Comprehensive Structure–Activity Relationship Studies of Macrocyclic

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Comprehensive Structure−Activity Relationship Studies of Macrocyclic Natural Products Enabled by Their Total Syntheses Hiroaki Itoh† and Masayuki Inoue*,† †

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Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan ABSTRACT: Macrocyclic natural products have been recognized and utilized as new platforms for designing drugs in pharmaceutical research because the constrained threedimensional shapes and the large surface areas of these complex structures enable selective binding to conventionally undruggable targets. Since natural products are not necessarily ideal for medicinal use, structural optimization is required to obtain superior drug candidates. However, the modifications to macrocyclic natural products that will afford the best pharmacological characteristics cannot be known a priori. Therefore, this optimization procedure requires the exploration of a vast array of natural product analogues to identify new compounds with more desirable properties. To fully explore the chemical space around complex macrocyclic natural products, the construction of a large number of analogues is required. In this review, we provide an overview of the efficient synthetic construction of the analogues of macrocyclic natural products and the evaluation of their biological activities. The examples of the comprehensive structure−activity relationship (SAR) studies depicted herein led to the discoveries of biologically useful analogues. These studies illustrate the importance of designing building blocks and coupling strategies to synthesize a variety of natural product based analogues.

CONTENTS 1. Introduction 1.1. Macrocyclic Natural Products 1.2. Methods for the Generation of Diverse Natural Product Based Macrocycles 1.2.1. Engineering Biosynthetic Gene Clusters 1.2.2. Semisynthetic Derivatization 1.2.3. Diverted Total Synthesis 1.3. Construction and Screening of a Synthetic Library of Macrocyclic Natural Product Analogues Based on Total Synthesis 1.4. Scope of this Review 2. Polymyxin 2.1. Background of Polymyxin 2.2. Cooper’s Synthetic Approach and SAR Study 3. Lysocin E 3.1. Background of Lysocin E 3.2. Inoue’s Synthetic Approach and SAR Study 4. Largazole 4.1. Background of Largazole 4.2. Williams’ Synthetic Approach and SAR Study 5. Vancomycin 5.1. Background of Vancomycin 5.2. Boger’s Synthetic Approach and SAR Study 6. Nannocystin Ax 6.1. Background of Nannocystin Ax 6.2. Fü rstner’s Synthetic Approach and SAR Study 7. Jasplakinolide 7.1. Background of Jasplakinolide

7.2. Arndt and Waldmann’s Synthetic Approach and SAR Study 8. Epothilone 8.1. Background of Epothilone 8.2. Danishefsky’s Synthetic Approach and SAR Study 8.3. Nicolaou’s Synthetic Approach and SAR Study 9. Bryostatin 9.1. Background of Bryostatin 9.2. Wender’s Synthetic Approach and SAR Study 9.3. Keck’s Synthetic Approach and SAR Study 10. Halichondrin 10.1. Background of Halichondrin 10.2. Kishi’s Synthetic Approach and SAR Study 11. Macrolide Antibiotics 11.1. Background of Macrolide Antibiotics 11.2. Myers’ Synthetic Approach and SAR Study 12. Conclusion Author Information Corresponding Author ORCID Notes Biographies Acknowledgments References

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Special Issue: Macrocycles Received: January 23, 2019

© XXXX American Chemical Society

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DOI: 10.1021/acs.chemrev.9b00063 Chem. Rev. XXXX, XXX, XXX−XXX

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1. INTRODUCTION 1.1. Macrocyclic Natural Products

Natural products are an invaluable source of bioactive compounds.1,2 These secondary metabolites are produced by a wide variety of organisms and have been optimized for interactions with biological macromolecules through evolutionary selection.3,4 This intrinsic biological relevance makes natural products promising scaffolds for the development of new drug candidates. In fact, structurally diverse natural products, including steroids, sugars, vitamins, and macrocycles, have been utilized as pharmaceuticals over the years. Macrocycles, cyclic structures containing a 12-membered or larger ring,5 are important members of natural products. In recent drug discovery studies, macrocyclic natural products have been regarded as new platforms for accessing undruggable targets6−11 because they possess properties that small or linear molecules cannot achieve. Namely, their constrained cyclic structure can serve as a preorganized ligand for target binding, thereby increasing the binding affinity through entropy− enthalpy compensation. In addition, the high molecular weight of macrocycles is expected to make them more suitable than small molecules for complexation to the large surface area of target proteins.12 These properties make them potentially useful as new pharmaceuticals of difficult and conventionally undruggable targets.

Figure 1. Classification of methods for the construction of diverse natural product-based macrocyclic compounds.

producer can allow the biosynthetic preparation of structurally altered analogues of the original macrocycles. In recent reports, modifications of the NRPS-PKS gene clusters successfully generated analogues of peptides, polyketides, and peptide− polyketide hybrids.22,23 Although great progress has been made in the reprogramming of natural biosynthetic pathways, access to the modified analogues with advantageous properties may be limited by the substrate specificity of the engineered NRPSs and PKSs. 1.2.2. Semisynthetic Derivatization. Chemical derivatizations of naturally occurring macrocyclic compounds have also provided a wide variety of analogues of macrocyclic natural products (e.g., amphotericin B,24 bafilomycin A1,25 and rapamycin26). When the parent macrocycles can be easily accessed in large quantities, semisynthetic approaches have been among the most effective methods for practically generating natural product like structures for drug discovery studies.27 Several medicines utilized in clinical practices have been elaborated by using this strategy. For example, ivermectin, a medication used to treat various types of parasites, is semisynthesized from avermectin, which was isolated from Streptomyces avermitilis.28 In this approach, peripheral substructures of the macrocycles are commonly derivatized by chemoselective reactions or degradations. Enzymatic modifications are also used to selectively alter the pendant structures on the parent natural products. However, structural modifications to the core of the molecule by semisynthetic strategies are generally difficult. 1.2.3. Diverted Total Synthesis. A diverted total synthesis was conceptualized three decades ago and has been used to construct a focused library consisting of the target macrocyclic natural product and its analogues.29−36 The term “diverted total synthesis” refers to diversification of advanced synthetic intermediates into artificial analogues by exploiting the synthetic route to the natural product (Figure 2). The application of this concept allows the introduction of structural variations to the core of the target macrocyclic natural product, thereby leading to a collection of de novo analogues that retain the structural complexity of the parent natural product. Unlike the semisynthetic approach, the core substructures within the macrocycle can be changed in a diverted total synthesis because all the structural motifs, including the backbone, are chemically constructed. As a result, the synthesized compounds can have greater structural diversity in comparison to what is available via the biosynthetic or semisynthetic approaches. In principle, the structural diversity of the synthesized compounds depends on the number of steps in the sequences after the branching point in the course of the synthesis.37 Hence, selecting a less advanced intermediate as the

1.2. Methods for the Generation of Diverse Natural Product Based Macrocycles

Although natural products have been historically regarded as excellent starting points for drug discovery, their physicochemical properties are not necessarily ideal. Therefore, the original natural products can be viewed as biologically relevant privileged templates, and they can be chemically modified to develop clinically useful pharmaceuticals. In fact, the chemical space around natural products has been demonstrated to contain a higher number of pharmaceutical compounds than are found in the general chemical space.13 To efficiently explore such chemical space, the generation of their analogues is of great importance. The construction and biological assessment of natural product analogues provides a great opportunity to discover first-in-class and best-in-class molecules with ideal biological activities and pharmacokinetic properties.14−18 In the diversification of the natural products, the structural factors necessary to achieve the ideal molecular properties for use as drug leads cannot be known a priori. Accordingly, a wide variety of natural product analogues must be prepared to identify the most desirable compounds. In general, architectural complexity and the large size of the parent natural products significantly increase the difficulty of both biological and chemical preparation of analogues. To take full advantage of the potential of structurally complex macrocyclic natural products as pharmaceuticals, a highly efficient strategy for constructing and screening diverse macrocyclic architectures must be devised for drug discovery. Ongoing research efforts have provided several chemical and biological methods for preparing such analogues. Here, three different methods are illustrated (Figure 1). By using these strategies, various natural product analogues can be prepared for biological evaluation. 1.2.1. Engineering Biosynthetic Gene Clusters. Nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs) are enzymes involved in the biosynthesis of macrocyclic nonribosomal peptides and polyketides, respectively.19−21 Engineering their gene clusters in the biological B

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Figure 3. Schematic diagram of the modular synthesis of macrocycles for obtaining a wide variety of structures. An example of a synthesis using five building blocks each with n variations is shown.

biological evaluations, high overall yields to the target structures are also essential. Although fulfilling all of these requirements is synthetically challenging, deep-seated structural variations enabled by diverted total synthesis provide a unique opportunity for uncovering unknown biologically important structural factors and for modulating potent biological activities. 1.4. Scope of this Review

This review focuses on comprehensive structure−activity relationship (SAR) studies of macrocyclic natural products based on total synthesis. Here, a comprehensive SAR is defined as the synthesis and evaluation of 10 or more analogues of a parent macrocyclic natural product. In addition, strategies for structural diversification of the core macrocycles are considered in this paper. Thus, derivatizations of only the pendant substructures of macrocycles, which can also be achieved by semisynthesis, are beyond the scope of this review. Although numerous examples meet these criteria (Figure 4),39−48 10 structurally distinct compounds (1, 3, 8, 9, 14−16, 18, 19, and 21) have been selected as representative examples on the basis of the class of compounds to which the natural product belongs and the synthetic strategies employed. All the natural products in sections 2−11 are macrocycles with rings having 14 or more members. The comprehensive SAR studies on peptidic (sections 2−5), peptide−polyketide hybrid (sections 6 and 7), and polyketide natural products (sections 8−11) will be discussed. An overview of these state-of-the-art synthetic strategies for elaborating structurally complex macrocyclic natural products to access a large number of analogues and assess their biological activities may illustrate the great potential of this class of natural products and their artificial analogues as drug leads. Moreover, several successful examples, such as macrocyclic natural product analogues that are now used as pharmaceuticals, will guide future studies on the development of synthetic macrocycle-based drug leads.

