Total Synthesis of Trapoxin A, a Fungal HDAC Inhibitor from Helicoma

Phil Servatius and Uli Kazmaier*. Saarland University , Organic Chemistry I, Campus, Building C4.2, D-66123 Saarbrücken , Germany. J. Org. Chem. , 20...
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Total Synthesis of Trapoxin A, a Fungal HDAC Inhibitor from Helicoma ambiens Phil Servatius and Uli Kazmaier* Saarland University, Organic Chemistry I, Campus, Building C4.2, D-66123 Saarbrücken, Germany

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S Supporting Information *

ABSTRACT: Peptide modification reactions, e.g., via palladium-catalyzed allylic alkylations, are useful tools for the synthesis of peptides containing interesting nonproteinogenic amino acids, which are often essential for the biological activity of natural products and drugs. Herein we report the utilization of such modification reactions in the first total synthesis of trapoxin A, a naturally occurring tetrapeptidic histone deacetylase (HDAC) inhibitor.

I

t has been known for several decades that post-translational reversible histone acetylation at the ε-amino groups of conserved lysins plays a major role in the regulation of gene expression.1 Enzymatic modulations of these processes are histone acetyltransferases (HATs), also known as writers, and their counterparts, the histone deacetylases (HDACs), known as erasers.2 While these enzymes are responsible for altering the histones through covalent modifications, bromodomains act as readers of the acetylation state and complement the epigenetic toolbox.3 The HDACs are involved in cellular pathways controlling all shapes and differentiation. Therefore, inhibitors of these enzymes are interesting candidates for the treatment of cancer. Four relatively simple compounds, such as SAHA (vorinostat),4 have recently been approved by the FDA for this purpose.5 So far, 11 human Zn2+-dependent isoforms (HDAC 1−11) have been discovered,6 which can be subdivided into HDACs class I, IIa, IIb, and IV. Class IIa enzymes show less deacetylase activity compared to class I enzymes due to changes in the otherwise highly conserved active site.7 In addition, seven enzymes called sirtuins (class III) have been described, containing no Zn2+ in the active site and being NAD+dependent.8 These class III enzymes differ significantly from the others and are not affected by inhibitors such as SAHA, containing typical zinc-binding motifs. SAHA is an example of a synthetic HDAC inhibitor, showing three important parts of HDAC inhibitors (Figure 1): (a) a zinc-binding motif, in general, a hydroxamic acid, (b) a linker (spacer), which simulates the lysine side chain of the natural substrate, and (c) a cap region, which should interact with the surface of the protein surrounding the active site. While SAHA’s linker and Zn2+-binding group are perfectly designed to bind into the active center of the HDACs, the rather small cap region in © 2018 American Chemical Society

Figure 1. Functional structure of SAHA and trapoxin.

general does not allow specific binding toward the different isoenzymes, simply because the contact area is too small for differentiation. Luckily, a wide range of macrocyclic peptides have also been identified as naturally occurring HDAC inhibitors.9 For example, trapoxin, a fungal metabolite from Helicoma ambiens RF-102310 was found to cause accumulation of highly acetylated histones in various mammalian cell lines by irreversible inhibition of the deacetylating enzymes.11 In comparison to SAHA, trapoxin can also be divided into three parts: (a) the epoxy ketone as a Zn2+-binding motif, (b) a spacer, and (c) the peptide ring as cap region. Reduction of the epoxy ketone results in a loss of activity, indicating that the epoxy ketone probably acts as an irreversible inhibitor by binding covalently to the HDAC.10,11 In contrast, recent studies by Porter and Christianson found the epoxide moiety to be intact in a trapoxin A-HDAC6 cocrystal. The reported results indicate that trapoxin A acts as a mimic of the natural substrate after addition of water to the carbonyl function.12 Received: June 22, 2018 Published: August 6, 2018 11341

DOI: 10.1021/acs.joc.8b01569 J. Org. Chem. 2018, 83, 11341−11349

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The Journal of Organic Chemistry The epoxy ketone side chain of the (2S,9S)-2-amino-8-oxo9,10-epoxydecanoic acid (Aoe), acting as a warhead, is not unique to trapoxin, but is also the essential motif in several cyclopeptides such as chlamydocin,13 HC-toxin,14 and many others.9 The different natural products differ in the amino acid sequence and their configuration in the tetrapeptide ring. They show different selectivity toward the various HDACs, indicating that the substitution pattern of the peptide ring plays a significant role in surface recognition and selectivity. But all natural HDAC inhibitors of this family show some common features. They all contain at least one (R)-amino acid, a (hetero)aromatic, and a secondary amino acid, such as proline or pipecolinic acid. Most of these compounds also show cytotoxicity toward a panel of cancer cell lines in the low nanomolar range, which makes them interesting candidates for the development of antitumor drugs.15 While several syntheses have been accomplished toward chlamydocin16 and the other representatives,9 including the unusual amino acid Aoe, to the best of our knowledge, only one synthesis of trapoxin B was reported by Schreiber et al. in the mid 1990s.17 Our group is involved in the synthesis of unusual amino acids and peptidic natural products, preferably with anticancer activity. Recently, we synthesized and evaluated tubulin binders such as pretubulysin18 and some actin binding cyclodepsipeptides.19 This brought our focus also on the HDACs as interesting targets for the development of new cytostatics.16f,20 Our aim was to develop a rather flexible protocol which allows us to introduce substituents and modifications at several positions, e.g., for SAR studies. Since the trapoxins are by far less investigated, compared to other cyclopeptide inhibitors, and nothing is reported about their cytotoxicity profile, we decided to develop exemplarily a synthesis of trapoxin A, based on a stereoselective peptide enolate modification approach.21 This concept goes back to the work of Seebach et al. developed in the mid 1980s22 when his group had shown that rather complex natural products, such as cyclosporin, could be alkylated regioselectively at sarcosine subunits.23 While cyclic peptides generally give good diastereoselectivities, the stereoselectivity of the alkylation step with linear peptides is a serious issue.24 This is mainly caused by an unknown conformation of the polydeprotonated peptide formed under the basic reaction conditions. We could solve this problem by adding multivalent metal salts, probably resulting in the formation of a metal−peptide enolate complex,25 in which one face of the peptide enolate is shielded by the side chain of the adjacent amino acid. Generally, an (S)amino acid generates an (R)-amino acid and the other way round. This effect is observed with intramolecular reactions, such as Claisen rearrangements,26 but also intermolecular ones, e.g., transition-metal-catalyzed allylic alkylations of peptides.27 We decided to apply a combination of stereoselective chelate− enolate Claisen rearrangement and diastereoselective allylic alkylation for the synthesis of the (R)-Pip-(S)-Aoe fragment A (Scheme 1). For stereoselective peptide enolate allylations, a N-terminal primary amine functionality is required, allowing deprotonation and peptide−metal complex formation. Therefore, a suitable precursor for the synthesis of B should be C with a functionalized side chain allowing subsequent cyclization toward the desired pipecolic acid moiety. This side chain can easily be introduced via asymmetric chelate Claisen rearrangement of chiral glycine ester D.28 The required chiral building blocks 1 and 2 (Scheme 2) for this approach could both easily be obtained from tartaric acids.

Scheme 1. Retrosynthetic Analysis for A

Scheme 2. Required Chiral Building Blocks from Tartaric Acids

Enantiomerically pure allyl alcohol 1 was prepared from Dtartaric acid,29 while L-tartaric acid was used for the synthesis of 2,17,20,30 which was converted into the carbonate 3 as substrate for the allylic alkylation. Esterification of 1 with Cbz-protected glycine using Steglich’s protocol31 afforded 4 in high yield (Scheme 3). Subsequent ester enolate Claisen rearrangement with LDA and ZnCl2 proceeded readily and with good transfer of the stereogenic information via a chairlike transition state. The obtained amino acid 5 was directly coupled to afford dipeptide 6 via a mixed anhydride. In principle, modifications on the side chain can be performed on this stage. But for the synthesis of Scheme 3. Synthesis of Dipeptide 9 via Chelate Claisen Rearrangement/Allylic Alkylation

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DOI: 10.1021/acs.joc.8b01569 J. Org. Chem. 2018, 83, 11341−11349

