also relatively high resistance to enzymatic degradation, and some

acids would have a molecular weight of more than 500, equipped with more than five H-bond donors and more than ten H-bond acceptors. In addition, peptide bonds are susceptible to enzymatic hydrolysis by proteases and peptidases present in the intestine, resulting in the rapid degradation of most natural peptides. As a result, these molecules display low oral bioavailability.4−6 The conformational lability of linear peptides also adversely affects their biological activity. A linear peptide must adopt the proper bioactive conformation upon binding to its protein target. If the flexibility of the molecule is high, then it can exist as a large number of different (inactive) conformations. As a result, the binding affinity is significantly reduced due to the entropy term that affects the free Gibbs energy (ΔG) of binding and, consequently, the dissociation constant (Kd) of the drug. Cyclic peptides, in contrast, are capable of preorganizing the cyclic scaffold and amino acid side chains, which leads to a decrease in PSA (polar surface area) and favors the formation of intramolecular H-bond networks.7−9 Aromatic heterocycles are important structural units of a vast number of small-molecule drugs. The inclusion of flat heterocyclic motifs in the structure of a cyclic peptide often results in the stabilization of its secondary structure by conserving an intramolecular network of hydrogen bonds in addition to the added advantage of a robust heterocyclic structure. This leads to an improvement in the metabolic stability, activity, and selectivity of peptide pharmaceuticals of C


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Figure 2. Cyclic peptides from Lycium chinense Mill. and Celosia argentea L.

even are available for oral use.16 Moreover, some macrocycles exhibit favorable transport properties due to their amphipathic character. Such behavior can be caused by conformational changes through a shift between intra- and intermolecular noncovalent interactions. Macrocyclic peptides consisting exclusively of natural amino acids, the products of their biochemical transformations, as well as compounds that include nonpeptide fragments are widely found in nature in the tissues of fungi, sea sponges, and microorganisms and also in higher plants.17−19 The vast majority of these molecules are metabolites of larger peptides and proteins.20−22 By occupying the intermediate space between small molecules and proteins, macrocycles can harness the exclusive specificity of biological drugs and the synthetic attainability of small-molecule drugs. The ability to adjust the metabolic stability (by bioisosteric replacement of fragments subject to cleavage by peptidases) and the conformational fixation of macrocyclic peptidomimetics opens wide horizons for the rational design, synthesis, and study of these compounds as promising inhibitors of various biological targets. The choice of building blocks and a wide arsenal of synthetic methods of organic chemistry make it possible to synthesize various classes of cyclic peptidomimetics in which individual fragments of amino acids or peptide bonds are replaced by other fragments. The purpose of these modifications is to (1) increase the selectivity and activity of the molecule with respect to the biological target, (2) increase the biological half life of the compound by decreasing its tendency for metabolic degradation, and (3) modify the lipophilicity and cell permeability of compound. The linear

analogues of macrocyclic peptides often demonstrate poor cell permeability. These compounds are proteolytically labile. As a result, intravenous, subcutaneous, or intramuscular routes of administration are most common for peptide drugs.23,24 Despite the intensive development of this field, there is still no way to systematize the structural space encompassed by macrocycles. The number of isolated and characterized natural macrocyclic peptides is too small to reliably detect any patterns; however, it has been reported that 18-membered rings tend to be the most prevalent ring size in amino-acidderived macrocyclic natural products.25 These macrocycles are difficult to modify to study the structure−activity relationship (SAR) or to switch their activity toward various biological targets. At the present, there are no tools for quantifying the effect of the macrocyclic topology on the effectiveness of the biological target engagement or for predicting the composition and size of the macrocyclic inhibitor of a given protein. However, different parameters, such as cellular permeability and oral bioavailability, are expected to be augmented when a macrocycle can engage in intramolecular hydrogen bonding.26 The introduction of rigid fragments does not a priori guarantee the improvement of pharmacokinetic parameters and will be manifested only when the applied “reinforcement” does not interfere with the binding of the molecule to the target protein.27−29 Because of the described advantages, an increasing number of synthetic macrocycles are in different stages of clinical trials, with a significant part of these drugs on the market. About 70 macrocyclic drugs are currently in clinical use, of which about 40 are peptides. The interest of the pharmaceutical industry in D


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Scheme 2. Total Synthesis of Lyciumins A (19) and B (20)

Figure 3. Structures of Psychrophilins A−H.

1). These compounds were prepared by the Friedel−Crafts acylation of 2-ethoxycarbonylpyrrole 1 with acyl chlorides (using 10-undecenoyl chloride and p-allyloxyphenylpropionyl chloride) in the presence of Yb(OTf)3. The hydrolysis of resulting esters 2 and 3, followed by the peptide coupling (HATU or EDCI) with the corresponding alkene-containing amino acid esters ((S)-allyl-Gly(OMe) or (S)-allyl-Tyr(OMe)) results in the formation of metathesis precursors. Cyclization of 4−6 with the second-generation Grubbs catalyst led to the formation of cyclic intermediates that were subsequently hydrogenated without isolation, leading to the formation of key macrocycles 7−9. The hydrolysis of methyl esters in these compounds, followed by the coupling of the resulting acids with (S)-leucinol or (S)-phenylalaninol in the presence of HATU gave macrocycles 10−15 in good yield. Finally, the oxidation of the C-terminal primary alcohols with

developing new therapeutic agents based on cyclic peptides is on the rise, and this structural space has not reached its peak of development.30−32 The present Review is devoted to macrocyclic peptides that incorporate aromatic heterocycles and their benzo-derivatives in their scaffold. The Review is organized according to the type of heterocycles incorporated in the peptide macrocycle.

2. PYRROLES IN MACROCYCLIC PEPTIDE SCAFFOLDS Only one work on the synthesis and biological activity of pyrrole-containing macrocyclic peptidomimetics (compounds 16−18) has been reported.33,34 These compounds demonstrated inhibitory activity against cathepsins S and L at picomolar concentrations. The key step in the synthesis of these macrocycles is the ring-closing metathesis (RCM) reaction of the corresponding acyclic bis-alkenes 4−6 (Scheme E


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Scheme 3. Total Synthesis of Psychrophilin E (25)

Scheme 4. Second Approach to the Total Synthesis of Psychrophilin E (25)

Scheme 5. Attempt To Synthesize the Precursor of Psychrophilin A

Scheme 6. Synthetic Efforts toward Psychrophilin C

F


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Figure 4. Structures of kapakahines A−E.

Dess−Martin periodinane furnished the desired macrocyclic aldehydes 16−18. These compounds form a β-sheet conformation, whereas the conformation of compound 18b is almost identical to the conformation of N-acetyl-L-Leu-L-phenylalanine bound to chymotrypsin, with both phenyl groups being similarly located in the receptor cavity.35 Pyrrole-containing macrocycles are of great interest in terms of their structure and biological activity; however, to date, these compounds are difficult to access, which is probably connected to the high reactivity and acid-sensitive nature of the pyrrole fragment. It can be expected that in the near future new synthetic approaches will appear for the preparation of such macrocycles.

Scheme 7. Synthesis of Linear Precursor 47 of Kapakahines B and F

3. INDOLES IN MACROCYCLIC PEPTIDE SCAFFOLDS Unlike pyrrole-containing substrates, the indole fragment is a frequently occurring structural motif of many natural macrocyclic peptides. Research in this area has been focused on obtaining key fragments of natural compounds, their total synthesis, and SAR investigations of their analogues. There is a large number of contributions devoted to the synthesis of new indole-containing macrocycles with no analogues in nature. An indole fragment in such compounds is created by three general methods: (1) alkylation of indole and its derivatives, (2) transformation of tryptophan, and (3) synthesis of the indole fragment via cross-coupling reactions.

Yahara et al. (1989) and were also detected in Lycium Barbarum L.36,37 In 2004, lyciumin A and C methylates as well as celogenamide A were found in Celosia argentea L.38,39 In 2018, an epimer of lyciumin A, celogentin L, was isolated from the seeds of this plant as well (Figure 2).40 Lyciumins A and B were found to exhibit inhibitory activity on angiotensinconverting enzyme, whereas no significant biological activity was reported for other compounds. Schmidt et al. achieved the total synthesis of lyciumins A (19) and B (20) in 1992 (Scheme 2).41 It begins with the reaction of N-Boc-Trp-OMe with glyoxylic acid and benzyl carbamate to produce the 1:1 mixture of aminals 21. After coupling to L-Val-Gly-OTMSE, the mixture of 22 and epi-22 was separated and separately subjected to the further reactions. In the course of these further reactions, it was found that only

3.1. Cross-Linking to Position 1 of the Indole of Tryptophan

Natural molecules with this topology are celogentin L, celogenamide A, and the families of psychrophilins, lyciumins, and kapakahines. Four monocyclic octapeptides, lyciumins A− D, were isolated from the roots of Lycium chinense Mill. by G


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Scheme 8. Synthesis and Mechanism of Formation of Pyrroloindolone Compound 52

Scheme 9. Completion of the Synthesis of Kapakahine F (43) and Its Conversion into Kapakahine B (42)

In 2004, Dalsgaard et al. discovered a new family of macrocyclic peptides containing a nitro group, the psychrophilins A−D, which were isolated from the frost-resistant fungi Penicillium ribeum and Penicillium algidum.42−44 In 2014, four structurally similar cyclic peptides, psychrophilins E−H, were detected by Peng and colleagues in the marine fungus Aspergillus versicolor ZLN-60 (Figure 3).45 Psychrophilins A− H are 13-membered macrocycles that have an unusual amide bond between the indole nitrogen of tryptophan and the anthranilic acid residue. Interestingly, the psychrophilins A−D contain a unique nitrotryptophan fragment and are the only whereas pyschrophilin G exhibits lipid-lowering effects in HepG2 (IC50 = 10 μg/mL).45 Psychrophilin E demonstrated

22 was able to successively undergo intramolecular cyclization to form 23. Thus 22 was deprotected at the N-terminus and coupled to N-Boc-Ser-OPfp yielding 23, which was converted to the Pfp ester and subsequently subjected to ring closure to produce 24. This transformation was realized in good yield (64% over three steps) without the need for high dilution conditions. The incorporation of the tripeptide side chains (Pyr-Pro-Tyr and Pyr-Pro-Trp for lyciumins A and B, respectively) was shown to proceed upon the activation with TBTU. The corresponding intermediate methyl esters were subsequently hydrolyzed to furnish desired products 19 and 20. H


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Scheme 10. Preparation of the Key Tryptophan Precursor of Kapakahines E and F

Scheme 11. Synthesis of R-Carboline 59a and Its Conversion to 62

strong antiproliferative activity and selectivity for the HCT116 cell line (IC50 = 28.5 μg/mL).46 In addition, this compound showed stronger cytotoxic activity than cisplatin, a known chemotherapeutic agent (IC50 = 33.4 μg/mL).46 Two methods for the synthesis of psychrophilin E (25) were proposed in 2016 by Brimble et al.47 Coupling of indole-3carboxaldehyde 26 to 2-nitrobenzoic acid 27 promoted by DCC gave 28 in 93% yield (Scheme 3). To achieve a high yield in this reaction, the presence of aldehyde in 26 and an onitro group in 27 was necessary, whereas the use of the reduced and protected derivatives of these compounds led to unsatisfactory yields. The reduction of aldehyde 28 with sodium borohydride and the subsequent reduction of the nitro group with stannous chloride resulted in the formation of alcohol 29 in 70% yield in two steps. Silylation of the hydroxyl group in 19, followed by peptide synthesis (DCC) with N-BocPro-OH and subsequent desilylation provided alcohol 30 in yields close to quantitative in two steps. 30 was converted to the corresponding bromide and reacted with benzyl nitroacetate 31 to produce the derivative 32, which was isolated as a

1:1 mixture of epimers in 31% yield over two steps. 32 was then reduced to the corresponding amine and acylated to give 33. The successive deprotection of C- and N-termini in 33, followed by macrolactamization under high dilution conditions (HATU, 6-Cl-HOBt, DIPEA) led to the desired product, psychrophilin E (25), which was formed in a yield of 49%. Despite the fact that the cyclization substrate 33 was introduced as a 1:1 mixture of epimers, 25 was formed as a single 2S-epimer. It was suggested that 2S-epimer of 33 undergoes macrolactamization, and the strain of the hypothetical 2R-epimer of 25 does not allow 2R-33 to undergo this reaction. This hypothesis was supported by quantum-chemical calculations, which showed that the 2S-epimer of 25 is 30 kcal/ mol more stable than the 2R-epimer.47 However, the unreacted 2R-33 was not isolated from the macrocyclization reaction mixture. The second version of the synthesis of this molecule uses the benzyl ester of N-acetyltryptophan 34 as a starting compound (Scheme 4). The formation of a key amide bond between the indole of tryptophan and isatoic anhydride at elevated I


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Scheme 12. Completion of the Synthesis of Kapakahines E (62) and F (43)

Scheme 13. Preparation of Synthetic Macrocycles Incorporating Indole by Positions 1 and 3

temperatures led to the formation of amide 35 in a 53% yield. The addition of N-Boc-proline promoted by DCC gave rise to tripeptide 36. The deprotection of both termini in 36, followed by macrocyclization via the same method as that used in the previous scheme furnished pyschrophilin E (25) in 73% yield. The overall yield of this six-step synthesis is 28% compared

with the original 13-step synthesis, which proceeded in a total yield of 9%. An attempt to synthesize psychrophilin A was unsuccessful. Thus under the hydrogenolysis conditions, benzyl ester 32 underwent decarboxylation to form nitroalkyl derivative 37 (Scheme 5). J


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Figure 5. Structures of amatoxins and phallotoxins.

Scheme 14. General Scheme for Preparation of Amanitin and Phalloidin Analogues 73

kapakahines A, C, and D, the presence or absence of an indole metabolite of tryptophan subjected to oxidative cyclization. These compounds show promising activity against leukemia. Thus kapakahines A, B, C, and E have a pronounced cytotoxic activity toward murine leukemia P388 cells. Kapakahine B also has cytotoxic activity against breast cancer cells DU4475.51,52 Baran et al. developed a method for the synthesis of kapakahines B (41) and F (43).51 Here the indole moiety was constructed by the Larock reaction between the corresponding o-iodoniline and a suitable terminal alkyne.52 The stereocontrolled oxidative nucleophilic addition of o-iodaniline to the protected Trp-Phe dipeptide resulted in the formation of the quaternary stereocenter. The resulting substrate was used in the Larock reaction with a suitable propargylated tripeptide to form a key substrate for cyclization, which was introduced into the peptide synthesis under unique kinetic control conditions. Starting from dipeptide 44, pyrroloindoline 45 was prepared by direct coupling of the former with o-iodoaniline in the absence of base. This oxidative addition tolerates a large protection/deprotection sequence and possesses exceptional exoselectivity. The absence of a base in the reaction system led to an increase in the reaction rate (Scheme 7). Larock annulation of 45 with propargyl-containing tripeptide 46

Scheme 15. Synthesis of Cyclic Tryptathionine 75

Synthesis of psychrophilin C was not achieved either: The attempts to run an intramolecular Mitsunobu-type reaction of nitroalcohol 38 or intramolecular alkylation of chloride 39 did not lead to the desired product 40. Nitro-alcohol 38 did not react with various azodicarboxylates, and compound 39 remained unreactive when treated with various bases at room temperature. With increasing temperature, 39 decomposed under the action of bases (Scheme 6). The family of kapakahines (Figure 4) was isolated from the marine sponge Cribrochalina olemda.48−50 The main structural feature of the macrocyclic peptides of this family is the presence of a C(3)−N(1′) bond between the side chains of tryptophan, where one of these amino acids is converted to Rcarboline. The structures differ from each other in a sequence of amino acids included in the cycle or, in the case of K


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Scheme 16. Synthesis of a Propargyl Analogue (77) of S-Deoxo-amanitin

Scheme 17. Synthesis of Pro2-Ile3-S-deoxo-amaninamide (78)

L


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Scheme 18. Synthesis of Glu7-phalloidin 67

indole in the presence of a base was used to prepare the first key structure 55. Under kinetic protonation conditions, 55 was converted to a single endoisomer and, after hydrolysis of the ester, was introduced into the peptide synthesis with Phe-OEt to give 56. The subsequent removal of both Boc groups in 56 and the selective formation of the sulfonamide provided the desired pyrroloindoline 57 in high yield. Treatment of 57 with aluminum methylate promoted by ultrasound resulted in the simultaneous isomerization of the substrate to R-carboline, the closure of the imidazolone moiety, and the removal of phenylsulfonic acid to form enamine 58a as the main product accompanied by a small amount of ketone 58b, the formation of which is explained by the interaction of the imidazolone fragment in 58a with AlMe3. In the absence of the elimination of phenylsulfonic acid in 57, the rearrangement product had an undesirable stereochemistry at position C39 (Scheme 11). The required stereochemistry at C39 was achieved by the reduction of 58a with sodium cyanoborohydride in the presence of AcOH. The diastereoselectivity of this process was low, and the product with desired configuration (59a) was prepared in a mixture with a significant amount of diastereomeric R-carboline 59b. However, this disadvantage is compensated for by the fact that the complex topology 59a is obtained in only three steps from the indoline heterodimer 57. Iodination at the C3 atom of the indole fragment of compound 59a resulted in the formation of iodindole 60, which was introduced into the Negishi reaction with a zinc alanine derivative 61 to form a fragment of tryptophan in compound 62 in 74% yield (Scheme 11). This was the first example of the synthesis of tryptophan derivatives using this reaction. Hydrogenation of 62 at low temperatures allowed the benzyl group to be selectively removed in the presence of the Fmoc

provided for the formation of a key structure 47, which contained all of the necessary fragments for the subsequent macrocyclization. The use of Pd(dppf)Cl2 in this step provided the shortest reaction time and also facilitated scale-up. The key stage of the isomerization of the pyrroloindoline fragment into the desired R-carboline was carried out by the simultaneous deprotection of the C- and N-termini of 47 and introducing the resulting amino acid into the intramolecular peptide synthesis reaction. EDC and HOAt systems in the absence of base demonstrated the best yields (64%) of the desired compound 52. The admixture of a small amount of isomer 51 (6%) could be separated chromatographically (Scheme 8). The selectivity of the formation of R-carboline 52 can be attributed to the relative reactivity of the two equilibrium forms 48 and 50 of the intermediate product resulting from the removal of Cbz and Bn groups in 47. The higher reactivity of the primary amine 50 as compared with the less reactive secondary amine 48 results in selective macrocyclization to form the desired product 52 (Scheme 9). The subsequent hydrolysis of the methyl ester in 52 and the introduction of the resulting acid into the reaction with oxalyl chloride to close the imidazolone ring and the subsequent removal of Boc group resulted in the formation of kapakahine F 43. It is noteworthy that the entire synthetic route was scaled up to 1 g of the target product. Peptide coupling between 43 and N-Boc-Phe, followed by the removal of the Boc group furnished kapakahine B 42 in 81% yield. A different approach to the synthesis of these compounds was employed by Rainier et al. in 2010.53 As shown in Scheme 10, coupling of Trp-derived bromopyrroloindoline 54 (which is readily available from fully protected tryptophan 53) with M


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Scheme 19. Synthesis of Ala7-phalloidin 89

assumed that other allyl-containing peptides can also be used in this stage. Cyclization was carried out under the metathesis conditions using the first-generation Grubbs catalyst. Commercially available indolylcarboxylic acids 65a−c were reacted with excess allyl bromide in the presence of a base to give a mixture of O- and N-allylated products, which were then hydrolyzed to obtain the required N-allyl-indolylcarboxylic acids 66a−c (Scheme 13). Peptide coupling (EDCl, DMAP) of these compounds with (N-1-Boc)-Lys-(S-allyl)-Gly(OMe) (67) and intramolecular RCM of the resulting intermediates 68a−c furnished the corresponding macrocycles 69a−c as inseparable mixtures of E- and Z-isomers, which were finally deprotected to give 70a−c. The conditions of individual reactions were not optimized, which makes it difficult to reliably judge the general pattern for each step; however, even with unoptimized conditions, it can be seen that the length of the peptide and its flexibility affect its ability to undergo macrocyclization efficiently under metathesis conditions, and these parameters have a certain optimum. Thus the formation of 69b from the linear peptide 68b containing two methylene linkers proceeds in virtually quantitative yield, whereas the shorter 68a and longer 68c precursors form the corresponding

protecting group (Scheme 12). Peptide coupling of the resulting acid with the all-L-Phe-Pro-Tyr-Ala(OBn) tetrapeptide using EDCI and HOBt afforded amino ester 63. The hydrogenolysis of the benzyl and Fmoc groups and the subsequent macrocyclization led to the formation of Bocprotected kapakahine E. The removal of the Boc protecting group results in the formation of the trifluoroacetate salt of kapakahine E (62). An identical approach was used for the synthesis of kapakahine F. Peptide synthesis of 62 with L-Ala-LLeu(OBn) resulted in the formation of 64. The removal of Fmoc and benzyl groups, cyclization, and the subsequent removal of the Boc protecting group furnished kapakahine F (43) in 35% yield over five steps starting from 62. Compounds 70a−c demonstrate the use of the RCM reaction for the synthesis of peptide macrocycles, which incorporate indole fragment at positions 1 and 3.54 Scaffolds of various sizes were prepared according to a general strategy: An indole fragment containing an allyl substituent at position 1 and an alkyl carboxyl moiety at position 3 was introduced into the peptide synthesis reaction with a suitable allyl-containing dipeptide. For the model reaction, only one protected dipeptide, D-Lys-L-allyl-Gly(OMe), was used, but it can be N


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Scheme 20. Synthesis of the Cyclic Heptapeptide 104

Scheme 21. Completion of Total Synthesis of α-Amanitin 98

macrocycles 69a and 69c significantly worse under the same conditions.

Amanitin is a bicyclic octapeptide that is a potent inhibitor of RNA polymerase II with an extremely high affinity for the transcription complex (Kd = 10−9).55,56 Phalloidin (a member of the phallotoxin family), isolated by Wieland et al. in 1937, is historically the first discovered macrocyclic peptide including the indole fragment in its backbone.57,58 Phalloidin is a bicyclic heptapeptide with a similar affinity for F-actin.59 Both of these peptides contain a signature bond between the tryptophan and


Amatoxins and phallotoxins (Figure 5) are two families of bicyclic peptides found in varying amounts in a number of fungi. In the highest concentration, they are contained in the fungus Amanita phalloides, better known as pale toadstool. αO


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carrying acid-labile protecting groups, were synthesized by classical methods of solution-phase peptide synthesis (Scheme 14). When treated with trifluoroacetic acid in the absence of a solvent for several hours at high dilution (∼3 mM), linear peptides were converted to the corresponding monocyclic products 72 containing the Trp-Cys thioether bond. The subsequent macrolactamization under peptide synthesis conditions ensures the closure of the second cycle in these structures to yield the corresponding bicyclic analogues (73) of amatoxins and phallotoxins. Numerous works used the intramolecular version of this transformation in the synthesis of many amanitin and phalloidin derivatives to investigate their SAR.61−69 The above-mentioned strategy was used to synthesize macrocyclic tryptathionine 75 from the appropriately protected tripeptide 74 (Scheme 15)70 as well as the propargyl analogue of deoxoamanitin 77 (Scheme 16).71 Thus the synthesis of the bicyclic structure is achieved by the sequence (1) of the intramolecular Savige−Fontana reaction and (2) the intramolecular reaction of peptide synthesis. In a number of other studies, these two steps were interchanged: First, a large macrocycle was constructed in which the tryptathionine fragment was then synthesized. The synthesis of Pro2-Ile3-S-deoxo-amaninamide 78 (Scheme 17) uses Hpi-Gly(OMe) 80 as a starting compound, which was obtained from N-Tr-Trp-Gly(OMe) 79 by oxidation with DMDO and subsequent detritylation.72 After the separation of the diastereomers, syn-cis product 81a was introduced to peptide coupling (PyBOP, DIPEA) with N-Fmoc-Ile to yield the corresponding fully protected tripeptide in which the methyl ester group was selectively deprotected using Me3SnOH to form the substrate 82. Next, octapeptide 83 was assembled via the common SPPS protocol on 2chlorotrityl resin. It was cleaved from the resin and subsequently introduced into the macrocyclization reaction (PyBOP, DIPEA) in 59% yield for macrocyclization and 16% overall yield. The cyclic peptide 84 was treated with TFA, which allowed the simultaneous removal of the Tr protecting group and a second ring closure between the cysteine and Hpi residues to yield 78. The yield of this step is particularly noteworthy: Despite relatively harsh conditions, the reaction mixture contained 90% of the desired product.

Figure 6. Crystal structure of β-amanitin. Reproduced from ref 75. Copyright 2018 American Chemical Society.

Scheme 22. Model Macrocyclization via Pd(0)-Catalyzed CH Activation

cysteine residues, a bridging fragment that connects two peptide macrocycles. In the structure of phalloidin, there is a sulfide fragment connecting the side chains of Trp and Ser, whereas in α-amanitin, this linkage is additionally oxidized to the (R)-sulfoxide fragment. Despite years of research, the influence of the composition of the side chains and the conformational aspects responsible for the extremely high affinity of these peptides to their protein targets has not yet been fully explored. Numerous analogues of phalloidin and amanitin have been synthesized using two basic methods of constructing the tryptathionine bond.60 One of the approaches uses the reaction of cysteine with hydroxypyrrolo[2,3-b]indoles (Hpi) resulting from the oxidation of the corresponding tryptophan derivatives (the formation of a tryptathionine bond by the nucleophilic opening of the Hpi fragment by the SH group in an acidic medium). The required Hpi-containing heptapeptides 71,

Figure 7. Examples of products of Pd-catalyzed indole C2−Ar coupling P


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Figure 8. Examples of synthesized small chiral macrocycles.

Scheme 23. Macrocyclization of Linear Peptides via Pd(0)-Catalyzed CH Activation

Glu7-phalloidin 85 was synthesized according to the same principle (Scheme 18).73 The requisite linear peptide 87 was synthesized under the classical SPPS conditions from allyl glutamate 86 bound to 2-chlorotrityl polystyrene resin from the side chain. After the liberation of N- and C-termini in 87, the unprotected peptide was subjected to macrocyclization by treatment with DPPA. No formation of cyclodimers and higher oligomers was observed in this stage. When the cyclic peptide 88 was treated with I2 in DMF, it was converted into a thioether in the absence of an adverse reaction of intermolecular disulfide formation. The removal of the protecting groups on the side chains of D-Thr and hydroxyproline resulted in the desired product 85 in 50% overall yield. In the synthesis of Ala7-phalloidin (89), a key Trp6-Cys3 fragment 90 was synthesized in the initial stages of synthesis (Scheme 19).74 The protected cysteine derivative 91 was subjected to the disulfide cleavage with sulfuryl chloride to

obtain sulfenyl chloride 92. This compound was then immediately reacted with an orthogonally protected tryptophan to form the thioether 93, in which the N-Boc group was changed to the N-Fmoc group (90) in two steps. The following assembly of linear precursor 96 via the SPPS protocol was conducted by successive coupling to fragment 94 (synthesized via the Mitsunobu reaction from N-Fmoc-transhydroxyproline), compound 95 (synthesized in two steps from N-Cbz-Ala), 90, D-threonine, and two alanine fragments. After the successive removal of C- and N-terminal protecting groups, the cyclization of the B-ring of the phalloidin (compound 97) was achieved with two reagent systems: (1) PyAOP/HOAt/DIPEA and (2) DPPA/DIPEA. Both sets of reagents resulted in identical yields of 97 without epimerization or cyclodimerization. For the cyclization of ring A, Ala5Tmse and Trp6-Ns groups were first deprotected, and the resulting intermediate product was subjected to the second Q


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Scheme 24. Synthesis of Complex Scaffolds from Linear Substrates by a Cross-Coupling Reaction

Scheme 25. Pd(0)-Catalyzed Macrocyclization Patterns for Short Peptides

R


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triflate (Scheme 20) to produce 101.76 The latter was then coupled to the corresponding polymer-bound hexapeptide to form 102 and upon cleavage yielded the mixture of heptapeptides 103a,b. Boronic ester in 103a was briefly converted to the free boronic acid 103b and successively oxidized to give the 6-hydroxytryptathione fragment in 104. The synthesis of enantiomerically pure (2S,3R,4R)-4,5dihydroxy-isoleucine (DHIle), a missing fragment for the synthesis of the octapeptide 106, is detailed in the article.75 The activated ester of DHIle (105) was coupled to 104, yielding the protected octapeptide (Scheme 21). After the deprotection of N- and C-termini, the resulting unprotected precursor 106 was subjected to intramolecular macrolactonization (HATU, DIPEA) to form a toxic S-deoxy-amanitin 107, which was then oxidized to the target molecule, α-amanitin 98. The crystal structure of β-amanitin, which differs from 98 by Asn to Asp interchange (Figure 6), suggests that the pro-R (leading to R configuration) electron pair of sulfur is much more open to attack than the pro-S pair, which is directed inward of the molecule. The diastereoselectivity of the sulfur atom oxidation can be controlled by stereoelectronics. This was demonstrated by oxidation of 107 with mCPBA in various solvents. For example, the use of DMF as the solvent resulted in the formation of unnatural (S)-sulfoxide exclusively, whereas the reaction in a solvent mixture of isopropanol−ethanol (8:3) led to the formation of (R)-sulfoxide in substantial excess (2.5:1). Several articles have been devoted to the development and use of an effective macrocyclization method based on the Pdcatalyzed CH activation, which allows the construction of macrocycles with indole-aryl bridges.77 The model reaction with this approach is shown in Scheme 22. Products of varying ring sizes and configurations of the aryl-indole fragment were synthesized. The reaction is not accompanied by epimeriza-

Scheme 26. Use of Mn-Catalyzed CH Activation for Peptidomimetic Macrocyclization

macrolactamization. The cyclization of ring A in 97 required careful examination of the reaction conditions. Of the three studied systems, (1) PyAOP/HOAt/DIPEA, (2) HBPyU/ DIPEA, and (3) DPPA/DIPEA, the first two did not lead to any conversion of substrate. This is an interesting observation because HBPyU has been successfully used for the synthesis of phallotoxins by macrolactamization using the same amide bond.62 The use of DPPA facilitated a complete conversion of the starting material to the cyclized product, but a significant degree of byproduct formation, including cyclooligomers, was observed. Finally, the cleavage of bicyclic peptide from the solid support, followed by removing the tert-butyl ester from the D-Thr2 fragment resulted in the formation of the desired product 89. The synthesis of α-amanitin (98) was reported in 2017 by the Perrin group.75 None of the methods discussed above is suitable for the formation of a tryptathionyl fragment from 6hydroxy-L-tryptophan, which is sensitive to the reaction conditions and is easily oxidized. This was overcome by using the 6-boronylpinacolic derivative of protected tryptophan 99, which was converted to B-MIDA (N-methyliminodiacetate) derivative 100 and reacted with 1-fluorocollidinium

Figure 9. Structures of celogentins A−J, moroidin, and stephanotic acid. S


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Scheme 27. Synthesis of Methyl Ester of Stephanotic Acid (122)

ylates are more easily dissociated from the electrophilic palladium complex, which contributes to the reaction of CH indole activation. This general and effective method makes it possible to obtain macrocyclic peptides with a cycle size of 15−25. Figure 7 shows seven examples of macrocycles of different sizes 108a−g having a para-phenyl moiety in their structures. Compounds 108a−c are a series of macrocycles with altering (o-, m-, p-) configuration of the binding aryl moiety. Compounds 108d−e represent examples that incorporate an additional chiral fragment, and 108f−g are macrocycles derived from acyclic substrates with a shorter linker. A few more examples of smaller macrocycles containing asymmetric centers 108h−m were synthesized by this method (Figure 8). A similar C−H activation protocol was later used to synthesize a series of functionalized macrocyclic peptides 109a−e (Scheme 23).78 The use of this protocol for double intramolecular arylation in substrate 110 containing a 3,5-diiodinated threonine unit (commercially available reagent) located between two tryptophan residues was reported. With an increased loading of the catalytic system (40 mol % Pd and 6.0 equiv AgBF4) and the use of excess pivalic acid, up to 25% conversion of the starting substrate to product 111 was possible (Scheme 24). Also noteworthy is the 3D bicyclic peptide 114, obtained in two stages from the acyclic substrate 112 through the CH− activation step and the macrolactamization of formed 113 in a total yield of 18%. Another work in this field was devoted to the investigation of the patterns that govern the formation of products of intraand intermolecular macrocyclization. A series of short

Scheme 28. Enantioselective Synthesis of Leu-Trp Fragment 135

tion, nor does it yield indole arylation products in positions other than C2. The best results were achieved using a palladium catalyst and the addition of silver(I) salts. AgBF4 has been found to be the best reagent for this reaction, possibly because of its higher solubility. In the catalytic cycle Pd(0)/ Pd(II), the silver salts capture the halide anion at the step of metathesis of the ligands between the halide and the carboxylate. Thus the solubility of silver salts should play an important role. In addition, pKa and the coordination ability of the carboxylic acid used had a significant effect on the yields in the reaction. Using poorly coordinating pivalic acid or a less potent p-NO2-C6H4CO2H instead of o-NO2-C6H4CO2H resulted in lower yields. Meanwhile, the coordination ability of the carboxylate is significant for the electrophilicity of the palladium compound. Moderately weakly coordinating carboxT


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Scheme 29. Total Synthesis of 122 by Lia et al.

Scheme 30. Synthesis of Ring A of Celogentin C (139)

cases of cyclization (compounds 119c and 119c′) were

oligopeptides containing Trp and Thr residues were subjected to the same reaction conditions as above (Scheme 25).79 It is noteworthy that only two types of products were obtained: cyclomonomer and cyclodimer peptides. No products of the cyclooligomerization or the polymerization of substrates were detected. It was shown that the fate of the cyclization/ dimerization is mainly determined by structural features and does not depend on the concentration and reaction conditions. Short-chain peptides (115 and 116) produced the corresponding cyclodimers 119a and 119b, and longer 118 gave monomeric product 119d, whereas in the case of 117, both

possible. An example of a manganese-catalyzed variant of CH activation was also reported (Scheme 26).80 Intramolecular indole C2-alkynylation was achieved in substrate 120 to yield macrocycle 121 in good yield. Dicyclohexylamine and DCE were proved to be the optimal base and solvent for this transformation. The addition of Lewis-acidic triphenylborane allowed the loading of Mn(I) catalyst to be reduced. U


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Scheme 31. Synthesis of 139 via Pd(0)-Catalyzed Macrocyclization

bicyclic peptides have an unusual structural motif consisting of two key links: the C−C bond connecting the β-position of leucine to the C6 indole of tryptophan and the C−N bond linking the indole C2 atom to the N1 atom imidazole in histidine. Celogentins A−J are structurally similar to the moroidin, which was first found in Australian shrubs of Laportea moroides and then also found in the seeds of Celosia argentea. The simplest member of this family is stephanotic acid, which was isolated from Stephanotis f loribunda, lacks the right histidine-containing ring, and has a fragment of leucineisoleucine.83 Moroidin and celogentins A−C are known to inhibit the polymerization of tubulin.84 Celogentin C is a stronger antimitotic agent than the well-known antitumor drug vinblastine (IC50 = 0.8 vs 3.0 mM). These compounds have also found applications as anti-inflammatory, antifungal, and antiparasitic agents.85 A strategy for the synthesis of methyl ester of stephanotic acid 122 as well as its diastereomer 123 was presented by the Moody group (Scheme 27).86 The starting material for this synthesis was N-Boc-6-isobutyrylindole 124, which was converted in three stages to a mixture of (E)- and (Z)-alkenes 127 via thiaoxazolidine 126 in 56% overall yield. The reduction of the mixture 127 with magnesium in methanol led to the formation of a 3:2 mixture of amino acid diastereomers, and the subsequent formylation of the major isomer with the simultaneous removal of the N-Boc protecting group provided the (±)-amino acid derivative 128 in low yield. The ester group in racemic 128 was saponified, and the resulting acid was introduced into the peptide synthesis reaction with the L -Ile(OBu t ) to give a mixture of diastereomers 129. The indole nitrogen in 129 was reprotected for the subsequent Horner−Wadsworth−Emmons (HWE) reaction with phosphonoglycine 130 to produce the fully protected linear precursor for macrocyclization as a 1:1 mixture of diastereomers 131a and 131b. The removal of Cand N-terminal protection groups as well as the indole N-Boc fragment in these substrates and the subsequent cyclization (HATU, HOAt) under high dilution conditions afforded macrocycles 132a and 132b. It was found that whereas 132b was formed without epimerization of asymmetric centers, a small epimerization occurred when 132a was formed. Each of macrocycles 132 was then individually subjected to the hydrogenolytic removal of the N-Cbz group, and the resulting free amino group was introduced into the peptide synthesis (HATU, HOAt) reaction with pyroglutamic acid. The product of coupling between pyroglutamic acid and 132b was formed

Scheme 32. Chloropeptins I (150) and II (151)

Scheme 33. Key Retrosynthetic Disconnections of Complestatin


Natural molecules with this topology, celogentins A−J (Figure 9), were obtained from the seeds of Celosia argentea.81,82 These V


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Scheme 34. Synthesis of Compounds 152 and 157

Scheme 35. Preparation of DEF Ring System (174) of Complestatin

Trp.87 This substance formed a Grignard reagent upon treatment with iPrMgCl, and the following 1,4-conjugated addition to oxazolidinone 134 and the bromination of the resulting intermediate with NBS led to the formation of 135, the key Leu-Trp fragment in this synthesis. The excellent stereoselectivity of the 1,4-addition and bromination reaction was noted, and the product 135 was formed as a single diastereomer (Scheme 28).

as a single diastereomer 123; however, as in the previous step of peptide synthesis, the product of coupling between pyroglutamic acid and 132a gave the target molecule 122 contaminated with an additional diastereomer as a result of epimerization. Another synthetic approach to compound 122 used protected 6-iodo-L-tryptophan 133 as the indole-containing building block, which is easily obtained in five stages from LW


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Scheme 36. Completion of Total Synthesis of Complestatin (151)

A similar strategy was implemented in the synthesis of the Aring of celogenin C (139, Scheme 30).88 Starting substrate 140 was used to construct the key Leu-Trp fragment 142 via onestep Pd-catalyzed CH insertion into the leucine derivative 141. The N-Phth fragment of compound 142 was converted into azide by deprotecting with ethylenediamine and treatment with TfN3 to form compound 143. Boc group protection of the amide group in 143, cleavage of the quinolinamide bond, and conversion of the resulting acid to the N-hydroxysuccinimide ester furnished 144. The latter was introduced into the peptide synthesis reaction with L-Val-L-Leu to form the peptide 145. After the removal of the Boc protecting group, 145 was macrocyclized (EDCl, HOBt) to give cyclic product 146 in 82% yield without detectable epimerization. The azido group in 146 was then reduced, and the resulting amine was introduced into the peptide synthesis reaction with pyroglutamic acid to form 147. After the removal of Ts and tBu protecting groups in 147, the ring A of celogentin C (139) was obtained.