Figure 2. Schematic diagram of the concept of the diverted total synthesis of a macrocyclic natural product to access its analogues.

branch point results in a more diverse library of synthesized compounds. 1.3. Construction and Screening of a Synthetic Library of Macrocyclic Natural Product Analogues Based on Total Synthesis

An assembly of multiple building blocks would be an excellent strategy to efficiently obtain a large number of natural product based macrocycles by a diverted total synthesis (Figure 3). Convergent and linear syntheses can be used for the assembly. Switching these building blocks with other fragments would readily afford diverse analogues while the same (or similar) conditions are used. For example, five building blocks each with n variations will give n5 different structures. To efficiently construct analogues of macrocycles, one needs to judiciously select the synthetic intermediates, including the building blocks, as well as the chemical transformations, including the coupling, macrocyclization,38 and functional group manipulation reactions. The artificial analogues should be accessed with minimum perturbation of the original synthetic route to the parent natural product, even when structurally different intermediates are used. Otherwise, each transformation must be optimized for each analogue, which severely lowers the overall efficiency of the analogue generation. Furthermore, to provide sufficient amounts of the final products for conducting

2. POLYMYXIN 2.1. Background of Polymyxin

Polymyxins, lipophilic peptides with antibiotic activities produced by Paenibacillus polymyxa,49 were independently reported by two groups (Figure 5).50,51 Polymyxin B (1) and polymyxin E (22, also known as colistin) vary at residue 6 (DPhe-6 for 1 and D-Leu-6 for 22) and show potent antimicrobial activities against a wide range of bacterial strains, including Gram-negative bacteria such as multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii. Since most new C

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Figure 4. Structures of macrocyclic natural products 1−21 that have been the subject of comprehensive structure−activity relationship studies.

been limited due to their high nephrotoxicity and neurotoxicity.52−54 The mechanism of action of polymyxins against Gramnegative bacteria is believed to involve initial binding to a lipid A (23a, Figure 5) component of the lipopolysaccharide (LPS) in the outer membrane and the subsequent disruption of the outer

antimicrobial agents in clinical trials are only active against Gram-positive bacterial infections, the clinical importance of polymyxin and its derivatives for treating infectious diseases caused by drug-resistant Gram-negative pathogens is increasing. However, the utilization of polymyxins in clinical practice has D

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Figure 5. Structures of polymyxins B (1) and E (colistin, 22), their biological target lipid A (23a), and derivatives of lipid A (23b,c) produced by polymyxin-resistant E. coli. The residues diversified by Cooper et al. are indicated in pink.

and inner membranes.55 The details of the mechanism of LPS recognition for polymyxins remain unclear.56,57 Recently, an infection caused by polymyxin-resistant Gram-negative P. aeruginosa and A. baumannii was reported. There are no effective methods for treating polymyxin-resistant infectious diseases. In such resistant bacteria, the negatively charged phosphate group of 23a is modified to positively charged 4amino-4-deoxy-L-arabinose and phosphoethanolamine to afford 23b,c.58−60 These molecular mechanisms of resistance are likely to originate from decreased electrostatic interactions between the cationic polymyxins with the less anionic 23b,c in comparison to 23a. In the current situation, the development of new polymyxin analogues that have both low nephro- and neurotoxicities and high antibacterial activity against polymyxinresistant Gram-negative bacteria has been demanded.

protecting group strategy is required. To utilize Fmoc-based peptide elongation, the side-chain amines of L-Dab-1, -3, -5, -8, and -9 were protected with acid-labile Boc groups. For the macrocyclization, the side-chain Cγ-amine of L-Dab-4 and Cαcarboxylic acid of L-Thr-10 were protected by alloc and allyl groups, respectively. The representative synthesis of N-terminus analogue 29 is shown in Figure 6. The stepwise chain elongation from DHP HM resin linked threonine 24 using piperidine for Fmoc removal and O-(6-chloro-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HCTU) as a condensing agent66 delivered resin-bound octapeptide 25. Pd(0)mediated removal of the alloc and allyl groups 67 and diphenylphosphoryl azide (DPPA)68 mediated macrocyclization of 26 afforded the 22-membered macrocycle 27. Condensation of the branched exocyclic chain was carried out by attaching three Fmoc-protected amino acids to 27, which gave rise to 28. Finally, acylation of the N-terminal amine and simultaneous global deprotection and release of the peptide from the resin by using TFA furnished biphenyl analogue 29. A total of 32 analogues of polymyxin were successfully synthesized using the same method, demonstrating the high generality of this solid-phase approach. Antibacterial assays against 12 pathogenic strains, including polymyxin-resistant bacteria, uncovered the SAR of polymyxin (Figure 7). The hydrophobicities of the N-terminal acyl chain, D-Phe-6, and L-Leu-7 are important for exerting potent antimicrobial activity. The substitution of these moieties with more hydrophobic substructures improved the activity against polymyxin-resistant strains. In fact, biphenyl analogue 29 exhibited 4- and 8-fold more potent antibacterial activities in comparison to 1 against polymyxin-resistant strains P. aeruginosa

2.2. Cooper’s Synthetic Approach and SAR Study

While syntheses and evaluations of polymyxins and their analogues have been reported by several research groups,61−63 Cooper et al. reported the synthesis and screening of 32 polymyxin analogues through a full solid-phase synthetic route.64 To decipher the SAR of polymyxins, most of the structures were designed to be diversified. As a result, L-Dab-1, LThr-2, L-Dab-3, L-Dab-5, D-Phe-6/D-Leu-6, L-Leu-7, L-Dab-8, LDab-9, and the hydrophobic acyl chain were selected as the sites of structural diversification (Figure 5). In Cooper’s synthesis, the Cβ-hydroxy group of L-Thr-10 was linked with a dihydropyran hydroxymethyl derived resin (DHP HM resin) for anchoring to the solid support (Figure 6).65 To construct the polymyxin structure, which consists of a 23membered macrocycle and an exocyclic tripeptide chain, by a full solid-phase synthesis, a three dimensionally orthogonal E

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Figure 6. Synthesis of biphenyl analogue of polymyxin 29 by Cooper et al. Abbreviations: Boc = tert-butoxycarbonyl; DPPA = diphenylphosphoryl azide; Fmoc = 9-fluorenylmethoxycarbonyl; HCTU = O-(6-chloro-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate; t-Bu = tert-butyl; TFA = trifluoroacetic acid.

Figure 7. Summary of SAR study of polymyxins by Cooper et al. Abbreviations: CC50 = 50% cytotoxic concentration; LDH = lactate dehydrogenase; MIC = minimum inhibitory concentration.

FADDI-PA070 (MIC = 8 μg/mL) and A. baumannii clinical isolate Ptyela 100734512:2 (MIC = 8 μg/mL), respectively. Intriguingly, lactate dehydrogenase (LDH) release of 29 from primary kidney cells was found to be suppressed in comparison to that of parent 1 (CC50 = 23 μg/mL for 1 and >128 μg/mL for 29). Since this LDH release assay has been reported as a model for predicting nephrotoxicity,69 29 is potentially a favorable candidate with attenuated nephrotoxicity and improved antibacterial activity in comparison to parent 1. The cationic

nature of Dab is required for the recognition of polymyxins by LPS. The relative significance of each of the four Dab residues was also clarified by the SAR data. L-Dab-5 and L-Dab-9 were of great importance for the antimicrobial activity of polymyxin, whereas L-Dab-3 and L-Dab-8 were found to be less important. The antimicrobial activity of polymyxin was retained upon substitution of L-Dab-3 with Gly and Ser. Moreover, L-Dab-8 can be substituted with a variety of side chains, such as those with basic, neutral, and zwitterionic functionalities. Mechanistically, F

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Figure 8. Structures of lysocin E (3) and its biological target menaquinone. The residues diversified in Inoue’s SAR study are indicated in pink. Abbreviation: Kd = dissociation constant.