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The Journal of Organic Chemistry trapoxin, hydrogenation of the double bond and simultaneous cleavage of the Cbz group with Pd/C afforded the free amine, which was directly TFA protected (7). This protecting group has been chosen because previous studies had revealed that the combination of TFA-protected N-termini with C-terminal tBu esters give the best diastereoselectivities in the allylation step.27 Therefore, dipeptide 7 was subjected to a Pd-catalyzed allylic alkylation using allyl carbonate 3, providing the allylated dipeptide 8 with good yield and diastereoselectivity in favor of the required (S)-configured Aoe precursor. Cleavage of the benzyl ether proved to be challenging and was accomplished only at pressures as high as 30 bar in THF for several hours. Finally, the corresponding alcohol was obtained in almost quantitative yield and could subsequently be subjected to a Mitsunobu cyclization, giving rise to dipeptide 9. Saponification of the TFA group in 9 under standard conditions seemed to proceed, but isolation of the free amine from the reaction mixture failed. Therefore, we utilized a protocol developed by Weygand and Frauendorfer to reduce the TFA-group with NaBH4 in ethanolic solution.32 The crude product was then coupled to Cbz-(S)-Phe-OH using TBTU as a coupling reagent. Subsequent cleavage of the Cbz protecting group and coupling to another Cbz-(S)-Phe-OH using the same protocol afforded linear tetrapeptide 11 in high yield (Scheme 4). Unfortunately, all attempts to cleave the tBu ester in 11 failed. Careful analysis of the reaction mixture indicated a progressive decomposition starting with TIPS deprotection. Therefore, we replaced the TIPS-protecting group by a tosylate through cleavage with TBAF and consecutive treatment with TosCl in pyridine (12). Installing the tosylate at this point of the synthesis diminished the number of transformations with the cyclic peptide, since the tosylate is used to build up the epoxide on a later stage. To our delight, cleavage of the tBu ester of 12 with TMSOTf proceeded without decomposition, but surprisingly, the yield of this reaction never exceeded 50% and the reaction suffered from poor reproducibility. We therefore decided to synthesize 13 by removal of the ketal, subsequent cleavage of the tBu ester, and reinstallation of the ketal in three steps without intermediate purification. This protocol proved to be more robust and convenient with higher yields compared to the previous one step transformation. With linear tetrapeptide 13 in hand, activation as the pentafluorophenyl (Pfp) ester proceeded readily and with excellent yields. Subsequent cyclization of this active ester 14 was not a trivial issue. Liberating the N-terminus by hydrogenation of the Cbz group was a severe problem and failed under a wide range of reaction conditions. Finally, performing the reaction at 85 °C and passing through a continuous stream of H2 yielded 28% of the cyclic tetrapeptide 15 as a single diastereomer. With this compound in hand, we were able to finish the total synthesis of trapoxin A using an approach following Schreiber’s synthesis17 of trapoxin B. Acidic cleavage of the ketal with aq HCl afforded the corresponding diol, which was then subjected to a basemediated epoxidation using DBU. Epoxy alcohol 16 was finally oxidized with Dess−Martin periodinane to give trapoxin A. The NMR spectra of our synthetic compound were in accordance to previously reported data of the isolated natural product.10 In conclusion, we have developed a straightforward protocol to synthesize the natural HDAC inhibitor trapoxin A. We could show that chelate enolate Claisen rearrangements, in combination with palladium-catalyzed allylic alkylations, are

Scheme 4. Synthesis of Trapoxin A

powerful tools for the construction of complex, nonproteinogenic amino acids. The developed protocol not only allows the synthesis of the natural product but should also be suitable for the synthesis of various derivatives by altering the allyl substrates in the peptide modification steps. Further investigations concerning the influence of different side chains on the biological activity and the selectivity toward the different HDAC isoforms are currently under investigation.

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EXPERIMENTAL SECTION

General Remarks. All air- or moisture-sensitive reactions were carried out in dried glassware (>100 °C) under an atmosphere of nitrogen or argon. THF was distilled over Na/benzophenone prior to use. Ethyl acetate (EtOAc) and petroleum ether (PE) were distilled prior to use. Reactions were monitored by analytical TLC, which was performed on precoated silica gel on TLC PET-foils. Visualization 11343

DOI: 10.1021/acs.joc.8b01569 J. Org. Chem. 2018, 83, 11341−11349

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The Journal of Organic Chemistry was accomplished with UV light (254 nm), KMnO4 solution, or Ce(IV) solution. The products were purified by flash chromatography on silica gel columns (0.063−0.2 mm) or by automated flash chromatography. Mixtures of EtOAc and PE were generally used as eluents. Melting points were determined with a melting point apparatus and are uncorrected. 1H and 13C NMR spectra were recorded with a 400 MHz (100 MHz) or 500 MHz (125 MHz) spectrometer in CDCl3 unless otherwise specified. Chemical shifts are reported in ppm relative to Si(CH3)4, and CHCl3 was used as the internal standard. Multiplicities are reported as br (broad signal), s (singlet), d (doublet), t (triplet), q (quartet), and m (multiplet). Mass spectra were recorded with a high-resolution quadrupole spectrometer (CI) or a UHR-TOF spectrometer using the ESI technique. HPLC analyses were performed using a diode array detector. Optical rotations were measured in a thermostated (20 ± 1 °C) cuvette. The radiation source used was a sodium vapor lamp (λ = 589 nm). The concentrations are given in g/100 mL. Preparation of Starting Materials. Unless otherwise stated, all starting materials were commercially available and were used without further purification. Allylic alcohols 133 and 220 were prepared according to literature procedures. (R)-5-((4S,5S)-2,2-Dimethyl-5-(((triisopropylsilyl)oxy)methyl)-1,3-dioxolan-4-yl)pent-1-en-3-yl Ethyl Carbonate (3). A solution of allylic alcohol 2 (2.18 g, 5.85 mmol) in dry pyridine (7.5 mL) was cooled to 0 °C before ethyl chloroformate (1.12 mL, 1.27 g, 11.7 mmol) was added carefully, and the reaction was allowed to warm to room temperature within 5 h. For workup, the reaction mixture was diluted with Et2O, and 1 M CuSO4 solution was added. The layers were separated, and the organic phase was washed three times with CuSO4 solution (1 M) and dried over Na2SO4. Purification by column chromatography (silica, PE/EtOAc 100:0, 90:10) afforded allylic carbonate 3 (2.41 g, 5.42 mmol, dr > 99:1, 93%) as a colorless oil. [α]20 D = −3.5 (c = 1.0, CHCl3). TLC: PE/EtOAc = 90:10, Rf = 0.39. 1H NMR (400 MHz, CDCl3): δ = 1.02−1.14 (m, 21 H), 1.30 (t, J = 7.2 Hz, 3 H), 1.36 (s, 3 H), 1.39 (s, 3 H), 1.59 (m, 1 H), 1.75− 1.93 (m, 3 H), 3.70 (m, 1 H), 3.72 (dd, J = 9.8 Hz, 6.4 Hz, 1 H), 3.88 (dd, J = 9.5 Hz, 3.2 Hz, 1 H), 3.91 (m, 1 H), 4.18 (q, J = 7.2 Hz, 2 H), 5.08 (dt, J = 6.2 Hz, 6.2 Hz, 1 H), 5.20 (d, J = 10.5 Hz, 1 H), 5.30 (d, J = 17.2 Hz, 1 H), 5.80 (ddd, J = 17.2 Hz, 10.5 Hz, 6.7 Hz, 1 H). 13 C NMR (100 MHz, CDCl3): δ = 11.8, 14.2, 17.9, 27.0, 27.4, 29.1, 30.9, 63.8, 64.2, 78.6, 79.2, 80.9, 108.5, 117.5, 135.9, 154.6. HRMS (CI): calcd for C23H45O6Si [M + H]+ 445.2980, found 445.2990. (S)-1-(Benzyloxy)but-3-en-2-yl ((Benzyloxy)carbonyl)glycinate (4). Cbz-Gly-OH (230 mg, 1.10 mmol) and alcohol 1 (178 mg, 1.00 mmol) were dissolved in dry CH2Cl2 (10 mL) and cooled to 0 °C before DCC (227 mg, 1.10 mmol) and 4-DMAP (12.4 mg, 0.101 mmol) were added subsequently. The reaction was allowed to warm to room temperature overnight. For workup, the solution was filtrated through a pad of Celite and washed with CH2Cl2. The filtrate was concentrated in vacuo. Purification by column chromatography (silica, PE/EtOAc 100:0, 80:20) afforded 4 (331 mg, 0.896 mmol, 90%) as an off-white solid. [α]20 D = +2.7 (c = 1.0, CHCl3). TLC: PE/ EtOAc = 70:30, Rf = 0.20. HPLC: Reprosil, n-hexane/iPrOH 80:20, 1.0 mL/min, 20 °C. (S)-4: tR = 15.1 min (>99%). 1H NMR (400 MHz, CDCl3): δ = 3.58 (d, J = 5.5 Hz, 2 H), 4.03 (d, J = 5.5 Hz, 2 H), 4.52 (d, J = 12.3 Hz, 1 H), 4.58 (d, J = 12.3 Hz, 1 H), 5.13 (s, 2 H), 5.24 (br, 1 H), 5.27 (d, J = 10.8 Hz, 1 H), 5.34 (d, J = 17.3 Hz, 1 H), 5.54 (dt, J = 6.3 Hz, 5.5 Hz, 1 H), 5.82 (ddd, J = 17.3 Hz, 10.8 Hz, 6.3 Hz, 1 H), 7.27−7.38 (m, 10 H). 13C NMR (100 MHz, CDCl3): δ = 42.9, 67.1, 71.0, 73.2, 74.5, 118.7, 127.6, 127.8, 128.1, 128.2, 128.4, 128.5, 132.5, 136.2, 137.7, 156.1, 169.2. HRMS (CI): calcd for C21H24NO5 [M + H]+ 370.1649, found 370.1644. (R,E)-6-(Benzyloxy)-2-(((benzyloxy)carbonyl)amino)hex-4enoic Acid (5). A solution of diisopropylamine (2.50 mL, 1.78 g, 17.6 mmol) in dry THF (17.5 mL) was cooled to −78 °C before nBuLi (9.4 mL, 15.0 mmol, 1.6 M in hexanes) was added dropwise. The cooling bath was removed, and the reaction was stirred for 10 min at room temperature. Zinc chloride (822 mg, 6.03 mmol, dried in high vacuo) was dissolved in dry THF (5.0 mL) and treated with a solution of 1.85 g (5.01 mmol) 4 in dry THF (20 mL) at room