The subsequent introduction of azide moiety in 135, followed by the hydrolysis of the imide group led to the formation of 136 (Scheme 29). Peptide coupling (HATU) between 136 and L-Ile-L-Val(OtBu) provided the linear precursor of stephanotic acid 137 in 82% yield. The simultaneous deprotection of N- and C-termini and subsequent macrolactamization (HATU, HOBT) under high dilution conditions led to the formation of macrocycle 138 in 48% total yield as a single product. Whereas in the previously described complete synthesis of stephanotic acid, the macrocyclization step was carried out through the formation of the amide linkage between Leu-Val residues and was accompanied by a small epimerization, in this work, ring closure via the Val-Trp bond is free of this deficiency, and the macrocycle is formed without detectable epimerization. Azide hydrogenation in 138 and peptide synthesis (HATU) of the resulting amine with pyroglutamic acid using HATU furnished the methyl ester of stephanotic acid 122 in 70% yield (4.6% over 14 steps). X


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exhibit activity against HIV-1-induced cytopathy and syncytium formation by CD4 lymphocytes and inhibit HIV replication by inhibiting the binding of gp120 and CD4 at concentrations of 2.0 and 3.3 μM respectively.93,94 These two compounds are considered together, despite the different types of indole inclusion in the macrocycle (3, 6 for 151 and 3, 7 for 150) due to the existence of an acid-catalyzed rearrangement (TFA, 50 ° C, > 90% yield) of more strained, 12-membered 151 to less strained, 13-membered 150.95 This rearrangement occurs with the preservation of the stereochemistry of atropisomers; therefore, all work in the field of total synthesis of these compounds reduces to the production of complestatin 151, from which cyclophane 150 is obtained in one simple step. The total synthesis of complestatin, which includes an interesting example of macrocyclization, in which the ring closure is accomplished through the synthesis of a heterocycle, was reported by the Boger group. The Larock cross-coupling reaction was used in the stage of macrocyclization, in which the fragment of indole of complestatin was created in the late stages of synthesis (Scheme 33).96,97 Despite the fact that 151 consists of seven extensively modified amino acid subunits, four of them (A, C, E, and G, Scheme 33) are readily available from commercial precursors, whereas the other three are prepared via complex synthetic operations. The B subunit was introduced as (R)-(4-fluoro-3nitrophenyl)alanine 152, modified for further use in the SNAr reaction and macrocyclic biaryl ether formation. 152 was prepared in five steps from bromide 153 by treatment with the Schöllkopf reagent 154, subsequent hydrolysis of the formed lactim 155, the Boc group protection, and hydrolysis of the methyl ester and N-methylation of the resultant amine 156 (Scheme 34). (R)-Propargylalanine 157 bearing the triethylsilyl-protected alkyne group necessary for the Larock annulation was obtained by the same strategy from propargyl diphenyl phosphate 158. The D subunit, which is central in structures 150 and 151, was obtained from commercially available 3-iodo-4,5-dimethoxybenzaldehyde 160, which was initially converted to the corresponding styrene 161 (Scheme 35). The asymmetric Sharpless aminohydroxylation of 161 provided the compound 162 in good yield (75%), regioselectivity (5:1), and

Scheme 37. Alternative Approach toward Complestatin

In 2017, a reliable procedure was developed for the preparation of cyclic peptides with Cβ−Ar bonds via the Pdcatalyzed activation of C(sp3)-H.89 The A ring of celogentin C 139 was prepared from the linear precursor peptide 148 containing commercially available 6-I-Trp without introducing and removing guiding groups (Scheme 31). Accordingly, the synthesized 6-I-Trp-containing peptide was subjected to macrocyclization, and subsequent coupling of formed macrocycle 149 with pyroglutamic acid resulted in the formation of the A ring of celogentin C 139 in high yield. A number of biologically important natural products, a family of vancomycin glycopeptide antibiotics contains a strained macrocyclic fragment with a specific atropisomer configuration. Among this family there are indole-containing structures, chloropeptin I (150), and complestatin (151) (Scheme 32) isolated from Streptomyces sp. WK- 3419 and Streptomyces lavendulae.90−92 Both natural bicyclic cyclophanes

Scheme 38. Synthesis of Indole-Containing Precursor 184 of DEFG Rings of Complestatin

Y


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Scheme 39. Synthesis of Fragment D (192) of Complestatin

Scheme 40. Assembly of DEFG Ring System (202) of Complestatin via Suzuki−Miyaura Reaction

Figure 10. Structure of streptide. Figure 11. Analogues of TMC-95A, 203.

enantioselectivity (>98% ee). The primary alcohol in 162 was protected as benzyl ester 163, and the latter was converted to the corresponding arylboronic acid for the Suzuki crosscoupling reaction with 2-bromo-5-iodoaninine 164, which was employed to synthesize compound 165. The subsequent acetylation of aniline nitrogen in 165, the removal of N-Boc

protecting group, and the coupling of the free amine with the acid 167 yielded compound 168. Phenolic oxygen in 168 was protected, followed by the removal of N-Fmoc group in 169, and peptide coupling (EDCl, HOAt) with acid 157 resulted in the formation of macrocyclization precursor 170. Under Z


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Scheme 41. Synthesis of TMC-95A Analogues

and the free amine was subjected to the peptide synthesis reaction (EDCl) with 157 to produce a precursor 182, which, under Larock conditions, was annulated to form the bimacrocyclic precursor 183 in 56% yield, which was converted to complestatin by the same methods as provided in Scheme 36. It is worth noting that compound 183 was obtained exclusively as a single atropisomer, which has a natural (R)-configuration. In this case, the complexity of the substrate and the reverse order of macrocyclization did not reduce the atropo-diastereoselectivity; rather, it provided an improvement over the 4:1 selectivity that was observed with a similar substrate using the first strategy. Another approach to the synthesis of the DEFG ring system of complestatin uses an intramolecular version of the Suzuki− Miyaura reaction for closing an indole-containing macrocycle.99 The indole fragment was incorporated into this compound as a tryptophan derivative 184 (Scheme 38). Pdcatalyzed annulation of aldehyde 185 with 2-iodo-5-nitroaniline 186 afforded protected 6-nitrotryptophan 187, which was then converted to the 6-amino derivative 188 under standard conditions. Transformation of amine 188 to iodide 189, followed by Miyaura reaction with B2Pin2 furnished the 6B(Pin)-tryptophan 190. The removal of N-Boc protecting groups in the latter, followed by peptide coupling with acid 179 resulted in the formation ketoamide 191, which was subsequently hydrolyzed to acid 184. The synthesis of fragment D (192) of complestatin is shown in Scheme 39. Commercially available 1-iodo-2,3-diisopropoxy-5-vinylbenzene 193 was converted to the corresponding (S)-diol 194 under Sharpless hydroxylation conditions (ADmix-α). 194 was converted to the corresponding protected

Larock conditions, 170 efficiently underwent macrocyclization, furnishing the indole fragment in compound 171 (71% yield in terms of R-atropisomer) and its (S)-atropoisomer (not shown) with complete regioselectivity of cyclization and with good atropo-diastereoselectivity (4:1 R/S) in favor of the natural isomer. The hydrogenolysis of benzyl ester in 171 and the twostage oxidation of free alcohol in 172 afforded carboxylic acid 173 (92%). Finally, a simultaneous removal of three arylmethyl ethers, TES, and Boc groups, followed by the reinstallation of the Boc group furnished the DEF ring system (174) of complestatin. Compound 174 was coupled (EDCI, HOAt) to tripeptide 175 (assembled via common methods) to produce compound 176 (Scheme 36). Macrocyclization of 176 was performed by adding K2CO3 in the presence of 18-crown-6 and 4 Å MS and gave 177 as a predominant atropisomer with a minor admixture of other atropisomers with conversion of up to 81%. The two-step removal of the activating nitro group in 177 allowed 178 to be obtained. The removal of the Boc group in 178 and the coupling of the free amine with missing ring G 179 (2-(3,5-dichloro-4-hydroxyphenyl)-2-oxoacetic acid) resulted in the formation of the final precursor 180. Saponification of 180 furnished complestatin 151. A small portion of 151 was converted to chloropeptin I 150. The same group proposed an alternative method for the complete synthesis of complestatin, in which a left macrocycle (SNAr cyclization) was initially constructed and then Larock cyclization was carried out to form a second indole-containing macrocycle (Scheme 37).98 Substrate 181 was synthesized by the same methods and from the same fragments as in the synthesis described above. The N-Fmoc group was removed AA


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Scheme 42. De Novo Synthesis of Indole-Containing Macrocycles via Intramolecular Friedel−Crafts Reaction

Scheme 43. Creation of 6H-Oxazole[5,4-e]indole Linker within Peptides of Different Lengths

Esterification with the simultaneous removal of the Boc group completed the synthesis of 192. Peptide synthesis of 192 with D-phenylglycine derivative 198 yielded dipeptide 199 in 80% yield (Scheme 40). The removal of the Boc groups and the peptide synthesis with tryptophan 184 completed the assembly of macrocyclization precursor 200, which underwent a Suzuki−Miyaura reaction to produce

amino alcohol 195 in three steps: TBS protection of the primary alcohol, Mitsunobu reaction between the secondary alcohol and DPPA, and reduction of the (R)-azide under Staudinger reaction conditions. The removal of O-TBS and NBoc protecting groups resulted in the formation of substrate 196, which was oxidized to the corresponding amino acid 197. AB


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Scheme 44. Synthesis of Carbazole-Containing Macrocycles 216a−d

Ni(0)-catalyzed intramolecular cross-coupling reaction was the formation of 203a,b in low yield, which was explained by the effect of a rigid sp2 hybrid bond at the C6 position.

cyclophane 201 as a single atropo-diastereomer, with the stereo configuration of the natural DEFG ring system of complestatin. The treatment of 201 with trifluoroacetic acid promoted its quantitative rearrangement into fragment 202 of chloropeptin I.

3.5. Other Methods

A template approach was proposed for the synthesis of macrocyclic peptidomimetics by unique macrocyclization under Friedel−Crafts conditions between tryptophan and tyrosine residues (compound 213, Scheme 42).103,104 With a single reaction, it was possible to obtain eight new macrocyclic structures. The composition of each macrocycle in the mixture of products showed a strong dependence on the choice of the acid catalyst and the geometry of the initial substrate. Rearrangement in conformationally preorganized macrocyclic ester 214 favored the ortho-alkylation of Tyr phenol. By reducing the acid concentration, this product was formed in a ratio of 20:1 compared with all other isomers. It is emphasized that the possibility of controlling the formation of specific isomers 215a−h by adjusting the reaction conditions depending on the Brønsted or Lewis acids used allows for a selective de novo synthesis of target macrocyclic structures. Suga et al. developed a new method for the cyclization of peptides, which includes the oxidative condensation of peptides containing fragments of 5-hydroxytryptophan and pbenzylamine analogue of phenylalanine synthesized by biotechnological methods.105 The selective coupling of this pair rapidly occurs upon the addition of K3Fe(CN)6 and generates a unique 6H-oxazole[5,4-e]indole fluorescent linker (Scheme 43). This protocol allows the conversion of linear peptides into fluorescent macrocycles. It is noteworthy that the reaction proceeds regardless of the size of the resulting cycle, at least in the range of peptides containing from 5 to 11 amino acids. Reactions with different substrates that do not contain side chains that are susceptible to oxidation passed equally well, and the reaction mixtures contain only small impurities in the mass spectra.


Recently, another macrocyclic indole-containing peptide has been found in streptococcal bacteria. Streptide is a product of cyclization of a linear peptide to form a bond between the Cβ lysine atom and the C7 atom of the indole side chain of tryptophan (Figure 10).100 The biological function for streptide is still unknown, and its total synthesis has not yet been developed. The synthesis of three macrocyclic peptide analogues of TMC-95A (203) as potential proteasome inhibitors has been described (Figure 11).101 TMC-95A is known as a powerful, reversible, and noncovalent inhibitor of peptidase activity (analogues of chymotrypsin, trypsin, and caspase) of the 20S proteasome.102 A key step in the synthesis of analogues TMC95A involves the Ni(0)-catalyzed macrocyclization of tripeptides 212 with a halogenated aromatic substituent to form TrpThr linkages. The synthesis is based on the assembly of the acyclic peptides and their further intramolecular closure to the corresponding macrocycles over the Thr-Trp residues. This strategy opens the way to ligand libraries for further biological analyses by varying R1 and R2 residues. The indole-containing precursor 208 was prepared in four steps from 204 via bromination, enantioselective alkylation of unstable bromide 205 with 206, and, finally, imine hydrolysis and trans-esterification in 207 (Scheme 41).101 Dipeptides 210a,b were synthesized by coupling the commercially available activated ester 209 to L-Ala(OMe) or L-Leu(OMe). The subsequent selective ortho-iodination of the benzyloxy group in 210a,b, followed by ether saponification in the resulting 211a,b and second peptide coupling (EDC, HOBt) with 208 gave linear precursors 212a,b. The result of the AC


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Scheme 45. Synthesis of Faa 225 and its Cyclotrimer 226

4. CARBAZOLES IN MACROCYCLIC PEPTIDE SCAFFOLDS Few examples of the incorporation of this heterocycle in the macrocyclic peptide scaffold are known.106 A series of such compounds 216a−d synthesized by Bremner et al. in 2003 showed potent antibacterial activity against S. aureus (Scheme 44). The starting substrate for the preparation of these compounds is carbazole 217, which was converted to the bromomethyl derivative 218 under radical bromination. The subsequent alkylation of deprotonated diethylacetamidomalonate 219, followed by reflux with lithium chloride gave αamido ester 220 in 70% total yield. Allylation of 220 via the Stille reaction led to the formation of the corresponding allylcarbazole in 91% yield, which was converted to acid 221 after manipulation with N and C protecting groups. Compound 221 was further used as a racemate because stereochemistry at the α-carbon was shown to be inconsequential for the antibacterial activity of the final compounds. Peptide synthesis between 221 and various allylglycine-containing dipeptides 222 led to the formation of the key linear tripeptide derivatives 223a−d in good yield (58−82%) as inseparable mixtures of diastereomers. RCM of 223a−d using the first-generation Grubbs catalyst at high dilution provided fully protected macrocyclic peptidomimetics 224a−d in excellent yield. Finally, the hydrogenation of the double bond resulted in the formation of 216a−d. The removal of protecting groups led to the formation of compounds for medical research.

of their biological activity as anion receptors. It is known that macrocyclic peptidomimetics that contain additional nitrogen or oxygen atoms in their structures may have receptor properties and effectively bind anions due to hydrogen interactions.107,108 In this case, because of the sufficient rigidity of the molecular framework, macrocycles create a cavity of a certain size predisposed for binding anions. Studies aimed at understanding how the carboxylate functionality of amino acids binds to furan-containing macrocycles have been performed. Macrocycles that display this kind of interaction have potential in medicine.109 Moreover, it was found that furan-containing cyclic tri- and tetrapeptides modified with cationogenic exocyclic fragments can stabilize the structures of the DNA G-quadruplexes that are used in antitumor therapy.107,108 5.1. Incorporation of Furan by Positions 2 and 5

5-(Aminomethyl)furan-2-carboxylic acid (Faa) 225 is commonly used as a key building block to incorporate furan in peptide macrocycles. This fragment may be regarded as an isostere of dipeptide moiety. The simplest macrocyclic scaffold based on Faa is its cyclotrimer 226.110 The synthesis of both compounds is shown in Scheme 45. The acidic treatment of Dfructose resulted in the formation of aldehyde 227 in 80% yield. Its oxidation by NaClO2/H2O2 system and esterification of the resulting acid with diazomethane leads to the corresponding methyl ester 228 in 85% yield. The chloromethyl substituent is then converted into a protected Boc-aminomethyl group in three steps: nucleophilic substitution with sodium azide, selective reduction of azide by Staudinger reaction, and in situ protection of the resulting amine using Boc2O to form protected N-Boc-Faa(OMe) 229 in 80% total yield. After the deprotection of carboxyl and amino groups, a solution of 225 was subjected to cyclotrimerization upon treatment with BOP at 0 °C, followed by the slow addition of trimethylamine, producing the cyclic trimer 226 in 65% yield. A computational study showed that the lowest point on the potential energy surface of compound 226 corresponds to the flat conformation with the cis orientation of all amide carbonyls (Figure 12).110 The average distance between furyl oxygens and their neighboring amide protons is 2.1 Å, which indicates the possibility of the existence of a network of intramolecular hydrogen bonds NH → O, where each amide proton is bound to two adjacent oxides of furan rings and vice

5. FURANS IN MACROCYCLIC PEPTIDE SCAFFOLDS Most of the work on synthetic macrocyclic peptides and peptidomimetics containing furan is associated with the study

Figure 12. Optimized geometry of Faa cyclotrimer 226. Reproduced with permission from ref 110. Copyright 2002 Elsevier. AD


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Scheme 46. Synthesis of Cyclic Trimers 236a−c from Chiral Faa Derivatives

Figure 13. Computed conformations (left to right) of 236a, 236b, and 236c.

Scheme 47. Synthesis of the Building Block 237

protecting group. The oxidation of the hydroxyl function in 234a−c under Swern or Jones conditions resulted in the formation of the corresponding aldehydes, which were further oxidized to acids 235a−c. After the subsequent removal of the N-Boc protecting group in 235a−c, the free amines were subjected to cyclooligomerization (DPP, DIPEA) to yield selectively cyclic trimers 236a−c in good yield. Calculations showed that in comparison with 226, compounds 236a−c are not planar.111 The incorporation in the structure of chiral side chains changes the planar geometry of these trimers to the form of a tripod bowl with S-cisorientation of all amide carbonyls and NH bonds directed to the same side. The torsion angle of HN-Cα-H for both 236a and 236c is ∼175°, and it is ∼180° (trans) for 236b. The average distance from any of the three-ring oxygens and neighboring amide protons in these compounds is about 2.4 to 2.5 Å (Figure 13). Compounds 236b and 236c showed excellent activity against E. coli. In the case of Pseudomonas aeruginosa, compound 236b showed a relatively higher activity

versa. The presence of polydentate sites for hydrogen bonding makes this macrocycle a good receptor for binding carboxylate ions. In further studies, optically active derivatives of H-Faa-OH were synthesized as well as their symmetric optically active macrocyclic trimers 236a−c.111 The starting materials in this synthesis are chiral N-Boc-amino aldehydes 230a−c derived from the corresponding amino acids and (S)-4-(2,2-dibromovinyl)-2,2-dimethyl-1,3-dioxolane 231 (Scheme 46). Upon the treatment of 231 with N-BuLi, an in situ formed acetylide reacted with the starting compounds 230a−c to form the mixture of corresponding diastereomeric alkynes, which upon cis-hydrogenation over P2−Ni led to the corresponding cisallyl alcohols 232a−c. The subsequent acidic deprotection of the diol function in 232a−c and selective acylation of terminal hydroxyl group yielded compounds 233a−c. The latter were then converted to the corresponding furfuryl alcohols 234a−c upon oxidation with PCC and treating the intermediate compounds with anhydrous K2CO3 to remove the acetyl AE


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Scheme 48. Preparation of Faa Cyclotrimers 245 and 246 Modified with Cationic Groups

Scheme 49. Synthesis of Tri- and Tetrapeptides 249 and 250

steps from the available substrate 238 (Scheme 47) in 50% overall yield. After deprotection, 237 was subjected to cyclooligomerization (FDPP) to obtain a mixture of trimer 244a and tetramer 244b in 30 and 11% yield, respectively. The azide groups in 244a were reduced by catalytic hydrogenation with simultaneous protection with Boc2O. The removal of the Boc group by TFA yielded compound 245. Peptide coupling (EDCl, HOBt) of the latter with Boc-β-Ala-OH and the subsequent removal of the Boc protecting group provided product 246 (Scheme 48).

level compared with 236a, whereas 236c was inactive against the same microorganism as compared with standard streptomycin. Compounds 236b and 236c showed comparable activity against Gram-positive bacteria, such as Bacillus cereus, as compared with streptomycin. Compound 236a exhibited very mild activity against fungi, such as Candida albicans, compared with nystatin.111 Further research in the development of furyl-containing macrocyclic peptides was devoted to the preparation of Faa cyclotrimers modified with cationic groups at position 4 of the furan ring.107 The building block for the synthesis of these compounds was compound 237, which was synthesized in 11 AF


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It was demonstrated that compounds 245 and 246 selectively bind to G-quadruplexes and also exhibit biological efficacy, reducing the transcription of c-MYC.112,113 Consequently, these ligands can act as key structures for developing quadruplex-selective drugs with lower toxicity and increased activity as well as for ligands that have the ability to efficiently differentiate between quadruplexes. In another study, low-symmetrical macrocyclic peptide macrocycles 249 and 250 were obtained (Scheme 49) on the basis of compounds 225 and 237.108 Di- and tripeptides 247 and 248 were synthesized by standard peptide synthesis methods (EDCI, HOBt): The addition of one or two fragments of 225 to 237 resulted in the formation of dipeptide 247 or tripeptide 248, respectively. The removal of C- and Nterminal protecting groups in these substrates, followed by macrocyclization (FDPP, DIPEA) and azide reduction yielded the cyclodimer 249a and macrocycle 250a. Peptide coupling (EDCl, HOBt) of these products with N-Boc-β-alanine, followed by deprotection furnished more complex derivatives 249b and 250b. These compounds, having one or two cationogenic side chains, can interact selectively with Gquadruplex structures and thereby stabilize them. It has been demonstrated that these ligands have low cytotoxicity and are able to effectively inhibit telomerase activity, which makes them promising ligands for the study of anticancer therapy.

Scheme 50. Synthesis of Building Block 252

Scheme 51. Synthesis of Compound 251

5.2. Incorporation of Furan by Positions 2 and 4

The only example of a macrocycle containing a 2,4disubstituted furan moiety is compound 251 (Scheme 50).114 The building block for its synthesis was compound 252, which was prepared as follows. Condensation of benzyl acetoacetate with D-xylose led to the formation of polyol 253. Azide function was installed into the C1 position of the polyol chain upon the conversion of 253 into the corresponding cyclic sulphite and its subsequent treatment with TMSN3/ TBAF to give 254 in good overall yield. Oxidative cleavage of diol in 254 and reduction of the resulting aldehyde produced 252. Hydrogenation of azide in 252, followed by Boc protection of the resulting amine and subsequent reaction with PyBOP and DIPEA resulted in an activated N-Boc-amino acid 255 (Scheme 51). Amino ester 256 was prepared by reducing the azide function at 252 using H2S. Solution-phase protocol was carried out between 255 and 256 under standard conditions to furnish dipeptide 257 in 78% yield. The subsequent benzyl ester hydrogenolysis in the latter and second peptide coupling with 256 gave the linear tripeptide 258 in good yield. The removal of C- and N-terminal protecting groups in 258, followed by macrolactamization (PyBOP, DIPEA) and final amine acetylation gave the desired furyl cyclopeptide 251 in 10% yield over four steps. The attempts to increase the yield of the cyclization step using FDPP and EDCl as activating reagents were unsuccessful. The comparatively low yield in the macrocyclization stage can be explained by the absence of intramolecular hydrogen bonds between the NH group and the oxygen of the furan ring in the intermediate unprotected acyclic peptide, which may be a key factor for providing a favorable conformation of the tripeptide before cyclization. Computational simulation showed that in compound 251 the value of the dihedral angles of the three HN-Cα-H amide bonds is 169°. Furan rings do not lie in the same plane but have a bowl-like structure with three CH2OAc groups (Figure 14). The average distance between the three oxygens of

Figure 14. Computed conformation of 251. Reproduced with permission from ref 114. Copyright 2010 Wiley.

AG


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Scheme 52. Synthesis of Peptide α-Loop Models 264a−d and 265

Figure 15. Conformation of peptides 265 in H2O/D2O (pink) and DMSO-d6 (brown). Reproduced from ref 115. Copyright 2014 American Chemical Society.

The rigid furyl fragment, which promotes and stabilizes the formation of intramolecular hydrogen bonds, simulates the most common type of α-loop (type I-αRS).116 The resulting structures are conformationally stable in both aqueous and aprotic solvents, and this property does not depend on the sequence of amino acid residues included in the macrocycle (Figure 15). This implies that the stability of the secondary structure is determined solely by the presence of a furyl moiety. The data collected in this section demonstrate that there are many methods for the incorporation of furyl fragment into the skeleton of macrocycles of various sizes. Such compounds have characteristic structural rigidity and the ability to form hydrogen bonds, so they find use as anion receptors and models of biologically active objects. However, at the moment, no unsymmetrical 2,5- and 2,4-derivatives of furan-containing macrocycles that could be of interest from the point of view of their biological activity have been synthesized.

acetoxy groups (oxygen bound to methylene groups) in the minimized structure is 7.2 Å. In the inner cavity of the cyclopeptide, the distance between NH fragments is 4.6 Å. These structural features make 251 an effective receptor for the binding of Cl−, CN−, and OAc− anions. 5.3. Incorporation of Furan by Positions 2 and3

A group of macrocycles containing a 2,3-substituted furan fragment was examined as models of a peptide α-loop that is stable in an aqueous medium (Scheme 52).115 In the synthesis of these compounds, the tert-butyl analogue of 253, compound 259, was transformed to the corresponding azide 261 over five steps. Hydrogenation of 261 and subsequent coupling (EDCl, HOBt) with tripeptides 262 resulted in the formation of linear peptides 263a−d in 75−85% yield. The simultaneous removal of Boc and tert-butyl protecting groups in compounds 263a−d and subsequent treatment with FDPP/DIPEA in acetonitrile under high dilution conditions (0.5 × 10−2 M) resulted in the formation of compounds 264a−d in 52−60% yield. Various polar fragments were attached to the carboxyfuryl fragment in 264a−d under the conditions of peptide synthesis (EDCl, HOBt) to furnish a total of 20 new compounds 265 with 2,3substituted furan topology.

6. THIOPHENES IN MACROCYCLIC PEPTIDE SCAFFOLDS Thiophene-derived peptide macrocycles are less accessible compared with their furan-incorporating neighbors. Whereas AH


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Scheme 53. Synthesis of Thiophene-Containing Macrocycles 273a and 273b

Scheme 54. Synthesis of Thiophene-Containing Macrocycles 273a and 273b

the corresponding linear precursors of these compounds are relatively easily attainable, the difficulties appear in the stage of their macrocyclization. The most frequently used building blocks for the synthesis of thiophene-containing macrocyclic peptides are the derivatives of 5-aminothiophenecarboxylic acid 266, which are isosteres of dipeptide fragments.117 The three-component Gewald reaction using methyl 2-O(TMS)cyclopropanecarboxylate 267 provides a simple and reliable method for the synthesis of these δ-amino acids (Scheme 53). Several syntheses of cyclic peptidomimetics have been described in the literature. Typically, the corresponding molecules are constructed from oligomers of 266 as well as condensation products of this fragment with proteinogenic amino acids. In contrast with its furyl analogue (225), the thiophenecontaining building block behaves poorly in cyclooligomeriza-

tion reactions. Thus the simplest cyclic scaffolds of 266, tetramer 273a, and hexamer 273b were synthesized via the cyclization or cyclodimerization of the corresponding linear substrates (Scheme 53). A stepwise elongation of the peptide chain by repeated peptide synthesis procedures using 266 was used to prepare the key dimers 270 and 271. Only the Cbz group was suitable for protecting the N-terminus of the peptide, and EDCl reagent demonstrated the best yields in the peptide synthesis and macrocyclization stages. Thiophenecontaining oligopeptides behave differently in macrocyclization than their furyl analogues. Thus unlike similar furyl compound 248, the cyclization of tripeptide 272a did not lead to the formation of an 18-membered cyclotrimer. Instead, a 36membered cyclohexamer 273a was formed in trace amounts (1%). Tetramer 272b led to the formation of the cyclization product 273b, albeit in poor yield (18%). AI


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Figure 16. Crystal structures of 273a (left) (Reproduced from ref 118. Copyright 2012 American Chemical Society) and 273b (right) (Reproduced with permission from ref 117. Copyright 2010 Wiley).

Scheme 55. Stereoselective Synthesis of C2-Symmetric Macrocycle 274

mixtures of oligomers, and the yields of macrocycles of different sizes were selectively altered by changing the concentration of the reaction mixture. As expected, a high dilution (∼10−4 M) resulted in good yields of cyclic tetra- and hexamers 273a and 273b, respectively, whereas at higher

It was shown that the yield of macrocyclization of these substrates can be improved when the combination of propylphosphonic anhydride (T3P) and ultrasonic activation is employed (Scheme 54).118 The overall strategy for the synthesis of macrocycles 273a−d was essentially the same as in Scheme 53. In most cases, these compounds were formed as AJ


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Scheme 56. Late-Stage Introduction of Thiophene Ring in Macrocycle via Modification of 1,3-Diyne Fragment

C5i, and C11i for the four corners of the rectangular cavity, the lengths of its sides are 7.4 (C5−C11) and 14.1 Å (C5−C11i). It is interesting to note that the macrocycle cavity was occupied not by a solvent molecule but by opposite 6butoxycarbonyl groups bound to C14 and C14i carbon atoms. Because of steric hindrances, these ester groups did not lie in the same plane but above and below the plane of the rectangle with an angle value between 12.8 and 18.5°. The synthesis of macrocycle 274, which incorporates both proteinogenic amino acids and thiophene subunits, was also reported (Scheme 55).119 Two synthetic strategies were reported: Starting from building block 266, appropriately protected dipeptides 275 and 276 were prepared and were subjected to peptide coupling under different conditions to yield bis-thiophene substrates 277 and 278. Upon deprotection at C- and N-termini, these compounds were transformed to 279, which was subjected to intermolecular macrolactamization via two different protocols. T3P/Et3N system and sonication showed better results for the construction of the linear precursor 277 but lower yields at the macrocyclization step. In contrast, the conventional protocol for peptide synthesis (PyBOP, DMAP) demonstrated better yields for the macrocyclization step and somewhat lower yields in the stage of preparation of linear precursor 278. A racemic (S,S)/(R,R) mixture of 274 as well as meso-274 were examined via X-ray crystallography. Of great interest is the fact that all of these molecules have different conformations that are induced by the chiral centers.119 This is more evidence that thiophene-containing macrocyclic peptides are conformationally labile, which is generally uncommon for other heterocycles. All of these features make thiophene a sort of unique block for the design of novel macrocyclic architectures. A unique method of introduction of heteroaryl rings in the structures of macrocyclic peptides was reported by Verniest et al. in 2016.120 This approach consists of the initial construction of 1,3-diyne-stapled macrocycle, followed by its treatment with various nucleophiles. Thus dipeptides 280a,b and 281a,b were pairwise-coupled (HOAt, EDC, or HATU) to form tetrapeptides 282a−c, which included two O-propargyl fragments at terminal serine residues (Scheme 56). The latter compounds were introduced to the Glaser−Hay-type oxidative coupling to

Scheme 57. C−H Activation-Macrocyclization of Thiophene-Containing Peptides 285

concentrations (∼10−1 M) octa- and nonamers 273c and 273d were preferably formed. The influence of ultrasound on the yields in this macrocyclization is explained by the high energy of cavitation, which easily overcomes the energy barrier of activation. Concentration plays an important role during the ultrasound treatment. The described reaction of peptide synthesis with T3P as a reagent occurred much faster (only 5−20 min) at high concentrations, whereas in the case of high dilution, ultrasound did not accelerate the reaction as compared with usual mixing. Macrocyclization depends on a large number of parameters of the reaction system, and it is not always possible to trace the universal pattern for this process. A large number of reaction protocols was investigated, which allowed the authors to examine the reaction time, the concentration of the reaction mixture, and the reagents for peptide synthesis (EDCl, PyBroP, TFFH, and T3P as activating reagents and Et3N and 2,4,6collidine as bases). The selectivity of formation and the yields of compounds 273a−d varied over a wide range. The cavity of the cyclotetramer 273b has a diameter on the order of 8 Å. It is a fairly rigid molecule with the geometry C5−C11−C5i−C11i close to a square (angles of 84.9 and 95.1°). Thiophene rings are oriented almost perpendicular to the plane determined by these four carbon atoms (Figure 16). Compared with 273b, the crystal structure of cyclohexamer 273a is an almost chairlike conformation with angles of 87.3 and 93.7°. Taking the sp3-hybridized carbon atoms C5, C11, AK


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identical. As part of the histidine side chain, the imidazole ring plays an important role in the biological functions of many peptides and proteins and is often the key structural element of active sites of enzymes. Theonellamides and aciculitins are the best known classes of naturally occurring macrocyclic peptides that contain imidazole.

give the corresponding macrocycles 283a−c in satisfactory yield. The best macrocyclization results (61%) were obtained with substrate 283a, which incorporated two turn-inducing proline residues. The treatment of 283a−c with NaHS at room temperature furnished thiophene-bridged macrocycles 284a− c, again in satisfactory yield and in up to 90% conversion. This approach was shown to be applicable for the introduction of several other heterocyclic motifs, including furans, thiophenes, pyrazoles, and isoxazoles.120 Use of Pd-catalyzed C−H activation−macrocyclization of thiophene-containing peptides is shown in Scheme 57.121 Peptides 285a,b capped with thiophenesulfonamide at Ntermini were heated with Pd(OAc)2 to produce macrocycles 286a,b, which incorporated thiophene at positions 2 and 3.

7.1. Natural Imidazole-Containing Macrocycles

7.1.1. Aciculitins. Aciculitins A, B, and C (Figure 17) were isolated by Bewley et al. from Aciculites orientalis in 1996.123 These bicyclic peptides are characterized by an unusual HisTyr linkage with the incorporation of a His-imidazole side chain at position 5. All compounds have similar structures. The Aciculitins A, B, and C inhibited the growth of Candida albicans at a loading of 2.5 μg and demonstrated cytotoxicity toward the HCT-116 cell line (IC50 = 0.5 μg/L). No total synthesis of these molecules has been reported thus far. 7.1.2. Theonellamides. Theonellamides A−F 287−292 were isolated from the antifungal sea sponge fraction Theonella swinhoei by Fusetani et al. (Figure 18).124,125 Two more members of this bicyclic family, theopalauamide 293 and theonegramide 294, were isolated and characterized by Faulkner et al.126−128 These compounds represent a unique class of macrocycles with a signature unusual τ-L-histidine-Dalanine (τ-HAL) bridge. In general, this is a class of dodecapeptides composed of L- and D-amino acids. Theonellamides A and B peptides 287 and 288 have three amino acid residues that are different from 292, 287 has an additional Dgalactose bound to the free nitrogen of imidazole, and 289 corresponds to the debrominated version 292. Compounds 290 and 291 are L-arabinoside and D-galactoside analogues of 293. In general, theonellamides demonstrated moderate inhibition of the growth of P388 leukemia cell lines. Cyclic peptides 293 and 294 demonstrated the inhibition of growth on Candida albicans. Theonellamide F (292) demonstrated cytotoxicity for L1210 (IC50 = 3.2 μg/mL) and antifungal activity (e.g., Candida spp., Trichophyton spp., and Aspergillus spp.). Two reports about the synthesis of two cyclic scaffolds (“hemispheres”) of theonellamide F (292) were published by Tohdo, Hamada, and Shioiri in 1994. Although both macrocyclic fragments were formed individually, the ultimate goal of the construction of the finished bicycle was not realized. Other members of the family of theonellamides were not the subject of any synthetic studies. Shioiri et al. reported on the synthesis of the southern hemisphere (295) of theonellamide F (Scheme 58).129 A linear heptapeptide 296 was prepared for subsequent macrocyclization between the fragments of β-alanine and (2S,4R)-2amino-4-hydroxyadipic acid (Ahad). The linear heptapeptide was obtained by the condensation of tripeptide and tetrapeptide fragments (297 and 298, respectively) upon the activation by DPPA or DEPC. For the assembly of linear peptides, DEPC was used because of its slightly higher reactivity and lower epimerization rate at the C-terminus of amino acids.130 C-terminal tetrapeptide Asn-eHyAsn-BPA-βAla 298 was constructed stepwise in the C → N direction in yields in the range of 74−97% per step. The N-terminal tripeptide fragment 297 was prepared in high yield by binding the τ-HAL dipeptide to Nα-Troc-lactonic acid with DEPC. The condensation of the oligopeptides proceeded in a good yield (56%) of the linear heptapeptide 296, whereas cyclization

7. IMIDAZOLES MACROCYCLIC PEPTIDE SCAFFOLDS The imidazole fragment is a key constituent of many current drugs.122 The basicity of imidazoles is significantly higher than

Figure 17. Structures of aciculitins A−C.

Figure 18. Family of theonellamides.

that of the corresponding oxazoles and thiazoles (pKa values of conjugated acids are 6.95, 0.8, and 2.5, respectively), whereas the corresponding geometric parameters are practically AL


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Scheme 58. Synthesis of the Southern Hemisphere (295) of Theonellamide F (292)

are devoted to the development of effective methods for the synthesis of these fragments and remain outside the scope of this Review.132,133

with DPPA led to the formation of macrolactam 295 in 21% yield. A follow-up report by Shioiri et al. was devoted to the synthesis of the northern hemisphere (299) of theonellamide F.131 This approach was accomplished by cyclizing the linear heptapeptide H-Aboa-Ser-τ-HAL-aThr-Ser-Phe(OH) (300) using DPPA. A linear approach consisted of the elongation of Phe(OMe) from the C-terminus using DPPA. The synthesis did not require hydroxyl group protection and provided a linear heptapeptide H-Aboa-Ser-τ-HAL-aThr-Ser-Phe(OH) 301 in 54−83% yield in each stage of the peptide synthesis (Scheme 59). Macrocyclization (DPPA) of 301 led to the formation of the northern hemisphere (300) of theonellamide F in 24% yield. The synthesis of this family of macrocyclic peptides is complicated by the fact that out of the 11 amino acids0 included in their composition, the following 4 are not commercially available: Aboa ((5E,7E)-3-amino-4-hydroxy-6methyl-8-n-bromophenyl-5,7-octadienic acid), eHyAsn ((2S,3R)-3-hydroxyasparagine), Ahad ((2S,4R)-2-amino-4-hydroxyadipic acid), and τ-HAL (τ-L-His-D-Ala). Modern studies

7.2. Artificial Imidazole-Containing Macrocycles

7.2.1. Incorporation of Imidazole by Positions 2 and 4. In 2002, the synthesis of symmetrical 18- and 24-membered imidazole-containing cyclic peptides 302a−c and 303a,b was published (Scheme 60).134 This approach begins with coupling of N-Boc-protected valine, phenylalanine, or bis-N-protected β-aminoalanine (304a−c) to the ketoester 305 via mixed anhydride method. The resulting amidoketones 306a−c were converted to imidazoles 307a−c by refluxing in xylene with methylamine in the presence of acetic acid. The removal of Cand N-terminal protecting groups in 307a−c resulted in the formation of amino acids 308a−c. Several methods of one-pot macrocyclization of 308a−c compounds have been investigated; the optimal way proved to be the interaction of monomers with DPPA in the presence of excess DIPEA in acetonitrile at a high dilution (0.05 M). This method resulted in obtaining cyclotrimers 302a−c in fairly good yield (25− 35%) in an admixture with cyclotetrameric compounds 303a AM


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Scheme 59. Synthesis of the Northern Hemisphere (300) of Theonellamide F (292)

Scheme 60. Synthesis of Trimers 302a−c and Tetramers 303a,b

and 303b, which were obtained in lower yield (5−10%). The formation of trace amounts of the tetramer 303c was observed only by mass spectrometry. For compound 302a, the results of XRD were obtained (Figure 19). Overall, this molecule is structurally similar to the Val-Faa-based cyclotrimer 236a (see Figure 13). No intramolecular hydrogen bonds are present in this compound. Their formation is hampered by the fact that all of the NH fragments are directed into the interior of the ring, and the carbonyl O atoms are directed outside the cycle. The valine residues in 302a lie on one side of the molecule and adopt an axial position, whereas the macrocycle scaffold forms a conical

Figure 19. Structure of trimer 302a.