groups of menaquinone or the polar head groups of the phospholipids, and aromatic−aromatic interaction between the phenyl ring of N-Me-D-Phe-5 or the indole ring of D-Trp-10 and the naphthoquinone moiety of menaquinone. The possible substructures and residues of 3 participating in the interactions with menaquinone on the basis of this hypothesis were derivatized to reveal the structural features within 3 that are important for the menaquinone-dependent membrane disruption. To synthesize and evaluate a wide variety of analogues of 3, robust synthetic methods had to be established. The total synthesis of 3 was accomplished by Inoue et al. in 2015 (Figure 9).74 The macrocycle bearing several nonproteinogenic amino acids was constructed by a full solid-phase synthesis. In this synthesis, the side chain of L-Glu-8 was tethered to Wang resin75 as a solid support. All the chain elongation and macrocyclization steps were carried out on the resin by utilizing a threedimensional orthogonal protecting group strategy. After the synthesis of precursor macrocycle 32, the C-terminal allyl group was selectively removed by Pd(PPh3)4. Subsequent condensation with 1H-benzotriazol-1-yloxy-tri(pyrrolidino)phosphonium hexafluorophosphate (PyBOP)76 afforded the resin-bound macrocycle. Finally, treatment of the resin with TFA gave 3. Structurally related macrocyclic peptides 34 and 42−44 were also synthesized in their resin-free form following the total synthesis of 3. The obtained macrocycles were further derivatized. To diversify the carboxylic acid of L-Glu-8, this group was condensed with benzyl amine 35 and Boc-polyethylene glycolamine 36 in the presence of PyBOP, giving rise to the corresponding amide analogues. The side-chain amines of 34 were diversified by 37, 38, and Ac2O, generating the dimethyl guanidine analogue, citrulline analogue, and acetyl amide analogue, respectively. N-terminal hydrophobic acyl group analogues were prepared from the common precursor 42 by condensation with the corresponding carboxylic acids using isobutyl chloroformate (IBCF) to activate the carboxylic acids. Alternatively, precursors 43 and 44 were amidated using carboxylic acid 51 to produce aromatic ring analogues. The biological functions of all the analogues were assessed by antimicrobial activity assays and membrane disruption assays using liposomes (Figure 10). The results indicated that the

L-Dab-3 and L-Dab-8 could be far from the molecular surface, and they might not interact with LPS due to the unfavorable orientation of these side chains for recognition, or they might participate in intramolecular interactions, such as hydrogen bonding. These results of the comprehensive SAR analysis should guide the development of promising polymyxin analogues that have potent activities against multidrug-resistant bacteria as well as reduced toxicities.

3. LYSOCIN E 3.1. Background of Lysocin E

Lysocin E (3, Figure 8) is a cyclic depsipeptide isolated from the culture supernatant of Lysobacter sp.70 Compound 3, a 37membered macrocycle, exerts potent antimicrobial activities against Gram-positive bacteria, including methicillin-resistant S. aureus (MRSA). Moreover, 3 exhibited a high therapeutic effect (0.5 mg/kg) in a MRSA-infected mouse model, and it was more potent than vancomycin (15, 5.8 mg/kg). These antibacterial activities of 3 make it highly promising for the treatment of widespread nosocomial MRSA infections, which are a major concern in clinical practice. A detailed biological analysis to reveal its biological target demonstrated that 3 can recognize menaquinone (Figure 8),71,72 which is a coenzyme in bacterial respiratory chains. Isothermal titration calorimetry (ITC) experiments revealed that 3 forms a 1:1 complex with menaquinone-4 (30) with a dissociation constant (Kd) of 4.5 μM. The complexation of 3 with menaquinone in a bacterial membrane is believed to disrupt the integrity of the bacterial membrane, leading to rapid bacteriolysis. 3.2. Inoue’s Synthetic Approach and SAR Study

To investigate the details of the mechanism of 3-induced membrane disruption, structural diversification and biological evaluations of 3 were conducted (Figure 8).73 Considering the substructures and their possible modes of interaction, the complexation of 3 with menaquinone may be caused by hydrophobic interactions between the hydrophobic acyl chains of L-Thr-1 and the prenyl chain of menaquinone, electrostatic/ hydrogen bond interactions between the basic groups of D-Arg-2 and D-Arg-7 or the carboxylic acid of L-Glu-8 and the carbonyl G

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Figure 9. Total synthesis of 3 and its analogues by Inoue et al. Abbreviations: IBCF = isobutyl chloroformate; Pbf = 2,2,4,6,7pentamethyldihydrobenzofuran-5-sulfonyl; PyBOP = 1H-benzotriazol-1-yloxy-tri(pyrrolidino)phosphonium hexafluorophosphate; TBS = tertbutyldimethylsilyl; Tr = triphenylmethyl.

clearer picture of the mode of action of parent compound 3. This new hypothetical mechanism of action provides valuable information for designing more active and selective antibiotics based on the lysocin structure.

carboxylic acid of L-Glu-8 is not important for the activity. In contrast, the hydrophobic acyl chain of L-Thr-1, the basic residues such as guanidines, and the aromatic rings of N-Me-DPhe-5 and D-Trp-10 have significant effects on the activity. Most remarkably, changing D-Trp-10 to D-Ala-10 caused a complete loss of activity, suggesting that the electron-rich indole ring of DTrp-10 and the electron-deficient naphthoquinone ring interact via aromatic−aromatic interactions. Moreover, the guanidine moieties of D-Arg-2 and D-Arg-7 could have an affinity toward the polar head groups of the phospholipids, while the hydrophobic acyl chains could interact with the alkyl chains of the phospholipids or the prenyl chain of menaquinone. Both polar and hydrophobic interactions can facilitate anchoring 3 in the menaquinone-containing membrane. A combination of solid-phase synthesis and solution-phase structural diversification allowed the successful synthesis of various analogues of 3. The SAR data of the analogues offered a

4. LARGAZOLE 4.1. Background of Largazole

Largazole (14, Figure 11) is a 16-membered macrocyclic depsipeptide natural product isolated from the cyanobacterium Symploca sp. by the Luesch group.77,78 This natural product exhibits 2−10-fold selective growth inhibition against transformed cell lines over normal cell lines, indicating its potential as a lead compound for the development of cancer chemotherapeutic agents. The macrocycle of 14 consists of thiazole and thiazoline rings, a valine, and a hydrophobic β-hydroxy carboxylic acid that forms a macrolactone with the carboxylic H

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Figure 10. Possible interactions of lysocin E (3) with a menaquinone-containing lipid bilayer.

of HDAC8. These observations suggested that the replacement of the thiazole ring of 14 with a cationic functionality could strengthen the electrostatic interactions. On the basis of this hypothesis, William’s SAR study focused on the replacement of the thiazole group with regioisomers of pyridine rings. In addition, the effect of the hydrophobic acyl group was evaluated by synthesizing thioester- and thiol-type analogues. Furthermore, the ester bond was switched to an amide bond to investigate its effect on the physiological stability of 14. Williams and Schreiber first reported the total synthesis of 14 (Figure 12).82 The synthesis was achieved by the assembly of three synthetic components starting from 53. A consecutive thiazoline−thiazole-linked structure was constructed by the cyclocondensation of thiazole cyanide 53 and α-methylcysteine 54,90 giving rise to 55. Further condensation of ester 56 with PyBOP, followed by removal of the TSE group and subsequent macrolactamization using O-(7-aza-1H-benzotriazol-1-yl)N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU)91 and 1-hydroxybenzotriazole (HOBt), afforded trityl-protected largazole thiol 57. Finally, removal of the Strityl group by i-Pr 3 SiH and thioester formation via condensation with octanoic acid chloride furnished 14. The analogues for the SAR study were prepared by using the same synthetic strategy (Figure 12). The synthesis of 61 is described as a representative example. Namely, exchanging synthetic fragment 53 with cyano-pyridine derivative 58 afforded pyridine ring containing largazole analogues (58 → 59 → 60 → 61). The synthesis and evaluation of the obtained analogues revealed that compound 61 exhibited growth inhibitory activities against the nuclear protein of the testis (NUT) midline carcinoma cell lines TC-797 (IC50 = 0.024 μM for 14 and 0.01 μM for 61) and 10326 (IC50 = 0.025 μM for 14 and 0.01 μM for 61), and these activities are 2-fold more potent than those of 14. Interestingly, the IC50 value of 61 against HDAC was larger than that of parent 14 (e.g., 10.09 nM for 14 and 340 nM for 61 against HDAC1). These results suggest several possibilities: for example, 61 could have better membrane permeability or physiological stability in the cells. Considering that 14 has multiple cellular targets, as described above, its higher affinity toward other biological targets would increase the growth inhibitory activity of 61 in comparison to parent 14. These new findings of the biological behaviors of 14 and 61 would increase the potential applicability of 14. Further

Figure 11. Structures of largazole (14) and biologically active largazole thiol (52). Substructures derivatized in Williams’ SAR study are indicated in pink.

acid of the valine moiety. Furthermore, the terminal sulfur atom of the β-hydroxy carboxylic acid forms a thioester with an octanoic acid. Compound 14 shares the same structural motif (Zn2+-binding arm) as the known histone deacetylase (HDAC) inhibitors79 FK228,80 FR901375,80 and spiruchostatin.81 In fact, the deacyl analogue of largazole, free thiol 52, can function as a class I HDAC (HDAC1−3) inhibitor by coordinating to the Zn2+ of HDAC.82 However, the growth inhibitory activity of thiol 52 against cancer cell lines was weaker than that of 14. These results suggest that parent thioester 14 is a masked class I HDAC inhibitor, and the octanoic acid moiety may increase the hydrophobicity and improve the plasma membrane permeability of 14. In addition, a recent report indicated that largazole inhibits ubiquitin activating enzyme (E1),83 which increases the potential of 14 and its analogues as useful biological tools. 4.2. Williams’ Synthetic Approach and SAR Study