temperature. The zinc chloride/amino acid ester solution was cooled to −78 °C and treated with the above-prepared LDA solution carefully. The remaining dry ice was removed, and the reaction was allowed to warm to room temperature overnight. For workup, the solution was diluted with Et2O, and 1 M KHSO4 solution was added. The layers were separated, and the aqueous phase was extracted three times with Et2O. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography (silica, CH2Cl2/MeOH 99:1, 98:2, 95:5) gave two fractions of 5 (302 mg, 0.695 mmol, 14%, slightly contaminated with allylic alcohol 1, and 1.44 g, 3.90 mmol, er 96:4, 78%) as a slightly yellow oil. [α]20 D = −27.2 (c = 1.0, CHCl3). TLC: PE/EtOAc = 50:50, Rf = 0.05. 1H NMR (400 MHz, CDCl3): δ = 2.54 (ddd, J = 13.9 Hz, 7.1 Hz, 6.5 Hz, 1 H), 2.63 (ddd, J = 13.9 Hz, 6.3 Hz, 5.8 Hz, 1 H), 3.96 (m, 2 H), 4.45−4.50 (m, 3 H), 5.10 (s, 2 H), 5.34 (d, J = 8.0 Hz, 1 H), 5.62 (dt, J = 15.3 Hz, 6.9 Hz, 1 H), 5.71 (dt, J = 15.3 Hz, 5.5 Hz, 1 H), 7.00 (br, 1 H), 7.26−7.37 (m, 10 H). 13C NMR (100 MHz, CDCl3): δ = 34.9, 53.1, 67.2, 70.0, 72.1, 127.1, 127.7, 127.8, 128.1, 128.2, 128.4, 128.5, 131.3, 136.0, 137.9, 155.9, 175.3. HRMS (CI) calcd for C21H24NO5 [M + H]+: 370.1649, found 370.1654. HPLC: A small sample was derivatized with TMS-diazomethane to obtain the corresponding Me ester for HPLC analysis: Reprosil, n-hexane/iPrOH 60:40, 1.0 mL/min, 20 °C. (R)-5: tR = 16.6 min (96%), (S)-5: tR = 22.2 min (4%). tert-Butyl (R,E)-(6-(Benzyloxy)-2-(((benzyloxy)carbonyl)amino)hex-4-enoyl)glycinate (6). To a solution of 5 (2.10 g, 5.68 mmol) in dry THF (55 mL) was added N-methylmorpholine (0.64 mL, 589 mg, 5.82 mmol) before isobutyl chloroformate (0.75 mL, 786 mg, 5.76 mmol) was added dropwise at −20 °C. The reaction was stirred for 10 min before HCl·H-Gly-OtBu (953 mg, 5.69 mmol) and further N-methylmorpholine (0.64 mL, 589 mg, 5.82 mmol) were added, and the reaction was allowed to warm to room temperature overnight. The reaction was then filtered and washed with Et2O. The filtrate was concentrated in vacuo and dissolved in Et2O. HCl solution (1 M) was added, and the layers were separated. The aqueous phase was extracted three times with Et2O. The combined organic layers were washed with satd NaHCO3 solution and dried over Na2SO4. The crude product was purified by column chromatography (silica, PE/EtOAc 90:10, 70:30). Dipeptide 6 (2.47 g, 5.12 mmol, er > 99:1, 90%) was obtained as a slightly yellow oil. [α]20 D = +0.8 (c = 1.0, CHCl3). TLC: PE/EtOAc = 50:50, Rf = 0.32. HPLC: Reprosil, n-hexane/iPrOH 80:20, 1.0 mL/min, 20 °C. (R)-6: tR = 33.8 min (>99%). 1H NMR (400 MHz, CDCl3): δ = 1.46 (s, 9 H), 2.55 (m, 2 H), 3.91 (m, 2 H), 3.96 (m, 2 H), 4.28 (m, 1 H), 4.47 (s, 2 H), 5.10 (s, 2 H), 5.35 (d, J = 6.0 Hz, 1 H), 5.62−5.75 (m, 2 H), 6.55 (br, 1 H), 7.26−7.35 (m, 10 H). 13C NMR (100 MHz, CDCl3): δ = 28.0, 35.4, 42.0, 54.2, 67.2, 70.2, 72.1, 82.4, 127.6, 127.8, 127.8, 128.1, 128.2, 128.4, 128.5, 131.3, 136.0, 138.1, 156.0, 168.6, 170.9. HRMS (CI): calcd for C27H35N2O6 [M + H]+ 483.2490, found 483.2493. tert-Butyl (R)-(6-(Benzyloxy)-2-(2,2,2-trifluoroacetamido)hexanoyl)glycinate (7). To a solution of 6 (1.60 g, 3.32 mmol) in MeOH (15 mL) was added palladium on carbon (163 mg, 10 wt % Pd) at room temperature. The reaction was set under a H 2 atmossphere and hydrogenated for 4 h. Afterward, the reaction was filtrated through a pad of Celite and washed with MeOH. The filtrate was concentrated in vacuo and dissolved in MeOH (15 mL). TFAOMe (0.67 mL, 853 mg, 6.66 mmol) was added at 0 °C, and the reaction was allowed to warm to room temperature overnight. The reaction mixture was concentrated and dissolved in Et2O. HCl solution (1 M) was added, and the layers were separated. The aqueous phase was extracted three times with Et2O, and the combined organic layers were dried over Na2SO4. Purification by column chromatography (silica, PE/EtOAc 70:30) gave dipeptide 7 (1.32 g, 2.96 mmol, er 95:5, 89%) as a colorless oil. [α]20 D = −2.1 (c = 1.0, CHCl3). TLC: PE/EtOAc = 50:50, Rf [7] = 0.48. HPLC: Reprosil, nhexane/iPrOH 90:10, 1.0 mL/min, 20 °C. (R)-7: tR = 11.2 min (95%). (S)-7: tR = 13.1 min (5%). 1H NMR (400 MHz, CDCl3): δ = 1.47 (s, 9 H,), 1.49 (m, 2 H), 1.62−1.79 (m, 3 H), 1.94 (m, 1 H), 3.48 (dt, J = 9.4 Hz, 6.2 Hz, 1 H), 3.53 (dt, J = 9.5 Hz, 6.0 Hz, 1 H), 11344