AN


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Scheme 61. Synthesis of Tetramer 303a

Scheme 62. Alternative Synthesis of Tetramer 303a

Alternatively, 303a was obtained by macrolactamization of the corresponding linear peptide 310a (Scheme 62).135 Compound 310 was converted to the corresponding C- and N-deprotected dipeptides, which were coupled (DPPA, DIPEA) to give linear tetrapeptide 310a. Macrolactamization (FDPP, DIPEA) of 310a furnished the corresponding cyclic product, albeit in lower overall yield than in the previous strategy. Subsequently, the synthesis of various functionalized imidazole-containing platforms 313−315 was reported.136 Using aminoketone 316 and N-Cbz-S-Val as starting materials, 1H-imidazole building block 318 was prepared in a two-step sequence, as shown in Scheme 63. The successive deprotection of C- and N-termini in 318 led to compound 319, which was subjected to cyclooligomerization (PyBOP, DIPEA) to give cyclohexapeptide 313a and cyclooctapeptide 313b in a satisfactory yield. A follow-up transformation of the benzyloxymethyl moieties in 313a allowed an unprotected hydroxylated derivative 314 to be obtained, which could be further converted to the corresponding chlorinated compound 315. When phthalimide-protected aminoketone 316 was used as the starting material, amine-functionalized molecules 317 and 318 were obtained (Scheme 64). The synthesis of the corresponding imidazoles 319 and their cyclization were accomplished in the same manner as in the previous scheme. (NH3 was used instead of MeNH2 for the synthesis of 319b.) Cyclooligomerization of imidazole 319a yielded the mixture of cyclic trimer 317a and cyclic tetramer 317b, whereas in the case of 319b, only the cyclic trimer 318 could be isolated. Both cyclotrimers 317a and 318 were obtained in good yield, and phthaloyl fragments in those could be easily removed or exchanged for other protecting groups.

Scheme 63. Synthesis of Functionalized Platforms 313−315

structure. The deviation from planar geometry is on the order of 33°. The dihedral angles NHαCH of three peptide linkages are in the range between 168 and 173°. Tetramer 303a was obtained in significantly higher yield by cyclodimerization of the corresponding bisimidazole precursor 310 (Scheme 61). Building block 307a was transformed to Nand C-deprotected derivatives 311 and 312, respectively. The latter were subjected to peptide coupling (DPPA, DIPEA) to furnish the requisite dimer 310 in 70% yield. After the removal of C- and N-terminal protecting groups, the resulting peptide was subjected to cyclodimerization (FDPP, DIPEA) to give the tetramer 303a in 29% total yield starting from imidazole 307a. AO


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Scheme 64. Synthesis of Functionalized Platforms 317 and 318

Scheme 65. Synthesis of Trimer 323

Scheme 66. Improved Synthesis of Trimer 323 and Its Modification to 325a−f

The synthesis of similar C3-symmetric tripodal structures that possess N1-demethylated imidazole units was elaborated as well (Scheme 65).137−139 The slightly modified approach used amidoketone 306a, which was condensed with ammonia to yield the desired imidazole 320. An attempt to hydrolyze the methyl ester in 320 led to racemization of the valine fragment. To overcome this problem, the Cbz group was replaced with Boc and protected the NH moiety of the imidazole ring with a benzyl group (compounds 321a and 321b). The successive deprotection of N-Boc, N-Bn, and ester groups in these compounds furnished the amino acid 322.

Cyclooligomerization (FDPP, DIPEA) of 322 under high dilution conditions furnished the desired platform 323 in a moderate yield. The crystal structure of 323 is similar to that of its N-methylated analogue compound 302a (Figure 19). A significantly better yield of compound 323 was achieved in an alternative method (Scheme 66). In this case, the protection in 321a was removed at the C- and N-termini, leaving the benzylimidazole amino acid, which was cyclotrimerized, as described above, to give the macrocycle 324 in 57% yield. The removal of benzyl groups by hydrogenolysis over palladium hydroxide allowed the desired macrocycle 323 to be obtained AP


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“hinges” 334a,b. These molecules are capable of an open− close motion upon complexation (closed) and decomplexation (open, Figure 21) of copper. The direction of this process is restricted by structural rigidity, and thus the dihedral angle between pyridine fragments varies exclusively between 0 and 180°. The 22-membered receptor 338 was synthesized in the same way (Scheme 70).142 330 was coupled (FDPP, DIPEA) to the commercially available building block 337. The deprotection of the C- and N-termini in 338,followed by cyclodimerization (FDPP, DIPEA) furnished the receptor 338 in a good yield (52%). Calculations showed that macrocycle 338 has a syn−syn NH conformation of amide groups of valine-imidazole fragments and a large cavity. The distance between azole cycles is ∼7 Å. All four hydrogen atoms of the amide groups are directed into the interior of the macrocycle (Figure 22). This compound demonstrated a high selectivity for H2PO4− anions. The synthesis of the C3-symmetric macrocycle 339 based on pyrroloimidazole fragments 340 was reported (Scheme 71).143 Coupling (EDCl, HOBt, NMM) of methyl 4S-hydroxyproline 341 with N-Cbz-L-Val, followed by the installation of protecting group at hydroxyl function and ester hydrolysis afforded dipeptide 342. The two-step conversion of carboxylic acid in 342 to α-ketoester in 343 was carried out by the oxidative cleavage of the corresponding α-ketocyanophosphorane. The condensation of 343 with ammonium trifluoroacetate resulted in the formation of bicyclic imidazole 340a in good yield. After hydrolysis of methyl ester in 340a, the resulting acid 340b was transformed to the Pfp ester, which was subjected to one-pot hydrogenolysis with the removal of Cbz protection and macrolactamization to form the corresponding cyclotrimer in a satisfactory yield (43%). The removal of TBS protecting groups provided the desired triol 339. The geometry of 339 is in good agreement with the data obtained from the X-ray crystal structure of similar tris-imidazole macrocycles described above. 7.2.2. Incorporation of Imidazole by Positions 4 and 5. In 2012, the synthesis of a library of macrocyclic peptides based on imidazole-4,5-dicarboxylic acid 344 was reported (Scheme 72).144 Compound 344 was transformed to diimidazopyrazine 345, which could be readily alkylated by a set of amino acid esters 346. Commercially available N,N′dialkylalkanediamines 348 and Boc-protected amino acids were used to synthesize a set of peptides 350 via common peptide chemistry. The combinatorial peptide synthesis of 347 with pyrazine building blocks 350 resulted in a library of 32 peptidomimetics 351. After the simultaneous removal of C-

Scheme 67. Synthesis of a Three-Dimensional Cage 326

in gram quantities. Benzylation of 323 to position 1 of imidazole fragments was used to create various macrocyclic receptors 325. An additional advantage of these systems is that benzyl fragments can be removed by hydrogenolysis. An interesting cage framework 326 was also synthesized in good yield (46%) by the treatment of 323 with 5,5′bis(bromomethyl)-2,2′-bipyridine under the same conditions (Scheme 67). XRD analysis of these compounds revealed that benzylation of the original platform 323 does not alter its original shape (Figure 20). Calculations showed that the lowest-energy conformation of 325a is a cone, where the iPr and Bn groups lie on opposite sides of the cycle. However, the calculated energy of inversion of one benzyl fragment was calculated only by 0.26 kcal/mol higher in energy relative to the lowest state.138 In another work, the synthesis of the C2-symmetric macrocycle 327 and its transformation into the bridged 3D structure 328 was described (Scheme 68).140 The imidazolecontaining amino acid 330 was coupled (FDPP, DIPEA) to LVal(OBut) to give the corresponding dipeptide 331 after the simultaneous removal of C- and N-terminal protecting groups. Compound 331 was cyclodimerized (FDPP, DIPEA) to give 327 in good yield. After the removal of two benzyl groups in 327 and alkylation of the resulting compound with two equivalents of 1,3-bis(bromomethyl)benzene, 333 gave the intermediate 329, which was treated with ammonia and TFA to furnish the C2-symmetric cage 328 as its trifluoroacetate salt. Macrocycle 327 was later used to create interesting “molecular hinges” 334a and 334b (Scheme 69).141 327 was alkylated with 3-methoxybenzyl bromide, yielding the corresponding amide, in which methoxy groups were subsequently removed to give 335. The subsequent SNAr reaction of 335 with dihalobipyridines 336a or 336b led to the desired

Figure 20. Crystal structures (from left to right) of 323, 325a, 325f, and 326. Reproduced from ref 138. Copyright 2005 Wiley. AQ


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Scheme 68. Synthesis of the C2-Symmetric Macrocycle 336 and Its Modification to 337

Scheme 69. Synthesis of “Molecular Hinges” 334a,b

7.2.3. Incorporation of Imidazole by Positions 1 and 5. The ruthenium-catalyzed Ullmann reaction between aryl chlorides and imidazoles was shown to be a useful method for the construction of medium-sized and highly constrained peptide macrocycles. An example of the synthesis of introducing the His-Phe linkage in N-Boc-Phe-Leu-His(OMe) tripeptide was reported (Scheme 73).145 It began with the complexation of ruthenium to N-Boc-(4Cl)Phe 353, followed by peptide coupling of formed 354 with Leu-His(OMe) to give the ruthenium-containing linear tripeptide 355. Cyclization under high dilution conditions (5 mM), followed by photolytic decomplexation of ruthenium led to the novel heteroaryl cyclized tripeptide 356 in 24% yield. 7.2.4. Incorporation of Imidazole by Positions 1 and 4. Later, macrocyclization of linear peptidomimetics via the copper-catalyzed Ullmann reaction was reported (Scheme 74).146 A linear depsipeptide 359 was synthesized by Oalkylation of ephedrine 357 and coupling of the resulting

Figure 21. Computed structures of 334a (left) and 334b (right). Reproduced with permission from ref 141. Copyright 2008 Wiley.

and N-terminal protecting groups, followed by lyophilization, these compounds were introduced to the intramolecular macrolactamization (EDCl, DMAP) to give the set of macrocycles 352. Individual reactions were not optimized, and yields averaged to 12 to 11%. It should be noted that the only attempt to perform macrocyclization under the action of HBTU/Et3N/DMF was unsuccessful. AR


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Scheme 70. Synthesis of a 22-Membered C2-Symmetric Macrocycle 338

macrocycle 366 in 78% yield. Coupling (BOP) between 366 and compounds 367a and 367b furnished the desired compounds 364a and 364b, respectively.

8. OXAZOLES IN MACROCYCLIC PEPTIDE SCAFFOLDS Oxazoles are less frequent constituents than thiazoles (see section 9) in the structures of macrocyclic peptides. Biosynthetically, oxazole rings are formed from Ser or Thr units in peptide chains during post-translational modification (Scheme 77).149 Thus oxazoles inherit the general substitution pattern from the peptide side chain and are incorporated in peptide macrocycles at positions 2 and 4.

Figure 22. Computed conformation of 338. Reproduced with permission from ref 142. Copyright 2009 Wiley.

amine 358 to N-Boc-His. Upon heating with copper iodide and 8-hydroxyisoquinoline under high dilution conditions, 359 furnished the corresponding cyclic product 360 after a short reaction time in 73% yield. Harran et al. reported a palladium-catalyzed macrocyclization of templated unprotected histidine-containing peptides (Scheme 75).147 A series of linear precursors 362 containing three to nine amino acid residues was easily obtained by the reaction of corresponding peptides with N-hydroxysuccimidiyl ester 361. Treatment with [Pd(C3H5)]2 and Xantphos afforded corresponding histidine-alkylated macrocycles 363a−h of various sizes in high yield. This process was not hampered by the amino acid side-chain functionalities, such as hydroxyls, carboxylic acids, or guanidines. Compounds 363a,b were designed as inhibitors of human plasma renin with IC50 of 2.2 and 0.28 nM, respectively (Scheme 76).148 These scaffolds share a common macrocyclic core 366, which was accessed starting from tripeptide N-BocPro-Phe-His(OBn) 365a. The alkylation of histidine imidazole on the τ-nitrogen with tert-butyl bromoacetate led to compound 365b in good yield. A sequence of deprotection at the N-terminus and the carboxymethylene fragment of histidine in 365b, followed by macrolactamization (BOP) and the final hydrogenation of the benzyl group afforded

8.1. Natural Oxazole-Containing Macrocycles

8.1.1. Discobahamins A and B. Discobahamins A and B are two macrocyclic peptides isolated from marine sponge Discodermia sp. by Gunasekera et al. in 1994 (Figure 23).150 These compounds displayed weak cytotoxicity against the yeast form of Candida albicans with MIC = 26 mM. No studies devoted to synthesis of these compounds were reported. 8.1.2. Keramamides B−E and M−N. Kobayashi et al. isolated keramamides B−D from Theonella sp. in 1991 and keramamides M and N from the same sponge in 1999 (Figure 24).151,152 Macrocyclic cores of these compounds feature a 2bromo-5-hydroxy-indole fragment in L-Trp subunit, an α-ketohomoleucine, L-Ala- or L-Abu-derived oxazole, and a fragment of isoleucic acid (ILA) at the N-terminus of the exocyclic peptide moiety. Keramamides B−D demonstrated micromolar inhibitory activity toward human neutrophil superoxide generation. Keramamide E showed cytotoxicity against KB carcinoma and L1210 cell lines with low-micromolar IC50 values. Keramamides M and N, which are sulfate ester derivatives of keramamides D and E, respectively, were cytotoxic against KB and L1210 cell lines with low-micromolar

Scheme 71. Synthesis of Pyrroloimidazole-Based Macrocycle 339

AS


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Scheme 72. Synthesis of the Library of Macrocyclic Peptides 352

Scheme 73. Synthesis of His-Phe-Linked Macrocyclic Peptide 356

D−F have a similar macrocyclic core as nazumazoles A−C, except for the presence of D-Abu or D-Ser subunits instead of DCys. These compounds did not show cytotoxic activity against P388; however, they inhibited chymotrypsin at IC50 values of 2, 3, and 10 μM, for nazumazole D, E, and F, respectively. No studies aimed at the synthesis of any of these compounds were reported. 8.1.4. Orbiculamide A. Orbiculamide A was isolated from Theonella sp. by Fusetani et al. in 1991 (Figure 26).156 This compound is structurally similar to keramamide E but differs by the substitution of ILA-Leu for (S)-3-methylpentanoic acid in the exocyclic peptide moiety. Orbiculamide A displayed weak cytotoxic activity against the P388 cell line. The total synthesis of this compound has not been reported. 8.1.5. Telomestatin. Telomestatin (368) was isolated from Streptomyces anulatus 3533-SV4 by Seto et al. in 2001 (Figure 27).157 Telomestatin specifically inhibits telomerase (IC50 = 5 nM) through the formation of a G-quadruplex structure and is widely used as a standard G-quadruplex binder. The total synthesis of telomestatin was reported by Takahashi et al. in 2006.158 The general approach consisted of assembling the two trisoxazole subunits 369 and 370 from the corresponding oxazole building blocks 371−373 (Scheme 78). Compounds 371b and 371c were derived from N-BocSer, which was initially coupled to Ser-OMe and converted to oxazolidine-oxazole compound 371a using a common two-step protocol of dehydrocyclization with DAST and aromatization with BrCCl3. Ester saponification in 371a afforded acid 371b, which was subsequently esterified with BnBr, yielding 371c.

Scheme 74. Synthesis of Cyclic Depsipeptide 360

IC50 values. No total syntheses of these compounds were achieved; however, Shioiri et al. reported the synthesis of key subunits of keramamide B in 2003.153 8.1.3. Nazumazoles A−F. These compounds were recently isolated from Theonella swinhoei by Matsunaga et al. (Figure 25).154,155 Nazumazoles A−C are pseudosymmetrical molecules consisting of two pentapeptide macrocycles tethered by a disulfide bridge. Each macrocycle features several unusual fragments: a cis-4-methylproline, an L-Ala-derived oxazole, an (S)-3-amino-2-formamidopropanoic acid, and an α-keto-βamino acid. The mixture of nazumazoles A−C displayed cytotoxicity against the P388 cell line (IC50 = 0.83 μM). The presence of ketoacid fragments and the disulfide linkage were shown to be crucial for the biological activity. Nazumazoles AT


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Scheme 75. Pd-Catalyzed Macrocyclization at His Side Chain

The same procedure, except for final-stage alkylation, was applied to N-Boc-Thr, which was elaborated to compound 372b. The synthesis of Cys-derived 5-methyloxazole building block 373 started with appropriately protected Cys-Thr dipeptide. The successive oxidation of the secondary alcohol in the Thr side chain of 374, followed by dehydrocyclization and ester saponification provided requisite compound 373 in 73% overall yield. Peptide coupling (PyBroP) between 373 and 372b afforded bisoxazole amide 375. Cyclodehydration of 375 using the Burgess reagent, followed by treatment with BrCCl3 afforded Cys-containing trisoxazole 370 in 75% yield. Trisoxazole unit 369 was obtained via coupling (PyBroP) between 371b and 371c, which afforded bisoxazole 376 in 84% yield from N-Boc-protected amine 371c. A three-step sequence of cyclodehydration, aromatization, and benzyl ester hydrogenolysis afforded trisoxazole subunit 369. The acidic removal of the Boc group in 370 and coupling (PyBroP) of the resulting amine with acid 369 afforded hexaoxazole amide 377 in 85% yield (Scheme 79). The successive cleavage of N-terminal acetonide and C-terminal ester in 377, followed by macrolactamization (DPPA, HOBt) afforded macrocycle 378 in 48% overall yield. The installation

of the last oxazole ring was accomplished in the following fourstep sequence: Dehydration of Ser residue in 378, followed by the installation of a methoxy group in 379 and subsequent cyclization afforded a 1:1 diastereomeric mixture of 4methoxyoxazoline derivatives 380. Treatment of 380 with CSA led to the desired heptaoxazole 381. Finally, cyclodehydration and deprotection of the SBut group in 381 afforded target compound 368, albeit in low yield. Later Takahashi et al. reported the synthesis of the (2S)isomer of telomestatin ((S)-368) using the same strategy, which employed the opposite enantiomers of trisoxazoles 369 and 370 (Scheme 80).159 The only synthetic difference is the use of 4-(dimethylamino)pyridine oxide (DMAPO) in the stage of macrocyclization of the linear precursor (2S,14R)-378. This additive allowed a 1.5-fold increase in the yield of this step and significantly reduced epimerization at the C2 position. Importantly, this epimer retained the potency (IC50 = 5 nM) of the natural compound. Moody et al. proposed a formal total synthesis of telomestatin, which employed another approach toward its trioxazole subunits (Scheme 81).160 This approach used the cycloaddition of metallocarbenoids with nitriles for the AU


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Scheme 76. Synthesis of Human Renin Inhibitors 364a,b

Scheme 77. Biosynthetic Transformation of Ser and Thr Residues to the Corresponding Oxazoles

Figure 23. Structures of discobahamins A and B Figure 24. Structures of keramamides B−E, M, and N.

synthesis of oxazole building blocks and well as Rh(II)catalyzed amide N−H insertion of diazocarbonyl compounds for the synthesis of 5-methyloxazole building blocks. Thus the synthesis of trisoxazole subunit 383 started with the protected cysteine carboxamide, which was reacted with methyl diazoacetoacetate 385 in the presence of dirhodium(II) tetraacetate, affording the ketoamide 386, which underwent cyclodehydration to give the oxazole building block 387 in excellent overall yield. The latter was converted to the corresponding amide and underwent a second N−H insertion of 385, followed by cyclodehydration to give the bisoxazole 388 in moderate overall yield. 388 was transformed to the

corresponding nitrile and underwent a Rh(II)-catalyzed cycloaddition to diazo compound 389, affording the requisite trisoxazole 383 in 26% yield (65% based on the recovered starting material). Building block 384 was elaborated using the same synthetic toolkit. Ser-derived nitrile 390 was converted into oxazole 391 by the Rh(II)-catalyzed reaction with 389 in 45% yield (82% based on recovered nitrile starting material). Two successive cycles of ester to nitrile group formation and cycloaddition to 389 provided the required trisoxazole 384. AV


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Figure 25. Structures of nazumazoles A−F.

prepared by the cyclotrimerization of the corresponding dioxazole precursor.172 8.1.6. Wewakazoles. Wewakazole was isolated by Gerwick et al. in 2003 from marine cyanobacteria Lyngbya majuscula.173 Thirteen years later, in 2016, a related compound, wewakazole B, was isolated from Moorea producens by Okino et al. (Figure 29).174 Both compounds are planar macrocyclic dodecapeptides incorporating three oxazole residues and differ by the presence or absence of a 5-methyl group in one oxazole ring and the identity of two peptide residues. Wewakazole B exhibited potent cytotoxicity toward human MCF7 (breast cancer) and H460 (lung cancer) cell lines with IC50 = 0.58 and 1.0 μM, respectively. Wewakazole demonstrated modest cytotoxicity (IC50 = 10 μM) against H460 cells. Several groups reported total syntheses of these compounds. Long et al. successively reported the synthesis of both natural products following the same general strategy.175,176 Requisite oxazole building blocks 402 and 403 were prepared starting from dipeptides N-Boc-Ile-Ser(OMe) and N-Phe-Ala-Ser(OMe), respectively (Scheme 83). The latter were converted to the corresponding oxazolines upon treatment with the Burgess reagent, which were subsequently dehydrated using DBU and CBrCl3. The optimal procedure for the synthesis of methyloxazole building blocks 404 and 405 consisted of DMP oxidation of threonine side chains of the corresponding dipeptides ((N-Boc-Ala-Thr(OMe) and N-Boc-PheThr(OMe), respectively), followed by the cyclodehydration of the resulting amidoketones using PPh3 in the presence of I2 and TEA. Fully protected building blocks 402 and 403 were obtained in excellent yield and ee. Importantly, the aforementioned methods were not applicable to the synthesis of Val-derived methyloxazole 406. The latter was elaborated from dipeptide N-Boc-Val-Ser(OMe), which was converted to β-halo-dehydroamino acid 407 upon dehydration with Boc2O/ DMAP and TMG, followed by treatment with NBS. The subsequent base-promoted cyclization of 407 afforded compound 406 in 87% overall yield. The assembly of subunit 409, which is common for both natural products, started from building block 402. The N-Boc protecting group in the latter was removed, and the resulting amine was coupled (HATU) to N-Cbz-Phe-Pro, followed by saponification of the C-terminal ester to give compound 408 in 66% yield. The N-Cbz group in 408 was replaced with N-Fmoc in a two-step procedure, and the resulting peptide was coupled (EDCl, HOBt) to Ala-Pro-Pro(OBut), followed by the removal of the N-terminal protecting group, affording hexapeptide 409 in 60% yield over these four steps.

Figure 26. Structure of orbiculamide A.

Figure 27. Structure of telomestatin.

Trisoxazole subunits 383 and 384 were deprotected at Nand C-termini, respectively, and subjected to peptide coupling (HBTU), affording the linear precursor 377 in 68% yield (Scheme 82). The successive removal of C- and N-terminal protecting groups in 377, followed by macrolactamization (HATU) gave macrocycle 378 in 51% overall yield, which was shown to be identical to the macrolactam prepared by Takahashi et al. Numerous telomestatin-inspired macrocycles have been reported (Figure 28). Their syntheses are entirely based on the originally proposed total synthesis of 368 by Takahashi et al., and they differ only in the choice of requisite subunits.161 Thus difunctionalized hexaoxazoles 393,162−165 tetrafunctionalized hexaoxazoles 395166 and 396,167 as well as heptaoxazoles 394168−170 were obtained using a general strategy: preparation of two trioxazole subunits bearing an amino acid at Nterminus, peptide synthesis of these subunits, macrolactamization, and final side- chain manipulations. Unsymmetrical compound 397 was synthesized from one tetraoxazole and one dioxazole subunit, whereas compound 398 was prepared from a trioxazole subunit, one Ser-oxazole, and one Leuoxazole-derived building block.171 Compound 399 was AW


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Scheme 78. Synthesis of Oxazole Building Blocks and Trioxazole Subunits

deprotection of methyloxazole 404 to give hexapeptide 416 in 72% yield. For the synthesis of second hexapeptide subunit 418, building block 402 was converted to the corresponding free amine and coupled (HATU) to N-Boc-Phe-Pro, affording tripeptide 419 in 81% yield. The removal of the N-Boc protecting group in 419 and the second peptide coupling (HATU) to Ala-Pro(OMe) afforded the requisite compound 418 in 71% yield. Saponification of C-terminal ester in 418 and the removal of N-Boc group in 416, followed by peptide synthesis (HATU) of the resulting compounds afforded the linear precursor 420 in 61% yield. The successive removal of C- and N-terminal protecting groups in 420, followed by macrolactamization (HATU) between Ala-oxazole and Phe residues afforded wewakazole B (401) in 72% yield over three steps. Moody et al. reported another strategy for the synthesis of both natural compounds.178 As in the formal synthesis of telomestatin, this approach employed Rh(II)-catalyzed reactions of diazo compounds for the preparation of oxazole building blocks (Scheme 86). Thus bisoxazole subunit 421 was elaborated starting from N-Boc-protected amides of valine and phenylalanine. N-Boc-Phe-NH2 was converted to the corresponding cyanide, which underwent cycloaddition with diazo compound 385 to give building block 403 in 38% yield (67%

The synthesis of subunits 410 and 411, which belong to wewakazole (400) and wewakazole B (401), respectively, started with methyloxazoles 405 and 406 (Scheme 84). The deprotection of N-termini in these compounds, followed by peptide synthesis (EDCl, HOBt) with N-Boc-Gly afforded dipeptides 412 and 413, respectively. The latter were subjected to ester hydrolysis and coupled to N-deprotected derivatives of 403 and 404 to afford the desired subunits 410 and 411, respectively, in 82−85% yield. Saponification of C-terminal ester in these compounds, followed by coupling (EDCl, HOBt) with hexapeptide 409 afforded linear precursors 414 and 415 of wewakazole and wewakazole B, respectively. The simultaneous acid-mediated removal of C- and N-terminal protecting groups, followed by macrolactamization (HATU) between Gly and Pro residues afforded the desired natural products 400 and 401 in good yield. Nayani et al. reported the total synthesis of wewakazole B (400), which employed other sites of macrocyclization of linear precursor to produce the target molecule (Scheme 85).177 For the synthesis of subunit 416, building block 405 was converted to the corresponding free amine and coupled (HATU) to N-Boc-Pro-Gly, affording tripeptide 417 in 79% yield. C-terminal ester in 417 was saponified, and the resulting acid was coupled (HATU) to free amine obtained from N-Boc AX


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Scheme 79. Total Synthesis of Telomestatin by Takahashi et al.

Scheme 80. Synthesis of (2S)-Stereoisomer of Telomestatin

yield based on the recovered starting material). A solution of N-Boc-valinamide was subjected to N−H insertion of diazo compound 423, followed by cyclodehydration of the resulting intermediate to give building block 406 in 61% overall yield. The same procedure was carried out with N-Boc-Ala-NH2 and N-Boc-Phe-NH2 to give 5-methyloxazole units 404 and 405, respectively. Upon ester saponification in 403 and the removal of N-Boc protecting group in 406, the resulting compounds were subjected to peptide coupling (HATU), followed by second ester saponification to give subunit 421 in 86% yield. This sequence was repeated with compounds 405 and 404 to give subunit 422.

Octapeptide 423, which is a common subunit for both natural products, was elaborated starting from N-Bocisoleucinamide (Scheme 87). The latter was dehydrated to form the corresponding nitrile and upon Rh(II)-mediated reaction with 385 was transformed to the oxazole building block 402 in 30% yield (86% yield based on recovered starting material). The successive removal of N-Boc protecting group in 402 and coupling (EDCl, HOBt) to dipeptide N-Boc-PhePro afforded tetrapeptide 419 in excellent yield. A follow-up ester saponification and second coupling (DMTMM) with tetrapeptide Ala-Pro-Pro-Gly(OMe) afforded the desired octapeptide 423 in 77% yield. The use of DMTMM was necessary because a set of other coupling agents demonstrated an unsatisfactory yield. This step could be carried out on a AY


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Scheme 81. Synthesis of Telomestatin Subunits by Moody et al.

8.2. Artificial Oxazole-Incorporating Macrocycles

Scheme 82. Construction of Macrocycle 378 in the Formal Synthesis of Telomestatin

8.2.1. Incorporation of Oxazole by Positions 2 and 4. Rebek et al. reported the synthesis of C3- and C4-symmetric oxazole-based platforms 426 and 427 derived from Asp- or Ser-derived oxazole building blocks 428a,b (Scheme 88).179,180 Two methods for the macrocyclization of desired scaffolds were examined: A one-pot cyclooligomerization (Scheme 88) consisted of the deprotection N-terminus of 428a,b, followed by treatment with a coupling reagent (PyBOP for 428a and DPPA for 428b) in the presence of DIPEA. Cyclotrimers 426a and 426b were obtained in reasonable yield via this protocol. Cyclotetramer 427a bearing protected Asp side chains could be obtained in 24% yield; however, the similar Serincorporating scaffold 427b could not be isolated. The authors also reported a stepwise construction of orthogonally protected C3-symmetric scaffold 429 (Scheme 89), which was constructed from three Asp-derived building blocks 430−432. Linear precursor 433 was assembled via common solution-phase chemistry, and the successive removal of C- and N-terminal protecting groups, followed by macrolactamization (PyBOP) afforded the desired scaffold 429, albeit in low overall yield. The stepwise removal of the side-chain ester protecting group was shown to give the corresponding mono-, di-, and triacid platforms. Haberhauer et al. demonstrated that the cyclotrimerization (DPPA) of the C-and N-termini deprotected variant of building block 402 could efficiently lead to platform 434 (Scheme 90).181 This compound is structurally similar to platform 302a. However, whereas in the case of the latter, the imidazole rings of the macrocycle form a cone-like structure, the oxazole moieties in 434 are almost coplanar. The C2-symmetric scaffold 435 based on building block 402 was also reported (Scheme 91).181 Saponification of methyl

gram scale load in 67% yield of octapeptide 423. The latter was then coupled (DMTMM) to each of the bisoxazole subunits 421 and 422 to give the cyclization precursors 424 and 425 in 69 and 76% yield, respectively. C- and N-terminal protecting groups were removed, and the resulting compounds were subjected to macrolactamization (DMTMM) between Gly/ Phe and Gly residues, affording wewakazole (400) and wewakazole B (401) in 66% yield over three steps. Once again, DMTMM was the optimal reagent for this step, whereas other reagents (including HBTU, which was used in the other syntheses) gave either significantly lower yields or inseparable side products. AZ


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Figure 28. Examples of reported telomestatin-inspired macrocyclic polyoxazole scaffolds.

the phthaloyl protecting group in compound 441b, the resulting triamine platform 447 was further derivatized to this dihydroxybenzoyl-containing compound 448. The latter showed good metal complexation properties with significant selectivity toward Ga(III) ions.183 Another interesting example is the 3D scaffolds 450a and 450b (Scheme 93).184 Acylation of scaffold 447 with triarylphosphine oxide 449 afforded compound 450a in low yield. The latter could be reduced to the corresponding triarylphosphine 450b. 8.2.2. Incorporation of Oxazole by Positions 4 and 5. The only example of the incorporation of oxazole by positions 4 and 5 was reported Kessler et al. (Scheme 94).185 The requisite oxazole building blocks 451a and 451b were derived from the Schiff base 452, which was initially acylated with NFmoc-Phe-Cl in a three-step sequence to give compound 453. The latter was coupled via mixed anhydride method to N-Bocβ-Ala or monomethyl succinate to afford compounds 444 (75%) and 445 (71%), respectively. Cyclodehydration of these compounds, followed by the hydrogenolytic removal of benzyl ester groups afforded building blocks 451a and 451b in excellent yield. The latter were used as subunits in the FmocSPPS synthesis along with protected L-Glu or L-Lys to afford a series of linear precursors 456a−c, which were subjected to macrolactamization (DPPA), affording C2-symmetrical platforms 457a and 457b as well as orthogonally protected platform 457c in excellent overall yield.

Figure 29. Structures of wewakazole and wewakazole B.

ester in 402 afforded the corresponding acid, which was subjected to peptide coupling (FDPP) with Val(OBut) without purification. Following the removal of the N-Boc protecting group, this sequence afforded tripeptide 436 in excellent yield. The cyclodimerization (FDPP) of 436 afforded the desired platform 435. A series of related oxazole building blocks 437a and 437b was used to construct several derivatized C3-symmetrical platforms.182 Oxazole subunits were derived from the Schiff bases 438a,b and protected glycine or hydroxyacetic acid, as shown in Scheme 92. Upon the successive removal of C- and N-terminal protecting groups in 437a and 444b, the resulting compounds were treated with PyBOP, affording the trimers 441a and 441b, respectively, accompanied by the corresponding cyclotetramers 442a and 442b. Compound 442a was subjected to the hydrogenolytic cleavage of benzyl ether groups, affording the scaffold 443, which was further elaborated to compounds 444 and 446 using common chlorination or alkylation procedures. Upon the cleavage of

9. THIAZOLES IN MACROCYCLIC PEPTIDE SCAFFOLDS To date, thiazole is the most commonly occurring heterocycle in natural products. A large number of macrocyclic scaffolds containing this heteroarene have been found in marine bacteria, algae, and invertebrates. In these compounds, thiazole BA


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Scheme 83. Synthesis of Key Building Blocks of Wewakazoles by Long et al.

Scheme 84. Total Synthesis of Wewakazoles by Long et al.

BB


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Scheme 85. Total Synthesis of Wewakazole B by Nayani et al.

Scheme 86. Synthesis of Key Building Blocks of Wewakazoles by Moody et al.

BC


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Scheme 87. Total Synthesis of Wewakazoles by Moody et al.