Williams et al. reported the SAR of 14 by diversification of its substructures (Figure 11).84−87 The crystal structure of 14bound HDAC888 and the analysis of the binding model between HDAC1 and 1489 by Wiest et al. showed the proximity of the thiazole ring of 14 to the negatively charged asparagine residue I

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Figure 12. Total synthesis and biological activity of 14 and analogue 61. Abbreviations: HATU = O-(7-aza-1H-benzotriazol-1-yl)-N,N,N′,N′tetramethyluronium hexafluorophosphate; HOBt = 1-hydroxybenzotriazole; TSE = trimethylsilylethyl.

catalyzes the elongation (transglycosylation) and bridging (transpeptidation) of the peptidoglycan.94,95 These actions result in a mechanically weak bacterial cell wall, facilitating bacteriolysis by 15. This mechanism of action of 15 may contribute to the slow emergence of 15-resistant genes. However, in 1986, vancomycin-resistant Enterococcus (VRE) was identified. Moreover, in 2002, the first infection caused by vancomycin-resistant S. aureus (VRSA) in the United States was reported.96 Because S. aureus is more pathogenic than VRE, the emergence of VRSA has been widely regarded as a severe concern for human health. Therefore, next-generation vancomycin derivatives that exhibit antimicrobial effects on these resistant species are required. The mechanism of resistance to 15 is illustrated in Figure 14. The introduction of the vanA or vanB gene to the bacteria changes the D-Ala-D-Ala of lipid II to a D-Ala-D-Lac moiety (lactic acid).97 For 15 to recognize the D-Ala-D-Ala motif in the binding pocket, hydrogen bonds must form between the amide NH group of the terminal D-Ala and the carbonyl group of 15. The substitution of D-Ala with D-Lac results in fewer potential hydrogen bonds due to a lack of hydrogen donors on the lipid II side. These mutations severely decrease the affinity of 15 for lipid II, making it unable to inhibit peptidoglycan synthesis.98

exploration of analogues of 14 and detailed analysis of their mechanisms would facilitate the use of de novo analogues of 14 as anticancer agents.

5. VANCOMYCIN 5.1. Background of Vancomycin

Vancomycin (15, Figure 13) is one of the most important glycopeptide antibiotics reported to date, and it is used to treat

5.2. Boger’s Synthetic Approach and SAR Study

Boger’s SAR study on 15 focused on the structural alterations of the carbonyl group of 15 that participates in the recognition of the D-Ala-D-Ala sequence as well as the carboxylic acid and the amine of vancosamine (Figure 13). Most importantly, analogues that have hydrogen bond donors instead of hydrogen bond acceptors were designed on the basis of the hypothesis that the introduction of a new hydrogen bond donor to 15 can reestablish the binding affinity toward D-Ala-D-Lac, the carbonyl oxygen atom of which can serve as a hydrogen bond acceptor. Figure 15 shows the total synthesis of one such analogue, [ψ[CH2NH]Tpg4]vancomycin (74), where the carbonyl group was replaced by a methylene group.99 The methylene moiety was first constructed though the oxidation of alcohol 62 and

Figure 13. Structure of vancomycin (15). Substructures derivatized in Boger’s SAR study are indicated in pink.

drug-resistant bacteria such as MRSA. In contrast to the rapid emergence of resistant bacteria for other antimicrobial agents, vancomycin-resistant bacteria were not reported for approximately 30 years after it was approved by the U.S. Food and Drug Administration (FDA) in 1958.92 The mechanism of action of 15 involves the recognition of the 93 D-Ala-D-Ala sequence of lipid II, which is a bacterial cell wall precursor, thereby inhibiting the access of the enzyme that J

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Figure 14. Molecular mechanism of vancomycin resistance induced by vanA or vanB genes. Abbreviation: Lac = lactic acid.

Figure 15. Total synthesis of [ψ[CH2NH]Tpg4]vancomycin (74) and 4-CBP analogue 75. Abbreviations: BCB = B-bromocatecholborane; Cbz = benzyloxycarbonyl; dba = dibenzylideneacetone; DEPBT = 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one; DMP = Dess−Martin periodinane; MEM = 2-methoxyethoxymethyl ether; UDP = uridine diphosphate.

K

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Figure 16. Summary of Boger’s SAR study of vancomycin. The MICs of 15, 75, and 76 against vancomycin-resistant bacterial strains are also displayed.

moiety and the hydrogen atom of the newly introduced amidine or methylene moiety. In contrast, when R1 was converted from a carboxylic acid to a hydroxy group, the antimicrobial activity did not change. Finally, the introduction of a (4-chlorobiphenyl)methyl (4-CBP) group on the peripheral amine enhanced the antimicrobial activity. For example, the activities of amidine analogue 76 against Enterococcus faecalis BM4166 expressing vanA (MIC = 0.005 μg/mL), Enterococcus faecium ATCC BAA-2317 expressing vanA (MIC = 0.005 μg/mL), and E. faecalis ATCC 51299 expressing vanB (MIC = 0.06 μg/mL) were 133−50000-fold more potent than those of 15 against the same vancomycinresistant strains. Methylene analogue 75 exhibited antimicrobial activities 16−4200-fold more potent than those of 15 against the same strains (0.13 μg/mL against E. faecalis BM4166, 0.06 μg/ mL against E. faecium ATCC BAA-2317, and 0.5 μg/mL against E. faecalis ATCC51299). Although the cause of this effect remains to be elucidated, the introduction of the hydrophobic 4CBP group may have allowed dimerization and membrane anchoring106 or prevented the bacteria from sensing the vancomycin derivative.107 Because of these effects, compounds 75 and 76 had superior activities against vancomycin-resistant strains. In this study, new antimicrobial compounds that are active against vancomycin-resistant strains were identified by preparing and evaluating a series of analogues of 15. The successful discovery of 75 and 76 clearly demonstrated the importance of generic synthetic routes to complex natural products and designing analogues based on the molecular mode of action of drug resistance in bacteria.

subsequent reductive amination of the aldehyde and amine 63, leading to 64. After conversion of 64 to carboxylic acid, condensation with aryl fluoride 65 by 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT)100 and SNAr macrocyclization using K2CO3 and CaCO3 generated a 16membered ring consisting of tripeptide units with sufficient atropodiastereoselectivity (desired:undesired atropisomer = 2.5−3:1). Suzuki coupling101 of aryl boronic acid 67 with aryl bromide 66 afforded a 1:1.3 mixture of desired (68) and undesired (69) atropisomers. Nevertheless, heating undesired 69 in o-dichlorobenzene102 provided a separable mixture of 68 and 69 in a ratio of 1:1.1, which allowed undesired atropisomer 69 to be recycled. Subsequent PyBOP-promoted macrolactamization of 68 afforded bimacrocycle 70. Then, a condensation with aryl fluoride 71 in the presence of DEPBT and a subsequent SNAr macrocyclization were conducted to transform 70 into trimacrocylic intermediate 72 with good atropodiastereoselectivity (desired:undesired atropisomer = 6− 7:1). Oxidation of the MEM-oxy methyl group to the carboxylic acid, transformation of the cyano group to an amide, and demethylation of the phenolic oxygen furnished the aglycon of [ψ[CH2NH]Tpg4]vancomycin (73) bearing a methylene moiety instead of the amide moiety. Finally, consecutive glycosylation was accomplished by the application of enzymes. Application of uridine diphosphate (UDP)-glucose and UDPvancosamine with recombinant glycosyltransferases GtfE and GtfD, respectively,103 delivered the desired [ψ[CH2NH]Tpg4]vancomycin (74). The primary amine of vancosamine was modified by a (4-chlorobiphenyl)methyl (4-CBP) group by reductive amination, giving rise to analogue 75. By exploitation of the above strategy, analogues with variations at the carbonyl, R1 group, and peripheral attachments were synthesized and assessed (Figure 16).104,105 The analogues with amidine and methylene substructures instead of the carbonyl groups indeed showed potent antimicrobial activities against vancomycin-resistant bacteria. By comparison of the results of the affinities of these compounds toward the synthetic model dipeptides bearing D-Ala-D-Ala or D-Ala-D-Lac, the restored antimicrobial activity was attributed to the formation of the expected hydrogen bond between the oxygen of the Lac

6. NANNOCYSTIN AX 6.1. Background of Nannocystin Ax

Nannocystins are peptide−polyketide hybrid natural products isolated from Nannocystis sp. of myxobacteria (Figure 17).108 Naturally occurring nannocystins exhibit distinct activities against a panel of 472 cancer cell lines, including cell lines that are resistant to clinically approved drugs. These cyclodepsipeptides are known to bind the eukaryotic translation elongation factor 1α (EF-1α) as their primary L