DOI: 10.1021/acs.joc.8b01569 J. Org. Chem. 2018, 83, 11341−11349

Note

The Journal of Organic Chemistry 3.73 (dd, J = 18.3 Hz, 4.8 Hz, 1 H), 3.91 (dd, J = 18.2 Hz, 5.7 Hz, 1 H), 4.49 (s, 2 H), 4.50 (m, 1 H), 6.36 (t, J = 4.9 Hz, 1 H), 7.25−7.37 (m, 6 H). 13C NMR (100 MHz, CDCl3): δ = 22.0, 28.0, 28.8, 32.5, 42.0, 53.1, 70.0, 73.0, 82.7, 115.7 (q, J = 288 Hz), 127.7, 127.8, 128.4, 138.2, 156.8 (q, J = 37 Hz), 168.3, 169.9. HRMS (CI): calcd for C21H30F3N2O5 [M + H]+ 447.2101, found 447.2104. tert-Butyl (S,E)-2-((R)-6-(Benzyloxy)-2-(2,2,2trifluoroacetamido)hexanamido)-7-((4S,5S)-2,2-dimethyl-5(((triisopropylsilyl)oxy)methyl)-1,3-dioxolan-4-yl)hept-4enoate (8). A solution of diisopropylamine (2.10 mL, 1.49 g, 14.7 mmol) in dry THF (30 mL) was treated with n-BuLi (8.30 mL, 13.3 mmol, 1.6 M in hexanes) at −78 °C. The cooling bath was removed, and the solution was stirred at room temperature for 15 min. Compound 7 (1.70 g, 3.81 mmol) was dissolved in dry THF (30 mL) before zinc chloride (637 mg, 4.67 mmol, dried in high vacuo) was added at room temperature. The resulting mixture was cooled to −78 °C, and the above-prepared LDA solution was added slowly at this temperature. The mixture was stirred at −78 °C for 30 min. [AllylPdCl]2 (25.5 mg, 69.7 μmol) and PPh3 (60.4 mg, 230 μmol) were dissolved in dry THF (7.5 mL) before 3 (1.14 g, 2.56 mmol) was added, and the mixture was stirred at room temperature for 5 min. Afterward, the catalyst/allylic substrate solution was transferred to the zinc enolate at −78 °C, and the mixture was allowed to warm to room temperature overnight (remaining dry ice was removed from the cooling bath). For workup, the solution was diluted with Et2O, and NH4OAc/HOAC buffer was added. The layers were separated, and the aqueous phase was extracted three times with Et2O. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (silica, PE/EtOAc 100:0, 90:10, 80:20, 70:30, 50:50) to obtain two fractions of 8 with different diastereomeric ratios (196 mg, 0.245 mmol, dr 64:36, and 1.55 g, 1.93 mmol, dr 82:18, 85% total yield) as slightly yellow oils. TLC: PE/EtOAc = 80:20, Rf = 0.11 (both diastereomers). HPLC: Reprosil, n-hexane/iPrOH 95:5, 1.0 mL/min, 20 °C. (2R,R)-8: tR = 16.1 min (18%). (2S,R)-8: tR = 17.9 min (82%). (2S,R)-Diastereomer: 1H NMR (400 MHz, CDCl3): δ = 1.02−1.15 (m, 21 H), 1.36 (s, 3 H), 1.39 (s, 3 H), 1.46 (s, 9 H), 1.46 (m, 2 H), 1.56−1.77 (m, 5 H), 1.90 (m, 1 H), 2.09 (m, 1 H), 2.19 (m, 1 H), 2.43 (dd, J = 14.0 Hz, 6.2 Hz, 1 H), 2.50 (dd, J = 14.1 Hz, 6.4 Hz, 1 H), 3.46 (m, 2 H), 3.69 (m, 1 H), 3.73 (dd, J = 10.0 Hz, 6.0 Hz, 1 H), 3.86 (dd, J = 10.0 Hz, 3.9 Hz, 1 H), 3.92 (td, J = 7.7 Hz, 3.4 Hz, 1 H), 4.44−4.54 (m, 2 H), 4.49 (s, 2 H), 5.28 (dt, J = 14.9 Hz, 7.3 Hz, 1 H), 5.51 (dt, J = 14.6 Hz, 7.0 Hz, 1 H), 6.33 (d, J = 7.5 Hz, 1 H), 7.22 (d, J = 7.6 Hz, 1 H), 7.27−7.36 (m, 5 H). 13C NMR (100 MHz, CDCl3): δ = 11.8, 17.9, 21.9, 27.0, 27.4, 28.0, 29.1 (2×), 32.7, 33.0, 35.4, 52.5, 53.3, 64.1, 69.6, 72.9, 78.6, 80.8, 82.6, 108.5, 123.5, 127.6, 127.7, 128.4, 134.8, 138.3, 156.7 (q, J = 37 Hz), 169.1, 170.2. The signal of −CF3 was not observed in the 13C NMR spectrum. (2R,R)diastereomer (selected signals): 1H NMR (400 MHz, CDCl3): δ = 1.38 (s, 3 H), 1.46 (s, 9 H), 2.56 (m, 2 H), 5.09 (m, 1 H), 6.37 (d, J = 7.2 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 27.9. HRMS (CI): calcd for C41H68F3N2O8Si [M + H]+ 801.4692, found 801.4702. tert-Butyl (S)-7-((4S,5S)-2,2-Dimethyl-5-(((triisopropylsilyl)oxy)methyl)-1,3-dioxolan-4-yl)-2-((R)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxamido)heptanoate (9). To a solution of 8 (1.52 g, 1.90 mmol) in THF (15 mL) was added palladium on charcoal (151 mg, 10 wt % Pd) at room temperature. The reaction was set under H2 atmosphere (20 bar) for 18 h and after addition of HOAc (5.4 μL, 5.7 mg, 94.9 μmol) for additional 22 h under 30 bar H2 atmosphere. The reaction was then filtrated through a pad of Celite and washed with Et2O. The filtrate was concentrated in vacuo. The crude product was purified by column chromatography (silica gel, PE/EA 70:30, 50:50) to yield the corresponding alcohol (1.34 g, 1.88 mmol, 99%) for subsequent cyclization. Then a solution of PPh3 (553 mg, 2.11 mmol) in dry THF (80 mL) was treated with DIAD (411 μL, 427 mg, 2.11 mmol) at 0 °C. Afterward, a solution of the above prepared alcohol (941 mg, 1.32 mmol) in dry THF (50 mL) was added dropwise, and the reaction was allowed to warm to room temperature overnight. For workup, the solution was concentrated in vacuo, and the crude product was purified by column chromatography

(silica, PE/EtOAc 80:20). Dipeptide 9 (902 mg, 1.30 mmol, dr 80:20, rotameric ratio 80:20, 98%) was obtained as a slightly yellow oil. TLC: PE/EtOAc = 70:30, Rf = 0.54 (both diastereomers). HPLC: Reprosil, n-hexane/iPrOH 95:5, 1.0 mL/min, 20 °C. (2R,R)-9: tR = 11.1 min (20%). (2S,R)-9: tR = 17.2 min (80%). Major diastereomer/ rotamer: 1H NMR (400 MHz, CDCl3): δ = 1.02−1.16 (m, 21 H), 1.28−1.41 (m, 5 H), 1.36 (s, 3 H), 1.39 (s, 3 H), 1.45 (s, 9 H), 1.50− 1.86 (m, 10-H), 2.31 (d, J = 12.8 Hz, 1 H), 3.35 (ddd, J = 14.1 Hz, 11.4 Hz, 2.5 Hz, 1 H), 3.68 (m, 1 H), 3.75 (dd, J = 10.2 Hz, 5.9 Hz, 1 H), 3.86 (dd, J = 10.3 Hz, 4.0 Hz, 1 H), 3.92 (m, 1 H), 3.95 (m, 1 H), 4.43 (dt, J = 7.4 Hz, 5.8 Hz, 1 H), 5.14 (d, J = 5.0 Hz, 1 H), 6.20 (d, J = 7.6 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 11.9, 17.9, 21.5, 25.0, 26.1, 26.9, 27.4, 28.0, 29.4, 31.7, 32.3, 32.7, 33.4, 52.9, 53.2, 62.1, 64.1, 79.1, 81.0, 82.6, 108.4, 115.7 (q, J = 288 Hz), 156.7 (q, J = 37 Hz), 169.3, 170.0. Minor diastereomer/rotamer (selected signals): 1 H NMR (400 MHz, CDCl3): δ = 1.35 (s, 3 H), 1.46 (s, 9 H), 2.49 (d, J = 12.8 Hz, 1 H), 3.03 (m, 1 H), 4.48 (m, 1 H), 4.55 (d, J = 13.9 Hz, 1 H), 4.62 (m, 1 H), 5.10 (m, 1 H), 6.22 (m, 1 H). 13C NMR (100 MHz, CDCl3): δ = 21.0, 25.9, 53.1. HRMS (CI): calcd for C34H62F3N2O7Si [M + H]+ 695.4273, found 695.4287. tert-Butyl (S)-2-((R)-1-(((Benzyloxy)carbonyl)-Lphenylalanyl)piperidine-2-carboxamido)-7-((4S,5S)-2,2-dimethyl-5-(((triisopropylsilyl)oxy)methyl)-1,3-dioxolan-4-yl)heptanoate (10). Dipeptide 9 (876 mg, 1.26 mmol) was dissolved in dry EtOH (6.5 mL) and cooled to 0 °C before NaBH4 (97 mg, 2.56 mmol) was added slowly. The solution was stirred at room temperature for 15 min before acetone was added, and stirring was continued for 15 min. The solution was concentrated in vacuo, and the residue was dissolved in CH2Cl2. K2CO3 solution (10 wt %) was added, and the layers were separated. The aqueous phase was extracted three times with CH2Cl2, and the combined organic layers were dried over Na2SO4. The corresponding amine was then dissolved in dry acetonitrile (15 mL) at room temperature before Cbz-(S)-Phe-OH (421 mg, 1.41 mmol), TBTU (446 mg, 1.39 mmol), and DIPEA (256 μL, 189 mg, 1.46 mmol) were added subsequently. The mixture was stirred at room temperature overnight. For workup, the solution was concentrated in vacuo, and the residue was dissolved in CH2Cl2. HCl solution (1 M) was added, and the layers were separated. The aqueous phase was extracted three times with CH2Cl2, and the combined organic layers were washed with satd NaHCO3 solution and dried over Na2SO4. Purification by column chromatography (silica, PE/EtOAc 70:30) gave tripeptide 10 (1.05 g, 1.19 mmol, dr 81:19, rotameric ratio 72:28, 94% over two steps) as an off-white solid. TLC: PE/EtOAc = 70:30, Rf = 0.30 (both diastereomers). HPLC: Reprosil, n-hexane/iPrOH 90:10, 1.0 mL/ min, 20 °C. (2R,R,S)-10: tR = 21.6 min (5%, minor rotamer). (2S,R,S)-10: tR = 25.2 min (25%, minor rotamer). (2R,R,S)-10: tR = 30.7 min (14%, major rotamer). (2S,R,S)-10: tR = 36.3 min (56%, major rotamer). Major diastereomer/rotamer: 1H NMR (500 MHz, 373 K, DMSO-d6): δ = 1.04−1.14 (m, 21 H), 1.25−1.35 (m, 7 H), 1.30 (s, 3 H), 1.31 (s, 3 H), 1.37−1.44 (m, 4 H), 1.40 (s, 9 H), 1.45− 1.66 (m, 3 H), 1.71 (m, 1 H), 2.16 (d, J = 10.0 Hz, 1 H), 2.94 (d, J = 6.9 Hz, 2 H), 2.98 (br, 2 H), 3.64 (m, 1 H), 3.75 (dd, J = 10.7 Hz, 4.8 Hz, 1 H), 3.80 (dd, J = 10.7 Hz, 4.5 Hz, 1 H), 3.85 (td, J = 7.6 Hz, 4.3 Hz, 1 H), 4.17 (dt, J = 7.1 Hz, 7.1 Hz, 1 H), 4.72 (br, 1 H), 4.96− 5.05 (m, 3 H), 7.19−7.36 (m, 11 H). The signal of Cbz-NH was not observed in the 1H NMR spectrum. 13C NMR (125 MHz, 373 K, DMSO-d6): δ = 11.1, 17.2, 19.4, 23.7, 24.6, 24.7, 26.4, 26.8, 27.2, 28.0, 30.4, 32.3, 37.1, 51.4, 52.4, 63.4, 65.1, 77.3, 80.0, 80.6, 107.2, 125.9, 126.9, 127.2, 127.6, 127.7, 128.8, 136.4, 170.4. The signals of six carbons were not observed in the 13C NMR spectrum. Minor diastereomer/rotamer (selected signals): 1H NMR (500 MHz, 373 K, DMSO-d6): δ = 1.79 (m, 1 H), 3.10 (dd, J = 14.1 Hz, 4.9 Hz, 1 H), 4.27 (m, 1 H), 4.40 (m, 1 H). HRMS (CI): calcd for C49H78N3O9Si [M + H]+ 880.5502, found 880.5510. tert-Butyl (S)-2-((R)-1-(((Benzyloxy)carbonyl)-L-phenylalanyl-L-phenylalanyl)piperidine-2-carboxamido)-7-((4S,5S)-2,2dimethyl-5-(((triisopropylsilyl)oxy)methyl)-1,3-dioxo-lan-4yl)heptanoate (11). A solution of 10 (770 mg, 0.875 mmol) in MeOH (7.5 mL) was treated with palladium on carbon (77 mg, 10 wt 11345