Scheme 88. Cyclooligomerization of Oxazole Building Blocks 428a,b

is biosynthesized by the oxidative cyclodehydration of cysteine subunits of the corresponding peptides (Scheme 95).186,187

In 2013 Serra and coworkers published the synthesis of aerucyclamide B (458).190 The key building blocks of this total synthesis are thiazoles 459, 460, and dipeptide L-Ile-L-allo-Thr (461) (Scheme 96). For the preparation of thiazole 460, the coupling between N-Boc-D-allo-Ile-OH and L-Ser-OMe was performed. The subsequent cyclodehydration using DAST (diethylaminosulfur trifluoride) furnished the corresponding oxazoline, which was used without purification. Its subsequent thiolysis rendered the corresponding thioamide. From this compound, thiazole 460 was obtained in excellent overall yield (80%) by employing the one-pot procedure with DAST and then BrCCl3/DBU. Dipeptide 461 was obtained in excellent yield (95%) by coupling (HBTU) the corresponding amino acid subunits. The synthesis of thiazole 459 utilized conventional Hantzsch’s methodology: Amide formation from N-BocGly-OH employing 2,2,2-trichloroethyl chloroformate/aque-

9.1. Natural Thiazole-Containing Macrocycles

9.1.1. Aerucyclamides. Aerucyclamides A, B, and D (Figure 30) are thiazole-containing hexameric cyclopeptides that were isolated in 2008 by Gademann and coworkers from the toxic freshwater cyanobacterium Microcystis aeruginosa PCC 7806.188,189 These compounds differ in hydrophobic amino acids and the identity of one thiazoline/thiazole heterocycle. Aerucyclamide B displays a submicromolar (0.7 μM) IC50 value against the chloroquine-resistant strain K1 of P. falciparum. In addition, this compound displays a large selectivity for the parasite with respect to the L6 rat myoblast cell line. Aerucyclamides A and D displayed low micromolar activity against P. falciparum. BD


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Deoxo-Fluor and DAST were similar, although Deoxo-Fluor displayed increased thermal stability and was already known to be effective in the synthesis of the cis,cis-ceratospongamide core.192 The use of these conditions led to aerucyclamide B (458) in 67% yield and an unexpected fluorinated side product 466 in 28% yield. 466 was produced by the intermolecular reaction between a fluoride and the activated intermediate generated by the reaction of 465 with Deoxo-Fluor. The formation of 466 could be explained by a loss of nucleophilicity of the β-hydroxyamide of 465. 9.1.2. Aeruginazole A. Aeruginazole A (Figure 31) is a macrocyclic dodecapeptide that was isolated from the cyanobacterium Microcystis sp. strain (IL-323) by Carmeli et al. in 2010.193 It was the first example of a polythiazolecontaining cyclic peptide isolated from a fresh water cyanobacterium. Its diverse macrocyclic core comprises an achiral region (northern sphere), two regions with L-amino acids in the eastern and western spheres, and a region with two D-amino acids (southern sphere). Aeruginazole A exhibited cytotoxic activity against MOLT-4 (IC50 = 41 μM) and PBL (IC50 = 22.5 μM) cell lines.194 The synthesis of aeruginazole A was reported by the Bruno group in 2011 (Scheme 97).195 The northern hemisphere of this compound featuring the Fmoc-protected pentapeptide 467 was smoothly synthesized by solid-phase peptide synthesis (SPSS) on 2-chlorotrityl chloride resin with HBTU as a coupling reagent. The thiazole building blocks 468−470 were readily accessed from N-Boc-protected L-Val-OH, D-Leu(OH), and L-Asp(OBn)−OH, respectively, via modified Hantzsch thiazole synthesis.196 The benzyl ester protecting group in Aspthiazole 470 was cleanly removed by hydrogenolysis, and the resulting acid was then converted into the corresponding amide (PyBOP, DIEA, NH4HCO3). The deprotection of the N-Boc group then furnished the Asn-thiazole building block 471. The latter was coupled to N-Boc-D-Tyr-OH, and the resulting dipeptide was deprotected to give rise to 472. L-Valderived thiazole 468 and D-Leu thiazole 469 were deprotected at their C- and N-termini, respectively, and coupled together (PyBOP, DIPEA) to yield, after hydrolysis, bisthiazole peptide 473. The amine 472 was then coupled to the acid 473 to form the tris-thiazole peptide 474. The Boc protecting group was then removed from compound 17 to afford the southern sphere of aeruginazole A. This part of the compound was directly coupled to northern sphere 467, producing 475 in good yield. Interestingly, the protocol (PyBOP, DIPEA in THF) used in all previous couplings was unsuccessful for this stage. Instead, EDCI/HOBt in the DCM/DMF system was used, which allowed the 79% yield. Thiazole dodecapeptide 475 was deprotected at its C- and N-termini and finally subjected to intramolecular macrolactamization under high dilution conditions (2.5 mM) by the activation with PyBOP

Scheme 89. Synthesis of Orthogonally Protected Platform 429

Scheme 90. Cyclotrimerization of Building Block 402

ous ammonia and further reaction with Lawesson’s reagent furnished thioamide 462. Hantzsch synthesis using ethyl bromopyruvate in Py/EtOH afforded thiazole 460 in 40% overall yield.191 Compound 463 was prepared by coupling of dipeptide 461 and the C-deprotected derivative of 460. For the synthesis of 464, methyl ester hydrolysis of 463 and coupling to the Ndeprotected derivative of 459 rendered 464 in 40% yield. Cand N-deprotection of the linear precursor 464 was achieved in quantitative yield. Macrocyclization was performed in diluted conditions (5 × 10−3 M) using HBTU. The desired macrocycle 465 was obtained from 464 in high yield (40%). The last reaction to obtain aerucyclamide B was realized using the cyclodehydrative reagent Deoxo-Fluor. The reactivities of Scheme 91. Synthesis of C2-Symmetric Scaffold 435

BE


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Scheme 92. Synthesis of Trifunctionalized Oxazole-Based Scaffolds

reagent 477 (Scheme 98).197 The subsequent conversion to the Weinreb amide, followed by the TBS protecting group provided compound 478. The reduction of the latter to the corresponding aldehyde and Evans aldol reaction with 479 established the remaining two chiral centers of the polyketide segment in the compound 480. Transformation of 480 to aldehyde 481 was achieved with the established sequence of Weinreb amide formation, installation of the TES protecting group, and DIBAL-H reduction. Olefination of 481 with Wittig reagent 482, prepared from α-bromoallyl ester and tribu-

and HOAt, affording the desired product in a 24% yield over the two steps of deprotection and cyclization. 9.1.3. Antalid. Antalid was isolated in 2001 from Polyangium sp. and was obtained and characterized by Tautz et al. in 2016.197 This cyclic depsipeptide contains a polyketide fragment, D-phenylalanine, and L-valine thiazole units (Figure 32). To date, no biological activity of antalid has been reported. The synthesis of the polyketide fragment 476 started with the Nagao aldol reaction between propanal and the auxiliary BF


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Scheme 93. Synthesis of 3D Structures 450a,b

Scheme 95. Biochemical Transformation of Cys Residue to Thiazole Ring

for their broad spectrum of biological activities such as immunomodulation and cytotoxicity.199,200 The first synthesis of argyrin B (489) was by Ley et al. and was reported in the same year that it was discovered.201,202 The described approach required the synthesis of three fragments: thiazole 490, tripeptide unit 491 containing the 4-methoxytryptophan residue, and selenophenyl-substituted tripeptide 492. Thiazole 490 was synthesized in a straightforward manner from N-Boc-D-alanine via thioamide 493, which was obtained by amidation with ammonia and thiolation with Belleau’s reagent. 493 was reacted with ethyl bromopyruvate and subsequently treated with trifluoroacetic anhydride and 2,6lutidine to yield 490 (Scheme 99). An efficient synthesis of the key 4-methoxytryptophan derivative 494 required for the synthesis of the tripeptide 491 was achieved via the enzyme resolution route using immobilized Penicillin G acylase. The highly selective hydrolysis of the racemic amide 495 afforded the required Samine, which was protected with the Cbz group to yield 494 in an overall 44% yield. This compound was then coupled using standard peptide coupling techniques with Gly(OMe) (496) and after the removal of the Cbz group reacted with N-Cbz-LTrp to afford the tripeptide 491 in excellent yield. Last, the tripeptide containing the selenophenyl group 492 was

tylphosphine, led to the polyketide fragment 483. Final deprotection of allyl ester with palladium and N-methylaniline delivered acid 476 in high yield. Thiazole 484 was synthesized from ester 468, which was deprotected and converted to the allyl ester. Acid 476 was reacted with 484 (EDC/HOBt), yielding 485, which was then directly coupled to N-Alloc-protected D-phenylalanine (486) to furnish the protected linear precursor for the macrocyclization 487. After the simultaneous removal of N- and Cterminal protecting groups (Pd(PPh)4, PhSiH3) in 487, the corresponding linear depsipeptide was directly introduced to cyclization conditions utilizing HATU. The desired product 488 was obtained in 63% yield and was transformed to antalid by removing the remaining TBS group with HF-pyridine in 90% yield. 9.1.4. Argyrins. Argyrins A−H (Figure 33) are a family of eight macrocyclic natural heptapeptides containing unusual thiazole and tryptophan residues, which were isolated from myxobacteria by Sasse et al. in 2002.198 They are well known

Scheme 94. Synthesis of 4,5-Oxazole-Incorporating Platforms 457a−c

BG


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Figure 30. Structures of aerucyclamides A, B, and D.

Scheme 96. Total Synthesis of Aerucyclamide B (458)

constructed from N-Boc-L-serine. This route proceeded via the formation of the corresponding β-lactone, which, after ring opening, afforded the selenide 497. The latter was coupled to ethyl sarcosine using PyBroP to give 498, which after deprotection to remove the butyloxycarbonyl group was coupled to N-Boc-D-amino butyric acid to give 492. The removal of the Cbz protecting group from 491 and coupling to the free acid from 490 gave the product 499 in 96% yield (Scheme 100). Similarly, hydrolysis of 499 to the

acid and coupling to the Boc-deprotected fragment from 492 gave the fully assembled heptapeptide 500. After deprotection of 500 at C- and N-termini it was subjected to intramolecular macrolactamization (TBTU/HOBt) to form 501 in an overall yield of 60%. Lastly, syn-elimination of the selenide was achieved using sodium periodate and bicarbonate to give argyrin B (489). The synthesis of argyrin F by Bülow et al. used the same tripeptide building block 491 and similar thiazole building BH


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Figure 32. Structure of antalid.

without enzymatic hydrolysis. The Horner−Wadsworth− Emmons reaction of aldehyde 503 yielded the corresponding alkene 504, which was subjected to catalytic hydrogenation (DuanPhos ligand, Rh(cod)2BF4) to provide the required amino acid 505 in quantitative yield (99%) and 99% ee (Scheme 101). The latter was transformed into 491, as shown

Figure 31. Structure of aeruginazole A.

block 502 derived from tert-butyl-protected serine.203 The requisite Trp-containing building block 491 was synthesized Scheme 97. Total Synthesis of Aeruginazole A

BI


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Scheme 98. Total Synthesis of Antalid

and peptide coupling (PyBroP) with the ammonium salt of the sarcosine ester provided building block 508. Ser-thiazole moiety 502 was prepared from tert-butyl-protected serine 509, which was first converted into the corresponding thioamide 510. The subsequent treatment of 510 with ethyl bromopyruvate provided building block 502. The assembly of argyrin F started with the coupling of thiazole 502 to the N-terminus of the tryptophan-containing building block 491, which gave 511 (Scheme 102). The subsequent hydrolysis of the ester moiety and coupling to 508 provided 512, the linear precursor of argyrin F. After deprotection at C- and N-termini, 512 was subjected to macrolactamization (TBTU, HOBt) (513). Finally, the tertbutyl protecting group was removed through treatment with trifluoroacetic acid (TFA). The synthesis of argyrin A and E was presented by Wu et al. in 2011.204 Here Trp-derivative intermediate 514 was obtained from commercially available 3-methoxybenzeneamine (515)

Figure 33. Structures of naturally occurring argyrins A−H.

above. Unlike the synthesis of argyrin B, where the synthesis of the dehydroalanine moiety was conducted in the last step, the authors installed the exomethylene moiety in the building block before the assembly of the linear precursor without the use of organoselenium chemistry. Thus dipeptide 506 was generated under standard peptide-coupling conditions, in which the subsequent copper(I)-catalyzed elimination of the serine hydroxy group yielded 507. Final ester hydrolysis in 507 BJ


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Scheme 99. Synthesis of Building Blocks of Argyrin B

sequence starting from N-methyl-N-Fmoc-Gly attached to 2chlorotrityl polystyrene resin, followed by the acidolytic (TFA−DCM−H2O−iPr3SiH) release of the linear peptide and the subsequent head-to-tail macrocyclization (PyBOP, HOBt). Thus the synthesized linear peptides 527a−h were subjected to PyBOP-mediated macrocyclization to yield 528a−h, followed by an oxidation−elimination reaction to afford the desired argyrin A 529h and related macrocycles 529a−g (Scheme 105). In 2018, Stempel et al. published the synthesis of an Ala1azulene derivative of argyrin C.207 The key step in the synthesis of tryptophan derivative 530 was based on a Negishi cross-coupling between C3-iodinated indole 531 and iodoalanine derivative 532, which was transformed into the corresponding organozinc reagent. For the synthesis of the azulene-containing building block, N-Boc-Azu-Ala-OH, azulene (533) was transformed into unstable 1-iodoazulene (534), which was rapidly used for the Negishi cross-coupling with the organozinc derivative of iodoalanine 532, yielding the required compound as its methyl ester 535 in excellent yield. Saponification of the methyl ester gave Boc-AzuAla-OH (536) in quantitative yield. Two other fragments, D-Ala-thiazole 537 and dehydroalanine-containing dipeptide 538, were synthesized as described above in the text (Scheme 106). For the synthesis of azulene-containing fragment 539, the tryptophan derivative 530 was simultaneously deprotected at ester and sulfonylamide moieties by treatment with 3 N NaOH in refluxing methanol. The carboxylic acid was then coupled to glycine methyl ester using standard peptide coupling conditions to obtain dipeptide 540 in 79% yield (Scheme 107). After deprotection at the N-terminus, 540 was then

(Scheme 103). Boc protection of 515, subsequent lithiation, followed by iodination with molecular iodine and Boc -deprotection yielded amine 516. The key intermediate 514 was easily derived in two steps through a palladium-catalyzed heteroannulation reaction between 516 and the aldehyde derivative of glutamic acid 517 and subsequent BiBr3-catalyzed selective deprotection of the Boc group in the intermediate 518. Hydrolysis of the methyl ester group in 514 and coupling to glycine methyl ester yielded the dipeptide 519. Dipeptide 520 was synthesized in a straightforward route from protected Ala-thiazole 491 via ester hydrolysis and coupling to LTrp(OMe). The tripeptide 521 was prepared from N-Boc-DAla (522). Sequential coupling of the latter to L-Ser(OMe) yielded the dipeptide 523, which was mesylated. The subsequent elimination provided the dehydroalanine moiety 524. Hydrolysis and peptide coupling (PyBroP) with sarcosine ethyl ester provided fragment 521. N-deprotected dipeptide 520 and C-deprotected tripeptide 521 were coupled to give the product 525 in 92% yield (Scheme 104). The subsequent hydrolysis of methyl ester in 525 and peptide coupling (EDC/HOBt) of the resulting acid with 519 or 519a yielded the linear heptapeptides 526 and 526a, respectively, in 66% yield. After deprotection of N- and C-termini in 526 and 526a, they were subjected to intramolecular macrolactamization (HATU, DMF, 0.7 mM) yielding argyrins A and E, respectively, in 56% yield. In 2014, Chen reported the Fmoc/tBu solid-phase approach to the synthesis of natural argyrin A and its synthetic analogues.205,206 The Fmoc-protected amino acids were used for the total chemical synthesis of argyrin A and its analogues. The process consists of the stepwise assembly of the peptide BK


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Scheme 100. Completion of Synthesis of Argyrin B by Ley et al.

Scheme 101. Synthesis of Building Blocks of Argyrin F

BL


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Scheme 102. Total Synthesis of Argyrin F by Bülow et al.

Scheme 103. Synthesis of Building Blocks for Argyrins A and E

BM


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Scheme 104. Total Synthesis of Argyrins A and E by Wu et al.

Scheme 105. Solid-Phase Synthesis of Argyrin A and Analogues by Chen

coupled to N-Boc-AzuAla-OH (536), forming dark-blue tripeptide 539 in 81% yield. Again, N-terminus deprotection in 539 and coupling to thiazole building block 537 resulted in the formation of tetrapeptide 541 in 86% yield. The subsequent hydrolysis of the ester moiety and coupling with dehydroalanine segment 538 provided the linear precursor 542 in 54% yield. The deprotection of C- and N-termini in 542 and

subsequent macrolactamization (TBTU, HOBt) gave the darkblue AzuAla1 derivative of argyrin C in 41% overall yield. 9.1.5. Ascidiacyclamide. Ascidiacyclamide (Figure 34) is the C2-symmetric cyclic octapeptide isolated from Lissoclinum patella in 1983 by Mizukawa et al.208 It was the first characterized metal binder among other natural peptide BN


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Scheme 106. Synthesis of Building Blocks for AzuAla1 Argyrin C

Scheme 107. Synthesis of AzuAla1 Argyrin C

Ile with D-Thr(OH) using DEPC and subsequent saponification of resulting dipeptide to give the carboxylic acid 543 in 63% overall yield. Coupling of 543 with D-valine-thiazole block 544 upon treatment with DEPC furnished the tripeptide 545 in 71% yield. The cis-oxazoline ring in this linear precursor was

macrocycles and, to date, its conformational behavior as well as its metal binding properties are extensively studied.209 The total synthesis of ascidiacyclamide was reported in 1985 by Hamada et al. (Scheme 108).210 It consists of the construction of dipeptide 543 by condensation of N-Boc-LBO


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yield (Scheme 109). The required components for the construction of linear precursor 551 were assembled by SPPS, and the latter was cyclized (HATU, DIPEA, 10−4 M in DMF) to yield ascidiacyclamide analogue 552 in 39% yield. Compounds 553−560 were synthesized according to the same protocol by replacing the amino acid at position 1. Authors noted than the replacement of amino acid did not affect the yield of any steps of the proposed synthesis. In 2018, Williams et al. published the synthesis of the heteroatom-interchanged (HI) diastereomer of ascidiacyclamide (Scheme 110).213 Dipeptide 561 was synthesized by coupling D-THr(OMe) and N-Boc-L-Ile using COMU in 64% yield. Hydrolysis and a second COMU coupling of 561 and LVal thiazole 562 afforded tripeptide 563 as the major product together with the desired epimer 564 as the minor product (≈ 8:1) in 61% overall yield. Hydrolysis of tripeptide 564 gave acid 565, whereas Boc group removal in 563 yielded 566. 565 and 566 were coupled using COMU to afford the linear peptide 567. The deprotection of C- and N-termini in 567 and the subsequent macrolactamization yielded cyclic peptide 568 in 41% yield over three steps. The final incorporation of oxazoline rings was achieved by cyclodehydration of threonine residues with Deoxo-Fluor, giving the HI-ascidiacyclamide diastereomer (569) in 51% yield. The most stable conformers of ascidiacyclamide 548 and its HI isomer 569 are shown in Figure 35. Both 569 and 548 adopt a saddle-shaped conformation of the 24-membered macrocycle. In both compounds, the peptide NH groups and oxazoline nitrogens point toward the interior of the ring. In

Figure 34. Structure of ascidiacyclamide.

installed by treatment of 545 with an excess of SOCl2 in THF, yielding the cis-oxazoline peptide 546 in excellent yield. Esterification of 546 was achieved by treatment with TMSCHN2 to give the trans-oxazoline derivative 547 in 76% yield and without epimerization. Treatment of 547 with TMSOTf and subsequent hydrolysis afforded the C- and Ndeprotected peptide which was subjected to cyclodimerization upon the addition of DPPA in the presence of KHPO4 to furnish the target molecule 548 in 27% yield from 547. Solid-phase synthesis of a few analogues of ascidiacyclamide was reported by several groups.211,212 The D-Val thiazole block 550 was synthesized in four steps from the N-protected Dvaline, which was converted to the corresponding aldehyde 549, which was condensed with cysteine methyl ester, followed by oxidation with MnO2 and deesterification with 33% overall

Scheme 108. Total Synthesis of Ascidiacyclamide by Hamada et al.

BP


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Scheme 109. Synthesis of Ascidiacyclamide Analogue 552

against A549, HT29, and MEL28 with IC50 values of 10−20 μg/mL. You et al. published the total synthesis of bistratamide F in 2005.224 The Val-thiazole building block 570 was synthesized from N-Fmoc-S(Tr)-L-Cys, which was converted to the dipeptide 571 (Scheme 111). Bis(triphenyl)oxodiphosphonium trifluoromethanesulfonate (bis(TP)ODP-TFMS) was utilized for the cyclodehydration of 571 into thiazoline 572 in 89% yield. Oxidation of 572 with activated manganese oxide afforded the Val-thiazole block 570 in 94% yield and >96% ee. For the synthesis of oxazoline building block 573, C- and Nprotected dipeptide 574 was treated with Burgess reagent in refluxing THF (87%). The removal of benzyl protecting group in 573 and Fmoc protecting group in 570, followed by amide coupling (HBTU, HOBt) yielded compound 575 in 79% yield. 575 was successively coupled (HBTU, HOBT, DIPEA) to NFmoc-allo-Thr and N-Fmoc-L-Val, affording 576 in 62% overall yield. Cyclodehydration of Thr-Val fragment in 576 upon treatment with Burgess reagent afforded the linear precursor for macrolactamization 577 in 38% yield. The removal of protecting groups from C- and N-termini of 577 and the final cyclization (PyBOP, DMAP) yielded bistratamide F in 35% yield. The total synthesis of bistratamides E and J was published by You et al. in 2004.225 The Val-thiazole core 578, which is generic for both natural products, was constructed by peptide coupling (HBTU, HOBt) of the N- and C-deprotected derivatives of 570 (compounds 579a and 579b, respectively, Scheme 112). For the synthesis of bistratamide J, deprotection at the N-terminus and coupling of 578 to N-Fmoc-O(trityl)Thr afforded 580, which was again deprotected and coupled to N-Fmoc-L-Val to give 581 in 85% overall yield. The

548, thiazole nitrogens point to the interior, whereas in 569, thiazole sulfurs point to the interior. The saddle of 569 is flatter and more elongated than that of 548: The distance between oxazoline nitrogens is 5.9 Å in 548 but 7.3 Å in 569; the distance between thiazole nitrogens is 6.4 Å in 548 and 4.3 Å in 569. 9.1.6. Balgacyclamides. In 2014, three cyclic peptides, balgacyclamides A−C (Figure 36), were isolated and identified by Portmann et al. from the extracts of Microcystis aerugunosa EAWAG 251.214 Balgacyclamides A and B showed antimalarial activity against Plasmodium falciparum K1 in the low micromolar range. The synthesis of these compounds has not yet been achieved; however, Hoang et al. published the synthesis of all-thiazoline analogues of balgacyclamide A, which showed enhanced cellular uptake and sought to be useful in drug delivery.215 9.1.7. Bistratamides, Didmolamides, and Related Synthetic Macrocycles. Bistratamides (Figure 37) are a family of thiazole-containing hexapeptide macrolactams, which were isolated from Lissoclinum bistratum.216−220 These hexapeptides were associated with the C3-symmetric trisoxazoline westiellamide isolated from the same organism.221,222 Bistratamide A exhibited cytotoxicity against MRC5CV1 fibroblasts and T24 bladder carcinoma cell lines at IC50 values of 50 μg/mL, respectively. Bistratamides E, F, and J exhibited cytotoxicity against the HCT-116 human colon tumor cell line at IC50 values of 7.9, 28.0, and 1.0 μg/mL, respectively. Didmolamides A and B (Figure 38) are two cyclic hexapeptides that are structurally akin to bistratamides. They were isolated by Rudi et al. from marine ascidian Didemnum molle in 2003.223 These compounds showed cytotoxic effects BQ


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Scheme 110. Synthesis of Heteroatom-Interchanged Diastereomer (569) of Ascidiacyclamide

Figure 35. Lowest energy conformations of ascidiacyclamide 548 (left) and HI-ascidiacyclamide 569 (right). Reproduced from with permission from ref 213. Copyright 2018 Wiley.

Figure 36. Structures of balgacyclamides A−C.

macrocyclization 584. The removal of the protecting groups at C- and N-termini of 584 resulted in the formation of the macrocycle precursor 585, which was subjected to macrolactamization (PyBOP, DMAP) to give 586 in 81% yield. The Val-Thr junction was then converted to the corresponding oxazoline ring using the Burgess reagent, providing bistratamide E in 63% yield. You et al. reported the solid-phase synthesis of didmolamides A and B as well as solution-phase synthesis of didmolamide B in 2005.226 The solid-phase synthesis consists of installing the Ala-thiazole unit 587 on Wang resin and step-

deprotection at C- and N-termini and subsequent macrocyclization of formed precursor 582 afforded 583. It was reported that among several coupling protocols, the combination of PyBOP and DMAP allowed the best yields in this transformation. The final step was to remove the O(Tr) protecting group of threonine residue in 583, which completed the total synthesis of bistratamide J. For the synthesis of bistratamide E, the core 578 was deprotected and successively coupled to N-Fmoc-allo-Thr and N-Fmoc-L-Val, affording the protected linear precursor for the BR


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Figure 37. Structures of bistratamides.

in 88% yield. After removing the O(Tr) group from the threonine residue in 592, didmolamide B was obtained in 48% overall yield. Cyclooligomerization of thiazole-based amino acids was studied in detail.227 In particular, several papers used this approach as a route to bistratamides and didmolamides as well as related non-natural macrocycles. It has been shown that treatment of Val- and Ala-thiazoles 593a or 593b with FDPP and DIPEA at room temperature under high dilution conditions led to the cyclic trimers 594a and 594b and the cyclic tetramers 595a and 595b, in ratios of 9:2 and 5:2, respectively, in very good overall yield (Scheme 116).228 Furthermore, the 1:1 mixture of 593a and 593b under similar conditions yielded the mixture of all possible cyclic trimers 594a−594d and only two possible cyclic tetramers, namely, 595b and 595f, in the ratio 2:7:5:8:1:1 and in a combined yield of 70%.229 The template effect of different metal and ammonium cation on this macrocyclization has also been studied. The addition of alkali and transition-metal salts as well as NH4PF6 in the reaction system was shown to change the 594:595 product ratio in ranges of to 2:1 to 11:2.230 These cyclic tri- and tetramers were also synthesized in a concise and stepwise manner from bisthiazole amides 596a− 596c. These, in turn, were obtained by pairwise-coupling the corresponding amino acid thiazoles 597 and 598 (Scheme 117).231 Saponification of the ethyl ester group in 596a and subsequent coupling of the resulting acid 599 with 597a yielded the tris-thiazole 600a. The deprotection of C- and Ntermini in 600a, followed by macrolactamization (FDPP, DIPEA) finally gave the cyclic peptide 594c. In a similar manner, the acid 599 was coupled to 597b, yielding tristhiazole 600b, which underwent macrocyclization to give cyclic peptide 594d (Scheme 118). Upon N-Boc deprotection, acid 599 was subjected to cyclodimerization under the same condition, yielding the C2-symmetric cyclic tetramer 595e.

Figure 38. Structures of didmolamides A and B.

by-step peptide coupling with another fragment 587, N-Fmocallo-Thr, and N-Fmoc-Phe, yielding 588. The HBTU/HOBt/ DIPEA system was used for the coupling, and treatment with 20% piperidine in DMF allowed the N-Fmoc deprotection at each step (Scheme 113). After the removal of the terminal NFmoc group in 588 and the cleavage of the resulting thiazolecontaining triamide from the resin, the resulting linear precursor was transformed into 589 (PyBOP, DMAP). Final cyclodehydration of the Ala-Thr moiety in 589 was achieved using the Burgess reagent, furnishing didmolamide A in 56% yield. Didmolamide B was synthesized utilizing the same approach using the trityl-protected allo-threonine, except for the last step of cyclodehydration of macrocycle (Scheme 114). The O-trityl protecting group was removed during cleavage of the linear peptide from the resin. Didmolamide B was obtained in 51% yield after the macrocyclization. For the solution-phase synthesis of didmolamide B, the Alathiazole carboxylic acid 587 was coupled to N-deprotected derivative of 589, yielding the bisthiazole core 590 of the target molecule in 95% yield (Scheme 115). Sequential coupling (HBTU, HOBt, DIPEA) of 590 to N-Fmoc-O(Tr)-L-Thr and N-Fmoc-L-Phe afforded 591 in 85% overall yield. The deprotection of C- and N-termini in 591 and subsequent macrolactamization (PyBOP, DMAP) yielded macrocycle 592 BS


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Scheme 111. Total Synthesis of Bistratamide F by You et al.

596c and L-Val-allo-Thr 604 was treated with DPPA/DIPEA or FDPP/DIPEA, which resulted in the formation of mixture of didmolamide B (7−9%) and cyclic tetramer 595a (5−13%). En route to didmolamide A, the oxazoline 605c was synthesized from the corresponding dipeptide L-Phe-L-alloThr 605a by cyclodehydration using DeoxoFluor and subsequent C- and N-termini deprotection. Again, treatment of a solution of 605c and 596c with FDPP/NMM yielded didmolamide A in 2% yield. The major product isolated from the reaction was the cyclic tetramer 595a (10−12%), accompanied by trace amounts of higher oligomers. A common synthetic route was used to prepare the Nmethylated compounds, similar to 595 and 596 (Scheme 120).232 N-methylation of Val-thiazole 468, followed by saponification of resulting compound 606, yielded the carboxylic acid 608a. The acidic treatment of 606 produced amine 608b in good yield. Thus coupling (EDCI, HOBt) between 607 and 608 yielded dipeptide 609. The deprotection

Other cyclic tetramers, 595c, 595d, and 595f, were synthesized in an iterative manner from corresponding bisthiazole fragments 596b and 596c. These were saponified to the corresponding carboxylic acids 601 and 602, respectively. 596a was deprotected at the N-terminus and coupled to 601 to yield the tetra-thiazole 603a. The removal of the protecting groups from 603a, followed by macrolactamization of the resulting amino acid 37, gave 595c. In a similar manner, the unsymmetrical cyclic tetramer 595d was prepared from a coupling reaction between the bisthiazole carboxylic acid 601 and the bisthiazole amine 602, followed by the deprotection of C- and N-termini in the product 603b and macrolactamization of the resulting amino acid. Similarly, the reaction between 602 and bisthiazole carboxylic acid 599 led to the tetra-thiazole 603c, which was converted into the cyclic tetramer 595f. The Ala-thiazole dipeptide 596b was deprotected at C- and N-termini to give 596b′, which was used in the synthesis of didmolamides A and B (Scheme 119). Thus a 1:1 mixture of BT


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Scheme 112. Total Syntheses of Bistratamides E and J by You et al.

peptides contain a polyketide-derived α,β-unsaturated Omethyl-Ser-thiazole moiety, a 5-hydroxytryptophan, and a formylated N-terminus. Both natural products show cytotoxicity against P388 with IC50 values of 3.9 and 0.9 μM, respectively.234 No synthetic works on these compounds have been published to date. 9.1.9. Ceratospongamide. Two isomers of bioactive thiazole-containing cyclic heptapeptides, cis,cis-ceratospongamide and trans,trans-ceratospongamide (Figure 41), were isolated by Gerwick et al. from the marine red algae Ceratodictyon spongiosum with the symbiotic sponge Sigmadocia symbiotica in 2000. These peptides consist of two L-Phe residues, one L-Ile-L-methyloxazoline residue, one L-Pro residue, and one L-Pro-thiazole residue. trans,trans-Ceratospongamide exhibited anti-inflammatory activity with potent sPLA2 expression inhibition at an ED50 value of 32 nM,

of the latter at C- and N-termini, followed by cyclodimerization (FDPP, DIPEA) gave the cyclic tetramer 610 in 51% yield. Alternatively, the saponification of 609, followed by a second coupling (EDCl, HOBt) with 608 led to the formation of linear trimer 611. The latter was deprotected at C- and N-termini and subjected to macrolactamization (FDPP, DIPEA) to form the mixture of cyclotrimer 612 (7%) and cyclohexamer 613 as the major product (29%). The structure and conformation of 613 was established by X-ray crystallography (Figure 39). The formation of the hexamer 613 indicated a preference for linear N-methylated units to form longer chain oligomers prior to macrocyclization over their corresponding nonmethylated units. 9.1.8. Calyxamides. Calyxamides A and B (Figure 40) are cyclic peptides that were isolated by Kimura et al. from Discodermia calyx in 2012.233 These diastereomeric cyclic BU


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Scheme 113. Solid-Phase Synthesis of Didmolamide A

Scheme 114. Solid-Phase Synthesis of Didmolamide B

by C- and N-termini, respectively).237 It was reported that system FDPP/DIPEA at room temperature in 2 × 10−3 M were the most suitable conditions for this transformation. Finally, cyclodehydration of the L-allo-Thr-L-Ile junction in 620 with DeoxoFluor produced the target compound 614 in 54% yield. An X-ray analysis of cis,cis-ceratospongamide showed that this molecule adapts a rectangular saddle-shaped conformation with Pro, Ile, Phe, and Pro residues at four angles (Figure 42). Both Phe-Pro amide bonds adopt cis orientation of ω torsion angle, whereas all other peptide bonds have a trans configuration. The main feature of this compound, as suggested by X-ray data, is the absence of intramolecular hydrogen bonding, which is usually inherent by many macrocyclic peptides. 9.1.10. Cyclodidemnamides. Cyclodidemnamide is a cyclic heptapeptide isolated from marine ascidian Didemnum molle by Fenical et al. in 1995.238 In 2002, Banaigs et al. reported the isolation and synthesis of cyclodidemnamide B from the same organism (Figure 43).239 Cyclodidemnamide was found to be weakly cytotoxic against HCT-116 with an ED50 value of 16 μg/mL. No data on the activity of cyclodidemnamide B were reported. Pattenden et al. reported the synthesis of cyclodidemnamide in 1996 (Scheme 123).240 It employs the use of protected Val-

whereas the cis,cis isomer was inactive. The trans,trans isomer exhibited the human-sPLA2 promoter-based inhibition by 90%.235 The first total synthesis of cis,cis-ceratospongamide 614 was published by Shioiri et al. in 2001.236 The L-Pro-thiazole fragment 615 was assembled from L-proline via the preparation of Weinreb amide, its subsequent reduction with LiAlH4, and the condensation of the resulting aldehyde with methyl Lcysteinate, yielding thiazolidine 616 in 73% overall yield. Treatment of 616 with activated manganese dioxide resulted in the formation of 615 in 51% yield (Scheme 121). The dipeptide segment 617 was obtained by peptide coupling (DEPC, Et3N) of N-Boc-L-Phe with L-Pro-OMe. The pentapeptide segment 618 was constructed by successive solution-phase peptide synthesis (DEPC, Et3N) of 615 with LPhe, L-allo-Thr, and L-Ile in good overall yield. Next, deprotection of N-terminus in 618 and C-terminus in 617, followed by peptide synthesis (DEPC, Et3N) gave the fully protected heptapeptide 619 in 94% yield (Scheme 122). After deprotection of C- and N-termini in 619, the unprotected precursor was subjected to macrolactamization to give the cyclic peptide 620 in 63% overall yield. It is noteworthy that the cyclization at the Thz/Phe site proceeded smoothly, in contrast with the case when the Pro/Ile site was selected (compound 621, derived from coupling 618 and 617 BV


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Scheme 115. Solution-Phase Synthesis of Didmolamide B

623, the resulting amine was thioacylated with a benzimidazolone derivative of L-proline thioacid 624, resulting in the formation of thiotetrapeptide 625 in 77% yield. The successive coupling of 625 at the N-terminus with N-Boc-L-Val, N-Boc-Lallo-Thr, and N-Boc-D-Phe furnished the key heptapeptide precursor 628 in 42% overall yield. The straightforward macrolactamization of 628 resulted in the degradation of starting material, presumably by the presence of unprotected hydroxyl groups of Thr and Ser residues. Thus the removal of protecting groups at C- and N-termini and the installation of acetyl protection on hydroxyl groups in 628 yielded the linear precursor 629. The latter underwent clean macrocyclization (DPPA, DIPEA) to produce the cyclopeptide 630 in 74% overall yield. Finally, the removal of the acetyl protecting group in 630, followed by double cyclodehydration of Phe-Thr and Pro-Ser to the thiazoline and oxazoline rings produced cyclodidemnamide 631 in 30% yield. In the report by Banaigs et al., the synthesis of cyclodidemnamide B begins with the construction of the bisthiazole core 633 by coupling (EDC, HOBt, TEA) of the corresponding D-Leu-thiazole 469 and L-Pro-thiazole blocks 632 (Scheme 124).239 Consecutive fusion (EDC, HOBt, TEA) of the N-terminus of 633 with N-Boc-L-Val, N-Boc-L-Thr, and N-Boc-D-allo-Ile furnished the linear precursor 636 in 73% overall yield. As in previous synthesis, the hydroxyl group of the Thr residue was protected prior to macrolactamization

Scheme 116. Cyclooligomerization of Thiazole Amino Acid Building Blocks 593a,b

thiazole 622, which was Boc-deprotected and coupled to NBoc-L-Ser, yielding dipeptide 623. After N-deprotection of Scheme 117. Synthesis of Bisthiazole Fragments 596a−c

BW


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Scheme 118. Synthesis of Cyclic Tri- and Tetramers of Thiazole Amino Acids

The synthesis of sanguinamide A (compound 642) was accomplished by Fairlie et al. in 2012 (Scheme 125).242 An SPSS strategy (HBTU, DIPEA) was employed for coupling of the corresponding N-Fmoc-L-amino acids and L-Ile-thiazole 639 to prepare the polymer-bound Boc-protected linear precursor 640, which was simultaneously N-deprotected and cleaved from resin with TFA/DCM (1:4). It is noteworthy that the peptide 641 was purified after this step via column chromatography, which is uncommon for other strategies, where the crude linear precursor is usually subjected to macrocyclization without purification. Macrolactamization of 641 was achieved in 1 mM DMF solution upon treatment with HBTU with excellent yield (94%). It was reported that HATU or BOP reagents were also suitable for this transformation, albeit giving lower yields. Sanguinamide A has inspired analogues exhibiting membrane permeation and oral absorption. A total of 16 analogues

(compound 637). Thus the N- and C-termini-deprotected precursor was treated with DPPA/DIPEA, producing the acylated derivative of cyclodidemnamide B in 70% yield, which after hydrolysis gave the desired molecule 638 in 10% yield. 9.1.11. Danamides D and F and Sanguinamide A. Sanguinamide A is a thiazole-containing cyclic heptapeptide isolated from sea slug Hexabranchus sanguineus by Molinski et al. in 2009.241 This compound incorporates an L-Ile-thiazole fragment and six natural L-amino acids, including two prolines that adopt cis and trans configurations. No biological activity is known for sanguinamide A; however it has been shown to have good oral bioavailability in rats. Danamides D and F are artificial compounds designed on the basis of sanguinamide A, which displays higher oral bioavailability. Danamide F bears tert-butyl-glycine moiety instead of Ala2, and danamide D, along with that, bears a N-methylated Phe3 residue (Figure 44). BX


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Scheme 119. Synthetic Approach toward Didmolamides A and B

thiazole-containing peptide precursors (Scheme 127). In the synthesis of 647 by Hamada et al., the linear precursor 650 was prepared from Gln-thiazole 648 by sequential peptide synthesis with the corresponding L-amino acids and 649 in 60% overall yield.250 The macrocyclization was carried out between Gln-thiazole and Gly-thiazole residues upon treatment with DPPA and TEA with relatively low yield of 23%. Schmidt et al. used a different approach, where precursor 653 was elaborated via peptide synthesis (DPPA), employing building blocks 651 and 652 in a similar overall yield.251 The C-terminus of 653 was transformed to the Pfp-activated ester, and the molecule was subjected to macrolactamization between L-Pro and Gly-thiazole fragments, which resulted in much higher yields of 647 in comparison with the previous approach (70 and 23%, respectively). All 15 diastereomers of 647 were also synthesized by Hamada et al. using the first strategy. A simplified analogue of dolastatin 3, which incorporates the Gly-thiazole moiety instead of Gln-thiazole, was synthesized.252,253 Building blocks 644 and 652 were used to construct the bisthiazole subunit 653, which was deprotected at the C-terminus and coupled to N-Boc-Pro-Leu-Val tripeptide, affording linear precursor 655 in good yield. The latter was elaborated to the analogue 656, as shown in Scheme 128 Computational and NMR studies revealed the conformation of dolastatin 3 (646) in solution. The saddle-shaped molecule

of this compound, including danamides D and F, were prepared using the same protocol as described above (Figure 45). Their adsorption profiles and cell permeability are thoroughly discussed elsewhere.243,244 9.1.12. Dolastatin and Homodolastatin. Dolastatin 3 is a cyclic peptide antibiotic initially isolated by Pettit et al. from sea hare Dolabella auricularia and later from sponges Aplysia pulmonica and Lyngbya majuscula.245 Both compounds incorporate all-L-amino acids and a Gly-thiazole-Glu-thiazole fragment. Dolastatin 3 exhibited a GI50 value of 95% HPLC purity and 16.7 g quantity (Scheme 143). 9.1.21. Largazole Analogues. Zinc Binding Group (ZBG) Modifications. Luesch et al. reported the syntheses and biological evaluation of two largazole analogues, 757 and 759.284 Acetyl analogue 757 was prepared by the crossmetathesis reaction between macrocycle 693 and but-3-enyl thioacetate. Similarly, the hydroxyl analogue 759 was prepared by the cross-metathesis between 693 and 1-TIPSO-but-3-ene, followed by the removal of a silyl protecting group. The acetyl

butene furnished compound 694 in 90% yield. Peptide coupling (HATU) between 698 and 696 provided compound 699 in 94% yield and 82.1 g scale. The removal of N- and Cterminal protecting groups in 699, followed by macrolactamization (HATU) afforded macrocycle 693 in 61% yield and 35 g quantity. A final cross-metathesis between 693 and 694 was carried out in three parallel reactions with Grela catalyst to furnish largazole 686 in 52% yield after Scheme 148. Synthesis of Largazole analogues 770−772

CR


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Scheme 150. Synthesis of Largazole Analogues 780a,b, 781, and 782

Scheme 151. Preparation of Largazole Analogues with Amine or Ketoamide Fragments

analogue 757 showed the same HDAC inhibitory activity as the parent compound, which highlights that the acyl fragment

of thioester serving as a protecting group in this prodrug can be varied as long as it retains the ability to hydrolyze. Because CS