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a new candidate for the development of cancer chemotherapeutic agents. Among the naturally occurring derivatives of nannocystins, nannocystin Ax (8) and nannocystin A (77) were found to exhibit equally potent activities against the HCT116 human colon cancer cell line (IC50 = 5.4 nM for 8 and 2.6 nM for 77). Their structures only differ by the presence of an epoxide or a conjugated trisubstituted olefin at the polyketide moiety, and both structures can serve as excellent structural platforms for diversification. In addition, this preliminary SAR analysis suggests that the epoxide of 77 is not essential for biological activity. 6.2. Fürstner’s Synthetic Approach and SAR Study

Fürstner’s SAR study of 8 focused on the derivatization of the βhydroxy valine moiety, the trisubstituted olefin, and the adjacent methyl ether (Figure 17).111 The structure of nannocystin can be retrosynthetically divided into the upper tripeptide fragment and the lower polyketide fragment. Upon generation of analogues for the SAR study, the β-hydroxy valine of the

Figure 17. Structures of nannocystins A (77) and Ax (8). Substructures derivatized in Fürstner’s SAR study are indicated in pink.

biological target.109 Since other compounds that bind EF-1α are known to be anticancer agents,110 nannocystin is expected to be

Figure 18. Synthesis of nannocystin Ax (8) and analogues 88−90. Abbreviations: CuTC = copper(I) 2-thiophenecarboxylate; DCC = N,N′dicyclohexylcarbodiimide; TBAF = tetrabutylammonium fluoride; Tf = trifluoromethanesulfonyl. M

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7. JASPLAKINOLIDE

upper part was replaced with a glycine moiety, while the ethereal methyl group of the lower part was deleted. More importantly, the lower trisubstituted alkene was structurally varied from the alkyne, which was constructed by the ring-closing alkyne metathesis (RCAM).112 This strategy allowed the diversification of the unsaturated substructures in the late stage of the syntheses. First, dipeptide 78 was hydrolyzed and converted to the corresponding acid, and amine 79 was subsequently coupled using N,N′-dicyclohexylcarbodiimide (DCC) to provide tripeptide 80 (Figure 18). Removal of the Boc group from 80 and subsequent condensation with acid chloride 81 afforded macrocyclization precursor 82. RCAM of 82 and detachment of the TBS group then produced internal alkyne 83. Vinyl stannane 84 was prepared as a single regio- and stereoisomer by trans-selective hydrostannation of 83.113 Compound 84 was then subjected to CuTC-mediated methylation114 to generate 85 with the requisite trisubstituted olefin. O-Methylation of 85 was achieved by generating a methyl cation equivalent via a Aucatalyzed cyclization reaction of 86,115 providing 87. Finally, reductive cleavage of the phenacyl group of the tyrosine moiety from 87 gave rise to the desired nannocystin Ax (8). Synthetic intermediates 83−85 were utilized to efficiently diversify the structure and prepare 10 analogues, including alcohol 88, fluoride 89, and desmethyl 90. The cytotoxicities of 8 and its analogues against the human colon cancer cell line HCT-116 and the human promyelocytic leukemia cell line HL-60 were evaluated (Figure 19). Deletion of

7.1. Background of Jasplakinolide

Jasplakinolide (9, Figure 20) is a 19-membered peptide− polyketide hybrid macrocycle originally isolated from the

Figure 20. Structures of jasplakinolide (9) and chondramides A (10a) and C (10b). Substructures derivatized in Arndt and Waldmann’s SAR study are indicated in pink.

marine sponge Jaspis splendans in 1986.116 This compound is also known as jaspamide, which was independently reported by another group.117 The biological mechanism of action of 9 is actin-related. A competitive binding assay using a filamentous actin (F-actin) binder, phalloidin,118 revealed that 9 binds to F-actin with a dissociation constant of 15 nM119 and stabilizes actin filaments. Compound 9 has various biologically useful activities, such as potent cytotoxicity against cancer cell lines. Furthermore, a structurally similar 18-membered macrocycle, chondramide A (10a), isolated from myxobacterium Chondromyces crocatus,120 is known to induce actin polymerization and shows cytostatic activity against human cancer cell lines.121 These natural products, 9 and 10a, share β-tyrosine, N-methyl tryptophan, Lalanine, and polyketide moieties and bear a trisubstituted olefin. These data suggested that 9, 10a, and related molecules have potential as lead compounds for the development of anticancer agents. Moreover, a high concentration of 9 inhibits the growth of Plasmodium falciparum as it stabilizes the actin filaments of the parasite. In 2017, the structure of 9-stabilized P. falciparum actin filaments was determined by cryo-electron microscopy,122 and 9 can noncovalently bind to three adjacent actin subunits by hydrophobic interactions.

Figure 19. Summary of Fürstner’s SAR study of 8.

the side chain of β-hydroxy valine caused a total loss of growth inhibitory activity against these cancer cell lines. In addition, changing the methyl ether group to a free hydroxy group dramatically decreased the activity. In contrast, modification of the trisubstituted olefin was relatively well tolerated. These results were contrary to the computational prediction using a docking model, which highlights the importance of SAR studies of synthetic analogues. Consequently, the diverted total synthesis of 8 by using latestage structural diversification allowed the synthesis and evaluation of analogues of 8 with variations in the core substructures. The results of the SAR study will help elucidate the binding mode of 8 with the target protein and will guide future derivatizations to produce new, biologically useful nannocystin-based compounds.

7.2. Arndt and Waldmann’s Synthetic Approach and SAR Study

The total synthesis of 9 and a comprehensive SAR study were first reported by Arndt, Waldmann, et al. (Figure 20).123,124 Maier et al. also reported an SAR study of this class of compounds.125 In the work by Arndt and Waldmann, a structurally and stereochemically diverse collection of analogues N

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Figure 21. Solid-phase-based synthesis of 9. Abbreviations: DMAP = 4-dimethylaminopyridine; EDC = 1-(3-(dimethylamino)propyl)-3ethylcarbodiimide; TIPS = triisopropylsilyl; Mes = mesityl.

of 9 and chondramide C (10b), a natural congener of 10a, was synthesized and evaluated. In the case of 9, the importance of the Br atom of the indole ring, the phenol moiety of the β-tyrosine, the L-alanine residue, and the C6-methyl group to the biological activity was assessed. On the other hand, the phenolic OH and N-methyl moieties were derivatized for the generation of analogues of 10b. Moreover, the configurations of the C2-, C6-, and C7-methyl groups and the C4-olefin of 10b were altered to evaluate their effects on the biological activities. The synthetic route to 9 is illustrated in Figure 21. The assembly of the building blocks by solid-phase synthesis began from 2-chlorotrityl resin126 loaded β-tyrosine 91. Elongation using Fmoc-based chemistry and cleavage from the resin afforded a tripeptide unit bearing a terminal olefin (92). Alcohol 93 with a terminal olefin was condensed with 92 by the action of N-(3-(dimethylamino)propyl)-N′-ethylcarbodiimide (EDC), leading to diene 94. Ring-closing metathesis (RCM)127 of 94 using Grubbs’ second-generation catalyst128 afforded macrocycle 95. Finally, the TBAF-promoted removal of the TIPS group from the β-tyrosine moiety successfully generated 9. Compound 10b and its analogues were also prepared by a combination of solid- and solution-phase syntheses according to the route to 9. By changes in the building blocks, the bromine atom, the L-alanine residue, the methyl group on the polyketide moiety, and the phenol moiety of the β-tyrosine were substituted with other substructures, resulting in the generation of a wide variety of analogues of 9 and 10b. The biological activities of the obtained analogues of 9 and 10b were evaluated by cytotoxicity assays against the human breast cancer cell line MCF-7 and the human colon cancer cell line HT-29. The cytotoxicities of all the synthesized analogues of 10b against these cell lines were at least one order of magnitude weaker than that of the parent compound. On the other hand, an evaluation of the analogues of 9 revealed that the bromine atom on the indole ring and the methyl group adjacent to the trisubstituted olefin did not substantially affect the biological activity of 9 (Figure 22). In contrast, the phenol moiety of the βtyrosine was found to be important for the activity. According to a different set of SAR studies using natural congeners by

Figure 22. Summary of Arndt and Waldmann’s SAR study of 9.

Zampella et al., the substitution of alanine with other amino acids was tolerated.129 Considering the above SAR data, a fluorescent probe based on 9 was designed and synthesized.124 Notably, the fluorophoreconjugated analogue has good membrane permeability and Factin-binding properties without potent cytotoxicity. Long-lived F-actin structures, such as stress fibers or actin arcs, in live cells were effectively labeled by this fluorescent probe. Detailed SAR studies on 9 and 10a,b classified the biologically important and unimportant substructures within these molecules. These data led to the preparation of a fluorescent probe that retained the binding affinity for the target molecule but showed attenuated cytotoxicity. The studies demonstrated that SAR analyses provide essential structural information for the design of chemical probes based on parent natural products.