DOI: 10.1021/acs.joc.8b01569 J. Org. Chem. 2018, 83, 11341−11349

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The Journal of Organic Chemistry

carbons were not observed in the 13C NMR spectrum. HRMS (CI): calcd for C56H73N4O12S [M + H]+ 1025.4940, found 1025.4942. (S)-2-((R)-1-(((Benzyloxy)carbonyl)- L -phenylalanyl- L phenylalanyl)piperidine-2-carboxamido)-7-((4S,5S)-2,2-dimethyl-5-((tosyloxy)methyl)-1,3-dioxolan-4-yl)heptanoic Acid (13). Method A: To a solution of 12 (25 mg, 24.4 μmol) in dry CH2Cl2 (0.25 mL) were added triethylamine (6.1 μL, 4.43 mg, 43.8 μmol) and TMSOTf (7.24 μL, 8.89 mg, 40.0 μmol) at 0 °C. The cooling bath was removed, and the reaction mixture was stirred at room temperature for 2 h. For workup, the solution was diluted with CH2Cl2 and water was added. The layers were separated, and the aqueous phase was extracted three times with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography (silica, CH2Cl2/MeOH 100:0, gradient 95:5) gave 13 (11.5 mg, 11.9 μmol, 49%) as an offwhite solid. Method B: Compound 12 (500 mg, 0.488 mmol) was dissolved in THF (2.5 mL) before aq HCl (2.5 mL, 5 wt %) was added at room temperature. The solution was heated to 60 °C overnight. For workup, the solution was diluted with CH2Cl2, and brine was added. The layers were separated, and the aqueous phase was extracted three times with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was dissolved in dry CH2Cl2 (2.5 mL), and TFA (2.5 mL, 3.73 g, 32.7 mmol) was added dropwise at room temperature. The mixture was stirred for 2 h at room temperature and concentrated in vacuo. The crude product was then treated with pTsOH·H2O (4.8 mg, 25.2 μmol) in acetone (5.0 mL) at 60 °C overnight. The reaction mixture was concentrated in vacuo and purified by column chromatography (silica, CH2Cl2/MeOH 100:0, gradient 95:5). Acid 13 (373 mg, 0.385 mmol, 79% over three steps) was obtained as an off-white solid. TLC: CH2Cl2/MeOH 95:5, Rf = 0.35. Major diastereomer: 1H NMR (400 MHz, CDCl3): δ = 1.17−1.37 (m, 9 H), 1.27 (s, 3 H), 1.33 (s, 3 H), 1.37−1.49 (m, 3 H), 1.54−1.68 (m, 2 H), 1.83 (m, 1 H), 2.20 (m, 1 H), 2.44 (s, 3 H), 2.82 (m, 1 H), 2.91 (dd, J = 12.9 Hz, 5.7 Hz, 1 H), 2.95 (m, 1 H), 3.02 (m, 1 H), 3.05 (dd, J = 13.5 Hz, 4.3 Hz, 1 H), 3.48 (d, J = 12.4 Hz, 1 H), 3.68−3.81 (m, 2 H), 4.05 (m, 2 H), 4.38−4.50 (m, 2 H), 4.92 (m, 1 H), 5.04 (m, 2 H), 5.18 (br, 1 H), 5.39 (d, J = 7.5 Hz, 1 H), 6.98−7.06 (m, 2 H), 7.11−7.38 (m, 17-H), 7.79 (d, J = 8.3 Hz, 2 H). 13C NMR (100 MHz, CDCl3): δ = 19.9, 21.6, 24.7, 24.7, 25.4, 25.6, 26.6, 27.3, 29.0, 31.5, 32.8, 38.0, 38.2, 43.7, 50.9, 52.1 (2×), 55.8, 67.3, 69.2, 77.6, 78.1, 109.3, 127.1, 128.0, 128.3, 128.6, 128.6, 129.4, 129.5, 129.9, 132.7, 136.0, 145.0, 171.0, 174.6. The signals of seven carbons were not observed in the 13C NMR spectrum. Minor diastereomer (selected signals): 1H NMR (400 MHz, CDCl3): δ = 4.68 (m, 1 H), 5.49 (m, 1 H). HRMS (CI): calcd for C52H65N4O12S [M + H]+ 969.4314, found 969.4326. Perfluorophenyl (S)-2-((R)-1-(((Benzyloxy)carbonyl)-L-phenylalanyl- L -phenylalanyl)piperidine-2-carboxamido)-7((4S,5S)-2,2-dimethyl-5-((tosyloxy)methyl)-1,3-dioxolan-4-yl)heptanoate (14). To a solution of 13 (53.5 mg, 55.2 μmol) in dry CH2Cl2 (0.55 mL) were added pentafluorophenol (12.7 mg, 69.0 μmol) and EDC·HCl (13.7 mg, 71.5 μmol) at 0 °C. The reaction mixture was allowed to warm to room temperature overnight. For workup, the solution was diluted with CH2Cl2, and 1 M HCl solution was added. The layers were separated, and the aqueous phase was extracted three times with CH2Cl2. The combined organic phases were washed with satd NaHCO3 solution and dried over Na2SO4. Pfp ester 14 (61.4 mg, 54.1 μmol, dr 76:24, 98%) was obtained as an offwhite solid. TLC: PE/EtOAc 50:50, Rf = 0.32 (major diastereomer) and 0.38 (minor diastereomer). Major diastereomer: 1H NMR (400 MHz, CDCl3): δ = 1.13−1.54 (m, 13 H), 1.26 (s, 3 H), 1.32 (s, 3 H), 1.74 (m, 1 H), 1.97 (m, 1 H), 2.36 (d, J = 12.5 Hz, 1 H), 2.44 (s, 3 H), 2.88 (m, 1 H), 2.94−3.07 (m, 3 H), 3.11 (m, 1 H), 3.58 (d, J = 13.0 Hz, 1 H), 3.69−3.81 (m, 2 H), 4.02 (dd, J = 10.9 Hz, 4.0 Hz, 1 H), 4.07 (dd, J = 10.6 Hz, 3.2 Hz, 1 H), 4.38 (br, 1 H), 4.70−4.80 (m, 2 H), 5.06 (m, 2 H), 5.19 (m, 1 H), 5.33 (d, J = 4.9 Hz, 1 H), 6.50 (br, 1 H), 7.09−7.39 (m, 18 H), 7.78 (d, J = 8.2 Hz, 2 H). 13C NMR (100 MHz, CDCl3): δ = 20.2, 21.6, 24.6, 25.0, 25.4, 25.6, 26.6, 27.2, 29.0, 31.0, 32.8, 37.9 (2×), 44.1, 51.1, 52.5, 52.5, 67.1, 69.1,