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The effect of the length of the aliphatic linker between the macrocycle and the octanoyl group in largazole was also investigated.298 A series of largazole analogues 766a−c were prepared, as shown in Scheme 147. Thioacylation of 3-bromo1-propene, 5-bromo-1-pentene, or 6-bromo-1-hexene with compound 756 was used to prepare thioesters 765a−c, respectively. Cross-metathesis between 693 and 765a−c in the presence of the Grubbs II catalyst afforded largazole analogues 766a−c, respectively. These compounds showed vanishingly small activity compared with the parent compound, which suggests that the four-atom linker is optimal for the inhibitory activity of largazole. It was shown that substitution of the trans-alkene in the linker with an aromatic group (compounds 767−769) results in the complete loss of activity (Figure 59).299 The general method for the incorporation of various ZBGs consists of the modification of largazole thiol.294 Analogues 770−772 were synthesized following the removal of the trityl group in 704 and alkylation of the free thiol with the corresponding halogenide or alcohol. These compounds were designed such that thiol and an aryl heteroatom were two to three atoms apart and were thus capable of interacting with Zn2+ via five- or six-membered cyclic transition states. However, these analogues were less potent than largazole (Scheme 148). Recently, another series of largazole analogues bearing different ZBGs were reported.300 Cross-metathesis was shown to have a limited substrate scope for the modification of compound 693 because among different largazole analogues (vide infra), only alkyl analogue 773 could be prepared with this reaction (Scheme 149). For the preparation of compounds 780a,b, the synthesis began with the cross-metathesis reaction of crotonaldehyde with ketone 774a or ester 774b, which afforded aldehydes 775a or 775b, respectively, in excellent yield. The latter were subjected to aldol condensation with Nagao auxiliary 707 to furnish the depsipeptide building blocks 776a,b. The rest of the synthesis uses the same strategy as that for the total synthesis of largazole. Thus the final macrolactamization step afforded ketone largazole analogue 780a as well as ester compound 780b, which was subsequently hydrolyzed to give acid function in compound 781, which could be modified to hydroxamic acid in compound 782 (Scheme 150). The preparation of the amine analogues 789 and 790 utilized the exact same approach and were elaborated from crotonaldehyde and Boc-protected aminoalkenes 783a and

Scheme 152. Preparation of Largazole Analogue (792) with Thiol Fragment

Scheme 153. Synthesis of Largazole-Azumamide Hybrid 801

hydroxyl groups do not chelate Zn2+, the hydroxyl analogue 759 did not show any inhibitory activity (Scheme 144). Cramer et al. reported the optimization of conditions for this cross-metathesis.288 Using Hoveyda−Grubbs II and nitroGrela catalysts, the derivatives 760a−e were prepared from precursor 693 and various alkenes 761 in comparable yields (37−92%) and E/Z selectivities (4:1 to 10:1). However, the obtained compounds did not show any significant activity (Scheme 145). Williams et al. expanded this series with several compounds: 762a,b, which bear R-aminobenzamide groups, 763a,b, which contain R-thioamides, and 764a,b, which contain R,Rthioketones.297 The Hoveyda−Grubbs II catalyst was reported to be much more efficient than the Grubbs II catalyst for these transformations. However, these compounds were found to be ineffective compared with the parent largazole (Scheme 146). Scheme 154. Synthesis of C2-Epimer of Largazole (806)

CT


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Scheme 155. Synthesis of Val-Ala Interchanged Analogue of Largazole (809)

Scheme 156. Synthesis of Largazole Analogues 813−818

Scheme 157. Synthesis of Gly and β-Ala-Incorporating Analogues of Largazole 822 and 823

783b, respectively. Upon the reaction with diketene, compound 790 was further modified to the ketoamide analogue 791 in 20% yield (Scheme 151). To prepare the mercaptosulfide analogue 792, the bromide analogue 793 was coupled to mono trityl-protected dithiol

794, followed by trityl deprotection. Whereas none of the analogues showed activity or selectivity comparable to that of largazole, the Zn2+ binding affinity of each compound correlated its their cytotoxicity and HDAC inhibition. The docking simulation study suggested that a more rigid ZBG CU


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not demonstrate biological activity. The replacement of Val with Tyr (compound 815) increased the selectivity toward human cancer cells over normal cells more than 100-fold (Scheme 156). Analogues 822 and 823, in which Val subunit is replaced with Gly and β-Ala, respectively, were also synthesized using the same approach. Despite being less potent than the parent molecule, these compounds retained nanomolar IC50 values (Scheme 157). Later, compounds 824−832 were prepared by replacing the valine residue with aromatic (Phe (824), Tyr (825)), basic (His, (826)), and acidic (Asp, (827)) amino acids as well as nonproteinogenic fragments (828−832) (Figure 60).299 In another study, a series of C2 side-chain-modified largazole analogues was reported.302 Upon the introduction of various nonproteinogenic R- and S-amino acids 833 to the structure of subunit 834, using a common approach for the synthesis of largazole, compounds 836a−c were obtained. Compound 836a was inactive, whereas 836b,c demonstrated similar activity values as those of largazole (Scheme 158). The substitution of Val to Pro fragment in compound 840 was conducted by switching N-Fmoc-Val to N-Fmoc-Pro in the strategy, reported by Williams et al. (Scheme 159).297 This route was suitable for the construction of the target molecule; 840 was obtained in only slightly diminished overall yield compared with largazole. This compound showed a 100-fold decrease in potency compared with the parent molecule. Depsipeptide Subunit Alterations. In the early study, it was shown that the incorporation of the minor adduct of Nagao aldol condensation (compound 841) leads to the C17-epimer 843 of largazole.298 The whole synthetic protocol was carried out as for natural epimer 686 and without any significant deviations in the yield of each step. Biological assays showed that 843 possesses 500-fold decreased activity compared with 686 (Scheme 160). The synthesis of largazole-psammaplin A hybrid 844, which incorporates an amide moiety instead of E-alkene, was reported.301 The requisite fragment was introduced in the final structure with the depsipeptide fragment 848, which was prepared starting from the commercially available L-malic acid 719. Upon condensation of the latter with chloral hydrate, the

Figure 60. Structures of largazole analogues bearing various fragments at position C2.

would increase the binding affinity of these compounds (Scheme 152). Williams et al. reported the synthesis of largazoleazumamide hybrid 801 (Scheme 153).297 This compound was obtained via a similar approach as the total synthesis of the parent compound by the same authors. Substitutions of Valine Fragment. Synthesis of C2-epimer 806 of largazole was described by Williams et al.297 Using the same approach as that for their total synthesis of largazole and switching N-Fmoc-L-valine for N-Fmoc-D-valine, the desired compound 806 was readily obtained without any alterations in the yields of each step (Scheme 154). C2-epimer retained the submicromolar inhibitory potency of the parent compound, which showed that D-amino acids maybe tolerated at this position. It was shown that the replacement of the valine residue over other moieties in largazole does not significantly hamper its biological activity. In the early studies, valine residue of largazole was replaced with alanine (compound 809).298 Because alanine is conformationally similar to valine, the synthesis of 809 proceed without any significant alterations compared with the total synthesis of largazole. This compound showed a two- to three-fold decrease in potency compared with largazole, which indicates that the Val subunit could be replaced in this molecule while retaining the nanomolar inhibitory concentration values (Scheme 155). In another work, upon choosing different N-Fmoc-protected amino acids 810a−c, six more analogues of largazole 813−818 were obtained.290 The biological evaluation of the analogues suggested that the geometry of the alkene is critical for the antiproliferative effect of largazole because all Z isomers did

Scheme 158. Synthesis of C2 Side-Chain-Modified Largazole Analogues 836a−c

CV


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Scheme 159. Synthesis of Val-Pro-Interchanged Largazole Analogue 850

Scheme 160. Synthesis of C17-Epimer of Largazole 843

Scheme 161. Synthesis of Largazole-psammaplin A Hybrid 844

masked acid 845 was obtained in 95% yield. Esterification of 845 with TSE−OH (compound 846), followed by dioxolane opening with S-trityl-protected aminothioethanol afforded amide 847. Esterification of the latter with N-Fmoc-Val under Yamaguchi conditions, followed by the removal of the

Fmoc protecting group, afforded subunit 848 in good yield. The final assembly of compound 844 from 848 and 698 was conducted using common approaches as for the total synthesis of largazole with an overall yield of 7%. This compound demonstrated poor biological activity, which further supported CW


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Scheme 162. Synthesis of C7-Epimer of Largazole 857

Scheme 163. Preparation of Modified Cysteine Building Blocks 859a,b

Scheme 165. Synthesis of Bisthiazole Largazole Analogue 865

the hypothesis that the E-olefin moiety in largazole is the key structural unit for the inhibition against HDACs (Scheme 161). Scheme 164. Synthesis of Largazole C7-Substituted Analogues 863a−c

CX


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Scheme 166. Synthesis of Bisthiazole Analogues (865 and 872) of Largazole

Scheme 167. Another Synthetic Route to Bisthiazole Largazole Thiol Analogue 876

Thiazoline Ring Modifications. The synthesis of the C7epimer of largazole was described.302 Upon switching (R)-2methylcysteine for (S)-2-methylcysteine (compound 852), the C7-epimer 857 of largazole was assembled using the same approach as that for the parent compound. It was shown that the inversion of the configuration at C7 resulted in a loss of inhibitory activity, which was attributed to conformational

changes associated with this stereochemical change, which affects binding of 857 to HDAC protein (Scheme 162). The replacement of methyl over other various residues in the thiazoline ring of largazole was reported.302 This was achieved via the condensation of thiazole building block 689 with a series of R-alkyl cysteines 859a,b and cysteine itself. Using the common approach, L-cysteine methyl ester was converted to the corresponding N-formyl thiazoline 754, CY


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Scheme 168. Synthesis of Analogue 878

Scheme 169. Synthesis of C12-Bn Derivative of Largazole 885

Scheme 170

Figure 61. Structures of lissoclinamides 1−8.

CZ


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Scheme 171. Total Synthesis of epi-Lissoclinamide 5 (895)

Scheme 172. Total Synthesis of Lissoclinamide 4

DA


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Figure 62. Structures of cyclic members of lyngbyabellin family.

Early-stage thiazoline-to-thiazole replacement in the largazole scaffold was reported in another paper.303 Bisthiazole subunit 867 was synthesized from thiazole building block 866 in two steps by thionation and the Hantzsch reaction in 57% yield over two steps and was further elaborated to the linear precursor 870. Upon the successive removal of C- and Nterminal protecting groups in 870, the resulting peptide was subjected to macrolactamization (HATU, HOAt), affording macrocycle 864 and cyclodimer 874 in a 2.5:1 ratio and 35% combined yield. The poor yield of this step compared with analogous thiazole-thiazoline-containing largazole precursors might be explained by the greater rigidity of the bisthiazole subunit in 870. The subsequent cross-metathesis of macrocycles 864 and 871 with the thioester 694 provided analogues 865 and 872, respectively. The C17-epimer of 865 was also prepared in this work using the R-enantiomer of compound 868. Compounds 865 and 872 demonstrated a 1000-fold decrease in IC50 compared with largazole, whereas the C17epimer of 865 was essentially inactive (Scheme 166). Williams et al. presented another synthetic route to bisthiazole analogue 876 of largazole thiol (752).297 The condensation of thiazole building block 689 with L-Cys

which was alkylated with ethyl iodide and benzyl bromide. Resulting compounds 858a,b were then transformed to the desired building blocks 859a,b, respectively. Various substituted halogenated aryl substituents were also introduced using the depicted approach; however, further steps of synthesis with them were unsuccessful, and the whole synthetic strategy was accomplished with only 859a,b and cysteine (Scheme 163). The follow-up protocol did not differ from total synthesis of largazole and proceeded in good yield. Thus cyclic depsipeptides 862a−c were subjected to cross-metathesis under the same conditions as those for parent largazole and produced corresponding analogues 863a−c in 20−23% yield (Scheme 164). Within the same paper, the application of the oxidative elimination conditions to the depsipeptide 862c was used to construct the bisthiazole derivative 864 in satisfactory yield. The subsequent installation of thioester fragment 694 furnished bisthiazole largazole analogue 865 (Scheme 165). Compounds 863a−c and 865 demonstrated good IC50 values, which were comparable to that of largazole. DB


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Scheme 173. Total Synthesis of Lyngbyabellin A (918)

product 876. An intermediate potency of this compound was reported (Scheme 167). The synthesis of analogue 878, in which thiazoline fragment is replaced with peptide moiety, was also described.295 Coupling of thiazole building block 879 with methyl αaminoisobutyrate afforded compound 880, which was elaborated to the desired compound in the same manner as described above. Compound 878 retained the nanomolar IC50 value of parent largazole (Scheme 168). The analogue of largazole, which bears an additional chiral fragment at the C12 position, was also reported.295 Starting with phenylalanine-derived thiazole 881, macrocycle 885 was constructed as described for largazole. Despite being a significantly weaker HDAC inhibitor than largazole, compound 885 demonstrated high cellular activity, which was attributed to the introduction of a lipophilic benzyl fragment (Scheme 169). Prodrug Modifications. Luesch et al. have also investigated different prodrug forms of largazole thiol in the search for modulation of its biological activity.304 Starting from the protected thiol 704, largazole disulfide analogues 887 and 888 as well as largazole homodimer 886 were synthesized following

Figure 63. Structure of marthiapeptide A.

afforded thiazole-thiazoline compound 860c in quantitative yield. Coupling (PyBOP) between 860c and depsipeptide subunit 750 afforded a mixture of compounds 873 and 874 in a 1:2 ratio. Importantly, the direct macrolactamization of bisthiazole precursor 876 did not yield compound 875. Instead, compound 873 was subjected to the tandem removal of C and N protecting groups and macrolactamization (HATU, HOBt) to yield compound 877. The subsequent oxidation of this compound under standard conditions provided 875, which was deprotected to give the desired DC


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Scheme 174. Total Synthesis of Marthiapeptide A

Figure 66. Structure of microcyclamide GL616.

Figure 64. Structures of mayotamides A and B

Figure 67. Structure of obyanamide

Figure 65. Structure of mollamide C.

(vide supra), patellamides, tawicyclamides, and ulithiacyclamides (vide infra).305−308 The cytotoxicity of these compounds is not significantly affected by the nature of their individual subunits but rather the overall conformation of the macrocyclic scaffold. Thus SAR revealed that lissoclinamide 5, which bears two thiazole rings, is two orders of magnitude less cytotoxic than lissoclinamide 4 (thiazole-thiazoline) against bladder carcinoma cells.309 Lissoclinamide 7, having two

standard iodine oxidation conditions in excellent yield (88− 93%). All compounds showed similar biological activity compared with largazole (Scheme 170). 9.1.22. Lissoclinamides. Lissoclinamides 1−8 are members of a family of natural thiazole macrocycles isolated from the ascidian Lissoclinum patella along with ascidiacyclamide DD


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Scheme 175. Total Synthesis of Obyanamide

Figure 68. Synthetic analogues of obyanamide.

Figure 70. Structure of patellamides A−G.

thiazoline rings, is the most potent compound of this family (Figure 61). Boden and Pattenden have achieved the total synthesis of lissoclinamides 4 and 5 as well as their epimers.310,311 For the synthesis of (C21,C31)-epimer of lissoclinamide 5 (compound 895), linear precursor 893 was assembled from two thiazolecontaining building blocks 550 and 890 (Scheme 171). The latter were derived from the protected iminoesters of D-valine (889a) and L-phenylalanine (889b), respectively, upon their

Figure 69. Structures of oriamide and cyclotheonellazoles A−C. DE


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Scheme 176. Total Synthesis of Patellamides A−C (945a−c) by Hamada et al.

condensation with methyl cysteinate and the oxidation with activated manganese oxide in satisfactory overall yield. Deprotection of 550 and peptide coupling (DCC, HOBt) with N-Boc-Pro-aThr produced tetrapeptide 891. Saponification of the ester group in 890 and coupling (FDPP) to PheOMe afforded tripeptide 892. Upon the removal of C- and N-terminal protecting groups in 892 and 891, respectively, the resulting compounds were coupled (DCC, HOBt) to yield the linear heptapeptide 893. The successive removal of C-band N protecting groups in this compound, followed by macrolactamization (DPPA) afforded macrocycle 894 in 35% yield. Cyclodehydration of allo-threonine moiety in 894 under standard conditions allowed the installation of the oxazoline ring in 74% yield, thus completing the synthesis of 895. Exactly the same strategy was used to synthesize the natural epimer using L-valine and D-phenylalanine. The synthesis of lissoclinamide 4 (compound 903) was achieved in a linear strategy starting from D-Phe-derived thiazole building block 896 (Scheme 172). Following the common solution-phase protocol, 896 was successively coupled (DCC, HOBt) to N-Boc-L-Ser, L-Val-derived thioacylating reagent 898, N-Boc-alloThr, and finally N-Boc-L-Phe-

L-Pro

to give heptapeptide 901 in good overall yield. Upon the removal of C- and N-terminal protecting groups in 901, followed by macrocyclization (DPPA) of the resulting compound, cyclopeptide 902 was obtained in 30% yield. Finally, the treatment of 902 with Burgess reagent produced target compound 903 in 71% yield. 9.1.23. Lyngbyabellins. This family of depsipeptides was isolated by several collectives from marine cyanobacteria Moorea bouillonii and Lyngbya majuscula (Figure 62).312−318 The corresponding molecules possess an unusual subunit of 7,7-dichloro-3-hydroxy-2-methyloctanoic acid and two thiazole rings (thiazole and thiazoline in the case of lyngbyabellin B). Another compound that is closely related to this family is hectochlorin (vide supra). Lyngbyabellins A, B, and C were found to be cytotoxic against LoVo and KB cell lines. Lyngbyabellin B was found to possess potent toxicity against the fungus Candida albicans and against brine shrimp. Lyngbyabellins E−H displayed significant cytotoxicity against NCI-H460 and neuro-2a cells. Lyngbyabellin N was cytotoxic against H-460 and HCT-116 cell lines.319,320 Yokokawa et al. reported a convergent total synthesis of lyngbyabellin A (918) in 2001 (Scheme 173).321 Target DF


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Scheme 177. Total Synthesis of Patellamide B (945b) by Schmidt et al.

compound was assembled from three key subunits: two thiazole building blocks 905 and 909, and dichlorinated βhydroxy acid 914. Compound 905 was derived from N-Boc(S)-isoleucine, which was converted to the Weinreb amide, reduced to aldehyde, and coupled to methyl L-cysteinate to produce thiazolidine 904. The latter was oxidized with MnO2 to produce the desired thiazole 905 in 32% yield over four steps. For the synthesis of thiazole 909, N-Fmoc-L-(STr)-Cys was esterified with TMSCHN2, underwent the removal of the N-Fmoc protecting group, and coupled (DEPC) to 3methylcrotonic aldehyde to give amide 906. The latter was subjected to Ti(IV)-mediated tandem deprotection−cyclodehydration to give thiazoline 907 in 88% yield. The latter was oxidized under common conditions and underwent the replacement of the ester protecting group from methyl to TSE to produce thiazole 908. Sharpless asymmetric dihydroxylation of the alkene moiety in 908 afforded the desired building block 909 in excellent yield and ee. Compound 914 was accessed via enantioselective aldol condensation of trimethylsilyl ketene acetal 910 and commercially available aldehyde 911 using a stoichiometric amount of chiral oxazaborolidinone 912 to give methyl ester 913, which was further derivatized to allyl ester 914. The assembly of target molecule was started with subunit 905, which underwent Ndeprotection and coupled (DEPC) to N-Boc-Gly to give dipeptide 915. The latter was saponified and coupled (DCC) to subunit 914, affording depsipeptide 916 in excellent yield. The removal of the allyl protecting group in 916 and coupling (DCC) the resulting acid to dihydroxythiazole subunit 909 produced the linear precursor 917 in 64% yield. The successive removal of C- and N-terminal protecting groups in this compound, followed by macrolactamization (DPPA) com-

pleted the synthesis of lyngbyabellin A (918) in 58% yield for the last step. 9.1.24. Marthiapeptide A. Marthiapeptide A is a tristhiazole-thiazoline-containing cyclic peptide that was isolated from Marinactinospora thermotolerans SCSIO 00652 by Ju et al. in 2012 (Figure 63).322 This compound showed antibacterial activity against Gram-positive bacteria and exhibited submicromolar cytotoxicity against a variety of human cancer cell lines. The total synthesis of this natural product (926) was achieved by McAlpine et al. in 2015.323 The tristhiazole subunit 922 was constructed in an iterative manner starting from D-Ala-derived thiazole 490 (Scheme 174). Each step consisted of ester amidation, treatment with the Lawesson reagent, and condensation of the resulting thioamide with ethyl bromopyruvate under Hantzsch conditions. Thus, compound 922 was obtained in 20% yield over eight steps. Upon the Boc group removal in 922, the resulting free amine was coupled (HATU) to N-Boc-D-Phe-L-Ile, affording compound 923 in 72% yield. The ester group in the latter was converted to nitrile in a two-step procedure, and the resulting compound 924 was condensed with L-cysteine, furnishing the linear precursor 925 of marthiapeptide A. After the removal of the N-Boc protecting group in 925, the resulting peptide was subjected to macrolactamization upon the treatment with a mixture of coupling agents: HATU, TBTU, and DMTMM. Target compound 926 was obtained in 3% yield for this step. The authors have also investigated an alternative strategy where macrocyclization should have occurred at the thiazoleisoleucine site; however, it was unsuccessful. 9.1.25. Mayotamides. Mayotamides A and B are two cyclic heptapeptides isolated from Didemnum molle by Kashman et al. in 1998 (Figure 64).324 These compounds DG


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Scheme 178. Total Synthesis of Patellamide A (945a) by VanNieuwenhze et al.

cytotoxic activity. No papers on its synthesis were reported (Figure 66). 9.1.28. Obyanamide. Obyanamide is a cyclic depsipeptide isolated from Lyngbya confervoides by Moore et al. in 2002 (Figure 67).327 This compound exhibited moderate cytotoxicity against KB and LoVo cell lines at IC50 values of 0.58 and 3.14 μg/mL, respectively. Obyanamide is structurally similar to guineamides (vide supra) and ulongamides (vide infra). The total synthesis of obyanamide (935) was achieved by Li et al. in 2006 (Scheme 175).328 This strategy uses two subunits: thiazole-containing dipeptide 929 and N-methylated tripeptide 933b. Subunit 929 was synthesized starting from N-

were shown to be moderately toxic against various tumor cell lines with IC50 values of 5−10 μg/mL. No synthetic works on these compounds were reported. 9.1.26. Mollamide C. Mollamide C is another cyclic hexapeptide that was isolated from Didemnum molle by Hamann et al. in 2008.325 This compound has not shown any significant biological activity, and no synthesis of Mollamide C has been reported (Figure 65). 9.1.27. Microcyclamide GL616. This compound, along with other macrocyclamides, was isolated from Mycrocystis sp. by Carmeli et al. in 2010.326 This compound did not show DH


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A, B, and C inhibited chymotrypsin with IC50 values of 0.62, 2.8, and 2.3 nM, respectively, as well as elastase with IC50 values of 0.034, 0.10, and 0.099 nM, respectively. No synthetic works on these compounds were reported; however, syntheses of several structurally related natural products, keramamide J and scleritodermin A, were accomplished. 9.1.30. Patellamides. Patellamides A−G are a family of natural cyclooctapeptides that share a common 24-membered scaffold with two thiazole and two oxazoline rings (one for patellamide G) and apparently are the most broadly structurally and synthetically investigated (Figure 70). These compounds, along with ascidiacyclamides (vide supra) and ulithiacyclamides, have been isolated from Lissoclinum patella by several groups.332−341 These compounds demonstrated moderate cytotoxicity against several multi-drug-resistant cancer cell lines (L1210, T24, MRC5CV1, HCT-116).342 The metal-binding properties of these compounds have also been highlighted.343 Hamada et al. reported a general approach for the synthesis of patellamides A, B, and C in 1995 (compounds 945a−c, Scheme 176).344,345 The macrocyclic core of these natural products was assembled from two subunits, 939a,b and 942a,b, which were derived from thiazole building blocks 544, 937, and 940. DEPC was used in each step of the peptide synthesis except for the macrocyclization of linear precursors 943a−c, which employed DPPA as an activating reagent. For the construction of subunits 939a−b, compounds 544 and 937 were initially coupled to N-Boc-L-allo-threonine, yielding dipeptides 938a and 938b, respectively. These compounds were then N-Boc-deprotected and further elongated with NBoc-L-Ile. After the saponification of methyl esters, compounds 939a (subunit of patellamide A) and 939b (common subunit of patellamides B and C) were obtained in good overall yield. The synthesis of subunits 942a−c was accomplished in a similar fashion starting from D-Val- and D-Ala-derived thiazole building blocks 544 and 940, respectively. Upon coupling 544 to N-Boc-L-serine and 940 with N-Boc-L-allo-threonine, dipeptides 941a,b were obtained. 941a was further elaborated to subunit 942a (which corresponds to patellamide A) by condensation with N-Boc-L-Val. Compounds 941b,c were reacted with N-Boc-L-Leu and N-Boc-L-Ile, respectively, to give subunits 942b (subunit of patellamide B) and 942c (subunit of

Figure 71. Structure of Scleritodermin A.

Boc-Abu 927. The latter was derivatized to β-aminoester 928 via the Wolff rearrangement of the corresponding diazoketone. The removal of the N-Boc group in 928, followed by the coupling (EDCl, HOAt) of the resulting free amine with L-Valderived thiazole 490 afforded dipeptide 929 in 98% yield. To construct fragment 933b, appropriately protected N-methylated amino acids 930 and 931 were coupled (EDCl, HOAt) to give dipeptide 932. The latter was subjected to the removal of the N-Cbz protecting group and coupled (EDCl, HOAt) to benzyl (S)-lactate and underwent hydrogenolysis to remove the benzyl fragment in formed 933a, furnishing subunit 933b in 85% yield over these three steps. Coupling between 929 and 933b was achieved under Yamaguchi conditions, providing linear pentapeptide 934 in 94% yield. The simultaneous removal of C- and N-terminal protecting groups in 934, followed by macrocyclization (HATU), allowed obyanamide (935) to be obtained in 59% yield over two steps. On the basis of these results, 21 analogues of this macrocycle were synthesized by the same group.329 Cyclic (depsi)peptides 936 were accessed via the same protocol as that for the total synthesis of parent obyanamide (Figure 68). 9.1.29. Oriamide and Cyclotheonellazoles. Oriamide was isolated from sea sponge Theonella sp. in 1997 by Kashman et al.330 Later, in 2017, three structurally similar natural products, cyclotheonellazoles A−C, were isolated from Theonella aff. swinhoei by Carmeli et al. (Figure 69).331 These compounds are structurally related to keramamides (vide supra) and scleritodermin A (vide infra). Cyclotheonellazoles Scheme 179. Synthesis of Key Subunits of Scleritodermin A

DI


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Scheme 180. Total Synthesis of Scleritodermin A (976)

Figure 72. Structures of tawicyclamides A and B.

Figure 73. Structure of trichamide.

patellamide C) after N-Boc deprotection. The assembly of target molecules 945a−c was conducted as follows: DEPCmediated peptide coupling between corresponding subunits 939a,b and 942a−c yielded compounds 943a−c in good yield. The successive removal of C- and N-terminal protecting

groups in the latter, followed by macrolactamization (DPPA) afforded macrocycles 944a−c. The installation of oxazoline rings in compounds 944b−c was accomplished by their onestep treatment with SOCl2, which afforded compounds 945b− c. In the case of compound 944a, treatment with SOCl2 DJ


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Scheme 181. Total Synthesis of Trichamide (981)

previous results. The synthesis of both peptide fragments 956 and 959 started from protected D-Val-thiazole 953 (Scheme 178). For the synthesis of the left-hand fragment 956, compound 953 was subjected to the removal of the N-Fmoc protecting group, followed by coupling (HOBt, HBTU) of the free amine with N-Fmoc-L-allo(OTr)threonine, providing tripeptide 954 in 86% yield. The subsequent N-Fmoc deprotection and coupling (HOBt, HBTU) with N-Fmoc-LIle provided tetrapeptide 955 in 92% yield. The removal of allyl ester in the latter afforded subunit 956 in 77% overall yield. Subunit 959 was elaborated in a similar manner in 85% overall yield, using N-Fmoc-L-(OTr)serine instead of analogously protected threonine. The resulting peptide 958 was Ndeprotected (959) and used in the further transformations. Coupling (HOBt, HBTU) between acid 956 and amine 959, followed by the removal of O-Tr protecting groups provided the linear octapeptide 960 in 84% yield. Cyclodehydration of Ser-Val and allo-Thr-Val junctions was achieved upon treatment of 960 with Burgess reagent and provided the fully elaborated linear precursor 961 of patellamide A. After the successive removal of C and N protecting groups in 961, the resulting compound was subjected to macrolactamization (PyBOP), providing patellamide A 945a in 55% yield over three steps. 9.1.31. Scleritodermin A. Scleritodermin A was isolated from marine sponge Scleritoderma nodosum by Schmidt et al. in 2004 (Figure 71).348 Scleritodermin A was found to induce apoptosis at an IC50 of 1.3 μM and was found to be cytotoxic against a panel of human tumor cell lines with IC50 values 3) or with small dimeric impurities (n = 3).

Another example of on-resin CuAAC is the synthesis of melanocornitin 4 receptor agonists.378 Seventeen linear precursors 1046 were assembled using the Fmoc-SPPS protocol and subjected to click-macrocyclization prior to cleavage from resin (Scheme 193). Several members of the obtained series 1047 displayed high selectivity (two orders of magnitude) toward MC4R over MC3R and MC5R receptor subtypes without compromising agonist potency. Compound 1048 is the largest known cyclic (i, i + 11) peptide obtained via on-resin click-macrocyclization (Scheme 194). After N-terminus labeling and cleavage from resin, the resulting macrocycles were examined as potential binders of curved phospholipid surfaces.379 Click-chemistry allows the construction of complex bicyclic frameworks in peptide molecules.380 Scheme 195 illustrates the synthesis of Gly-based bicyclic octapeptide 1051a. The requisite linear precursor 1049 was assembled on solid support and, upon cleavage from the latter, was subjected to macrolactamization (PyBOP) to give macrocycle 1050 in 8% overall yield. The subsequent click-reaction was achieved with excellent conversion of the monomacrocyclic substrate to bicyclic compound 1051a, accompanied by the formation of small amounts of cage-like structure 1051b due to the intermolecular CuAAC side reaction. 10.2. Other Peptidomimetic Fragments

Click-chemistry can be easily applied to synthesize macrocycles with various peptide bond analogues. The synthesis of a series of 14-membered depsipeptides 1053 demonstrates the broad applicability of CuAAC (Scheme 196).381 Linear tripeptide surrogates 1052 were assembled from L-amino acid (Leu, Ile, Val) propargyl esters, N-Boc-protected L-amino acids (Gly, Ala, Val, Leu, Ile, Phe), and 3-azidopropanoic acid using DS


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Scheme 195. Synthesis of Bicyclic Peptidomimetic 1051a

Scheme 196. Synthesis of Macrocyclic Triazole-Containing Depsipeptides 1053

Scheme 197. Synthesis of Macrocyclic Triazole-Containing Bis-ureas 1057a, b

furanoid aminoazido sugar succinimidyl ester 1055 to give the linear ureido-azidoalkynes 1056a and 1056b, respectively, in good yields. The latter were subjected to CuAAC conditions to produce the desired compounds 1057a,b (Scheme 197). C2-symmetic glycopeptide hybrids 1062a,b were also reported (Scheme 198). The synthetic strategy involved the

conventional chemistry. Macrocyclization of 1052 afforded the series 1053 in good yield. C2-symmetric bis-ureas 1057a,b, which represent a novel class of macrocyclic peptidomimetics, were reported by Chattopadhyay et al.382 D-Phe- and propargylamine-derived aminoalkynes 1054a and 1054b were reacted with cis-βDT


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Scheme 198. Synthesis of Macrocyclic Triazole-Glycopeptide Hybrids 1062

Scheme 199. Overview of “Double-Stapling” Technique

and bear additional functional groups. Nonsymmetrical staples would normally give rise to two different macrocyclic products, and thus the general limitation of this approach is the use of symmetrical dialkynyl reagents (Scheme 199). Such staples can be introduced between residues separated between different numbers of amino acids: Lau et al. reported an optimized strategy for the “double-click” preparation of [i, i + 7]constrained bis-triazolyl peptides,384−386 Xu et al. reported the synthesis of several [i, i + 4] and [i, i + 7] double-stapled macrocyclic inhibitors of tankyrase,387 Wu et al. reported the synthesis of the [i, i + 6] double-stapled macrocyclic inhibitor of Ctf4.388 10.4. MCR and CuAAC

Cyclic glycopeptidomimetics 1064 illustrate the applicability of the combination of Ugi-4CR and CuAAC for the synthesis of biologically relevant compounds (Scheme 200).389 Ugi-4CR between a set of azidoacids, aldehydes, protected glucopyranosyl amines, and propargyloxycarbonyl-protected aminoalkyl isonitriles afforded a set of eight linear precursors 1063, which underwent click-macrocyclization to give the set of macrocycles 1064 in good overall yield, accompanied by a small amount of cyclodimers and byproducts in the last step. Another feature of this series is the presence of the carbamate fragment in the macrocyclic core. Two sets of 14- and 12-membered macrocyclic peptidomimetics, 1066 and 1068, respectively, were also reported.390 These derivatives were prepared in two successive steps starting from commercially available precursors (Scheme 201). The synthesis of series peptidomimetics 1086 started with the MCR between O-propargyl-2′-hydroxyacetophenone, 3-bro-

coupling (DIC, HOBt) of an appropriately protected glycopyranozide 1058 simultaneously containing azido and amino groups to dipeptide propiolamides 1059a or 1059b to obtain the corresponding precursors 1060a and 1060b. Clickcyclodimerization of the latter afforded macrocycles 1061a,b, and the subsequent removal of Mtr and Bz protecting groups furnished scaffolds 1062a,b.383 10.3. Double-Click Stapling

Another approach for the stabilization of peptide helical conformation consists of the introduction of bis-triazolyl macrocycle via so-called “double click” stapling. A distinguishing feature of this approach is the efficiency with which peptides bearing different staple linkages can be synthesized; staples may vary by the distance between alkynyl fragments

Scheme 200. Synthesis of Series 1064 Using Ugi-4CR-CuAAC Approach

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Scheme 201. Synthesis of Peptidomimetic Series 1066 and 1068

Scheme 202. Ugi-4CR-Click Approach to Macrocycles 1072a−c

cyanobenzaldehyde, cyclohexyl isocyanide, and azido-functionalized amino acid or dipeptide. The subsequent CuAACmacrocyclization of 1076 and 1078 afforded desired compounds 1077 and 1079, respectively, in excellent yield. Recently, Zakharova et al. investigated the applicability of the Ugi-CuAAC approach for the synthesis of cyclomonomeric/cyclodimeric peptide compounds.393 In this work, the azido group was introduced to the isocyanide component of the Ugi reaction, whereas the alkyne fragment was introduced to the acid component. A series of peptidomimetics 1080 were prepared using these substrates and subjected to CuAAC conditions. It was found that the main factors that influence the cyclization/cyclodimerization outcome (i.e., ratio 1081/ 1082) are the distance between azide and alkyne fragments and the general rigidity of linear precursors. For example, compounds 1089 bearing a flexible residue of hex-5-ynamide (X = (CH2)3) underwent intramolecular cyclization to the corresponding monomeric products 1081. In contrast, compounds bearing a fragment of 4-ethynylbenzamide (X = 1,4-Ph) were essentially unable to undergo the intermolecular CuAAC reaction due to their molecular rigidity, therefore providing dimeric products in satisfactory to good yield. The results of this work are illustrated in Scheme 204.

mopropanenitrile, acetyl chloride, and two-substituted benzaldehyde. This reaction afforded the corresponding propargylcontaining β-amidoketones in 58−74% yield, in which the azide function was subsequently installed to furnish linear precursors 1065. Macrocyclization under click conditions afforded series 1066 in good yield. Six examples of 12membered macrocycles 1068 were prepared in an analogous manner from linear precursors 1067. Recently, a set of 27 macrocyclic peptidomimetics 1072a−c was constructed using the Ugi-CuAAC approach.391 Ugi-4CR between azidocarboxylic acids 1069, various amines, isonitriles, and propargyloxy aldehyde 1070 afforded a set of acylamino carboxamides 1071, which were generated in moderate to good yields (Scheme 202). Microwave-assisted click-macrocyclization of these linear precursors furnished 20-, 21-, and 22-membered macrocycles 1072a−c, respectively, in satisfactory to good yield. The SAR of these compounds was reported in the same paper: Preliminary assays indicated that these compounds could serve as candidates for further optimization. The synthesis of two triazole-bridged heptapeptides 1077 and 1079 based on Ugi-click strategy was reported by Balalaie in 2014 (Scheme 203).392 Both compounds shared a common sequence motif Ser-Ala-Pro-Pro-Pro as well as an exocyclic amide fragment. Linear precursors 1076 and 1078 were assembled in excellent yields via four-component reaction of the above-mentioned tetrapeptide (acid component), p-

10.5. Flow Chemistry

Flow chemistry protocols have also been developed for the CuAAC macrocyclization of peptides and peptidomimetics. A DV


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Scheme 203. Application of Ugi-4CR-Click Macrocyclization for the Synthesis of Macrocycles 1077 and 1079

Scheme 204. Synthesis of Monomeric Macrocycles 1081 and Cyclodimers 1082

head-to-tail macrocyclization of linear azido-iodoalkynes 1083 using copper tubing as the catalyst source was reported (Scheme 205).394,395 This protocol allowed the construction of a series of 12- to 31-membered macrocyclic peptidomimetics 1084, which incorporated a 5-iodo-1,2,3-triazole ring along with various amino acid residues. Unlike typical macrocyclization strategies that generate no new reactive centers upon ring closure, this method allows the further diversification of obtained scaffolds at the iodotriazole moiety, which was demonstrated by several examples of Pd(0)-catalyzed crosscoupling (compounds 1085), thereby opening the way to their use in library development. The impact of ring size and shape on the thermodynamics of macrocyclization under these conditions was studied. Notable changes in geometry and ring strain were observed as ring size was decreased from 14 to

10 atoms, with the CuAAC chemistry being able to tolerate up to 21 kcal/mol of strain energy before forming primarily oligomeric side products.396 A scale-up copper-catalyzed azideiodoalkyne cycloaddition (CuAiAC) using nontoxic and nonvolatile PEG media at relatively high concentrations (30−300 mM) was also reported (Scheme 205).397 A total of 13 examples of iodotriazole-containing macrocycles 1086 were obtained in good to excellent yield using the phase separation strategy, which was adapted to a continuous flow protocol. A combination of Ugi-4CR and CuAAC reactions was conducted under a flow protocol to prepare the series of macrocycles 1088 (Scheme 206).398 The Ugi reaction was used to assemble the linear peptidomimetics 1087, which underwent a head-to-tail macrocyclization under elevated DW


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Scheme 205. Flow Synthesis of Triazole-Containing Peptidomimetics

Scheme 206. Flow Protocol for Ugi-4CR-Click Macrocyclization

Scheme 207. B/C/P Approach to Stereodiverse Scaffolds 1094 and 1095

enantiomers of O-PMB-protected alanilol 1089 were prepared. In the couple step, these building blocks were reacted to give a set of the corresponding amides, which, in turn, were reduced to secondary amines 1091. In the pair phase, the set of eight stereoisomers of 1091 was derivatized by N-acylation with 4azidobutanioc acid 1095 and O-alkylation with propargyl bromide to give the set of linear precursors 1093. The latter were subjected to Ru- or Cu-mediated AAC, furnishing a diverse collection of scaffolds 1094 and 1095, respectively, each with a complete set of stereoisomers. Spring et al. developed an advanced density of states (DOS) strategy based on the B/C/P algorithm, which enabled the construction of a library of over 200 triazole-containing peptidomimetics based around several distinct scaffolds.401−403 The approach is illustrated in Scheme 208 and involved the construction of “azido-amine” and “alkyne-acid” building blocks 1096 and 1097, respectively, from simple, readily available amino acid starting materials. The former were coupled using common methods to produce a range of stereochemically diverse linear peptides 1098, which were elaborated to 1,4- or 1,5-triazole-grafted macrocyclic scaffolds 1099 and 1100, respectively, using Cu- or Ru-mediated AAC.

temperature and pressure to give the desired compounds 1088 in good yields. 10.6. Diversity-Oriented Synthesis

Several approaches to the diversity-oriented synthesis of macrocyclic scaffolds are based on AAC macrocyclization. Using the build/couple/pair (B/C/P) method introduced by Nielsen and Schreiber allows for the combinatorial construction of large sets of stereochemically and regiochemically diverse scaffolds.399 The build step consists of an asymmetric synthesis of appropriately protected building blocks. In the couple step, individual building blocks are pairwise-coupled using conventional SPPS or solution-phase chemistry. Finally, the pair step involves the intramolecular azide−alkyne cycloaddition reaction to form the final macrocycle, with additional regiochemical diversity introduced depending on the cyclization strategy. Marcaurelle et al. reported the B/C/P synthesis of macrocyclic series 1094 and 1095 (Scheme 207).400 In the build phase, four stereoisomers of γ-amino acid 1090 and two DX


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Scheme 208. B/C/P Approach to Scaffolds 1099 and 1100

Scheme 209. Example of Click-Stapling of Ribosomally Synthesized Peptide

Scheme 211. Synthesis of Series 1104

10.7. Biotechnology

By using mutated aminoacyl tRNA synthetases, it has been possible to assemble recombinant protein precursors, in which a variable peptide target sequence is framed between a

genetically encoded non-natural amino acids.404−406 In the early studies, Suga et al. reported CuAAC for the cyclization of

Scheme 210. Synthesis of MOrPHs via Click Chemistry

DY


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Figure 77. Structure of bis-macrocyclic inhibitor of botulinum neurotoxin 1105.