8. EPOTHILONE 8.1. Background of Epothilone

Epothilones A and B (96 and 16, respectively, Figure 23) are anticancer natural products isolated from myxobacterium Sorangium cellulosum strain 90.130 The 16-membered macrocyclic core of epothilones contains an epoxide and an ester moiety. An exocyclic thiazole ring is also present. Compounds 96 and 16 only differ in the presence or absence of a methyl group adjacent to the epoxide. O

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lines, including those resistant to taxol,133 indicating the importance of these macrocyclic natural products as cancer chemotherapeutics. These findings have motivated many researchers to conduct total syntheses, semisyntheses, and SAR studies on epothilones,134 leading to the development of an artificial analogue of epothilone that is clinically used. Specifically, a lactam analogue of 16, ixabepilone (97),135 which is designed to offer enhanced stability against degradation by esterase,136 is an FDA-approved epothilone analogue.137 8.2. Danishefsky’s Synthetic Approach and SAR Study

Höfle et al. reported that epothilone 490 (98) is a natural congener that possesses conjugated C10−C11 and C12−C13 olefins in the macrocycle instead of the epoxide moiety.138 The high in vitro cytotoxicity of 98 suggested that the epoxide moieties of 96 and 16 are not essential for potency. Danishefsky et al. constructed a focused library of des-epoxide epothilone analogues by changing the functional groups adjacent to the C12-olefins.139−145 The structures of representative analogues are displayed in Figure 23. These (E)-9,10-dehydro analogues, 101 and 102, were synthesized via RCM, and they also served as intermediates in the preparation of C9,10-saturated analogues 99 and 100, respectively. (E)-9,10-Dehydro analogue 101 and CF3-substituted (E)-9,10-dehydro analogue 102 were designated dehydelone and fludelone, respectively. It is of note that they further optimized the structure of the analogues to discover the 17-iso-oxazole analogue of 102, iso-fludelone 103, with more desirable features as pharmaceuticals. Analogues 101 and 103 have entered phase II and phase I clinical trials, respectively. The synthesis of fludelone (102) and 100 with the C12-CF3 group is shown in Figure 24. The enolate formed by the deprotonation of ketone 104 with LDA attacked chiral aldehyde 105, affording the adduct 106 in a stereoselective manner. TBS protection of 106 and deprotection of the aldehyde, followed by a second stereoselective aldol reaction using tert-butyl acetate, extended the left-hand carbon chain. Subsequent introduction of a right-hand terminal olefin produced 107. The t-Bu ester of

Figure 23. Structures of epothilones A (96) and B (16), ixabepilone (97), epothilone 490 (98), and epothilone B analogues 99−103 designed by Danishefsky et al. Diversified substructures are indicated in pink.

The cytotoxicities of epothilones against cancer cells involve the induction of tubulin assembly and stabilization of microtubules.131 This mechanism of action is similar to that of the well-known anticancer agent paclitaxel (taxol).132 Moreover, epothilones are active against multidrug-resistant cancer cell

Figure 24. Synthesis of fludelone (102) and analogue 100. Abbreviations: LDA = lithium diisopropylamide; NMO = 4-methylmorpholine N-oxide; TES = triethylsilyl; TMS = trimethylsilyl; TPAP = tetrapropylammonium perruthenate; Tris = 2,4,6-triisopropylbenzenesulfonyl. P

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122 with methyl(trifluoromethyl)dioxirane (TFDO),150 gave rise to epothilone A (96). By using the thus-established solid-phase synthetic protocol, Nicolaou et al. conducted a comprehensive SAR study of epothilones (Figure 27). The molecular architecture of epothilone was structurally diversified by changing the three synthetic building blocks, namely, compounds 124, 125 or 126, and 127. Furthermore, all four diastereomers originating from the aldol reactions were derivatized into analogues. To identify each analogue, radiofrequency encoding technology151,152 was utilized for the construction of the epothilone library. Remarkably, the on-resin sequential assembly of the building blocks generated 44 epothilone A analogues. Assessment of the biological activities of the 112 analogues including the above 44 analogues revealed the details of the SAR of these epothilone structures (Figure 28). Although most of the structural alterations resulted in weaker activity in a tubulin assembly assay, changing the epoxide to an E or a Z olefin had no significant effect on the activity. Moreover, replacing the thiazole ring with an oxazole ring also did not affect tubulin assembly. Cell growth assays using 20 selected compounds indicated that 10 and 6 of the analogues exhibited nanomolar IC50 values against the 1A9 human ovarian cancer cell line and the MCF-7 human breast cancer cell line, respectively. Similarly to natural epothilones, these analogues were effective against paclitaxelresistant ovarian cancer cell lines, suggesting that the selected analogues with growth inhibitory activities retain the biological functions of the parent epothilones. Nicolaou’s total synthesis of 44 epothilone A analogues clearly shows the power and efficiency of solid-phase synthesis for the structural diversification of complex natural macrocycles.

107 was in turn removed by TESOTf, giving rise to the free carboxylic acid. Then, the carboxylic acid was condensed with secondary alcohol 108 to generate 109, the substrate of the macrocyclization. RCM successfully transformed diene 109 into macrocycle 110. The side-chain structure containing a thiazole ring was introduced to ketone 110 by a Wittig olefination using KN(TMS)2 and 111. Finally, HF-mediated deprotection of the silyl protecting groups afforded fludelone (102). Furthermore, treatment of 102 with TrisNHNH2 resulted in a C9−C10 chemoselective reduction, leading to 100. Evaluation of the synthesized epothilone analogues revealed that unsaturated analogues, fludelone (102, Figure 23) and dehydelone (101), exhibited remarkable in vivo antitumor effects on human xenograft tumors in nude mice.146 The artificial analogue 102 differs from naturally occurring 98 not only in the C12 substituent (CH3 vs CF3) but also in the position (C10 vs C9) and geometry (Z vs E) of the olefin. Its successful discovery illustrates the benefit of the total synthesis for exploring analogues that cannot be accessed by derivatization of the natural product. 8.3. Nicolaou’s Synthetic Approach and SAR Study

Nicolaou et al. established a solid-phase synthetic strategy for accessing epothilone analogues to diversify the entire structure of 96 (Figure 25).147,148 In this comprehensive synthesis of the

9. BRYOSTATIN 9.1. Background of Bryostatin

Bryostatins, a family of macrolides biosynthesized by a bacterial symbiont of the marine-derived bryozoan Bugula neritina, were originally isolated by Pettit et al.153 A total of 21 natural congeners have been reported thus far.154,155 All of the analogues consist of a 20-membered macrocycle with three functionalized tetrahydropyran (THP) rings. Bryostatin 1 (18, Figure 29) has been extensively studied for its medicinal applications. In fact, 18 is now in clinical trials as a latency reversal agent for the eradication of HIV/AIDS,156 as a treatment for Alzheimer’s disease,157 and as an immunotherapeutic agent against cancer.158 The intracellular target of bryostatins is protein kinase C (PKC), which could further expand the clinical application of bryostatins as therapeutics for other unmet medical needs.159 On the basis of biological studies, the macrocyclic structure of bryostatins can be functionally divided into two domains (Figure 29).160 The lower part (highlighted in yellow) is classified as the recognition domain for the binding of 18 to PKC. The upper part (highlighted in cyan), which contains THP A and B rings, is regarded as the spacer domain because it has no direct interactions with PKC.

Figure 25. Diversified substructures of 96 in Nicolaou’s SAR study.

analogues, the substructures indicated in pink were derivatized by replacing the synthetic components used in the solid-phase synthesis. Specifically, the C3−(S)-OH group, the dimethyl group at the C4 position, the C8−(S)-methyl group, the R group at C12, the C12-epoxide moiety, the C15 configuration, the C16-trisubstituted olefin, the thiazole ring, and the C21-methyl group were altered in the SAR study. All of the analogues were prepared on the basis of the solidphase total synthesis of 96, which is illustrated in Figure 26. The entire structure of 96 was assembled from three building blocks, 114, 117, and 119. Phosphorane 113 was formed on Merrifield resin (112)149 and coupled with aldehyde 114 to generate resinbound cis-olefin 115. The TBS group of 115 was removed, and the primary hydroxy group was oxidized to afford aldehyde 116. An on-resin aldol reaction of the enolate derived from ketone 117 with aldehyde 116 furnished 118 as a mixture of four diastereomers. Esterification between carboxylic acid 118 and secondary alcohol 119 produced 120, the substrate of the macrocyclization. Finally, RCM of 120 involved simultaneous macrocyclization and resin removal, liberating four diastereomers, 121a−d, from the resin. After separation of the diastereomer 121a from the other three isomers (121b−d), removal of the TBS group of 121a, followed by epoxidation of

9.2. Wender’s Synthetic Approach and SAR Study

Wender et al. completed the total synthesis of bryostatins161,162 and an extensive SAR study and exploration of useful analogues of bryostatins (Figure 29).163−173 Wender’s group named these analogues bryologs. Their design principle was based on the diversification of the A and B rings of the spacer domain while the recognition domain was maintained (Figure 30). SpecifiQ

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Figure 26. Solid-phase total synthesis of 96.