% Pd) at room temperature. CH2Cl2 (3 mL) was added to guarantee stirring, and the solution was subjected to hydrogenation (1 bar) for 22.5 h. The solution was then filtrated through a pad of Celite and washed with MeOH. The filtrated was concentrated in vacuo, and the crude product was dissolved in acetonitrile (7.0 mL). Afterward, Cbz(S)-Phe-OH (290 mg, 0.969 mmol), TBTU (309 mg, 0.962 mmol), and DIPEA (176 μL, 130 mg, 1.01 mmol) were added subsequently at room temperature. The solution was stirred overnight and concentrated in vacuo. The residue was dissolved in CH2Cl2, and HCl solution (1 M) was added. The layers were separated, and the aqueous phase was extracted three times with CH2Cl2. The combined organic layers were washed with satd NaHCO3 solution and dried over Na 2 SO4 . The crude product was purified by column chromatography (silica, PE/EtOAc 100:0, 80:20, 50:50). Tetrapeptide 11 (831 mg, 0.808 mmol, dr 87:13, 92% over two steps) was obtained as an off-white solid. TLC: PE/EtOAc = 50:50, Rf = 0.46 (both diastereomers). HPLC: Reprosil, n-hexane/iPrOH 80:20, 1.0 mL/min, 20 °C: tR1 = 20.2 min (13%), tR2 = 26.6 min (87%). Major diastereomer: 1H NMR (400 MHz, CDCl3): δ = 1.02−1.14 (m, 21 H), 1.18−1.49 (m, 11 H), 1.34 (s, 3 H), 1.37 (s, 3 H), 1.41 (s, 9 H), 1.50−1.65 (m, 3 H), 1.77 (m, 1 H), 2.30 (d, J = 13.0 Hz, 1 H), 2.88 (m, 1 H), 2.96−3.08 (m, 3 H), 3.13 (dd, J = 12.4 Hz, 12.4 Hz, 1 H), 3.59 (d, J = 14.0 Hz, 1 H), 3.64 (m, 1 H), 3.73 (dd, J = 10.4 Hz, 5.5 Hz, 1 H), 3.83 (dd, J = 10.3 Hz, 4.1 Hz, 1 H), 3.89 (td, J = 7.8 Hz, 3.6 Hz, 1 H), 4.35 (td, J = 7.5 Hz, 6.5 Hz, 1 H), 4.39 (m, 1 H), 4.83 (dt, J = 7.5 Hz, 6.3 Hz, 1 H), 5.07 (s, 2 H), 5.24 (d, J = 4.3 Hz, 1 H), 5.42 (d, J = 7.0 Hz, 1 H), 6.54 (br, 1 H), 6.92 (d, J = 7.6 Hz, 1 H), 7.09 (d, J = 7.6 Hz, 2 H), 7.17−7.37 (m, 13 H). 13C NMR (100 MHz, CDCl3): δ = 11.8, 17.9, 20.2, 24.7, 25.2, 25.5, 26.1, 26.9, 27.4, 28.0, 29.4, 31.8, 33.5, 38.1, 38.2, 43.9, 51.1, 52.6, 53.0, 55.6, 64.1, 67.0, 78.9, 81.1, 81.4, 108.3, 127.0, 127.2, 128.0, 128.2, 128.5, 128.6, 128.7, 129.4, 129.6, 135.7, 136.2 (2×), 155.9, 169.6, 170.6, 170.8, 171.9. Minor diastereomer (selected signals): 1H NMR (400 MHz, CDCl3): δ = 1.45 (s, 9 H), 4.67 (m, 1 H), 5.20 (d, J = 6.2 Hz, 1 H), 5.33 (d, J = 8.4 Hz, 1 H), 6.64 (m, 1 H), 6.83 (m, 1 H). HRMS (CI): calcd for C58H87N4O10Si [M + H]+ 1027.6186, found 1027.6199. tert-Butyl (S)-2-((R)-1-(((Benzyloxy)carbonyl)-L-phenylalanyl-L-phenylalanyl)piperidine-2-carboxamido)-7-((4S,5S)-2,2dimethyl-5-((tosyloxy)methyl)-1,3-dioxolan-4-yl)heptanoate (12). Tetrapeptide 11 (508 mg, 0.494 mmol) was dissolved in THF (5.0 mL) at room temperature before TBAF (742 μL, 0.742 mmol, 1 M in THF) was added, and the reaction mixture was stirred for 2 h. For workup, the solution was concentrated in vacuo at room temperature. The residue was dissolved in CH2Cl2, and water was added. The layers were separated, and the aqueous phase was extracted three times with CH2Cl2. The combined organic layers were dried over Na2SO4, and the crude product was dissolved in dry pyridine (5.0 mL) at room temperature. The mixture was cooled to 0 °C before 4-DMAP (6.9 mg, 56.5 μmol) and tosyl chloride (141 mg, 0.742 mmol) were added. The reaction mixture was allowed to warm to room temperature overnight. For workup, the solution was diluted with Et2O, and HCl solution (1 M) was added. The layers were separated, and the aqueous phase was extracted three times with Et2O. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. After purification by column chromatography (silica, PE/EtOAc 50:50), tosylate 12 (415 mg, 0.405 mmol, 82% over two steps) was obtained as an off-white solid. TLC: PE/EtOAc = 50:50, Rf = 0.24. 1H NMR (400 MHz, CDCl3): δ = 1.18−1.48 (m, 12 H), 1.26 (s, 3 H), 1.32 (s, 3 H), 1.41 (s, 9 H), 1.50−1.60 (m, 2 H), 1.77 (m, 1 H), 2.32 (d, J = 12.4 Hz, 1 H), 2.44 (s, 3 H), 2.87 (m, 1 H), 2.98−3.09 (m, 3 H), 3.15 (dd, J = 13.3 Hz, 13.3 Hz, 1 H), 3.60 (d, J = 13.8 Hz, 1 H), 3.68−3.78 (m, 2 H), 4.06 (m, 2 H), 4.33−4.43 (m, 2 H), 4.82 (dt, J = 7.8 Hz, 5.4 Hz, 1 H), 5.07 (s, 2 H), 5.24 (d, J = 3.6 Hz, 1 H), 5.40 (d, J = 6.5 Hz, 1 H), 6.51 (br, 1 H), 6.95 (d, J = 7.3 Hz, 1 H), 7.09 (d, J = 6.9 Hz, 2 H), 7.12−7.37 (m, 15 H), 7.79 (d, J = 8.2 Hz, 2 H). 13C NMR (100 MHz, CDCl3): δ = 20.3, 21.6, 24.7, 25.2, 25.4, 25.7, 26.6, 27.3, 28.0, 29.2, 31.7, 32.9, 38.0, 38.2, 43.9, 51.1, 52.7, 52.9, 55.7, 67.0, 69.2, 77.6, 78.1, 81.5, 109.3, 127.1, 127.3, 128.0, 128.2, 128.5, 128.7, 128.8, 129.4, 129.6, 129.8, 132.7, 136.2 (2×), 145.0, 155.9, 169.6, 170.6, 170.8, 171.8. The signals of two 11346

DOI: 10.1021/acs.joc.8b01569 J. Org. Chem. 2018, 83, 11341−11349

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The Journal of Organic Chemistry