Scheme 212. Synthesis of [i, i + 4] Triazole-Bridged Helical Peptides

ribosomally synthesized peptides between azidohomoalanine (Aha) and propargylglycine (Pgl) residues: A triazole bridge could be installed in an unstapled peptide (Scheme 209) as well as in preliminarily sulfhydryl-chloroacetyl stapled compounds.407 Later, the Fasan group developed the macrocyclic organopeptide hybrid (MOrPH) methodology, which enabled the synthesis of macrocyclic scaffolds from ribosomally synthesized peptides that incorporate a variety of non-natural amino acid fragments.408−410 An example of the implementation of this strategy is illustrated in Scheme 210. A set of recombinant protein precursors bearing an O-propargyl tyrosine subunit (OpgY) was subjected to the CuAAC reaction with bifunctional azide/hydrazide compounds 1101, followed by the

Figure 78. Structures of [i, i + 5] triazole-bridged cyclopeptides 1110 and 1111. DZ


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would connect the two macrocycles in the optimal orientation to achieve maximum inhibitory activity. 10.8. Stabilization of Peptide Secondary Structure

It was demonstrated that the incorporation of 1,2,3-triazolyl bridge via i-to-(i + 4) side-chain-to-side-chain macrocyclization allows the stabilization of helical and other noncanonical structures.415−417 Two model series of macrocyclic nonapeptides, which incorporate 1,4- and 4,1-disubstituted 1,2,3triazole bridges (1108a−d and 1109a−d, respectively) in linkers of different lengths, were prepared via the straightforward SPPS approach (series 1106 and 1107, respectively), followed by CuAAC-mediated macrocyclization (Scheme 212). NMR conformational analysis of these compounds revealed several distinct features of triazole linkages. Compounds with five or six methylene units in the bridge accommodate the α-helical structure. Cyclo-nonapeptides 3 and 5, containing 1,4-[1,2,3]triazolyl moieties within bridges composed of seven CH2 groups, are characterized by the prevalence of type-I β-turn structures. Compounds 1 and 4, in which the [1,2,3]triazolyl moiety is in 1,4- and 4,1-orientations and is flanked by chains composed of a total of four methylenes, show conformational ensembles characterized by classic and inverse γ-turns. Compounds 2 and 6, in which the 4,1-[1,2,3]triazolyl moiety is flanked by chains composed of a total of four and seven methylenes, are flexible, forming a widespread of β-turn and γ-turn conformations. The same group has reported the synthesis of [i, i + 5] triazole-bridged cyclopeptides.418 Compound 1110 is characterized by a 310 helix-like structure, and cyclopeptide 1111 formed a β-sheet (Figure 78). Multiple click-macrocyclizations in a single peptide molecule are also possible and can serve as a powerful tool for the stabilization of its secondary structure. Compounds 1112a−c were prepared from the corresponding linear precursors, which contained two azide and two alkyne groups (Figure 79).419 These peptides were >90% in helical propensities and demonstrated potent binding to β-catenin. In another study, the folding propensities of different bridging fragments were evaluated. Several model macrocyclic peptides derived from vasoactive intestinal peptide were prepared, and their secondary structure was investigated (Figure 80).420 The triazole-bridged macrocycle 1113d demonstrated the highest propensity of folding, whereas lactam analogue 1113a and RCM-derived compounds 1113b and 113c showed random conformations in water. The folding thermodynamics of several bridged peptides 1114a−c derived from a helix-rich sequence of the villin headpiece (HVP) domain was evaluated (Figure 81).421 The analysis of the folding free energy revealed only minute differences based on the chemistry of the cross-link. Backbone preorganization was the dominant factor, regardless of the

Figure 79. Double-bridged peptides 1112a−c.

removal of copper catalyst and fast buffer exchange. Upon reversible N → S acyl transfer in the formed compounds, hydrazide attack onto the thioester, followed by the removal of intein (GyrA) afforded the desired MOrPHs of variable sequence lengths (4-mer to 12-mer) and structurally different phenyl/biphenyl-based synthetic precursors. The Heath group developed a strategy of target-guided synthesis of macrocyclic ligands based on peptide libraries by in situ click chemistry in the presence of the target protein. This strategy has been successful in identifying linear or macrocyclic peptides able to bind specific epitopes in proteins with antibody-like affinities.411,412 Scheme 211 illustrates the implementation of this concept, or the synthesis of the library of triazole-containing macrocycles. The library of linear peptides 1102 bearing propargylglycine (Pgl) and azidolysine (Az4) residues at N- and C-termini, respectively, was assembled using conventional SPPS procedures. The subsequent macrocyclization and installation of an additional click handle at the N-termini of the resulting macrocycles 1103 afforded the desired compounds 1104, which were used to target 12 therapeutically relevant protein targets, achieving affinities in the picomolar to nanomolar range in most cases.413 A similar strategy was used to develop a potent inhibitor of botulinum neurotoxin, compound 1105, which demonstrated a picomolar IC50 value (Figure 77).414 Two macrocyclic peptides, which bind different subdomains of the neurotoxin, were identified from respective peptide libraries. An in situ click screen was then performed with a library of linkers that

Figure 80. Structures of compounds 1113a−d. EA


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Figure 81. Structures of compounds 1114a−c.

solvation and the efficiency of side-chain cross-linking is strongly sequence-dependent. β-Hairpin stabilization was studied on model peptides based on the Trpzip2 scaffold (Figure 82).422 Triazole linkages of various length were inserted at different positions to evaluate their performance as β-hairpin stabilizers. The length of methylene spacers at both sites of the triazole substitution was varied separately to obtain the optimal linker configuration. Two works encompassed the introduction of triazole bridges between i-to-i + 7 residues at different positions of peptide chain. Compounds 1115a−i were designed so the triazole bridges were located within the hydrogen-bonded positions of the β-hairpin.423 Triazole bridges of compounds 1116a−i were located in less constrained (non-hydrogen-bonded) positions.424 β-hairpin folding trends turned out to be quite straightforward: Peptides with the same number of methylene units in the bridge (i.e., equal values of n + m) showed similar β-hairpin content, which increased with the increase in bridge length. This pattern was observed for both sets of compounds. Slightly more complicated trends were observed in the case when the triazole bridge was introduced at non-hydrogenbonded positions of the model peptide at an i-to-i + 5 distance (compounds 1117a−l).425 The length of methylene linkers as well as the substitution pattern of triazole ring had a great impact on secondary structure stabilization. Thus the β-hairpin content was maximal in the case of compounds 1117g and 1117h, and it was shown to decrease significantly when the number of methylene units in the C-terminal strand was increased or its number in the N-terminal strand was decreased. As evidenced by NMR experiments, the triazole bridge in compound 1117h promoted the interstrand hydrogen-bonding pattern of the parent trpzip2. The reported data suggest one more pattern of how to choose a triazole bridge for side-chain-to-side-chain linkage of peptides: More constrained positions (i.e., hydrogen-bonded) require a more flexible bridge to achieve the maximal β-hairpin stabilization. A series of β-turn tetrapeptides were constructed using clickmacrocyclization of linear precursors 1118 incorporating an Lor D-proline fragment and up to two N-methylated amino acids (Scheme 213).426 These were assembled using common chemistry and subjected to intermolecular CuAAC under optimized conditions to give series 1119. The secondary structure was investigated by NMR and XRD analyses. The incorporation of N-methylated residues enabled sufficiently low PSA values (up to 81 Å2) to be achieved, which makes these compounds potentially cell-permeable.

Figure 82. Structures of compounds 1115−1117 and peptide trpzip2.

cross-linking chemistry employed. Nevertheless, among three similar motifs examined, cyclization via a triazole proved to be best. The improvement in stability as a function of cross-link chemistry followed the trend triazole > lactam > oxime and was entirely entropic in origin for all three cases. This supported the hypothesis that backbone preorganization is a general mechanism by which side-chain to side-chain crosslinks stabilize folded α-helices. Overall, these results suggest that covalent constraint via cross-linking stabilizes α-helices by reducing the disorder of the unfolded state and altering its

10.9. Disulfide Mimetics

Both 1,4- and 1,5-substituted triazoles were shown to function as disulfide bond mimics. In the report by Empting et al., two analogues of SFTI-1, compounds 1121 and 1122, were EB


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Scheme 213. Synthesis of Series 1119

Scheme 214. Synthesis of Triazole Analogues (1121 and 1122) of SFTI-1

Scheme 215. Synthesis of Bis-triazole Analogues of Tachyplestin I

prepared from the same linear substrate 1120 via Cu-AAC and Rh-AAC protocols, respectively (Scheme 214).427 Both compounds were obtained in reasonable yield, and peptidomimetic 1122 retained the nanomolar biological activity of the parent compound. Compounds 1124a and 1124b. exemplify the use of CuAAC chemistry for the construction of multiple disulfide bond mimics in a single molecule.428 1124a,b were designed as analogues of tachyplesin I, which is a potent antimicrobial natural product (Scheme 215).429 Linear precursors (1123a and 1123b) of these compounds were assembled using conventional Fmoc-SPPS chemistry. Under optimized CuAAC conditions, these compounds were transformed to the desired macrocycles 1124a and 1124b in low yield. These compounds retained the β-hairpin structure of the parent compound as well as the positions of most of the side chains in the required orientation. Biological assays revealed that both triazole analogues have comparable (and in some cases improved) MIC values to those of the parent compound against several microorganisms. Compounds 1127a−d (Scheme 216) are examples of bimacrocyclic molecules, which possess both the disulfide

bridge and its triazole mimic at the same time.430 These compounds were designed as synthetic analogues of conotoxin MrIA and displayed improved stability in rat plasma compared with the natural molecule. As in the previous cases, linear precursors of these compounds (1125 and 1126) were synthesized by using Fmoc chemistry. The successive CuAAC macrocyclization, followed by the simultaneous I2mediated removal of Acm protecting groups and the oxidative formation of disulfide bonds furnished compounds 1127a−d. 10.10. Analogues of Natural Products

Triazole analogues of sansalvamide A were reported (Scheme 217).431 The natural product is known for its micromolar inhibitory activity against several cancer cell lines.432 The linear precursors 1129a,b were assembled via common solutionphase chemistry and were transformed to the target macrocycles 1130a,b, albeit in low yield. These heterocylic analogues demonstrated the same activity as the parent compound against HeLa cell lines. EC


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Scheme 216. Synthesis of Mono-Triazole Analogues of Conotoxin MrIA

Scheme 217. Synthesis of Triazole Analogues of Sansalvamide A

1134a−c were subjected to conventional macrolactamization conditions (HATU), the yield of each macrocyclic analogue 1133a−c exceeded 95%, with no respect to the stereochemistry of the reactants. Another series of related 1,4triazole-containing macrocycles 1136 were prepared via the CuAAC macrocyclization of the corresponding linear substrates 1135, albeit in low yield.434 The synthesis of segetalin B analogue 1138 was also reported.435 This compound was

Several triazole-containing analogues of apicidin were obtained via both AAC macrocyclization and macrolactamization approaches (Scheme 218).433 Peptides 1131a,b were synthesized and subjected to the intramolecular CuAAC reaction, affording 1,4-triazole-containing analogues 1132a,b in 50% yield. The uncatalyzed MW-assisted macrocyclization of 1131a afforded 1,5-substituted analogue 1133a in 8% yield. In contrast, when 1,5-triazole-containing linear precursors ED


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Scheme 218. Synthesis of Triazole Analogues of Apicidin and Segetalin B

accessed in reasonable yield from linear precursor 1137 upon CuAAC macrocyclization. The synthesis of 12 analogues (compounds 1143) of natural depsipeptide jasplakinolide were reported by Waldmann in 2007 (Scheme 219).436 Two approaches, macrolactamization (macrolactonization) and click-macrocyclization, were investigated, and the latter proved to be much more efficient. Both pathways followed the initial construction of linear precursors 1139 via the common Fmoc-SPPS protocol. In the macrolactamization (macrolactonization) pathway, the azide function in 1139 was reacted with a set of alkyne-alcohols or alkyneamines 1140 to produce linear precursors 1141 after cleavage

from solid support. The latter were subjected to intramolecular esterification (X = O) or peptide coupling (X = NH), which afforded the desired compounds 1142 in a scattered yield range (5−59%). In an alternative pathway, the resin-bound azides 1139 were cleaved from the solid support and subsequently coupled to alkynes 1140 to give terminal azidoalkynes 1143 in 50−82% yields (Scheme 3). The intermolecular CuAAC reaction of 1143 proceeded cleanly to give compounds 1142 in good to excellent yield and without the formation of cyclodimers or higher oligomers. The synthesis of the triazole analogue of cryptophycin-52, a so-called “clicktophycin-52” (compound 1155), was reported EE


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Scheme 219. Synthesis of Jasplakinolide Analogues 1142

by Sewald et al. in 2010.437 The former is a natural macrocyclic depsipeptide, a known cytotoxic compound.438 Compound 1145 exhibited a three-fold decrease in potency against the KB-V1 cell line compared with the parent molecule. The same as the above-described jasplakinolide analogues, compound 1145 was assembled via two pathways: macrolactamization and click-macrocyclization, with the former being more efficient. Both pathways began with the preparation of the first two building blocks. Alkyne 1147 was obtained in two steps via the Seyferth−Gilbert homologation procedure, the reduction of amino ester 1146 with DIBAL-H, followed by reaction with ylide of dimethyldiazomethylphosphonate, to give the desired compound. The second building block 1145 was obtained via E-selective olefin metathesis between 1144 and tert-butyl acrylate (Scheme 220). For the macrolactamization pathway, the third building block 1151 was obtained by coupling (DCC, DMAP) between the compounds 1149 and 1150. A follow-up click reaction between 1151 and 1147 afforded compound 1152, which after hydrogenolysis was esterified (DCC, DMAP) with unit building block 1145, furnishing compound 1153 in 94% overall yield. Upon the simultaneous acidic removal of all protecting groups in 1153, the resulting compound was subjected to macrolactamization conditions (HATU, DIPEA), affording the desired macrocyclic core 1154 of the target molecule in 74% yield. Finally, the epoxide ring was installed in 1154 in three consecutive steps, affording 1155 in 56% yield. For the click-macrocyclization pathway, compound 1144 was elaborated to methyl ester 1156, saponified, and coupled

(EDCl, HOAt) to the free amine obtained by the removal of the N-Boc protecting group from 1147 (compound 1148). The resulting compound 1157 was subsequently coupled to TBS-protected building block 1158 and, after the successive removal of silyl protecting group, yielded compound 1159 (Scheme 221). Esterification of 1159 with azidopivalic acid afforded precursor 1160, which was subjected to the clickmacrocyclization reaction to give a mixture of cyclomonomer 1154 and the corresponding cyclodimer (not shown) in 84% combined yield. Cyclomonomer 1154 was isolated as the main product in 32% yield over two steps and could be further elaborated to the target compound 1155. Thus compared with the common macrolactonization protocol, the CuAAC reaction was less efficient for the construction of the macrocyclic core of the desired compound 10.11. De Novo Design

Among all heterocyclic grafts, triazoles are the most convenient and synthetically attainable for the de novo design of biologically active compounds. The versatility of azide−alkyne cycloaddition allows the efficient construction of meaningful molecular architectures. Among all synthetic heteroarenecontaining peptide macrocycles, those that contain triazole are the most numerous. Both cyclomonomeric and cyclodimeric compounds were shown to possess activity toward various biological targets. Figure 83 shows some examples of biologically active monomeric triazole-containing macrocycles. Compounds 1161a−d were designed by Tala et al. as neurochemical probes for murine melanocornitin receptors EF


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Scheme 220. Macrolactamization Approach for 1145

respectively.448 Further structural optimization identified compound 1167, which binds to XIAP BIR3 proteins with an IC50 value of 0.8 nM.449 Macrocycle 1168 was created based on the Grb2 SH2 domain-binding motif and demonstrated strong binding to this domain with Kd1 = 1.8 nM and Kd2 = 4.0 nM.450

(mMC3R, mMC4R, and mMC5R) and demonstrated nanomolar values of IC50.439 Macrocyclic aldehydes 1162a,b were designed as protease inhibitors.440−443 The most potent members of these series demonstrated low nanomolar inhibitory activity against cathepsin S (IC50 < 5 nM), and calpain II (IC50 = 89 nM). Peptidomimetic 1163 is an inhibitor of STAT3 protein (signal transducer and activator of transcription 3) which displayed a Ki of 7.3 μM.444 Compounds 1164a,b with RGD (Arg-Gly-Asp) and NGR (Asn-Gly-Arg) motifs were designed as integrin domainbinding antagonists and demonstrated activity at submicromolar (up to 5 nM) concentrations against various cancer cell lines.445,446 Peptide 1165 was designed as an inhibitor of protein−protein interactions between RAP1 (repressor activator protein 1) and TRF2 (telomeric repeat-binding factor 2). This compound demonstrated Ki = 7 nM toward RAP1.447 Figure 84 demonstrates dimeric compounds, which showed improved biological activity compared with their monomeric analogues. Compound 1166 was identified as an inhibitor of XIAP (chromosome-linked inhibitor of apoptosis protein) BIR2 and BIR3 domains with IC50 = 0.097 and 0.036 μM,

11. OXA - AND THIADIAZOLES IN MACROCYCLIC PEPTIDE SCAFFOLDS The xamination of the effect of these heterocycles on the properties of macrocycles has started fairly recently. Macrocyclic inhibitors 1169a−h of norovirus 3CL protease, reported in 2016 by Damalanka et al., contain oxadiazole rings in their structures.451 The general strategy toward their synthesis involves the incorporation of a oxadiazole ring in the peptide structure in the early stage (Scheme 222). Starting from one of five ω-N-Cbz-protected alkylcarboxylic acids 1170a−e, oxadiazole-incorporating peptide precursors of varying length 1173a−h were synthesized in several steps. Compounds 1170a−e were converted to the corresponding Boc-protected hydrazides, followed by N-Boc-deprotection and peptide coupling (EDCl, HOBt) with N-Boc-L-Glu(OMe) or N-BocEG


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Scheme 221. Click-Macrocyclization Approach for 1155

Figure 83. Examples of monomeric triazole-containing biologically active compounds. L-Asp(OMe)

to yield compounds 1171a−f. Treatment with TsCl/DIPEA allowed the cyclization of 1,3,4-oxadiazole rings

in these compounds, and the subsequent hydrolysis furnished the corresponding oxadiazole-containing ω-amino acids EH


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corresponding dipeptide, which afforded compounds 1173a− d. Compounds 1173e−h were obtained via successive coupling (EDCl, HOBt) of 1172b−f with L-Cha(OMe) and t L-(OBu )Glu(OMe). After the simultaneous deprotection of Cand N-termini in 1173a−h, the resulting peptides were subjected to macrolactamization (EDCl, HOBt), which gave the cyclic products 1174a−h in good yields. For biomedical studies, these products were converted to the corresponding Cterminal aldehydes 1169a−h by reduction with lithium borohydride and oxidation by DMP. With the exception of compound 1169h, all macrocycles demonstrated satisfactory cell permeability, and compounds 1169c−g showed singledigit micromolar EC50 values. In the recent work by Yudin et al. (2016), the oxadiazole ring was installed in the cyclic scaffold at the macrolactamization step.452 Peptide precursors of various lengths and amino acid compositions were converted to oxadiazolegrafted macrocycles in a high-yielding one-step procedure (Scheme 223). A series of 27 different tetra-, penta-, hexa-, and heptapeptides were reacted to generate 15-, 18-, 21-, and 24membered rings, respectively. The method is based on the 4CR reaction between C- and N-termini of linear peptides, aldehydes, and N-(isocyanimino)triphenylphosphorane. Besides enabling the macrocyclization itself, the aldehyde component allows the introduction of various functional groups by altering the nature of the aldehyde component. One of the synthesized compounds, 1175, inhibited the MAdCAM−α4β7 interaction with an IC50 of 1.6 μM.453 It is noteworthy that oligomerization products were not formed despite the relatively high reaction concentrations (25−100 mM). The was true for the more constrained tetra- as well as the more flexible hexa- and heptapeptide sequences. The authors attribute these observations to the involvement of zwitterionic control within the cyclization process (Scheme 224).

Figure 84. Examples of dimeric triazole-containing biologically active compounds

1172a−f. Next, L-Leu-L-(OBut)Glu(OMe) residue was installed into these compounds by direct coupling with the

Scheme 222. Synthesis of Oxadiazole-Based Inhibitors 1169a−h of Norovirus 3CL Protease

EI


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Scheme 223. General Scheme for Peptide Macrocyclization and Synthesis of 1175

Scheme 224. Proposed Reaction Mechanism for Macrocycle Formation

Scheme 225. Synthesis of Thiadiazole-Grafted Macrocycles 1179

Figure 85. Hydrogen-bonding pattern of 1176 in solid state and solution. Reproduced from ref 453. Copyright 2018 American Chemical Society.

XRD analysis revealed that during cyclization of all-L-ProGly-Leu-Gly-Phe with propanal, compound 1176 is preferentially formed. For this substrate, the newly formed stereocenter forms were found to have (S)-configuration. The general revealed feature of oxadiazole-containing macrocycles is a

conserved hydrogen-bonding network, which does not depend on the peptide or aldehyde component. (Figure 85).

Figure 86. Oxadiazole-grafted macrocycles mimic the protein structural features. Reproduced from ref 453. Copyright 2018 American Chemical Society. EJ


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oligomeric peptides were diluted with a mixture of tBuOH/1 M HCl (5:1) and heated to 70 °C. The authors note that under these conditions, the formation of 17- and 21-membered rings, that is, the addition products of two or three monomers 1178 to 1177, predominated. In some cases HPLC/MC showed the formation of larger macrocycles in small amounts. A stepwise addition of two different monomers in the reaction mixture resulted in the formation of mixtures of novel thiadiazole-grafted macrocycles in a combinatorial fashion. The described protocol allows the synthesis of cyclic adducts, which incorporate two to four monomer subunits (Scheme 226). The reactions were carried out on semipreparative scales (1 μmol of 1177); however, the authors stated the possibility of scaling the loads to 100 μmol without significant changes in the distribution of the reaction products. Albeit the products of the reaction mixture were inseparable and were only studied via MS−LC, this method allows the preparation of solutions of novel peptides suitable for biological research by simply diluting the reaction mixtures to form solutions of micromolar concentrations.

Scheme 226. Synthesis of Libraries of Thiadiazole-Grafted Macrocycles

The NMR experiments and NOE-based calculations were conducted to study the conformation of this type of macrocycles. The reported molecules possess a stable oxadiazole-induced β-turn, which is a known structural factor of highly membrane-permeable compounds (Figure 86). Twelve of 27 compounds were tested using PAMPA and exhibited high values of membrane permeability. The calculated PSA values were matched very closely between the oxadiazole-containing macrocycles and their homodetic analogues. Despite the paucity of published data, the available articles highlight the unique properties of oxadiazoles as macrocycle backbone supports. Their dual properties allow them to participate as stabilizers of the intramolecular network of hydrogen bonds that plays the key role in the consolidation of the macrocycle secondary structure. On the contrary, they increase the PSA value of macrocycles, facilitating oral bioavailability. In 2018, the synthesis of cyclic peptides based on β-amino acids containing a thiadiazole fragment was published.454 In the reported approach, macrocyclization and heterocycle formation were conducted in a one-pot procedure (Scheme 225). The building block in this reaction is an α-keto acid comprising N′-Boc thiohydrazide fragment 1177 and elongation monomers 1178, whose synthesis is detailed in the article. The work consisted of a one-pot reaction between 1177 and 1178 under neutral conditions (tBuOH/H2O) to form oligopeptides containing two to four monomeric units and their subsequent macrocyclization, accompanied by the formation of a thiadiazole ring in compounds 1179. To promote Boc-deprotection and thiadiazole-forming macrocyclization, the reaction mixtures containing mixtures of

12. TETRAZOLES IN MACROCYCLIC PEPTIDE SCAFFOLDS Recent works of the Dömling group introduced tetrazolecontaining macrocyclic peptides as a novel structural space for combinatorial drug discovery.455,456 This heterocyclic fragment is readily incorporated in the peptide scaffold via a fourcomponent azido-Ugi reaction (UT-4CR), and thus the synthesis of these compounds inherits all of the benefits MCR chemistry: the use of commercially available building blocks, broad functional group compatibility, scalability, short and economical synthesis routes, and so on. The biomimetic cis-peptide bond character of the tetrazole ring makes this structural space even more promising.457 Surprisingly, MCR chemistry is rarely used for the synthesis of peptide macrocycles despite all of its synthetic advantages.458 Tetrazole can be introduced in the macrocyclic structure in the first steps of the synthesis of the macrocyclic precursor (Scheme 227). This strategy employed two successive MCRs to construct a series of compounds with ring sizes 16−21. In the first UT-4CR, an aldehyde, tritylamine, TMSN3, and ωisocyanoalkyl ester were reacted to give the corresponding αamino tetrazoles, which upon detritylation were transformed into 1180 in good to excellent yields. The latter were acylated with ω-isocyanoalkyl acids to give 1181. These compounds were then subjected to the second U-4CR, which allowed the ring closure to furnish macrocycles 1182 in satisfactory yields. The overall reaction sequence is quite general, and the substrate scope of this strategy is broad, including aromatic,

Scheme 227. Incorporation of Tetrazole in the Early Stages of Macrocycle Synthesis

EK


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Scheme 228. One-Pot Tetrazole Synthesis and Macrocyclization of Linear Peptidomimetics 1183

known natural cyclic peptides as well as the de novo synthesis of new macrocycles that include this fragment.

aliphatic, and heteroaromatic oxo-components as aldehydes and ketones and substituted aromatic or aliphatic amines. Later, the use of a UT-4CR in the macrocyclization step was reported (Scheme 228).459 A straightforward protocol included the initial linking of isocyanide and amine components as α-isocyano-ω-amines 1183. A series of these compounds are readily accessible from commercially available precursors in good yields ranging from 42 to 65% on a gram scale. Thus the macrocyclic ring closure by UT-4CR at 0.01 M dilution afforded a series of the corresponding macrocycles 1184. Of particular interest is the high concentration of the reaction mixture. In contrast with other macrocyclization protocols, which usually employ millimolar concentrations of reagents, this procedure provided high yields using concentrations of reagents increased to 0.02 M.

13.1. Pyridine Largazole Analogues

Inspired by the natural product largazole, several pyridinecontaining derivatives were targeted as selective HDAC (histone deacetylase) inhibitors (Figure 87). A significant increase in potency with pyridine substitution of the thiazole was observed (compound 1185), and replacing the thiazolethiazoline fragment with 2,2′-bipyridyl moiety (compound 1186) had no deleterious effect on HDAX inhibition activity despite the considerable change of macrocycle conformation. Whereas the compounds 1187−1192 did not demonstrate improved activity in comparison with largazole, they expand the structural space of this promising natural compound. The synthesis of 1185 was reported in 2009 (Scheme 229).460 The depsipeptide fragment 701 was prepared starting from methyl 2,4-pentadienoate 1193 by the initial conversion into α,β-unsaturated aldehyde 1194. A follow-up reaction of 1194 with Nagao auxiliary 1195 afforded thiazolidinethione 1196. The latter was protected as a TSE ester and subsequently coupled to N-Fmoc-L-valine to afford 701. Nitrile 1197 was N-Boc-protected and then condensed with α-methyl cysteine to provide acid 1198. The subsequent deprotection of 1198 and peptide coupling (PyBOP, DIPEA) with 701 afforded the linear precursor 1199 in good yield. The Nand C-terminal protecting groups in 1199 were simultaneously removed, and the resulting peptide was subjected to macrolactamization (HATU, HOBt), followed by detritylation, providing the largazole analogue 1185 in good yield. This compound demonstrated subnanomolar activity against Class I HDACi’s and appeared to be the most biochemically potent Class I HDAC inhibitor known, being approximately three to four times more potent than largazole against HDACs 1, 2, and 3. In 2016, the synthesis of seven more pyridine-containing largazole analogues 1186−1192 was reported.461 This work features one more approach to the construction of thiazolidinethione 746 in addition to those described in sections 9.1.20 and 9.1.21 (Scheme 230). Acrolein was reacted with TrSH to form aldehyde 1200, which was converted to the 5:1 E/Z mixture of nitriles 1201 via the Wittig reaction with (cyanomethyl)triphenylphosphonium chloride. This mixture was reduced with DIBAL-H to form a 5:1 E/Z mixture of the corresponding aldehydes, which isomerized into the desired Eisomer 1194 upon passing through the silica gel column. The subsequent reaction of 1194 with Nagao auxiliary 707 yielded building block 746 in 63% overall yield. For the synthesis of the bipyridyl fragment of analogue 1186, 2-bromo-6-methylpyridine 1202 was converted to tin derivative 1203 (Scheme 231). The subsequent Stille coupling

Figure 87. Pyridyl-containing largazole analogues.

13. PYRIDINES IN MACROCYCLIC PEPTIDE SCAFFOLDS In natural products, pyridine is typically found in the form of a polysubstituted central fragment of thiazolyl peptides (section 16). Examples include amythiamicins, promothiocins, and nosiheptide. However, macrocyclic peptides containing pyridine as the only aromatic heterocycle are not found in nature. Nevertheless, a substantial number of works are devoted to the development of synthetic pyridine-containing analogues of EL


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Scheme 229. Synthesis of Thiazole-Pyridine-Replaced Largazole Analogue 1185

Scheme 230. Alternative Synthesis of Building Block 746

Scheme 231. Synthesis of Bipyridyl Fragment 1205a

Scheme 233. Synthesis of Largazole Analogues 1186−1192

Scheme 232. Synthesis of Pyridyl Building Blocks 1205b−g

The synthesis of pyridyl-containing moiety for analogues 1187−1192 starts with 2,6-dihydroxymethylpyridine 1206, which was initially converted to the monotosylated derivative 1207. The latter was then used to produce the Ts-protected azidoalcohol 1208 (Scheme 232). The alkylation of amines 1209 with 1208, followed by catalytic hydrogenation of the

of 1203 to 2,6-dibromopyridine yielded bipyridyl compound 1204. Aminoester 1205a was then prepared in a four-step sequence of Jones oxidation, esterification, bromide substitution with cyanide, and hydrogenation. EM


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Scheme 234. Synthesis of DMP-757 Pyridyl Analogue 1213

Scheme 235. Synthesis of Pyridine-Containing Di- and Tetrapeptide Building Blocks

resulting compounds furnished the building blocks 1205b−g in good yield. The general approach to the synthesis of compounds 1186− 1192 is shown in Scheme 233. The reaction of 746 with amines 1205a−g in the presence of DMAP furnished the corresponding amides 1210a−g, which were coupled to NFmoc-L-Val under Yamaguchi conditions to afford esters 1211a−g. The subsequent removal of N- and C-terminal protecting groups, followed by macrolactamization (HATU, HOAt, DIPEA) afforded the macrocyclic depsipeptide intermediates 1212a−g. The removal of the trityl protecting group and the subsequent esterification of resulting thiols with octanoyl chloride yielded the target analogues 1186−1192.

DMF and subsequent catalytic hydrogenation produced the amino ester 1215. N-Boc protection ad C-terminus deprotection afforded the linker 1216, ready for incorporation into the cyclic peptide. 1216 was condensed with p-nitrobenzophenone oxime, N-deprotected, and coupled to BocAsp(Cy)-OH to give oxime ester 1217. The subsequent solution-phase protocol was employed for coupling 1217 to tripeptide N-Boc-D-Val-Nα(Me)Arg(Ts)-Gly. The resulting peptide was subjected to Boc-deprotection, macrocyclization, and, finally, the removal of Ts and Cy groups to give the desired compound 1213. The choice of cyclization between the D-Val residue and the activated linker prevented epimerization during cyclization.

13.2. DMP 757 Analogue

13.3. Bipicolyl Fragments in Cyclic Peptides

DMP 757 is a representative of cyclic peptides that are potent and selective glycoprotein IIb/IIIa receptor antagonists.462 Among others, the pyridine analogue 1213 of this compound was synthesized; however, the phenyl/pyridyl replacement did not improve the in vitro activity of the resulting compound (Scheme 234). 463 Starting from ester 1214, benzylic bromination, followed by treatment with sodium azide in

Bipicolinic acid is a naturally occurring dicarboxylic acid that is mainly found in bacterial endospores, as indicated by the spectrometric analysis of Bacillus spores.464 Macrocyclic peptides containing this fragment as well as the fragment of pyridine-3,5-dicarboxylic acid have been investigated. To date, a large number of examples of symmetric and asymmetric macrocyclic peptidomimetics have been synthesized. The EN


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Scheme 236. Synthesis of Macrocycles Based on Series 1221

Scheme 237. Synthesis of Arylimide-Linked C2-Symmetric Tetra- and Octapeptides

EO


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Scheme 238. Synthesis of Pyridine-Containing Peptidocalixarenes

Scheme 239. Synthesis of Pyridine-Containing Cyclic Tri- and Pentapeptides

starting compounds for the synthesis of pyridine-containing linear precursors for macrocyclization are the pyridine-2,6dicarboxylate and pyridine-3,5-dicarboxylate chlorides. The general principle for the synthesis of such compounds is the sequential reaction of amino acid esters with the pyridinecontaining building block. The corresponding macrocycles are then synthesized from substrates containing two or four amino acids linked by a pyridine moiety.

The synthesis of pyridine-containing di- and tetrapeptide building blocks 1219−1224 starts from dichlorides 1218 and amino acid methyl esters, which were directly coupled to form diesters 1219 (Scheme 235). The latter were either subjected to hydrazinolysis to form compounds 1221 or hydrolyzed to the corresponding diacids 1220. Both 1220 and 1221 can serve as linear precursors for macrocyclization, or they can be subjected to peptide synthesis to furnish the corresponding EP


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Scheme 240. Use of Pyridine N-Oxides as Cyclization Promoters in Linear Peptides

80%).470 The condensation of 1221 with 3,3′-binaphthyldialdehyde in refluxing methanol afforded the corresponding macrocyclic hydrazone 1229. 471 One example of the condensation of tetrapeptide dihydrazide containing 3,5dipicolinic fragment 1222a with 2 6-diacetylpyridine under similar conditions was also published; the corresponding macrocycle 1230 was formed in good yield. The condensation of 1221 or 1224 with benzenetetracarboxylic and naphthalene tetracarboxylic acids in glacial acetic acid furnished conformationally restricted bridged tetra- and octapeptides 1231a−d and 1232a−f, respectively (Scheme 237).472−474 Several examples of pyridine-containing macrocyclic peptidocalixarenes based on distally substituted upper-rim diaminocalixarenes were synthesized using a common approach (Scheme 238). The cyclization of some of the pyridylcontaining dipeptides 1220 and 1221 with calix[4]arene

tetrapeptides 1222. The mixed anhydride method [A] proved to be practically more convenient than the azide or carbodiimide methodologies for 2,6-dipicolinic substrates; however, the azide method [B] proved to be much more effective for 3,5-dipicolinic substrates.465−469 Compounds 1222 were subsequently deprotected via either hydrazinolysis or hydrolysis to form the corresponding dihydrazides 1224 or diacids 1223. Several published examples demonstrate that dihydrazides 1221 containing the 2,6-dipicolinic fragment can effectively undergo a macrocyclization reaction with various rigid bifunctionalized compounds (Scheme 236). Upon treatment with 2,6-pyridinedicarbonyl dichloride, 1221 was converted into corresponding macrocycles 1225a−c in moderate to good yield. The treatment of 1221 with 2,6-diacetylpyridine or 2,6pyridinedicarboxaldehyde in refluxing ethanol yielded compounds 1226−1228, again in moderate to good yield (50− EQ


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Scheme 241. Introduction of Pyridine-3,5-thionyl Linkage in Linear Peptide

Scheme 242. Synthesis of Pyrimidine-and Purine-Linked Macrocyclic Peptides

bipyridyl-containing macrocyclic peptidocalixarenes were reported. Both mixed anhydride [A] and azide methods [B] of coupling were successfully applied for the intramolecular cyclization of linear pyridine-containing di- and tetrapeptides through diamine linkage. Cyclization of dipeptides 1220 and 1221 or tetrapeptides 1223 and 1224 with different diamino linkers (1238a−e) afforded the corresponding series of cyclic tri- or pentapeptide esters 1240 and 1239, respectively (Scheme 239).475−477

molecular baskets provided novel molecular architectures. The condensation of 2,6-dipicolyl-containing hydrazides 1221 with formylated calix[4]arene 1233 in refluxing ethanol yielded the corresponding macrocyclic peptidocalix[4]arenes 1234a−c (45−60%). The condensation of 1220 and 1221 with diamino-containing calix[4]arenes 1235a,b via mixed anhydride [A] and azide [B] protocols, respectively, afforded the corresponding series 1236 and 1237. The azide protocol [B] gives significantly better yields in this reaction for all substrates except Tyr-containing 1220 and 1221. No examples of 3,5ER


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attachment of 2,4,6-trichloropyrimidine 1246a was assigned to nucleophilic attack at the four-position of the pyrimidine ring (1247, ratio of regioisomers 3:2), whereas the main product resulting from the attachment of the purine derivative 1246c attributed to the attack at position 8 (1249, 3:1 ratio of regioisomers). Macrocyclization at increased temperatures and microwave irradiation resulted in almost quantitative yields of

Macrocycle 1239a was reported to have outstanding properties as a metal sensor, with high affinity for divalent cations and high selectivity toward Pb2+ ions. It also showed moderate anticancer activity against MCF7 (breast) and SF268 (CNS) cell lines. Some of the above-mentioned compounds demonstrated promising results as potential antiinflammatory drugs. It is noteworthy that the cyclic compounds proved to be more potent than their linear counterparts. Many of the reported compounds exhibited antibacterial and antifungal activities against different microorganisms representing Gram-positive and Gram-negative bacteria and yeast at 50 μg/L.