Figure 27. Construction of the epothilone library. Abbreviations: P = protecting group; RCM = ring-closing metathesis.

acetalization with the aldehyde, which gave macrocyclic product 131 with an acetal-type B ring via 130. In contrast, to construct THP-type B rings, such as that in natural bryostatins, the deprotection of C11−OH and a subsequent Prins annulation176 induced by PPTS or TMSOTf were carried out to produce analogue 135 with a THP-type B ring via 134. This synthetic strategy was successfully utilized to generate a large number of bryologs with diverse A and B rings in the spacer domain. The biological evaluation of the synthesized compounds revealed that acetal-type analogue 136 was more active than the parent bryostatin against several cancer cell lines. Structurally simplified 136 is a promising clinical candidate due to its higher

cally, the structures of building blocks 128 and 132 were diversified by changing the R1−4 substituents to various alkyl and aryl groups. To efficiently synthesize various A and B ring analogues, the whole macrocycle of bryostatin was constructed by coupling two building blocks (128 + 129 or 132 + 133). Briefly, an esterification using Yamaguchi conditions174 or bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP)175 as a condensing agent afforded the precursor of the macrocyclization. For the subsequent macrocyclization, two distinct sets of conditions were applied depending on the substructure of the B ring. To construct an acetal-type ring, HF/ pyridine was used for the deprotection of the diol and R

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Figure 28. Summary of Nicolaou’s SAR study of epothilones.

discovery of compounds exhibiting biological properties different from those of the original natural products.

10. HALICHONDRIN 10.1. Background of Halichondrin

Halichondrins are polyether macrolides that were first isolated from the marine sponge Halichondria okadai Kadota.186,187 Norhalichondrins and homohalichondrins, natural congeners that differ in the length of their backbone, have also been isolated. Halichondrins, including halichondrin B (19, Figure 32), exhibit potent anticancer activities in vitro and in vivo. A biological study on 19 revealed that its anticancer activity is based on tubulin depolymerization, which is similar to the mechanism of vinca alkaloids.188 However, the patterns of the interactions with tubulin are highly specific and unique to each tubulin depolymerizer. Therefore, 19 would be utilized for the development of compounds with unique cancer selectivity and molecular characteristics that are useful for clinical applications.

Figure 29. Structure of bryostatin 1 (18). Substructures derivatized in Wender’s SAR study are indicated in pink. Abbreviation: PKC = protein kinase C.

10.2. Kishi’s Synthetic Approach and SAR Study

synthetic accessibility and comparable biological activity.177 In addition, known PKC activators are candidates for clinical use in the clearance of latent HIV because PKC is involved in the reactivation of latent HIV.178 Considering their PKC activation activity, bryostatins are potential candidates for HIV eradication. In fact, analogue 137 is better able to reactivate HIV from latency than parent 18, making 137 a good lead compound in the development of chemotherapeutics for HIV/AIDS.179 Furthermore, several bryologs were found to have PKC selectivity different from that of their parent bryostatin, indicating the potential usefulness of the synthesized analogues. For example, THP-type analogue 138, bearing an (E)-enoate in its B ring, exhibited PKC-δ selective inhibition, although its parent compound, 18, shows PKC-βI selectivity.161 These findings suggest the potential of the bryostatin architecture for modulating the function of PKC and addressing several unmet medical needs, such as HIV eradication.

The total synthesis of 19 was achieved by Kishi et al.189 and the left half of 19 was chemically diversified in an SAR study conducted in collaboration with Eisai Company (Figure 32).190,191 Since the biological evaluation of synthetic fragments of 19 revealed that right-half diols 140a,b retained the anticancer activity of parent compound 19,192 the right-half diols were utilized as advanced starting points for the SAR study (Figure 33). Accordingly, the left half of 19 was simplified, and the THP ring bearing C32 and C33 stereocenters was changed. To optimize the ring size, THP analogues and tetrahydrofuran (THF) analogues possessing various substituents were prepared. These studies lead to the discovery of eribulin (149) as an anticancer agent. In the total synthesis of natural 19, four building blocks were coupled to generate the right half of the compound (Figure 33). Alcohol 141 was oxidized to the corresponding aldehyde and then coupled with β-keto phosphonate 142 to provide the enone. Sequential reduction of the enone by Stryker’s reagent193 and NaBH4 provided the corresponding alcohol. The alcohol was then mesylated by using Ms2O to give 143. A Ni(II)/Cr(II)mediated coupling of vinyl iodide 143 and aldehyde 144 gave the corresponding alcohol,194−196 which was then subjected to base-induced cyclization to produce THP derivative 145. Removal of the pivaloyl ester by LiAlH4 and oxidation gave the aldehyde as the coupling substrate. A second Ni(II)/Cr(II)mediated coupling between the above aldehyde and vinyl iodide 146 and subsequent macrolactonization under Yamaguchi conditions successfully constructed the right half 147a. To complete the synthesis, a third Ni(II)/Cr(II)-mediated

9.3. Keck’s Synthetic Approach and SAR Study

Keck et al. also carried out a comprehensive SAR study on analogues of bryostatin.180−185 The key synthetic strategy involves constructions of the A and B rings by two Prins annulation reactions and subsequent macrolactonization. Significantly, they discovered bryolog 139 (Figure 31) to have functions similar to that of tumor-promoting phorbol 12myristate 13-acetate. Namely, 139 inhibited proliferation of U937 leukemia cells and induced their attachment, while the original bryostatin had a much-reduced effect. The distinct activity of 139 highlights the possibility that the synthesis and evaluation of natural product analogues could lead to the S

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Figure 30. SAR study of the spacer domain of 18. Abbreviations: PPTS = pyridinium p-toluenesulfonate; PyBroP = bromotripyrrolidinophosphonium hexafluorophosphate.

Figure 31. Keck’s bryostatin analogue 139 with phorbol 12-myristate 13-acetate like activity.

Figure 32. Structure of halichondrin B (19). Substructures derivatized in Kishi and Eisai Company’s SAR study are indicated in pink.

coupling was used as the key reaction for connecting right half 147a and left half 148. The convergent total synthesis of the extremely complex natural product 19 demonstrated the power and robustness of the Ni(II)-/Cr(II)-mediated reactions. Next, structural diversification of the junction of the right and left hemispheres was investigated to optimize the activity (Figure 33). For this optimization, structural diversification of the THP ring (A ring of 147) was carried out by changing the structure of the corresponding building block 144. Kishi and

Eisai Company investigated both the THP-type (147, n = 1) and the THF-type analogues (147, n = 0) in the SAR study. Following the established total synthesis of 19, sequential couplings of four building blocks, 143−146, by one Horner− Emmons olefination and three Ni(II)/Cr(II)-mediated reactions generated the structural variants of right half 147. Among these derivatives, THF-type analogue 147b exhibited the most potent anticancer effect. Namely, 147b was found to retain the growth inhibitory activity of parent 19 against the human colon T

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Figure 33. Kishi’s total synthesis of halichondrin B (19) and SAR study of the right half of 19. Abbreviations: CSA = 10-camphorsulfonic acid; DDQ = 2,3-dichloro-5,6-dicyano-p-benzoquinone; MPM = methoxybenzyl; Ms = methanesulfonyl; Piv = pivaloyl.

most clinically important macrolide natural products is erythromycin (21, Figure 34), which was isolated from the fermentation broth of the fungus Saccharopolyspora erythraea,198 because 21 and its derivatives are widely used for the clinical treatment of infectious diseases. Structurally, 21 and its derivatives are bisglycosylated 14-membered macrolactone rings possessing cladinose and desosamine moieties at C3-OH and C5-OH, respectively. Clinically used derivatives of 21 include 14-membered (roxithromycin, clarithromycin, and dirithromycin), 15-membered (azithromycin), and 16-membered (josamycin and spiramycin) rings.199 The mechanism of action of 21 and its derivatives involves the inhibition of ribosomal protein synthesis of bacteria by binding to 23S rRNA of the 50S subunit.200 The binding induces the dissociation of peptidyl t-RNA from the ribosome in the translocation step.201 Due to its instability under the acidic conditions of the stomach, 21 has low bioavailability and induces gastrointestinal side effects.202 To overcome these issues, chemically modified erythromycin derivatives have been developed. For example,

cancer cell line DLD-1 and the human lymphoma cell line U937 (IC50 = 0.67 nM against DLD-1 and 15 nM against U937 for 147b, 0.74 nM against DLD-1 and 25 nM against U937 for 19). Further lead optimization generated terminal amine derivative ER-086526 149 without the ester moiety; this compound is also known as eribulin. The mesylate of 149 (150, halaven) has been utilized for the treatment of late-stage breast cancer and liposarcoma, and several formulations of 150 have been investigated for other clinical uses.197 The synthesis of 19 and its analogues highlights the importance of general and efficient coupling reactions and the appropriate design of building blocks for the assembly and lead optimization of structurally complex macrocycles.