(125 MHz, CDCl3): δ = 19.2, 24.0, 25.0, 25.1, 25.2, 29.0 (2×), 34.1, 35.2, 36.5, 43.9, 45.1, 49.9, 50.9, 53.6, 55.3, 62.8, 71.4, 126.7, 126.9, 128.5, 128.6, 128.9, 129.1, 136.9, 137.0, 171.4, 173.3, 173.6, 175.8. HRMS (CI): calcd for C34H45N4O6 [M + H]+ 605.3334, found 605.3331. Trapoxin A. To a solution of 16 (3.9 mg, 6.45 μmol) in dry CH2Cl2 (2.0 mL) was added Dess−Martin periodinane (5.8 mg, 13.7 μmol) at room temperature. The reaction mixture was stirred for 2 h, filtrated through a pad of Celite, and washed with CH2Cl2. The filtrate was concentrated in vacuo. Purification by reversed-phase column chromatography (silica C-18, MeCN/H2O 10:90, gradient 90:10) yielded trapoxin A (1.7 mg, 2.82 μmol, 44%) as an off-white solid. [α]22 D = −81.7 (c = 0.425, MeOH). TLC: EtOAc:MeOH = 95:5, Rf = 0.36. 1H NMR (500 MHz, CDCl3): δ = 1.16−1.31 (m, 5 H), 1.48− 1.58 (m, 4 H), 1.69−1.81 (m, 3 H), 1.97 (m, 1 H), 2.09 (m, 1 H), 2.25 (dt, J = 17.5 Hz, 7.2 Hz, 1 H), 2.41 (dt, J = 17.5 Hz, 7.3 Hz, 1 H), 2.86 (dd, J = 5.7 Hz, 2.5 Hz, 1 H), 3.00 (dd, J = 6.0 Hz, 4.7 Hz, 1 H), 3.01 (m, 1 H), 3.08 (dd, J = 13.9 Hz, 7.3 Hz, 1 H), 3.20 (dd, J = 13.4 Hz, 6.2 Hz, 1 H), 3.25 (dd, J = 13.9 Hz, 8.2 Hz, 1 H), 3.42 (dd, J = 4.7 Hz, 2.5 Hz, 1 H), 3.64 (dd, J = 13.4 Hz, 10.9 Hz, 1 H), 3.73 (dt, J = 11.0 Hz, 5.7 Hz, 1 H), 3.95 (d, J = 13.9 Hz, 1 H), 4.16 (dt, J = 8.4 Hz, 8.4 Hz, 1 H), 5.01 (d, J = 6.0 Hz, 1 H), 5.35 (dt, J = 10.2 Hz, 7.8 Hz, 1 H), 6.38 (d, J = 5.4 Hz, 1 H), 6.43 (d, J = 10.1 Hz, 1 H), 7.10 (d, J = 6.3 Hz, 2 H), 7.21−7.31 (m, 8 H), 7.45 (d, J = 10.1 Hz, 1 H). 13 C NMR (125 MHz, CDCl3): δ = 19.2, 22.7, 24.0, 25.1, 25.2, 28.6, 28.9, 35.2, 36.2, 36.5, 43.9, 46.1, 50.0, 50.9, 53.4, 53.5, 62.8, 126.7, 127.0, 128.5, 128.6, 128.9, 129.1, 136.9 (2×), 171.4, 173.3, 173.6, 175.7, 207.6. HRMS (CI): calcd for C34H43N4O6 [M + H]+ 603.3177, found 603.3182.

77.6, 78.1, 109.3, 127.1, 127.2, 127.5, 128.0, 128.3, 128.5, 128.7, 128.9, 129.3, 129.6, 129.8, 132.7, 145.0, 169.0, 170.3, 170.7, 171.4. The signals of nine carbons were not observed in the 13C NMR spectrum. Minor diastereomer (selected signals): 1H NMR (400 MHz, CDCl3): δ = 1.33 (s, 3 H), 4.86 (br, 1 H), 5.04 (s, 2 H), 5.31 (m, 1 H). 13C NMR (100 MHz, CDCl3): δ = 128.2, 128.5, 128.8, 129.9. HRMS (CI): calcd for C58H64F5N4O12S [M + H]+ 1135.4156, found 1135.4153. ((4S,5S)-5-(5-((3S,6S,9S,15aR)-6,9-Dibenzyl-1,4,7,10-tetraoxotetradecahydro-2H-pyrido[1,2-a][1,4,7,10]tetraazacyclododecin-3-yl)pentyl)-2,2-dimethyl-1,3-dioxolan4-yl)methyl 4-Methylbenzenesulfonate (15). A solution of 14 (330 mg, 0.291 mmol) in dioxane (70 mL) was added dropwise to a vigorously stirred suspension of palladium on carbon (332 mg, 10 wt % Pd) in dioxane (450 mL) and EtOH (11 mL) at 85 °C within 6 h. During the course of the reaction, H2 was bubbled through the reaction mixture. After complete addition, the mixture was stirred for further 1 h at 85 °C. After being cooled to rt, the mixture was filtrated through a pad of Celite and washed with chloroform. The filtrate was concentrated in vacuo and purified by column chromatography (silica, PE/EtOAc 100:0, 80:20, 50:50, then CH2Cl2/MeOH 95:5). Cyclic peptide 15 (84 mg, 82.3 μmol, 80% pure, dr > 99:1, 28%) was obtained as an off-white solid. A small sample was further purified by reversed-phase column chromatography (silica gel C-18, MeCN/H2O 50:50, gradient 90:10) for analytical purposes. [α]20 D = −51 (c = 0.1, CHCl3). TLC: CH2Cl2/MeOH = 95:5, Rf = 0.38. 1H NMR (500 MHz, CDCl3): δ = 1.17−1.33 (m, 6 H), 1.31 (s, 3 H), 1.37 (s, 3 H), 1.42 (m, 1 H), 1.47−1.59 (m, 4 H), 1.67−1.81 (m, 3 H), 1.98 (m, 1 H), 2.09 (m, 1 H), 2.46 (s, 3 H), 3.01 (ddd, J = 13.2 Hz, 13.2 Hz, 2.7 Hz, 1 H), 3.07 (dd, J = 14.0 Hz, 7.1 Hz, 1 H), 3.21 (dd, J = 13.7 Hz, 6.8 Hz, 1 H), 3.24 (dd, J = 13.9 Hz, 7.6 Hz, 1 H), 3.62 (dd, J = 13.9 Hz, 10.7 Hz, 1 H), 3.74−3.83 (m, 3 H), 3.94 (d, J = 13.9 Hz, 1 H), 4.07 (dd, J = 10.7 Hz, 4.4 Hz, 1 H), 4.11 (dd, J = 10.6 Hz, 4.3 Hz, 1 H), 4.18 (dt, J = 8.6 Hz, 8.6 Hz, 1 H), 5.02 (d, J = 6.3 Hz, 1 H), 5.35 (dt, J = 10.0 Hz, 7.7 Hz, 1 H), 6.39 (d, J = 6.0 Hz, 1 H), 6.42 (d, J = 10.1 Hz, 1 H), 7.10 (d, J = 6.6 Hz, 2 H), 7.19−7.31 (m, 8 H), 7.36 (d, J = 7.9 Hz, 2 H), 7.43 (d, J = 10.4 Hz, 1 H), 7.81 (d, J = 8.5 Hz, 2 H). 13 C NMR (125 MHz, CDCl3): δ = 19.2, 21.7, 24.0, 25.1, 25.2, 25.6, 26.7, 27.3, 29.0 (2×), 32.8, 35.2, 36.6, 44.0, 49.9, 50.9, 53.6, 62.6, 69.1, 77.8, 78.1, 109.3, 126.7, 126.9, 128.0, 128.6 (2×), 128.9, 129.1, 129.9, 132.6, 136.9, 136.9, 145.1, 171.4, 173.3, 173.6, 175.7. HRMS (CI): calcd for C44H57N4O9S [M + H]+ 817.3841, found 817.3886. (3S,6S,9S,15aR)-6,9-Dibenzyl-3-((S)-6-hydroxy-6-((S)-oxiran2-yl)hexyl)octahydro-2H-pyrido[1,2-a][1,4,7,10]tetraazacycldodecine-1,4,7,10(3H,12H)-tetraone (16). To a solution of 15 (12.5 mg, 15.3 μmol) in THF (1.0 mL) was added aq HCl (1.0 mL, 5 wt %) at room temperature, and the reaction was stirred overnight. The mixture was concentrated in vacuo, and the residue was dissolved in CH2Cl2. Brine was added, and the layers were separated. The aqueous phase was extracted three times with CH2Cl2, and the combined organic layers were dried over Na2SO4. The crude product was dissolved in dry MeOH (3.0 mL) and cooled to 0 °C before DBU (12.0 μL, 12.1 mg, 79.5 μmol) was added. The reaction was stirred at 0 °C for 4 h. For workup, the solution was filtrated through a pad of Celite and washed with 10% MeOH/EA. The filtrate was concentrated in vacuo and purified by reversed-phase column chromatography (silica C-18, MeCN/H2O 10:90, gradient 90:10). Epoxy alcohol 16 (5.7 mg, 9.42 μmol, 62% over two steps) was obtained as an off-white solid. [α]20 D = −77 (c = 0.1, CHCl3). TLC: EtOAc/MeOH = 95:5, Rf = 0.25. 1H NMR (500 MHz, CDCl3): δ = 1.19−1.26 (m, 3 H), 1.30−1.38 (m, 2 H), 1.45−1.59 (m, 6 H), 1.72 (m, 1 H), 1.79 (m, 1 H), 1.93−1.99 (m, 2 H), 2.09 (m, 1 H), 2.72 (dd, J = 4.9 Hz, 2.7 Hz, 1 H), 2.83 (dd, J = 5.0 Hz, 4.1 Hz, 1 H), 2.96 (m, 1 H), 3.01 (ddd, J = 13.6 Hz, 13.6 Hz, 2.6 Hz, 1 H), 3.08 (dd, J = 14.0 Hz, 7.1 Hz, 1 H), 3.20 (dd, J = 13.6 Hz, 6.0 Hz, 1 H), 3.25 (dd, J = 14.0 Hz, 8.0 Hz, 1 H), 3.44 (m, 1 H), 3.65 (dd, J = 13.2 Hz, 10.7 Hz, 1 H), 3.73 (dt, J = 11.1 Hz, 6.0 Hz, 1 H), 3.95 (d, J = 13.6 Hz, 1 H), 4.17 (dt, J = 9.4 Hz, 9.4 Hz, 1 H), 5.01 (d, J = 5.4 Hz, 1 H), 5.35 (dt, J = 10.0 Hz, 7.8 Hz, 1 H), 6.43−6.47 (m, 2 H), 7.10 (d, J = 6.6 Hz, 2 H), 7.20−7.31 (m, 8 H), 7.46 (d, J = 10.4 Hz, 1 H). 13C NMR

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01569.