Scheme 243. Synthesis of Triazine-Linked Macrocycles 1253 and 1254

13.4. Other Methods

PyBroP reagent was found to serve as a mild pyridine-N-oxide activator for the intramolecular addition of varied N, O, S, and C nucleophiles to afford the corresponding two-substituted pyridines. A general procedure was developed for the macrocyclization of peptides using this transformation (Scheme 240).478 In this case, the N-termini of linear peptide precursors were converted to various pyridine-N-oxidecarboxamide moieties, which then acted as the corresponding electrophiles in further reactions with natural nucleophilic amino acid side chains of tyrosine (phenol), lysine (alkylamine), and histidine (imidazole). Various pyrindine N-oxide carboxamides 1241a−q were readily synthesized via the amide coupling of linear di-, tri-, and tetrapeptides and corresponding linkers. Upon the exposure of 1241a−q to PyBroP and DIPEA in THF at 25 °C, the corresponding macrocycles 1242a−q were formed after 1 h. It was found that the order of addition and the reaction concentration were critical to the success of this macrocyclization. A slow addition of substrates 1241a−q to a THF solution of PyBroP and DIPEA (pseudo-high dilution) allowed the oligo- and polymerization side processes to be minimized. The use of a sulfonated biarylphosphine ligand (sSPhos) to promote the chemoselective modification of Cys-containing proteins and peptides with palladium reagents in aqueous media was reported (Scheme 241).479 Under these conditions, it was found that a mixture of 3,5-dibromopyridine, sSPhos ligand, and [(1,5-COD)Pd-(CH2TMS)2] dissolved in tetrahydrofuran (THF) afforded the desired palladium complex 1243 in excellent yield. Macrocyclization of a model peptide was prepared with two cysteines separated by seven amino acids using this sSPhos supported reagent. The reaction required only 10 min to proceed at room temperature in aqueous buffer, followed by the addition of 3-thiopropionic acid to quench the reaction. Pyridine-stapled peptide 1244 was obtained in excellent yield without side products of intermolecular crosslinking.

corresponding cyclic peptides 1247−1249 as inseparable mixtures of their regioisomers in good HPLC purities.

15. TRIAZINES AND TETRAZINES IN MACROCYCLIC PEPTIDE SCAFFOLDS 15.1. Triazine

Because of their relative ease of synthesis, triazine-containing macrocyclic peptides are receiving much attention. The incorporation of a triazine ring into the peptide backbone usually imposes additional conformational restrictions on cyclic peptides, enabling them to have preorganized structures. Wenschuh et al. were the first to report the use of cyanuric chloride (2,4,6-trichloro-[1,3,5]triazine, 1250) as a versatile reagent for the macrocyclization of linear peptides in 2001 (Scheme 243).480 Linear peptides of varying length tethered to a photolabile cellulose membrane, 1251 and 1252, were subjected to an SNAr-type reaction with 1250 to yield the Ntriazine-capped derivatives. The subsequent removal of the NBoc protecting group in the lysine side chain and the direct cyclization via nucleophilic attack of the released amino function at the heterocycle moiety yielded the corresponding cellulose-tethered cyclic products 1253 and 1254 with varying ring sizes (11- to 37-membered rings) with satisfactory to good HPLC purities. Lim et al. reported the synthesis of macrocyclic scaffolds with intramolecular Cys-triazine linkages in 2010.481 A series of compounds 1255 with different ring sizes (3 to 10 amino acid residues) was prepared via the SPPS procedure with a photocleavable linker, 3-amino-3-(2-nitrophenyl)propionic acid (ANP). The latter was installed on resin, followed by the coupling sequence with four γ-aminobutanoic acids (Abu) as spacers and N-Fmoc-S(Mmt)Cys (Scheme 244). The Ntermini of the linear precursors 1256 were capped with cyanuric chloride to yield 1257. The subsequent removal of the S-Mmt group of the Cys residue and macrocyclization was achieved in a similar manner as in Scheme 141. Arylation of

14. PYRIMIDINES AND PURINES IN MACROCYCLIC PEPTIDE SCAFFOLDS The role of pyrimidines and purines in macrocyclic scaffolds has not been extensively investigated. Wenschuh et al. reported some notable examples in 2001.480 The cyclization procedure of the model peptide (Ala-Phe-Lys) via sequential nucleophilic substitution to 2,4,6-trichloropyrimidine,2,6,8-trichloro-7methylpurine, and 4,6-dichloro-5-nitropyrimidine was studied. The model peptide 1245, attached to a cellulose membrane via a photocleavable linker, was treated with halogenated heterocycles 1246a−c to yield the corresponding N-heterocyclecapped peptides (Scheme 242). The major product of ES


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Scheme 244. Synthesis of Triazine-Linked Macrocycles 1255

Scheme 245. Synthesis of Bicyclic Triazine-Bridged Peptide Macrocycles 1259

Scheme 246. Tetrazine Stapling of Cys Residues in Tripeptides

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oxytocin 1263 from its appropriately protected and resinbound derivative 1264 in good HPLC purity (Scheme 247).486 Later, a facile and rapid phase-transfer protocol for the synthesis of tetrazine-stapled oligopeptides was developed (Scheme 248).487 Oligopeptides 1265 with up to 38 amino acid units and with various spacings of two Cys residues were prepared via the common SPPS protocol and without Sprotection in Cys side chains. Upon the treatment of 1265 with 1261 in biphasic medium CHCl3/NaH2PO4 buffer, macrocycles 1266 were obtained in a short reaction time and in satisfactory to good yield. This protocol allows a variety of (i, i + 3-to-i, i + 28)-spaced cysteines to be linked by the tetrazine ring as well as tolerates a wide range of functionalities and ring topologies in the peptide sequence.

Scheme 247. Synthesis of Tetrazole-Stapled Oxytocin 1263

primary amines with these macrocycles finally yielded compounds 1255 in 77−88% HPLC purity. Later, Lim et al. used the same approach for the synthesis of bicyclic Cys-triazine-bridged scaffolds (Scheme 245).482 It was shown that if two cysteine residues are incorporated in peptide sequence, then the N-terminal dichlorotriazine can react with two thiol functions, forming a new type of rigidified peptide frameworks. Similar to the previous study, peptides of various lengths 1258 were synthesized on a solid support with a photocleavable linker (ANP) using standard Fmoc chemistry in the same manner as in previous schemes. After N-terminus deprotection, the linear peptides were reacted with cyanuric chloride. S(Mmt)-deprotection of cysteine side chains, followed by heating of the resulting compounds in DMF in the presence of DIPEA allowed the cyclization of the desired bicyclic scaffolds, which were finally cleaved form the solid support upon UV irradiation to give series 1259. The cell permeability of these macrocyclic peptidomimetics was later examined.483 It was shown that the cyclic peptides are far more cell-permeable than their linear counterparts, irrespective of their size and the nature of their side chains. This feature, along with the conformational rigidity, the proteolytic stability, and the ease of synthesis, makes triazine-bridged macrocyclic peptides a good platform for the development of novel proteinbinding compounds in a combinatorial fashion.

16. THIAZOLYL PEPTIDES Thiazolyl peptides are a large class of naturally occurring antibiotics produced by various soil and marine prokaryotic organisms. This family of highly modified sulfur-rich macrocyclic peptides shares a series of common motifs that differentiate them from other peptide-derived or azolecontaining natural products. Their most characteristic feature is the central nitrogen-containing six-membered ring, which serves as a scaffold to at least one macrocycle and a side chain, both of which can be decorated with various dehydroamino acids and azoles, such as thiazoles, oxazoles, and thiazolines. The general feature of these compounds is high in vitro activity against Gram-positive bacteria. In addition, many thiopeptides have been found to possess a wide range of biological properties, including anticancer, antiplasmodial, immunosuppressive, and so on. However, these compounds suffer from low aqueous solubility, which limits their use as clinical agents. The generalized representation of thiopeptide structures is given in Figure 88A. Every member of this family possesses at least one macrocycle decorated with various five-membered heterocycles and a six-membered nitrogen cycle that is bound to the side chain to the macrocyclic core. The biosynthetic classification of these compounds is as follows: Type I compounds arise from the genes encoding the indolic acid side ring (marked in purple in Figure 88A), Type II possess those for quinalic acid moiety formation in a differently connected side ring (marked in orange), and Type III contain none of the above, hence being the monomacrocyclic compounds. This classification is useful in genome mining because the specific tailoring genes can help define the structure-predicted thiopeptide before its isolation and characterization. The second criterion for the classification of these compounds arises from the oxidation state of the central sixmembered nitrogen heterocycle (Figure 88B). The “a” series presents a completely reduced central piperidine, whereas the “b” series is further oxidized and contains a 1,2-dehydropiperidine ring. Only one thiopeptide of the “c” series has been

15.2. s-Tetrazine

Tetrazine-containing peptide macrocycles were also investigated. They are interesting as photolabile triggers for peptide dynamics studies. A tetrazine bridge can be installed between two cysteine residues, spaced by one amino acid unit (Scheme 246).484 Various tripeptides, which contain two S-Mmt protected Cys residues 1260, were assembled via the standard Fmoc-SPPS protocol. The selective removal of the S-Mmt groups, followed by treatment with 3,6-dichlorotetrazine 1261 under mildly basic conditions and, finally, resin cleavage of formed macrocycles, furnished tripeptides 1262 in satisfactory overall yield. These tetrazine-derived compounds were shown to be stable under peptide synthesis conditions and were successfully elongated from both N- and C-termini to create large constrained α-helical oligopeptides.485 This protocol was successfully implemented in biochemical studies, for example, for the creation of tetrazine-stapled

Scheme 248. Phase-Transfer Protocol for Synthesis of Tetrazole-Stapled Oligopeptides

EU


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Figure 88. Overview of thiazolyl peptide family: (A) General representation. (B) Classification by the oxidation state of central six-membered ring. (C) Classification by central heteroaromatic scaffold.

isolated to date, and its core moiety is somewhat unexpected because it features a piperidine ring fused with imidazoline. The “d” series is further oxidized and contains a trisubstituted

pyridine ring, which is the landmark of this subgroup, present in the largest number of thiopeptides. The “e” series is even EV


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Figure 89. Structures of saalfelduracin, sch 18640, and thiopeptins A−Ba.

Figure 90. Structures of siomycins, thiopeptins Ab−Bb, and thiostreptons.

Scheme 249. Synthesis of Precursor 1267 of Thiostrepton Dehydropiperidine Core

more oxidized and is easily differentiated by the hydroxyl group in the central pyridine, which is tetrasubstituted. Combining these two criteria to classify all known thiopeptides, one can see several interesting patterns (Figure 88C). All members of series a, b, and c are type II macrocycles and bear a second macrocycle, which contains a quinaldic acid moiety. Compounds of series d are type III thiopeptides, which are monomacrocyclic substances. The e series belongs to type I thiopeptides and bears a second macrocycle formed by a modified 3,4-dimethylindolic acid moiety. In this section, we

discuss the synthetic approaches toward thiopeptides following the increase in the oxidation state of the central azine ring, that is, from series a to c. 16.1. Group 1 (Type II, Series a Compounds)

This subcategory consists of six structurally different compounds: saalfelduracin, sch 18640, and thiopeptins A−Ba (Figure 89). The main 26-membered macrocycle is common for all of these compounds and differs only by the identity of one amide/thioamide bond. The quinaldic-acid-containing 27membered macrocycle can differ by the identity of three out of EW


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Scheme 250. Synthesis of Thiostrepton Dehydropiperidine Core 1278

the identity of two amino acid residues in the side ring, substituent of quinaldic acid, and side-chain sequence. Thiostreptons were discovered by Dutcher et al. in Streptomyces azureus in 1955.493−495 Siomycins were isolated from Streptomyces sioyaensis by Ebata et al. in 1969.496−499 16.2.1. Thiostrepton. The total synthesis of thiostrepton was accomplished by Nicolaou et al. in 2005.500,501 The synthesis of precursor 1267 of the central dehydropiperidine scaffold of thiostrepton is summarized in Scheme 249. Cysderived and Thr-derived amides 1269 and 1271 were transformed to the corresponding thiazoles 1270 and 1272, respectively, via the modified Hantzsch protocol. The subsequent reduction of ester group in 1272 with DIBAL-H afforded aldehyde 1268 in 87% yield. The acidic cleavage of NBoc and acetonide groups in 1270 produced the corresponding amino thiol, which was reacted with 1268 to give thiazolidine 1267 in a 1:1 mixture of diastereomers in 90% combined yield.

four amino acids. The structure of the thiazole carboxamide is varied by appending one or two dehydroalanine units such as amides, methyl esters, or free acids. Thiopeptins were isolated by Miyairi et al. from Streptomyces tateyamensis in 1970.488−490 Compound sch 18640 was isolated by MacFarlane et al. in 1981 from Micromonospora arborensis.491 Saalfelduracin was predicted by genome mining in Amycolatopsis saalfeldensis and isolated by Mitchell et al. in 2018.492 All of these compounds possess strong activity against Gram-positive bacteria (e.g., S. aureus, E. faecium, and E. coli) 16.2. Group 2 (Type II, Series b Compounds)

This subgroup consists of siomycins A−C, thiopeptins A1b− B1b, and thiostreptons A and B (Figure 90). Note that these compounds closely resemble the previous subgroup with the main difference only in the oxidation state of the central sixmembered nitrogen ring. As in the previous case, the members of this subgroup share a common central scaffold and differ by EX


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Scheme 251. Synthesis of Subunit 1282

Scheme 252. Sytnthesis of Thiostrepton Macrocyclic Peptide Sequence 1288

Upon the treatment of thiazolidine 1267 with Ag2CO3 and DBU in pyridine at −12 °C, azadiene 1273 was formed and subsequently dimerized via the hetero-Diels−Alder reaction (TS 1273), affording the intermediate scaffold 1274 as a 1:1

mixture of diastereomers (Scheme 250). Two transformation pathways were possible for the latter. In path A, compound 1274 underwent the addition of nucleophile (compound 1277), followed by the hydrolytic release of the requisite EY


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Scheme 253. Synthesis of Quinaldic-Acid-Containing Side-Ring Sequence 1307

Macrocyclic peptide sequence 1288 was assembled from two precursors: thiazoline subunit 1286 and thiazole subunit 1287 (Scheme 252). The former was constructed from fully protected L-Thr-D-Ser dipeptide 1283, which was converted to the corresponding thioamide, subjected to the removal of the N-Fmoc group, and coupled to the L-Thr derivative 1284, affording tripeptide 1285 in 54% yield over three steps. TES protecting group at the primary hydroxyl group was selectively removed, and the resulting compound was converted to the corresponding thiazoline upon treatment with DAST. The removal of methyl ester with Me3SnOH finally afforded carboxylic acid 1286 in 53% yield over three steps. Compound 1287 was elaborated starting from angelic acid 1289, which was converted to its acid chloride and was used to acylate (−)-menthol, producing angelic acid menthyl ester 1290 in 70% yield over two steps. Sharpless asymmetric dihydroxylation of 1290 (90% yield, 90:10 dr), followed by the acetonide protection of the resulting 1,2-diol afforded compound 1291. The treatment of the latter with DIBAL-H resulted in the cleavage of the chiral auxiliary group formation of primary alcohol 1292 in 90% yield. The oxidation of 1292

primary amine 1278. Path B consisted of an imine-to-enamine rearrangement (1274 to 1275), followed by an aza-Mannich cyclization to give an undesired product 1276. Thus the addition of benzylamine to the reaction mixture was crucial because it allowed the transformation via path A to be accelerated and the formation of product 1276 to be suppressed, which could then be observed in only trace amounts. The combined yield of inseparable diastereomers 1278 and 1278′ was 60% under the optimized conditions. Compound 1268, which is the byproduct of this transformation, could be isolated and recycled, as shown in Scheme 249. Acylation of the primary amine of 1278 (+ 1278′) with 1279, followed by trans-esterification (n-Bu2SnO, MeOH, 75 °C), furnished the mixture of bis-methyl esters 1280 (+ 1280′) in 80% combined yield (Scheme 251). The subsequent reduction of azido groups in the latter produced the amines 1281 and 1281′, which could be chromatographically separated. The requisite compound 1281 was isolated in 44% yield and was transformed to the N-Alloc derivative 1282 in 61% yield. EZ


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Scheme 254. Synthesis of the Main Macrocycle 1312 of Thiostrepton

with DMP, the condensation of the resulting aldehyde with benzylamide, and the subsequent Strecker reaction of the formed imine with TMSCN resulted in the formation of nitrile 1293 in 90% overall yield and >95:5 dr. The hydrogenolytic cleavage of the benzyl group in this compound in the presence of Boc2O produced the corresponding N-Boc derivative, which was transformed to the thioamide 1294 in 68% yield over two steps. The latter was converted to the thiazole trifluoroacetate 1295 via the Hantzsch protocol in 82% overall yield. The treatment of 1295 with NaOMe in MeOH allowed the cleavage of the trifluoroacetate group and the transesterification of the ethyl ester. Finally, the acidic removal of N-Boc and acetonide groups in the resulting compound, followed by TBS protection of the secondary hydroxyl group afforded the desired thiazole 1287 in 80% overall yield. Coupling (EDC, HOBt) of thiazole amine 1287 to thiazoline carboxylic acid 1286, followed by the removal of the methyl ester group in the resulting compound afforded the requisite thiazoline-thiazole subunit 1288. The quinaldic acid fragment 1307 was prepared starting from methyl quinoline-2-carboxylate 1296, which was initially reduced to the pyridine system 1297, in 60% yield (Scheme 253). The subsequent p-substitution in 1297 by acetyl radical afforded methyl ketone 1298 in quantitative yield. Asymmetric reduction of the latter employing chiral ligand 1299 afforded the corresponding secondary alcohol (95% yield, 90% ee) which was then protected as TBS ether 1300. The latter was then converted to 1301 via the three-step Matsumura− Boekelheide sequence in 75% overall yield. The hydroxyl group in 1301 was eliminated upon the treatment with the Burgess reagent, affording compound 1302 in 60% yield. The subsequent asymmetric epoxidation of 1302 mediated by the Katsuki catalyst gave compound 1303 (82% yield, 87:13 dr). Bromination of the latter, followed by HBr elimination

afforded allylic epoxide 1304. Regio- and stereoselective epoxide ring opening in 1304 by the amino group of L-IleOAllyl, followed by TBS protection of the resulting alcohol and the two-step replacement of methyl ester for 9fluorenylmethyl (Fm) ester afforded compound 1305. Cleavage of the allyl group in the latter and coupling (HATU, HOAt) of the resulting acid with dipeptide 1306, followed by a second removal of allyl ester furnished the requisite building block 1307 in 85% yield over three steps. The assembly of the target molecule began with the acidic removal of N-Boc and acetonide protecting groups in 1282, followed by the coupling (HATU, HOAt) of the resulting amino alcohol with thiazole-thiazoline building block 1288, producing compound 1308 in 73% yield over two steps (Scheme 254). The regioselective hydrolysis of methyl ester in 1308 was not fully achieved, and under the best conditions (Me3SnOH, DCE, 50 °C) the latter was converted to an unseparable 2:1 mixture of monoacids (1309 and 1309′, major diastereomer unknown) in 52% combined yield. The reduction of azido groups in this mixture gave the corresponding amino acids, which were subjected to macrolactamization (HATU, HOAt) to afford a single macrocycle 1310 in 32% yield over two steps. After the quantitative hydrolysis of the methyl ester in the latter, the resulting carboxylic acid was coupled (HATU, HOAt) to dipeptide 1311 in 83% yield, and upon the removal of the N-Alloc group, it was converted to compound 1312. For the introduction of the second macrocycle in the target molecule, compound 1312 was coupled (HATU, HOAt) to building block 1307, producing compound 1313 in 68% yield. The removal of Fm ester in 1313, followed by a Yamaguchitype macrolactonization afforded compound 1314 in 42% yield. The subsequent oxidative elimination of all phenylselenyl groups in 1314 allowed installation of the requisite dehydroalanine fragments in compound 1315 in 68% yield. FA


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Scheme 255. Completion of Total Synthesis of Thiostrepton (1316) by Nicolaou et al.

Finally, the treatment of 1315 with HF·Py resulted in the simultaneous removal of all silyl protecting groups as well as an antiperiplanar elimination of the oxygen associated with the TES group, affording the desired Z-trisubstituted double bond in the target compound 1316 (Scheme 255). 16.2.2. Siomycin A. The synthesis of siomycin A was achieved by Mori et al. in 2008.502,503 Although this compound differs from thiostrepton only by the identity of two amino acids, the authors reported a different strategy for the

preparation of its key subunits and their assembly to the target structure. The synthesis of the central dehydropiperidine scaffold 1329 started with diester 1317, which was converted to bisthioamide 1318 in a common four-step procedure in 33% overall yield (Scheme 256). The installation of two thiazole rings via the Hantzsch synthesis, followed by the one-pot chlorination−dehydrochlorination protocol afforded target dehydropyrrolidine 1319 in 58% yield over two steps. Next, FB


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Scheme 256. Assembly of Central Dihydropiperidine Core 1329 of Siomycin

prepared according to Scheme 257. L-Thr was converted in a two-step procedure to its protected form 1330, which was coupled (PyBOP) to β-lactone 1331 to give 1332 in 66% yield. Phenylselenylation of 1332 under optimized conditions afforded dipeptide 1333 in excellent yield. Coupling (DMTMM) between 1333 and D-Ser-OMe, followed by methyl ester hydrolysis afforded tripeptide 1334. The synthesis of dihydroxyisoleucine block 1341 started with the condensation of thiazole aldehyde 1335 with sulfinamide 1336, which quantitatively afforded imine 1337. The latter was converted to 1339 upon the addition of vinylzinc reagent, formed from vinyllithium compound 1338. To introduce the vicinal diol moiety, 1339 was converted to the N-Bocprotected compound 1340, which underwent conventional Sharpless hydroxylation, affording the desired diastereomer in 56% yield. The introduction of TES protecting groups in this diol was accompanied by the cleavage of the N-Boc group, thus

the condensation of 1320 with sulfinamide 1321 provided imine 1322, which was subjected to 1,2-addition with 1319 without purification, affording compound 1323 in 71% overall yield. Acid-promoted desulfinylation of 1323 afforded the equilibrium mixture of 1324 and 1325, which was subjected to reduction with NaBH3CN to afford piperidine 1326 in 52% yield as the only product. The subsequent transformation of 1326 was carried out as follows: ethyl ester groups were converted to the corresponding bis-TMSE esters, oxazolidinone nitrogen was Boc-protected, and the resulting compound was coupled (CIP, HOAt) to N-Bpoc-Ala-OH (1327), affording 1328 in 59% yield over three steps. The selective deprotection of the oxazolidinone and the successive one-pot chlorination−dehydrochlorination of the piperidine ring afforded the desired subunit 1329 in 61% yield over two steps. Subunit 1344, which served as the building block for the construction of the main macrocycle of siomycin A, was FC


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Scheme 257. Synthesis of Precursor 1344

was elaborated from pyridine 1296 over 12 steps and subjected to Yb(OTf)3-assisted epoxide opening with L-Val-OFm, affording 1346 in 48% yield. After silylation of 1346, followed by the removal of tert-butyl ester, compound 1347 was obtained in 76% yield over two steps. Precursors for the dehydroalanine sequences of the second macrocycle of siomycin A and its side chain were elaborated starting from L-Ser-derived lactone 1348. Phenylselenylation of the latter afforded 1349, which was converted to the requisite precursors, as shown in Scheme 259. Ester protection and amino group deprotection in 1349 afforded the corresponding amine, which was condensed (CIP, HOAt) with another equivalent of 1349 to give, after deprotection, dipeptide 1350 in 77% overall yield. In another transformation, acid 1349 was converted to the corresponding N-deprotected amide, followed by coupling (CIP, HOAt) with the second equivalent 1349 and second Boc deprotection to give dipeptide 1351 in 68% overall yield. The assembly of the target compound started with the construction of the side macrocycle (Scheme 260). Coupling (CIP) between 1329 and 1347 afforded 1352 in 67% yield.

Scheme 258. Synthesis of Quinaldic Acid Subunit 1347

producing compound 1341 in 51% yield from alkene 1340. The condensation (CIP, HOAt) of 1335 with 1341 afforded pentapeptide 1342 in 83% yield. The treatment of the latter with DAST gave oxazoline 1343 in 85% yield, which was converted to the corresponding thioamide and subjected to ester hydrolysis, providing the requisite subunit 1344 in 90% yield over two steps. The fragment of quinalinic acid was introduced in the final structure as subunit 1347 (Scheme 258). Compound 1345 FD


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Scheme 259. Synthesis of Precursors 1350 and 1351

Scheme 260. Assembly of Bimacrocyclic Framework 1356 of Siomycin A

the resulting free amine with 1344 produced compound 1356 in 60% yield. The treatment of 1356 with DAST promoted thiazoline ring formation in compound 1357 in 87% yield (Scheme 261). The latter was subjected to the simultaneous deprotection of three kinds of protecting groups (Teoc, acetonide, and TMSE) using ZnCl2·OEt2. The resulting precursor 1358 underwent one-pot macrocyclization and peptide coupling with 1351, affording

The removal of the Fm ester in 1352, followed by coupling (CIP, HOAt) of the resulting carboxylic acid with subunit 1350 afforded compound 1353 in excellent yield. The successive removal of N- and C-terminal protecting groups in 1353, followed by macrolactamization (HATU) of the resulting peptide afforded compound 1355 in 79% yield. The removal of N-Boc group in the latter and coupling (HATU) of FE


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Scheme 261. Completion of Total Synthesis of Siomycin A (1360) by Mori et al.

16.4. Group 4 (Type III, Series d Compounds)

fully assembled scaffold 1359 of siomycin A. The successive removal of silyl protecting groups and the oxidative elimination of selenophenyl moieties in 1359 furnished siomycin A (1360) in 7% yield over a four-step sequence, which consisted of 14 chemical transformations.

This subgroup includes amythiamicins A−D, GE2270 A−T, and thiomuracins A−I (Figure 92). All of these compounds feature a single 30-membered macrocycle. Cores of amythiamicins and GE2270s differ by the identity of the substituents at two out of five thiazole rings (thiazole, methylthiazole, or methoxymethyl thiazole), the presence of the N-methyl group at the Asn subunit, and the identity of one amino acid (valine or phenylserine). Cores of thiomuracins differ by the identities of two amino acids. Side chains of amythiamicins and GE2270s incorporate Ser-Pro dipeptide (except for amythiamicin D) in various transformed variants, as shown in the scheme. The side chain of thiomuracins is dipeptide Dha-Dha. Amythiamicins

16.3. Group 3 (Type II, Series c Compounds)

Sch 40832 is a unique representative of this structural subgroup and series c, in particular (Figure 91). It was isolated from Micromonospora carbonacea by MacFarlane et al. in 1998.504 This compound did not receive significant attention because no synthesis, structure elucidation, or biological activity was reported. FF


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Although the synthesis of thiomuracins was not achieved, it was produced via fermentation and chemically modified to give multiple analogues.512,513 16.4.1. GE2270. The synthesis of GE2270 A was reported in 2007 by Bach et al.514,515 The synthesis started from protected (S)-mandelate 1361, which was reacted with lithiated thiazole derivative 1362 to give the single addition product 1363 in excellent yield (Scheme 262). The stereoselective reduction of ketone moiety in 1363 with L-selectride provided the required threo-diol 1364, which was subsequently converted to 1365 upon the mesylation and the removal of the silyl protecting group. The latter procedure was necessary because the outcome of subsequent mesylate substitution suffered from the steric congestion by the TBS fragment. Thus a sequence of nucleophilic substitution with sodium azide, followed by the reinstallation of the TBS protecting group at the free hydroxyl moiety and the final Staudinger reduction of azido group afforded amino alcohol 1366 in excellent yield over three steps. The latter was coupled (PyBrop) to N-Fmocglycine to give amide 1367 in quantitative yield. Bromide 1367

Figure 91. Structure of Sch 40832.

were isolated from Amycolatopsis sp. by Takeuchi et al. in 1994.505−507 GE2270s were isolated by Selva et al. in 1991− 1995 from Planobispora rosea.508−510 Thiomuracins were isolated by Krastel et al. in 2009 from Nonomuraea sp.511

Figure 92. Structures of amythiamicins, GE2270 A−T, and thiomuracins. FG


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Nicolaou et al. reported the total synthesis of GE2270 A, GE2270 C1, and GE2270 T shortly after their synthesis of thiostrepton A.516 The strategy for the preparation of central pyridine scaffold 1394 was also based on the key hetero-Diels− Alder reaction (Scheme 265). Thiazolidine 1378 was obtained in two steps from L-Cys-derived ester 1385 and L-Ser-derived aldehyde 1386 and converted to azadiene 1388 upon the reaction with Ag2CO3 to give dehydropiperidine 1389 as a 1:1 mixture of diastereomers in 64% yield. The oxidative aromatization of 1389, accompanied by the extrusion of ammonia, afforded pyridine 1390 in moderate yield. The latter was subjected to the acid-mediated removal of acetonide and Boc protecting groups and coupled to carboxylic acid 1391, affording compound 1392 in 85% yield over two steps. The peptide bond in 1392 was converted to a thioamide bond in a three-step sequence, affording compound 1393 in 60% yield. Finally, the sequence of dehydrocyclization and aromatization afforded the requisite subunit 1394 in 69% yield over two steps. An improved and shorter route to compound 1394 was also reported (Scheme 266). It started with phenylalanine derivative 1391, which was converted to thioamide 1395 and condensed with bromoketone 1396, affording the requisite bisthiazole 1397 in 82% yield. The latter was converted to the corresponding aldehyde and reacted with 1398, affording thiazolidine 1399 in 78% yield. The latter was converted to azadiene 1400, which underwent Diels−Alder dimerization, affording 1401 as a 1:1 mixture of diastereomers. Notably, comparing substrates 1388 and 1400, the increase in molecular complexity did not hamper the outcome of Diels−Alder reaction. Finally, deamination−aromatization of 1401 afforded the desired pyridine 1394 in 33% yield. Bis-thiazole peptides 1404 and 1405 were prepared by coupling between acid 1402 and the N-deprotected versions of compounds 598b and 1403, respectively. Thus the removal of Boc groups in the latter, followed by the HATU-mediated peptide synthesis of resulting amines with 1402 and the final saponification of resulting peptide esters furnished the desired subunits 1404 and 1405 in 76 and 80% overall yield, respectively (Scheme 267). The assembly of GE2270 C1 is shown in Scheme 268. The removal of the N-Boc group in 1394, followed by the peptide

was converted into the corresponding stannane by a Pdcatalyzed stannylation−debromination with hexamethylditin and directly introduced to Stille cross-coupling with dibromide 1368, producing compound 1369 in 80% overall yield. The stannylation−debromination reaction was repeated under similar conditions on this substrate, followed by the removal of the N-Fmoc protecting group to afford subunit 1370 in 64% yield over two steps. Compound 1371 was easily accessed via the common alkylation of the Tr-protected version of N-Boc-thiazole 468, followed by the cleavage of the trityl group. Asn-derived thiazole 1373 was obtained in two steps from orthogonally protected Asp-thiazole 1372 upon the cleavage of tert-butyl ester, followed by the coupling (CIP) of the resulting carboxylic acid with methylamine. The successive saponification of methyl ester in 1373 and the coupling with fragment 1371 uneventfully afforded bis-thiazole compound 1374. The removal of the N-Boc protecting group and the coupling (EDC, HOBt) of the resulting amine with 2-iodothiazole-4carboxylic acid 1375 afforded subunit 1376 in excellent yield. The trisubstituted pyridine topology was introduced in subunit 1376 by coupling of the latter with the organozinc reagent 1377 (obtained via the metalation of 2,6-dibromo-3iodopyridine), affording compound 1378 in 87% yield. A second coupling was carried out between 1378 and zinc reagent 1379, affording 1380 in significantly lower yield. Peptide coupling between subunit 1370 and carboxylic acid obtained from the saponification of ester 1380 furnished the fully assembled macrocyclization precursor 1381 (Scheme 263). The key macrocyclization of 1381 was carried out via intramolecular Pd-catalyzed cross-coupling, affording compound 1382 in 75% yield (Scheme 264). The hydrolysis of tert-butyl ester in the latter compound, followed by the coupling (TOTU) of the resulting acid with Ser-Pro-NH2 provided precursor 1383 in 65% yield over two steps. Finally, the DAST-mediated formation of the oxazoline ring in the side chain of 1383, followed by the cleavage of the silyl ether from the phenylserine unit of the macrocycle afforded GE2270 A (1384) in 55% yield over the last two steps and in 4.8% overall yield. FH


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Scheme 263. Synthesis of Macrocyclization Precursor 1381 of GE2270 A

coupling (HATU) of the resulting amine with N-Boc-glycine afforded compound 1406 in excellent yield. The same two-step procedure was carried out between 1406 and subunit 1404, producing macrocyclization precursor 1407. The successive removal of C- and N-terminal protecting groups in this compound, followed by one-pot macrolactamization and coupling to Ser-OMe furnished compound 1409 in 35% yield over these three steps. Dehydrocyclization of serine side chain in 1409 allowed the installation of an oxazoline ring in compound 1410 in 74% yield. Finally, the successive cleavage of methyl ester in the latter compound, followed by the coupling (HATU) of the resulting amine with prolinamide and the removal of the silyl protecting group in the phenylserine unit of the macrocycle furnished target molecule 1412 in 41% yield over three steps. The assembly of the macrocyclic core of GE2270 A (1384) and GE2270 T (1418) consisted of the following steps. The removal of the N-Boc protecting group in 1406, followed by

peptide synthesis (HATU) between the resulting free amine and acid 1405 afforded the fully protected macrocyclization precursor 1413. Saponification of both methyl ester groups with excess Me3SnOH gave the corresponding diacid 1414. The latter was subjected to the removal of the N-Boc group, followed by one-pot macrocyclization (HATU) and coupling of L-Ser-OMe, affording macrocyclic core 1415 of both natural products in 33% yield over three steps (Scheme 269). The successive cyclodehydration of 1415 with DAST, followed by the removal of the silyl protecting group afforded compound 1416 in 80% yield over two steps. For the synthesis of GE2270A (1384), the latter intermediate was subjected to saponification and coupling (HATU) with L-Pro-NH2, affording the desired compound in 60% yield. For the completion of the synthesis of GE2270T (1418), the oxazoline ring in 1416 was subjected to aromatization with BrCCl3, affording the oxazole fragment in compound 1417. Methyl ester in the latter was saponified and coupled (HATU) to LFI


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Scheme 264. Completion of Total Synthesis of GE2270 A (1384) by Bach et al.

diastereomers. Finally, the oxidative aromatization of 1428 gave tristhiazolylpyridine 1429 in 36% yield. Tripeptide 1430, required for the construction of the amythiamicins macrocyclic core, was derived from the previously discussed compound 1404 by coupling (HATU) of the latter with methyl glycinate, followed by ester saponification in 54% overall yield (Scheme 273). The assembly of target structures began with the removal of the N-Boc protecting group in the Val subunit of compound 1429, followed by the coupling (HATU) of the resulting amine with carboxylic acid 1430 to give the macrocyclization precursor 1431 in 60% yield over two steps. The successive removal of C- and N-terminal protecting groups in this compound, followed by one-pot macrocyclization and coupling to Ser-Pro-NH2 delivered amythiamicin B (1432) in 25% yield over three steps. The treatment of the latter compound with DAST allowed the installation of the exocyclic thiazoline unit, thus furnishing amythiamicin A (1433) in 70% yield. The acidcatalyzed rearrangement of the thiazoline-prolinamide moiety to the Ser-Pro diketopiperazine allowed the conversion of 1433 to amythiamicin C (1434) in 60% yield (Scheme 274). Moody et al. reported the total synthesis of amythiamicin D.524 Their approach also included the construction of a central pyridine scaffold via the hetero-Diels−Alder reaction; however, it was not employed in dimerization. Instead, this reaction was conducted between a different diene 1439 and dienophile 1436 (Scheme 275). Compound 1436 was prepared starting from ethyl serinate, which was converted to thiazole ketone 1435 in 55% yield via a common procedure, employing the condensation with pyruvic aldehyde, followed by the oxidation of the resulting thiazoline with MnO2. A twostep Me to Bn ester replacement in 1435, followed by the

Pro-NH2, furnishing the target molecule in 50% overall yield from 1416 (Scheme 270). Given its poor pharmacokinetic profile (mainly due to low solubility), multiple analogues of GE2270A were prepared by LaMarche et al. via the modification of the side chain.517−519 The most potent analogue LFF571 (1423) was reported in 2012 and was synthesized as shown in Scheme 271.520 The acid-mediated rearrangement of the oxazolidine-proline fragment in 1384 afforded Ser-Pro diketopiperazine ester in 1419. This compound was subjected to basic hydrolysis to give the corresponding acid, which was, in turn, converted to acylazide 1420. The latter was immediately subjected to the Curtius rearrangement in the presence of methyl trans-4-hydroxycyclohexane carboxylate 1421 to give the corresponding urethane in 48% yield from ester 1419. Amide nitrogen in the latter was alkylated with methyl 5-bromovalerate (1422) in good yield, and the resulting diester was subjected to saponification, affording 1423 in 13% overall yield from the parent GE2270A. This compound is currently under clinical trials for the treatment of Clostridium dif f icile intestinal infections in humans.521,522 16.4.2. Amythiamicins. The synthesis of amythiamicins A, B, and C was reported by Nicolaou et al. in 2008.523 The strategy for the preparation of these molecules does not significantly differ from that of GE2270s. The preparation of the central pyridine scaffold 12 is depicted in Scheme 272. The condensation of bromoketone 1390 with thioamide 1424 gave bis-thiazole 1425 in 78% yield. The latter was reduced to the corresponding aldehyde and subjected to a second condensation with Cys-derived thiazole 1426. The treatment of the resulting thiazolidine 1427 with Ag2CO3 afforded dehydropiperidine 1428 in 51% yield as a 1:1 mixture of FJ