11. MACROLIDE ANTIBIOTICS 11.1. Background of Macrolide Antibiotics

Macrolide antibiotics are among the most important classes of molecules for treating infectious diseases. To date, many macrolides have been approved for use as drugs. One of the U

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Figure 34. Previous semisynthetic strategy from erythromycin (21) and Myers’ synthetic strategy for solithromycin (151). Synthetic components derivatized in Myers’ synthesis are coded in eight different colors.

using thioglycoside 157209 in the presence of AgOTf, giving rise to 158. Alkyne 161 was diastereoselectively prepared by the addition of 160 to ketone 159 in the presence of lithium (1S,2R)-1-phenyl-2-(pyrrolidine-1-yl)-1-propanolate.210 Generation of a vinyl Grignard reagent by hydromagnesiation of internal alkyne 161 was achieved by treatment with cyclopentylmagnesium bromide and Cp2TiCl2,211 and subsequent addition to aldehyde 158 afforded the adduct, which was derivatized into 162. Thermolysis of 162 promoted the macrolactonization to 163. Then, fluorination by using FN(SO2Ph)2212 transformed 163 into 164. Subsequent coupling with amine 167 prepared by a Huisgen cycloaddition reaction between azide 165 and alkyne 166 furnished 151. The above fully synthetic method was applied to the comprehensive syntheses of macrolide analogues (Figure 36). Remarkably, exchanging the 8 synthetic components with other building blocks provided 300 artificial analogues of macrolide antibiotics by application of the same synthetic strategy. The bioactivities of these analogues were assessed against a panel of pathogens, including several drug-resistant strains. This screening revealed that several of the analogues exhibited potent antimicrobial activities against bacteria, including drug-resistant pathogens. Notably, 152 and 153 were active against Streptococcus pneumoniae expressing ribosome-modifying methyltransferase (ermB) and efflux (mefA) genes (MIC ≤ 0.03 μg/ mL for 152 and 153). Furthermore, compounds 152 and 153 were also effective against vancomycin-resistant Enterococcus faecalis expressing an ermB gene (MIC = 1 μg/mL for 152 and 2 μg/mL for 153). These two strains are resistant to parent erythromycin (minimum inhibitory concentration, MIC ≥ 256 μg/mL). Thus, the study demonstrated the successful discovery of artificial analogues with advantageous functions. Myers’ work confirmed that a highly convergent synthetic route to a natural product can permit the preparation of a larger number of de novo analogues for their comprehensive SAR study and can accelerate the discovery of new analogues with properties superior to those of the parent natural product.

clarithromycin, which is a widely prescribed antibiotic in hospitals, is prepared from erythromycin by a six-step transformation.203 Furthermore, advanced clinical candidate solithromycin (151)204,205 is synthesized through a 16-step chemical derivatization process (Figure 34). These structural modifications of antibiotics are of great importance in the context of antibiotic development, because resistance to clinically used antibiotics continues to emerge. In fact, resistance to clarithromycin and azithromycin has been widely observed in nosocomial infection and community-acquired infections. Chemical modification of the natural architecture is not sufficient for combating the threat of macrolide-resistant bacteria because of the limited variations possible on the binding sites. The most direct methods for obtaining a diverse set of macrolide-derived antibiotics are the establishment of fully synthetic methods and the application of these methods for the construction of analogues. Despite many reports on the total synthesis of macrolide antibiotics,206 to date, an entirely chemically synthesized macrolide antibiotic has not been clinically utilized. 11.2. Myers’ Synthetic Approach and SAR Study

Myers et al. reported a comprehensive SAR study on macrolide antibiotics (Figure 34).207 They developed a fully synthetic and robust route for accessing 14- and 15-membered macrolide antibiotics by assembling 8 building blocks using a combination of anion or Lewis acid mediated C−C bond forming reactions. This important strategy allowed the stereoselective introduction of various functional groups within the backbone of the macrolide architecture. The route to 14-membered 151 from the 8 components (152, 153, 155, 157, 159, 160, 165, and 166) is illustrated as a representative example in Figure 35. The lithium enolate derived from ketone 153 was coupled with iodide 152, and the adduct was then converted to aldehyde 154. The Mukaiyama aldol reaction208 between aldehyde 154 and 155 stereoselectively generated 156. The free alcohol of 156 was in turn glycosylated V

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Figure 35. Strategy of Myers’ convergent synthesis of macrolide antibiotics and the route to 151. Abbreviations: DBU = 1,8-diazabicyclo[5.4.0]undec7-ene; Im = imidazole; Mc = methoxycarbonyl; Pym = pyrimidyl.

12. CONCLUSION

peptide synthesis, the solid-phase synthesis of epothilone A (96) and their analogues clarified the utility of such strategies in the preparation of polyketides (Figures 26 and 27).213,214 In addition, the coupling reactions of building blocks must be highly applicable to the structurally complex intermediates en route to complex macrocyclic natural products. In fact, mild and powerful Ni(II)/Cr(II)-mediated coupling reactions realized the successful preparation of a variety of THF or THP fragments of halichondrin B (19, Figure 33), and acetalizations or Prins annulations generated a large number of structurally related macrocyclic analogues of bryostatin 1 (18, Figure 30). Moreover, the application of a larger number of building blocks is beneficial for obtaining a larger number of analogues. The careful design of the 8 building blocks was essential for preparing 300 analogues of erythromycin (21) (Figure 35). Altogether, only a judicious combination of the appropriate synthetic components and reliable reactions can lead to successful and comprehensive SAR studies of the target natural products. Natural product architectures have been proven to be matchless starting points for discovering biologically useful molecules and novel therapeutic agents. Thus, the development

In this review, 10 examples of comprehensive syntheses and SAR studies of macrocyclic natural products were described. A robust synthetic strategy based on the total synthesis of natural products enables the construction of various analogues of these macrocyclic natural products. The examples of the discovery of superior drug candidates demonstrated that the optimization of naturally occurring complex architectures can result in the development of more useful candidates of chemotherapeutic agents. Most importantly, the basis of these SAR studies is a robust synthetic route toward the target natural product itself. This is because the overall synthetic efficiency of the route (step count, convergence, overall yield, and operational simplicity) directly affects the accessibility of structural diversity and the total numbers of analogues of the original natural product. For example, operationally simple solid-phase syntheses were shown to be useful for generating a large number of polymyxin B (1) and lysocin E (3) analogues (Figures 6 and 9). Although solidphase synthesis techniques have been widely employed for W

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Figure 36. Discovery of 152 and 153, which are active against macrolide-resistant strains selected by a screening against a panel of pathogens.

Biographies

of synthetic routes to the parent natural products and analogues is one of the most valuable strategies for rapidly preparing biologically active compounds. The reported diverted total syntheses can construct a library of the structurally diverse 10− 300 analogues of the parent natural products with significantly high hit rate. However, the numbers of the generated analogues are substantially smaller than those prepared by using biological systems, such as phage and mRNA display.215,216 This fact indicates that most of the chemical space surrounding the natural products remains unexplored. To fully utilize the wisdom of nature, the number of analogues obtained from diverted total syntheses should be further increased because detailed mapping of the SARs in the chemical space of interest will facilitate rapid drug discovery. Hence, synthetic strategies for randomly accessing thousands of compounds or more are desirable for covering a much larger chemical space and pinpointing promising compounds. To achieve this, convergent synthetic strategies for complex natural products and analogues need to be further simplified or automated217 and coupling reactions of building blocks must be more powerful, selective, and robust.218 In addition, the efficiency of the screening process should also be maximized. These advancements will lead to the discovery and development of novel therapeutic agents based on macrocyclic natural products in a shorter amount of time. In this regard, the sophistication of diverted total syntheses of complex natural products continues to be important for a myriad of applications in pharmaceutical sciences.

Hiroaki Itoh was born in Mie, Japan, in 1985. He received his B.Sc. degree in Pharmaceutical Sciences from The University of Tokyo in 2008, and he received his Ph.D. from the same university under the supervision of Prof. Masayuki Inoue. After working for FUJIFILM Corporation for two years, he was appointed as an assistant professor in the Graduate School of Pharmaceutical Sciences at the University of Tokyo. His research interests include the synthesis and chemical biology of biologically active natural products and their analogues with a particular focus on peptidic natural products and related molecules. Masayuki Inoue was born in Tokyo in 1971. He received his B.Sc. degree in Chemistry from the University of Tokyo in 1993. In 1998, he obtained his Ph.D. from the same university, working under the supervision of Prof. Kazuo Tachibana. After spending two years with Prof. Samuel J. Danishefsky at the Sloan-Kettering Institute for Cancer Research (1998−2000), he joined the Graduate School of Science at Tohoku University as an assistant professor in the research group of Prof. Masahiro Hirama. At Tohoku University, he was promoted to Lecturer in 2003 and then to Associate Professor in 2004. In 2007, he moved to the Graduate School of Pharmaceutical Sciences, The University of Tokyo, as a full professor. He has been honored with the Young Scientist’s Research Award in Natural Product Chemistry (2001), the First Merck-Banyu Lectureship Award (2004), The Chemical Society of Japan Award for Young Chemists (2004), Novartis Chemistry Lectureship 2008/2009, fifth JSPS Prize (2008), the Mukaiyama Award 2014, the Swiss Chemical Society Lectureship Award 2017/2018, and the Yomiuri Techno Forum Gold Medal Prize (2018). His research interests include the synthesis, design, and study of biologically important molecules, with particular emphasis on the total synthesis of structurally complex natural products.

AUTHOR INFORMATION Corresponding Author

*E-mail for M.I.: [email protected]. ORCID

ACKNOWLEDGMENTS

Hiroaki Itoh: 0000-0002-1329-6109 Masayuki Inoue: 0000-0003-3274-551X

This research was financially supported by Grants-in-Aid for Scientific Research (S) (17H06110) for Scientific Research on Innovative Areas (17H06452) to M.I. and for Young Scientists (B) (17K15421) to H.I. from JSPS.

Notes

The authors declare no competing financial interest. X

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