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Scheme 265. Synthesis of Pyridine Core 1394 of GE2270s

afforded the “right half” portion 1441 of amythiamicin D. Hydrogenolysis of benzyl ester in this compound, followed by a second coupling (PyBOP) of the resulting free acid with bisthiazole peptide 1442 afforded the fully assembled macrocyclization precursor 1443. After the simultaneous removal of Boc and tert-butyl protecting groups in 1443, the resulting compound was subjected to macrolactamization (DPPA) to furnish the desired amythiamicin D (1444) in 73% yield over two steps. Bach et al. reported a different approach toward amythiamicins C and D in 2010.525 In this approach, bisthiazole peptide 1445 was deprotected at the N-terminus and

conversion of ketone moiety into the oxime and its subsequent reduction, afforded N-acetyl enamine 1436 in 50% yield over four steps. The 2-azadiene component 1439 was constructed from the Ser-derived thiazole 1438 and bis-thiazole 1425. The latter was converted to the corresponding amide and then reacted with triethyloxonium hexafluorophosphate to give imidate 1437 in almost quantitative yield over two steps. The reaction of this compound with 1438 furnished the requisite diene 1439 in 63% yield. Microwave-assisted heating of subunits 1436 and 1439 afforded pyridine 1440 in 33% yield (Scheme 276). The deprotection of N-Boc in this compound, followed by coupling (PyBOP) of the resulting free amine with N-Boc-glycine FK


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Scheme 266. Improved Synthetic Route toward 1394

Scheme 267. Synthesis of Subunits 1404 and 1405

coupled (EDC) to 2-iodo thiazole-4-carboxylic acid 1375 to give tripeptide 1446 in 64% yield (Scheme 277). Bromination of aminopyridine 1447 with NBS, followed by Sandmeyer iodination delivered 3-iodopyridine 1448 in 41% yield over two steps. The reductive metalation of 1448 afforded its iodozincated derivative, which subsequently

underwent Negishi cross-coupling with iodide 1446, affording subunit 1449 in 79% yield for the cross-coupling procedure. The remaining building block 1454 was constructed starting from dibromothiazole 1368. The latter was converted to the corresponding Grignard reagent, which was then allowed to react with imine 1450, affording compound 1451 in 72% yield FL


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Scheme 268. Completion of Total Synthesis of GE2270 C1 (1412) by Nicolaou et al.

subunit 1454 to give the macrocyclization precursor 1457 in 65% yield. The macrocyclic core of amytiamicin C was formed by subjecting 1457 to an intramolecular Stille cross-coupling and the subsequent hydrolysis of tert-butyl ester in the exocyclic thiazole carboxylate, followed by the attachment of diketopiperazine 1458 to the free acid, affording amythiamicin C (1434) in 20% yield over three steps. For the preparation of amythiamicin D (1444), the ester group in pyridine 1449 was saponified, and the resulting acid was coupled (DPPA) to subunit 1454, affording compound 1459. The subsequent Stille cross-coupling afforded the fully assembled macrocyclic core 1460 of amythiamicin D, albeit in low yield. Finally, the cross-coupling between 1460 and zinc derivative 1461 afforded target compound 1444 in 43% yield. This strategy was later used by Bach et al. for the construction of synthetic analogues of amythiamicin D.526

and >95:5 dr. After the acid-mediated cleavage of the sulfinyl amide fragment in 1451 and coupling (PyBroP) of the resulting amine to N-Fmoc-glycine, dipeptide 1452 was afforded in 84% yield. Next, Pd-catalyzed stannylationdebromination of 1452, followed by Stille cross-coupling of the resulting stannane with dibromide 1368 afforded bisthiazole 1453 in 87% yield. A second stannyl-debromination protocol conducted with this substrate, followed by the removal of the N-Fmoc group furnished subunit 1454 in 85% yield over two steps (Scheme 278). The assembly of amythiamicins C (1434) and D (1444) is shown in Scheme 279. For the synthesis of 1444, pyridine subunit 1449 was subjected to Negishi cross-coupling with 1455, followed by saponification of ethyl ester in the Valthiazole fragment to produce compound 1456 in 47% yield over two steps. This acid was coupled (DPPA) to bis-thiazole FM


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Scheme 269. Synthesis of Macrocyclic Core 1415 of GE2270 A and GE2270 T

family.532−535 Compounds YM-266184 were the first thiopeptides obtained from a marine source. They were isolated from the marine sponge Halichondria japonica.536 16.5.1. Micrococcin P1. Since the discovery of micrococcin P1 (often abbreviated as MP1), the challenge of the elucidation of its actual structure remained unresolved for over 60 years.537 Several structures of this compound were proposed during this time, and only in 2009 did Ciufolini and Lefranc reveal the structure of this natural product by its total synthesis.538 Precursors of macrocyclic core of MP1 were prepared as shown in Scheme 282. Known thiazole amide 1459 was transformed to the corresponding bis-thiazole using the modified Hantzsch procedure with ethyl bromopyruvate, followed by the removal of the acetate protecting group and the oxidation of free alcohol with PCC. Compound 1460 was obtained in 41% yield over these four steps and was further elaborated to enone 1461 via the Grignard addition of vinylmagnesium bromide and the oxidation of the resulting alcohol with MnO2.539 Precursor 1465 was obtained starting from threonine derivative 1462, which was uneventfully elaborated to thiazole 1463 via the modified Hantzsch protocol in excellent yield over four steps. Ester moiety in 1463 was alkylated with compound 1454, affording bisthiazole ketone 1465. The macrocyclic sequence 1469 of MP1 was constructed starting from thiazole 1463. The latter was subjected to the removal of the oxazolidine protecting group in threonine motif and the subsequent saponification to give compound 1466. The latter was coupled (DCC, HOBt) to Val-thiazole 597b to give the corresponding dipeptide, which was subjected to the

Different amino-acid-derived thiazoles were converted to sulfonamides 1462a−c and further elaborated to subunits 1465b−c in the same manner as discussed for structure 1454 (Scheme 280). These building blocks were combined with subunit 1456 (Scheme 281) to give macrocyclization precursors 1466a−c, which were elaborated to amythiamicin D C2-modified analogues 1468a−c in a similar fashion as the total synthesis of the parent compound. Compound 1468a showed enhanced potency in EF-Tu inhibition relative to amythiamicin D, whereas 1468b and 1468c were inactive. This is one of very few reports devoted to the synthesis of thiopeptide analogues bearing modifications in the macrocyclic core. 16.5. Group 5 (Type III, Series d Compounds)

This structural subgroup includes micrococcins P1 and P2, nocardithiocin, QN3323 A−Y, thiocillins I−IV, YM-26683, and YM-26684 (Figure 93). All of these compounds share a common 26-membered macrocyclic core, which differs by the identity of three amino acid residues. The exocyclic side chain in these compounds is rather common and differs by the oxidation state of the hydroxyl group in the terminal amide residue. Micrococcin was the first thiopeptide ever discovered. It was isolated in 1948 by Su from Micrococcus sp.527 Nocardithiocin was isolated in 2009 by Mukai et al. from Nocardia pseudobrasiliensis.528 Compounds QN3323 A−Y were isolated in 2002 by Kamigiri et al. from Bacillus sp.529 Thiocillins were isolated from Bacillus cereus by Shoji et al. in 1976.530,531 Numerous works on the manipulation of thiocillin biosynthesis gathered significant attention for this particular compound FN


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Scheme 270. Completion of Total Synthesis of GE2270 A (1384) and GE2270 T (1418) by Nicolaou et al.

removal of the N-Boc protecting group, thus producing 1467. This compound underwent a second coupling (DCC) to threonine derivative 1468, affording the corresponding tripeptide, in which unmasked threonine fragment was dehydrated to the requisite Z-alkene. Finally, the simultaneous cleavage of oxazolidine and the Boc protecting group in the Nterminal threonine furnished compound 1469. The addition of ketone 1465 to enone 1461 afforded diketone 1470 in almost quantitative yield. This compound was converted to the requisite pyridine 1471 upon dihydropyridine ring closure with NH4OAc, followed by aromatization with DDQ in excellent overall yield (Scheme 283). Ester saponification in 1471, followed by the installation of the N-Boc protecting group and the coupling (BOP-Cl) with amide 1472 afforded compound 1473 in 77% yield over three steps. This compound was converted to the fully assembled northern hemisphere 1474 of MP1 upon the dehydration of the threonine residue and the two-step conversion of TBS-protected primary alcohol to the aldehyde group. The latter was further oxidized to give the corresponding acid, which was coupled (BOP-Cl) to subunit 1469, affording the macrocyclization precursor 1475 in 59% yield over two steps. Saponification of ester functionalities in

this compound, followed by the acidic removal of protecting groups at the N-terminal threonine residue afforded the deprotected peptide, which was treated with DPPA to give target compound 1476 in 41% yield from 82. 16.5.2. Thiocillin I. The synthesis of thiocillin I was reported by Ciufolini and Aulakh in 2011.540 This compound differs from micrococcin P1 by the identity of one amino acid subunit, hydroxyvaline over valine, in the macrocyclic core. Thus the macrocyclic sequence of thiocillin I was introduced in the final structure as subunit 1482, which was elaborated from the known alcohol 1477 (Scheme 284). This compound was oxidized to the corresponding aldehyde and upon condensation with methyl cysteinate and oxidative aromatization with MnO2 was converted to thiazole 1478. The removal of the NBoc group in 1478, followed by the coupling (EDCl, HOBt) of the resulting free amine to Thr-thiazole 1479 afforded dipeptide 1480 in 65% yield. This compound was elaborated to segment 1482 in the same manner as compound 1467 was transformed to 1469. In this work, the authors employed an improved method for the construction of pyridine core 1484, which is common for micrococcins and thiocillins (Scheme 285). Previously described aldehyde 1460 was alkylated with ethynylmagnesium FO


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Scheme 271. Synthesis of LFF571 (1423)

Scheme 272. Synthesis of Central Pyridine Core 1429 of Amythiamicins

bromide and oxidized to ynone 1483. This compound was subjected to Bohlmann−Rahtz pyridine synthesis with previously described 1465 to give the desired scaffold 1484, in which primary alcohol was concomitantly desilylated and acylated under the reaction conditions. After the reinstallation of TBS protecting group, this compound was transformed to

thiocillin I (1486) using the same chemistry as described for micrococcin P1. In 2019, Walczak et al. reported another approach for the preparation of micrococcin P1 and thiocillin I.541 Their approach featured a novel mild method for the Mo(VI)catalyzed cyclodehydration of Cys residues in the later stages FP


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cyclodehydrated with MoO2(acac)2 to give the corresponding thiazolines, which were subsequently aromatized with DBU to produce thiazoles 1501a and 1501b in excellent yield over two steps. The removal of N-Boc groups in these compounds and the coupling of resulting free amines with acid 1499′ afforded tripeptides 1502a and 1502b, which were deprotected to furnish requisite subunits 1503a and 1503b. Coupling (HATU) of free amines 1503a,b with subunit 1497 produced peptides 1504a and 1504b in 82 and 58% yield, respectively. The final steps of the synthesis were carried out as outlined in Scheme 288. i-Pr esters in 1504a and 1504b were removed, and side-chain precursor of the target molecules was introduced by coupling of the resulting acids with dipeptide 1505. The elimination of the Thr hydroxyl group completed the assembly of side-chain structure. The simultaneous acid-mediated deprotection of all alcohol, amine, and carboxylic acid protective groups, followed by macrocyclization (PyAOP) of the resulting amino acid intermediate converted 1504a into micrococcin P1 (1476) and compound 1504b into 1506, the TBS-protected version of thiocillin I (1486). The removal of the TBS protecting group in 1506 furnished 1486 in 15% yield from 1504b.


of synthesis as well as an alternative method for the construction of a central pyridine core. The pyridine core was introduced in the structure of target compounds with subunit 1497 (Scheme 286). The synthesis of this structure started with the fusion of thiazole 1488 and bromide 1487 via Pd-catalyzed C−H activation, followed by transesterification of the resulting compound to produce 1489 in 73% yield. The latter was selectively chlorinated to give chloride 1490. The removal of tert-butyl ester in this compound, followed by coupling (HATU) to Cys-thiazole 1491 afforded amide 1492. The removal of the rityl group, followed by MoO2(acac)2catalyzed cyclodehydration and oxidation produced 1493 in 86% yield. The subsequent Stille cross-coupling between 1493 and 1494 followed by bromination afforded bromoketone 1495. Finally, this compound was subjected to Hantzsch synthesis with thioamide 1496 to give, after saponification, the desired scaffold 1497. Macrocyclic sequences 1503a and 1503b of MP1 and thiocillin, respectively, were elaborated starting from known thiazole 1272 (Scheme 287). A two-step procedure of N-Boc deprotection and coupling of the free amine with protected threonine derivative 1497 afforded dipeptide 1498, which was subjected to stereoselective dehydration to install the Z-alkene fragment in place of the threonine residue in compound 1499. Two-step ester saponification in the latter compound afforded free acid 1499′. Next, dipeptides 1500a and 1500b were


This structural group includes compounds GE37468 A−C and baringolin (Figure 94). These four compounds share a common 29-membered ring, which differs only by the substituents in the proline residue. The GE37468 cluster was discovered by Walsh and Young in 2011 in the Streptomyces genus.542 Baringolin was isolated from Kocuria sp. by BioMar SA in 2012. An identical compound, named kocurin, was isolated by Reyes et al. from Kocuria palustris in 2013.543 The synthesis of baringolin analogues was reported.544 16.6.1. Baringolin. The total synthesis of baringolin was achieved by Just-Baringo et al. in 2013.545 The central pyridine core 1514 was constructed starting from 2,6-dichloro-nicotinic

Scheme 274. Completion of Total Synthesis of Amythiamicins A−C by Nicolaou et al.

FQ


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Scheme 275. Synthesis of Dienophile 1436 and Diene 1439

Scheme 276. Completion of Total Synthesis of Amythiamicin D (1444) by Moody et al.

was coupled (PyBOP) to Thr-OBn to give the corresponding amide, in which Thr hydroxyl was oxidized to ketone and the resulting compound was cyclized to oxazole in structure 1509. Stille cross-coupling between 1509 and stannyl derivative 1510 afforded compound 1511 in excellent yield. The methoxy group in the latter was converted to the corresponding triflate 1512 in a three-step sequence, and this compound was finally subjected to Negishi cross-coupling with zinc bromide 1513 to furnish the target subunit 1514 in quantitative yield. Pentapeptide 1515, which served as the precursor of the side chain of baringolin, was prepared using the conventional


acid 1507, which was initially converted into 2-chloro-6methoxynicotinic acid 1508 (Scheme 289). This compound FR


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Scheme 278. Synthesis of Building Blocks 1449 and 1454

Fmoc-SPPS procedure. Thiazoline 1517 was prepared via common chemistry from the protected Phe-Cys dipeptide 1516 upon dehydrocyclization with Ph3PO/Tf2O system and the subsequent saponification of methyl ester (Scheme 290). The assembly of the target compound consisted of sequence stepwise deprotection−couplings (EDC, HOAt) of 1514 with Asn-derived thiazole 1518, N-Fmoc-tyrosine, and thiazoline 1517, which rendered the macrocyclization precursor 1521 in 36% yield over six steps (Scheme 291). The simultaneous catalytic removal of all allyl groups in 1521 and the treatment of the resulting deprotected peptide with EDC/HOAt system afforded the fully assembled macrocyclic core 1522 of baringolin in 20% yield over two steps. The hydrolysis of ethyl ester in the latter compound, followed by the coupling (EDC, HOAt) with side-chain precursor 1515 produced compound 1523 in excellent yield. Finally, the oxidative elimination of all selenophenyl fragments in 1523 furnished the target compound 1524 in 66% yield.

Methylsulfomycin was isolated by Vijaya Kumar et al. in 1999.561 Radamycin was isolated by Holgado et al. in 2002.562 16.8.1. Promothiocin. The synthesis of promothiocin A was reported by Moody et al. in 2000.563,564 The synthesis of the central pyridine core started with N-Boc-alaninamide, which underwent the Rh-catalyzed N−H insertion of methyl diazoacetoacetate 385, affording ketoamide 1525 in 80% yield (Scheme 292). Cyclodehydration of this compound produced oxazole 1526 in good yield. 1526 was then hydrolyzed to the corresponding acid and converted to ketoester 1527 via mixedanhydride formation and the reaction with magnesium ethyl malonate. The reaction of 1527 with ammonium acetate produced enamine 1528 in 85% yield. This compound underwent the Bohlmann−Rathz reaction with ynone 1529, producing the pyridine ring in compound 1530 in good yield. The latter was converted to 2-oxazolyl-3-thiazolylpyridine 1531 via the four-step modified Hantzsch protocol, with ethyl bromopyruvate in 33% overall yield. The authors described two approaches for the macrocycle of promothiocin A, which used two different peptide subunits 1534 and 1535 (Scheme 293). Both compounds were elaborated from methyloxazole 1532, which was coupled to N-Boc-valine via the mixed-anhydride method, affording dipeptide 1533 in 87% yield. The removal of the N-Boc protecting group in this compound afforded subunit 1534. In another route, ester saponification in 1533, followed by the coupling of the resulting acid with Ala-thiazole 597a and the removal of the N-Boc protecting group afforded subunit 1535 in 78% yield over three steps. The saponification of ethyl ester in pyridine scaffold 1531 and the coupling of the resulting acid with subunits 1534 or 1535 via the mixed-anhydride method afforded compounds 1536 (45% yield) and 1537 (65% yield), respectively. Ethyl ester in compound 1537 was converted to Pfp-activated ester, and upon the removal of the N-Boc group the resulting compound was macrocyclized to give the desired scaffold 1538 in 54% yield over these four steps. Compound 1536 was subjected to the removal of the N-Boc group and underwent additional coupling with Ala-thiazole 598a, producing macrocyclization precursor 1539. The latter was elaborated to 1538


Compounds of this subgroup feature a 35-membered macrocycle tailored with different heteroarenes, such as thiazole, oxhazole, and methyloxazole (Figure 95). Cluster A10255 was isolated from Streptomyces gardneri by Boeck et al. in 1992.546,547 Thioactin, thioxamycin, thiotipin, and geninthiocin were all isolated from Streptomyces sp. by Yun et al. in 1994.548−550 Antibiotic TP-1161 was isolated by Engelhardt et al. in 2010 from Nocardiopsis sp.551 Promoinducin was isolated by Seto et al. in 1995 from Streptomyces sp.552 Sulfomycins were isolated from Streptomyces viridochromogenes by Egawa et al. in 1969.553,554 Berninamycin was isolated by Liesch et al. from Streptomyces bernensis in 1976.555−558 So far, none of these compounds has been synthesized. 16.8. Group 8 (Type III, Series d Compounds)

Compounds with this topology of a central pyridine scaffold exist as 26- or 36-membered macrocycles (Figure 96). Promothiocins were isolated by Yun et al. from Streptomyces sp. in 1994.559 Their derivatives, JBIR-83 and -84, were isolated from the same bacteria by Takagi et al. in 2010.560 FS


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Scheme 279. Completion of Total Synthesis of Amythiamicins C and D by Bach et al.

NH2 to give compound 1539 in 11% yield over four steps. Finally, the removal of the TBS protecting group from the Ser residue and the subsequent dehydration afforded target compound 1540 in 32% yield over the two last steps.

in the same manner as compound 1537 in 65% yield over four steps (Scheme 294). As the complete macrocyclic core of promothiocin A was assembled, the remaining task was to attach the side-chain sequence to the pyridine ring (Scheme 295). The cleavage of the benzyl ether was shown to be difficult, as the best 39% yield was achieved by the treatment of 1538 with the BCl3· Me2S complex, which allowed the corresponding carbinol to be produced. The latter underwent the two-step oxidation to the corresponding acid, which was finally coupled to L-(OTBS)Ser-


Compounds incorporating this type of central pyridine scaffold exist as unique structures without a traceable pattern (Figure 97). Globimycin is a 35-membered macrocycle isolated by Kaweewan et al. from Streptomyces globisporus in 2018.565 FT


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Scheme 280. Synthesis of Subunits 1465a−c

Scheme 281. Synthesis of Amythiamicin D Analogues 1468a−c

synthesis of compounds with improved properties, was reported.572−579 Antibiotic S54832 A−I and related compounds were isolated from Micromonospora globose by KelerJuslen et al. in 1984.580 Thiazomycins were isolated by Singh et al. in 2009 from Amycolatopsis fastidiosa.581 Nosiheptide was isolated in 1980 by Benazet et al. from Streptomyces actuosus.582 Philipimycin was isolated by Zhang et al. from Actinoplanes philippinensis in 2008.583 16.10.1. Nosiheptide. The synthesis of nosiheptide was reported by Arndt et al. in 2016.584 Pyridine core 1552 of this natural product was constructed starting from bromothiazole 1541 (Scheme 296).585,586 Coupling of the latter with 3-butyn2-ol under Sonogashira conditions, followed by the oxidation of the hydroxyl group afforded ynone 1542 in 90% yield over two steps. The hetero-Diels−Alder reaction between 1542 and azadiene 1543 afforded tetrasubstituted pyridine 1544 in 55%

Lactazoles are 32-membered macrocycles, which were predicted by genome mining and isolated by Hayashi et al. in 2014.566 Cyclothiazomycins were discovered by several groups between 1991 and 2006.567,568 16.10. Group 10 (Type I, Series e Compounds)

Compounds of this group feature a common tricyclic scaffold composed of the main 26-membered macrocycle and the 19membered Type I macrocycle, which is additionally constrained with an oxymethylene bridge (except for nosiheptide and philipimycin, Figure 98). Glycothiohexide alpha was isolated by Northcote et al. from Sebekia sp. in 1994.569 Antibiotics MJ347-81F4 A and B were isolated by Sasaki et al. from Amycolatopsis sp. in 1998.570 Nocathicacins were isolated by Li et al. from Nocardia sp. in 2003.571 Recently, the structural modification of nocathiacins, leading to the semiFU


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Figure 93. Structures of thiazolyl peptides of group 5.

group cleavage afforded compound 1559. This acid was coupled (PyAOP) to 1560 and transformed into thiazole 1561 via Staudinger ring closure and thiazoline oxidation in 86% yield over three steps. The conversion of the Boc group in 1561 into a silyl carbamate, followed by coupling (HATU, HOAt) with N-Fmoc-protected dipeptide 1562 and the final removal of the N-Fmoc protecting group furnished subunit 1563 in 67% yield over three steps. Coupling (PyDOP) between subunits 1563 and 1552 afforded scaffold 1564 in excellent yield (Scheme 298). The simultaneous Pd-catalyzed Alloc and allyl deprotection of 1564 and the subsequent macrocyclization (HATU) produced compound 1565 in 89% yield over two steps. The removal of S-trityl and O-Dpm groups in 1565, followed by macrothiolactonization (PyAOP) allowed the installation of the Type I side ring in compound 1566. TIPS ether in this scaffold was selectively removed, and deprotected serine fragment was dehydrated to give the protected version 1567 of nosiheptide in 35% yield over two steps. Finally, the successive desilylation and the HOBt-mediated removal of Ts group in 1567 rendered target compound 1568 in 36% yield over the last two steps.

yield. The hydroxyl group in this compound was capped with triflate, and the ketone fragment was converted to silylenol ether, producing compound 1545 in 79% yield over two steps. The latter was transformed to the corresponding bromoketone and was subjected to Hantzsch thiazole synthesis with thioamide 1546, producing compound 1547 in 58% yield over three steps. The removal of triflate from the latter compound and the selective hydrolysis of ester group at pyridine ring produced acid 1548 in excellent yield over two steps. The cleavage of thioaminal in 1548, followed by the installation of STr and NHAlloc protecting groups afforded compound 1549. This hydroxy acid was coupled to dipeptide 1550 upon the activation with phosgene. The subsequent thiazoline ring closure and its oxidation to thiazole afforded 1551 in 46% yield over four steps. The protection of the hydroxy group of pyridine and the saponification of methyl ester in 1551 furnished the requisite subunit 1552. A fragment of indolyl acid was introduced in the structure of the target molecule with subunit 1563 (Scheme 297). 3-Nitro2-methyl benzyl alcohol 1553 was O-THP-protected, acylated with diethyl oxalate, and converted to nitroarylenone 1555 upon treatment with Eschenmoser’s salt (1554). The reductive cyclization of this compound afforded indole 1556. The THP protecting group was removed from this compound, and the ethyl ester was exchanged for a Dpm group, producing compound 1557 in 56% yield over three steps. The latter was alkylated with TCE-protected lactam 1558 and upon TCE FV


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Scheme 282. Synthesis of Building Blocks 1461, 1465, and 1469

17. MACROCYCLES WITH MULTIPLE DIFFERENT HETEROARENES

was isolated in 2002 from marine sponge Leucetta microraphis by Kehraus et al.597 This compound demonstrated modest cytotoxicity against several tumor cell lines. The synthesis of leucamide A was reported by Nan et al. in 2003.598 Venturamides A and B were isolated from Oscillatoria sp. by Gerwick et al. in 2007.599 These compounds displayed potent activity against Plasmodium falciparum with IC50 = 8.2 and 5.6 μM, respectively. The total synthesis of both natural products was achieved in 2018 by Du et al.600 Nostocyclamide was isolated by Todorova et al. from Nostoc sp. in 1995.601 This compound demonstrated strong growth inhibition toward various cyanobacteria, being most active against Anabaena P-9 with LC50 = 0.1 μM. The total synthesis of nostocyclamide was achieved by Moody and Bagley in 1998.602 Raocyclamides were isolated from Oscillatoria raoi by Admi et al. in 1996.603 Raocyclamide A demonstrated moderate cytotoxic activity against sea urchin embryos. The total synthesis of both natural compounds was reported by Pattenden et al. in 1998.604

17.1. Macrocycles Related to Bistratamides and Lissoclinamides

The compounds shown in Figure 99 are topologically related to all-thiazole-containing bistratamides (section 9.1.7) and lissoclinamides (section 9.1.22). The syntheses of these compounds follow the same general strategy as those for the above-mentioned classes: Both linear (preparation of peptide precursor, followed by macrolactamization) and convergent (preparation of two subunits, followed by two successive peptide couplings) approaches were reported. Tenuecyclamides A−D were isolated from cyanobacterium Nostoc spongiaeforme in 1998 by Carmeli et al.587 Teunecyclamide A demonstrated cytotoxic activity against sea urchin embryos with ED100 = 10.8 μM. Two strategies for the total synthesis of these compounds as well as their diastereomers were reported.588,589 Dolastatin E and I were isolated between 1995 and 1997 by Yamada et al. from sea sponge Dolabella auricularia.590,591 Dolastatin I demonstrated cytotoxicity against HeLa cells with IC50 = 12 μM. Syntheses of both compounds were reported.592,593 Dendroamides A−C were isolated from Stigonema dendroideum by Ogino et al. in 1996.594 Dendroamide A was shown to reverse the drug resistance in breast cancer cells. Two approaches for the total synthesis of this compound were reported.595,596 Leucamide A

17.2. Macrocycles Related to Telomestatin and Marthiapeptide A

Compounds shown in Figure 100 are structurally related to alloxazole-containing telomestatin (compound 368, section 8.1.5) and all-thiazole-containing marthiapeptide A (compound 926, section 9.1.24). The synthesis of these compounds follows a similar strategy as that for the preparation of 368 or 926. Urukthapelstatin was isolated by Matsuo et al. from FW


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Scheme 283. Completion of Total Synthesis of Micrococcin P1 (1476) by Ciufolini et al.


Mechercharimyces asporophorigenens in 2007.605 Mechercharmycin A (also called mechercharstatin or IB-01211) was isolated by Kanoh et al. from Thermoactinomyces sp. in 2005.606 YM-216391 was isolated by Sohda et al. in 2005 from Streptomyces nobilis.607,608 Despite the fact that these compounds are produced by different species, they share a common structural motif, and all show high cytotoxic activity against various cancer cell lines. Total syntheses of

urukthapelstatin A and mechercharmycin were elaborated.609−611 17.3. Celogentin C and Moroidin

The first total synthesis of celogentin C was achieved by Castle et al. in 2009.612,613 The synthesis of the indole-containing portion of this compound (146) is discussed in section 3.3. Thus tert-butyl ester in 146 was removed, and the resulting compound 146a was coupled to Pro-OBn to give hexapeptide FX


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Scheme 285. Completion of Total Synthesis of Thiocillin I (1486) by Ciufolini et al.

1569. Under optimized conditions, this compound underwent oxidative coupling of fully protected Arg-His dipeptide, furnishing an indole-imidazole linkage in compound 1570. Finally, macrolactamization between Arg and Pro subunits in

1570, followed by the removal of the Pbf protecting group furnished celogentin C (1571) in 73% yield over two steps (Scheme 299). Approaches toward this compound by Chen and Jia utilize the same late-stage strategy and differ in the methods of the construction of precursor 146.87,88 Importantly, moroidin could not be accessed via this strategy.87 Several attempts for the construction of target compound 1575 were made, starting from compound 136 (Scheme 300). In the first pathway, methyl ester in 136 was changed to benzyl ester in a two-step sequence, followed by the oxidative coupling of the resulting compounds with fully protected Arg-Gly-His tripeptide. Thus structure 1572 was obtained in 61% yield over three steps. However, the final sequence of the hydrogenolytic removal of N- and C-terminal protecting groups, followed by macrolactamization (HATU) did not yield the desired product. In the second pathway, 136 was converted to precursor 1573 via oxidative coupling with

Figure 94. Structures of GE37468 A−C and baringolin. FY


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Scheme 286. Synthesis of Central Pyridine Scaffold 1497

Scheme 287. Synthesis of Macrocyclic Sequences (1503a,b) of MP1 and Thiocillin I

FZ


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Scheme 288. Completion of Total Synthesis of MP1 and Thiocillin I by Walczak et al.

Scheme 289. Synthesis of Central Pyridine Core 1514 of Baringolin

GA


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Scheme 290. Synthesis of Building Blocks 1515 and 1517

Scheme 291. Completion of Total Synthesis of Baringolin (1524) by Just-Baringo et al.

GB


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GC


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Scheme 292. Synthesis of Central Pyridine Core 1531 of Promothiocin A

Scheme 293. Synthesis of Subunits 1534 and 1535

GD


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Scheme 294. Synthesis of Macrocyclic Core 1538 of Promothiocin A

Scheme 295. Completion of Total Synthesis of Promothiocin A (1540) by Moody et al.

GE


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Figure 97. Structures of cyclothiazomycins, globimycin, and lactazoles

Scheme 296. Synthesis of Central Hydroxypyridine Core 1552 of Nosiheptide

GF


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18. CONCLUSIONS The goal of this Review has been to summarize original contributions that illuminate the role of heteroaryls as structural constituents of macrocycles. Over the years, synthetic chemists have managed to extract many lessons from natural products. One of these lessons is that heteroaryl motifs provide attractive features to macrocycles. As more and more researchers in both academia and industry realize that the relatively high content of amino acid residues in cyclic peptides prevents them from becoming a widely used therapeutic modality, efforts to reduce the amino acid content of macrocycles are expected to continue. Concerning the

fully protected dipeptide Gly-His, followed by the saponification of methyl ester and peptide coupling (HBTU, HOBt) to Arg(Pbf)-OMe. Compound 1573 was obtained in 27% yield over this three-step sequence. The removal of the protecting groups at Arg and Gly residues and the macrolactamization (HATU, HOBt) also failed. In the third pathway, compound 136 was oxidatively coupled to protected histidine, followed by peptide coupling to H-Arg(Pbf)-Gly-OMe, affording precursor 1574 in 57% yield. Again, the successive removal of C- and Nterminal protecting groups in this compound, followed by macrolactamization between His and Gly subunits did not yield the desired compound 1575. GG


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Scheme 298. Completion of Total Synthesis of Nosiheptide (1568) by Arndt et al.

GH


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Figure 99. Structures of macrocycles related to bistratamide, dolastatin, and lissoclinamides.

Scheme 299. Completion of Total Synthesis of Celogentin C (1571) by Castle et al.

GI


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Figure 100. Structures of compounds related to telomestatin and marthiapeptide A.

Scheme 300. Synthetic Attempts toward Moroidin (1575)

GJ


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synthesis of heteroaryl-containing macrocycles, the chemoselectivity of bond-forming reactions needs to be improved. It is also significant to have more synthetic options to modify the backbones of existing cyclic peptides such that chemists could site-selectively incorporate heteroaryl groups into desired locations. The synthesis community knows relatively little about the metabolic fate of macrocycles that contain heteroaryls, which represents another area that stands to improve. Another component that needs attention is the relationship between the electronic properties of a given heteroaryl ring and the overall macrocyclic conformation. This knowledge is expected to empower studies to improve the cellular permeability of macrocycles. In closing, it is clear that this area of research will continue to thrive in the years to come as more advanced synthetic technologies are adopted by practitioners of the field.

Foundation in 2005, and Moscow State University Awards in 2006, 2007, and 2008.

ACKNOWLEDGMENTS We acknowledge the support of the RFBR (grant no. 18-5334002) and the Program of Leading Scientific Schools (grant no. 4687.2018.3). REFERENCES (1) Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Delivery Rev. 1997, 23, 3−25. (2) Lipinski, C. A. Drug-like properties and the causes of poor solubility and poor permeability. J. Pharmacol. Toxicol. Methods 2000, 44, 235−249. (3) Veber, D. F.; Johnson, S. R.; Cheng, H. Y.; Smith, B. R.; Ward, K. W.; Kopple, K. D. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem. 2002, 45, 2615− 2623. (4) Haines, D. J.; Swan, C. H.; Green, J. R.; Woodley, J. F. Mucosal peptide hydrolase and brush-border marker enzyme activities in three regions of the small intestine of rats with experimental uraemia. Clin. Sci. 1990, 79, 663−668. (5) Woodley, J. F. Enzymatic barriers for GI peptide and protein delivery. Crit. Rev. Ther. Drug Carrier Syst. 1994, 11, 61−95. (6) Lin, J. H. Pharmacokinetics of biotech drugs: peptides, proteins and monoclonal antibodies. Curr. Drug Metab. 2009, 10, 661−691. (7) Rezai, T.; Yu, B.; Millhauser, G. L.; Jacobson, M. P.; Lokey, R. S. Testing the Conformational Hypothesis of Passive Membrane Permeability Using Synthetic Cyclic Peptide Diastereomers. J. Am. Chem. Soc. 2006, 128, 2510−2511. (8) Rezai, T.; Bock, J. E.; Zhou, M. V.; Kalyanaraman, C.; Lokey, R. S.; Jacobson, M. P. Conformational Flexibility, Internal Hydrogen Bonding, and Passive Membrane Permeability: Successful in Silico Prediction of the Relative Permeabilities of Cyclic Peptides. J. Am. Chem. Soc. 2006, 128, 14073−14080. (9) Bockus, A. T.; McEwen, C. M.; Lokey, R. S. Form and Function in Cyclic Peptide Natural Products: A Pharmacokinetic Perspective. Curr. Top. Med. Chem. 2013, 13, 821−836. (10) Webster, A. M.; Cobb, S. L. Recent Advances in the Synthesis of Peptoid Macrocycles. Chem. - Eur. J. 2018, 24, 7560−7573. (11) Wu, J.; Tang, J.; Chen, H.; He, Y.; Wang, H.; Yao, H. Recent developments in peptide macrocyclization. Tetrahedron Lett. 2018, 59, 325−333. (12) Zaretsky, S.; Yudin, A. K. Recent advances in the synthesis of cyclic pseudopeptides. Drug Discovery Today: Technol. 2017, 26, 3− 10. (13) Soor, H. S.; Appavoo, S. D.; Yudin, A. K. Heterocycles: Versatile control elements in bioactive macrocycles. Bioorg. Med. Chem. 2018, 26, 2774−2779. (14) Kaldas, S. J.; Yudin, A. K. Achieving Skeletal Diversity in Peptide Macrocycles through The Use of Heterocyclic Grafts. Chem. Eur. J. 2018, 24, 7074−7082. (15) Appavoo, S. D.; Kaji, T.; Frost, J. R.; Scully, C. C. G.; Yudin, A. K. Development of Endocyclic Control Elements for Peptide Macrocycles. J. Am. Chem. Soc. 2018, 140, 8763−8770. (16) Nielsen, D. S.; Shepherd, N. E.; Xu, W.; Lucke, A. J.; Stoermer, M. J.; Fairlie, D. P. Orally Absorbed Cyclic Peptides. Chem. Rev. 2017, 117, 8094−8128. (17) Herrmann, J.; Fayad, A. A.; Müller, R. Natural products from myxobacteria: novel metabolites and bioactivities. Nat. Prod. Rep. 2017, 34, 135−160. (18) Gogineni, V.; Hamann, M. T. Marine natural product peptides with therapeutic potential: Chemistry, biosynthesis, and pharmacology. Biochim. Biophys. Acta, Gen. Subj. 2018, 1862, 81−196. (19) Jin, Z. Muscarine, imidazole, oxazole and thiazole alkaloids. Nat. Prod. Rep. 2016, 33, 1268−1317.

AUTHOR INFORMATION Corresponding Authors

*E-mail: [email protected] (A.K.Y.). *E-mail: [email protected] (V.G.N.) ORCID

Andrei K. Yudin: 0000-0003-3170-9103 Valentine G. Nenajdenko: 0000-0001-9162-5169 Notes

The authors declare no competing financial interest. Biographies Ivan Smolyar graduated from Moscow State University in 2018. He was a student in the laboratory of V. G. Nenajdenko since 2013. His diploma work was connected to triazole-containing macrocyclic peptidomimetics. Andrei K. Yudin received his undergraduate degree at Moscow State University in 1992. He subsequently worked in the laboratories of G. K. S. Prakash and the Nobel Laureate George A. Olah at USC, where he obtained his Ph.D. in 1996. In 1998, following postdoctoral training in the laboratory of the Nobel Laureate K. Barry Sharpless at the Scripps Research Institute, Professor Yudin started his independent career at the University of Toronto. He became an Associate Professor in 2002, which was followed by a promotion to the rank of a Full Professor in 2007. In addition to his University of Toronto appointment, Professor Yudin is an Associate Editor for Chemical Science. His research addresses the fundamental challenges of synthetic organic chemistry. Valentine G. Nenajdenko graduated from Moscow State University (Lomonosov) in 1991. He received his Ph.D. degree under the supervision of Professor E. S. Balenkova in 1994, researching the synthesis and application of unsaturated CF3 ketones. In 2000, he received his Dr. of Chemistry degree involving the chemistry of sulfonium and iminium salts. In 2003, he became a full Professor of Organic Chemistry at the Department of Chemistry of Moscow State University. Since 2014, he has been the Head of Organic Chemistry of Moscow State University. He has been a supervisor of 15 postgraduate studies. Prof. Nenajdenko is the head of the Scientific Committee and Jury of the International Mendeleev Chemistry Olympiad. He was the winner of the Academiae Europeae Award in 1997, the Russian President Award in 1996, the Prize for the best scientific work at the Department of Chemistry of Moscow State University in 2001 and 2007, the Shuvalov Award in 2001, the Russian President Award in 2004, the Russian Science Support GK


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