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NMR spectra (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Uli Kazmaier: 0000-0001-9756-0589 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Deutsche Forschungsgemeinschaft. The authors also acknowledge financial support and a fellowship for P.S. by the Fonds der Chemischen Industrie.

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REFERENCES

(1) (a) Allfrey, V. G.; Faulkner, R.; Mirsky, A. E. Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis. Proc. Natl. Acad. Sci. U. S. A. 1964, 51, 786−794. (b) Grunstein, M. Histone acetylation in chromatin structure and transcription. Nature 1997, 389, 349−352. (c) Kouzarides, T. Acetylation: a regulatory modification to rival phosphorylation? EMBO J. 2000, 19, 1176−1179. (2) (a) Kim, S. C.; Sprung, R.; Chen, Y.; Xu, Y.; Ball, H.; Pei, J.; Cheng, T.; Kho, Y.; Xiao, H.; Xiao, L.; Grishin, N. V.; White, M.; Yang, X. J.; Zhao, Y. Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. Mol. Cell 2006, 23, 607− 618. (b) Choudhary, C.; Kumar, C.; Gnad, F.; Nielsen, M. L.; Rehman, M.; Walther, T. C.; Olsen, J. V.; Mann, M. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 2009, 325, 834−840.

11347

DOI: 10.1021/acs.joc.8b01569 J. Org. Chem. 2018, 83, 11341−11349

Note

The Journal of Organic Chemistry (3) Falkenberg, K. J.; Johnstone, R. W. Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat. Rev. Drug Discovery 2014, 13, 673−691. (4) Marks, P. A.; Breslow, R. Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug. Nat. Biotechnol. 2007, 25, 84−90. (5) (a) Ueda, H.; Nakajima, H.; Hori, Y.; Fujita, T.; Nishimura, M.; Goto, T.; Okuhara, M. FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum no. 968. J. Antibiot. 1994, 47, 301−310. (b) Plumb, J. A.; Finn, P. W.; Williams, R. J.; Bandara, M. J.; Romero, M. R.; Watkins, C. J.; La Thangue, N. B.; Brown, R. Pharmacodynamic response and inhibition of growth of human tumor xenografts by the novel histone deacetylase inhibitor PXD101. Mol. Cancer Ther. 2003, 2, 721−728. (c) Atadja, P. Development of the pan-DAC inhibitor panobinostat (LBH589): successes and challenges. Cancer Lett. 2009, 280, 233−241. (d) VanderMolen, K. M.; McCulloch, W.; Pearce, C. J.; Oberlies, N. H. Romidepsin (Istodax, NSC 630176, FR901228, FK228, depsipeptide): a natural product recently approved for cutaneous Tcell lymphoma. J. Antibiot. 2011, 64, 525−531. (6) (a) De Ruijter, A.; Van Gennip, A.; Caron, H.; Kemp, S.; van Kuilenburg, A. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem. J. 2003, 370, 737−749. (b) Gregoretti, I.; Lee, Y.-M.; Goodson, H. V. Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis. J. Mol. Biol. 2004, 338, 17−31. (c) Haberland, M.; Montgomery, R. L.; Olson, E. N. The many roles of histone deacetylases in development and physiology: implications for diseases and therapy. Nat. Rev. Genet. 2009, 10, 32−42. (d) Arrowsmith, C. H.; Bountra, C.; Fish, P. V.; Lee, K.; Schapira, M. Epigenetic protein families: a new frontier for drug discovery. Nat. Rev. Drug Discovery 2012, 11, 384−400. (7) Lahm, A.; Paolini, C.; Pallaoro, M.; Nardi, M. C.; Jones, P.; Neddermann, P.; Sambucini, S.; Bottomley, M. J.; Lo Surdo, P.; Carfi, A.; Koch, U.; De Francesco, R.; Steinkühler, C.; Gallinari, P. Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases. Proc. Natl. Acad. Sci. U. S. A. 2007, 104, 17335−17340. (8) (a) Blander, G.; Guarente, L. The Sir2 family of protein deacetylases. Annu. Rev. Biochem. 2004, 73, 417−435. (b) Finkel, T.; Deng, C.-X.; Mostoslavsky, R. Recent progress in the biology and physiology of sirtuins. Nature 2009, 460, 587−591. (c) Chalkiadaki, A.; Guarente, L. The multifaceted functions of sirtuins in cancer. Nat. Rev. Cancer 2015, 15, 608−624. (9) Recent review: Maolanon, A. R.; Kristensen, H. M. E.; Leman, L. J.; Ghadiri, M. R.; Olsen, C. A. Natural and synthetic macrocyclic inhibitors of the histone deacetylase enzymes. ChemBioChem 2017, 18, 5−49. (10) (a) Itazaki, H.; Nagashima, K.; Sugita, K.; Yoshida, H.; Kawamura, Y.; Yasuda, Y.; Matsumoto, K.; Ishii, K.; Uotani, N.; Nakai, H.; Terui, A.; Yoshimatsu, S.; Ikenishi, Y.; Nakagawa, Y. Isolation and structural elucidation of new cyclotetrapeptides, trapoxins A and B, having detransformation activities as antitumor agents. J. Antibiot. 1990, 43, 1524−1532. (b) Nakai, H.; Nagashima, K.; Itazaki, H. Structure of a new cyclotetrapeptide trapoxin A. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1991, 47, 1496−1499. (11) Kijima, M.; Yoshida, M.; Sugita, K.; Horinouchi, S.; Beppu, T. Trapoxin, an antitumor cyclic tetrapeptide, is an irreversible inhibitor of mammalian histone deacetylases. J. Biol. Chem. 1993, 268, 22429− 22435. (12) Porter, N. J.; Christianson, D. W. Binding of the microbial cyclic tetrapeptide trapoxin A to the class I histone deacetylase HDAC8. ACS Chem. Biol. 2017, 12, 2281−2286. (13) Closse, A.; Huguenin, R. Isolierung und Strukturaufklärung von Chlamydocin. Helv. Chim. Acta 1974, 57, 533−545. (14) (a) Brosch, G.; Ransom, R.; Lechner, T.; Walton, J. D.; Loidl, P. Inhibition of maize histone deacetylases by HC toxin, the hostselective toxin of Cochliobolus carbonum. Plant Cell 1995, 7, 1941− 1950. (b) Walton, J. D. HC-toxin. Phytochemistry 2006, 67, 1406− 1413.

(15) (a) Stähelin, H.; Trippmacher, A. Cytostatic activity of chlamydocin, a rapidly inactivated cyclic tetrapeptide. Eur. J. Cancer 1974, 10, 801−808. (b) Frühwald, M. C.; Witt, O. The epigenetics of cancer in children. Klin. Paediatr. 2008, 220, 333−341. (c) Deubzer, H. E.; Ehemann, V.; Westermann, F.; Heinrich, R.; Mechtersheimer, G.; Kulozik, A. E.; Schwab, M.; Witt, O. Histone deacetylase inhibitor Helminthosporium carbonum (HC)-toxin suppresses the malignant phenotype of neurobastoma cells. Int. J. Cancer 2008, 122, 1891− 1900. (16) (a) Schmidt, U.; Beuttler, T.; Lieberknecht, A.; Griesser, H. Aminosäuren und Peptide − XXXXII. Synthese von Chlamydocin + epi-Chlamydocin. Tetrahedron Lett. 1983, 24, 3573−3576. (b) Rich, D. H.; Gardner, J. H. Synthesis of the cyclic cytostatic tetrapeptide, chlamydocin. Tetrahedron Lett. 1983, 24, 5305−5308. (c) Schmidt, U.; Lieberknecht, A.; Griesser, H.; Bartkowiak, F. Stereoselective total synthesis of chlamydocin and dihydrochlamydocin. Angew. Chem., Int. Ed. Engl. 1984, 23, 318−320. (d) Kawai, M.; Gardner, J. H.; Rich, D. H. Stereoselective synthesis and absolute configuration of epoxyketones in chlamydocin and related cyclic tetrapeptides. Tetrahedron Lett. 1986, 27, 1877−1880. (e) Baldwin, J. E.; Adlington, R. M.; Godfrey, C. R.; Patel, V. K. Stereospecific synthesis of chlamydocin. Tetrahedron 1993, 49, 7837−7856. (f) Quirin, C.; Kazmaier, U. Synthesis of chlamydocin by chelate-Claisen rearrangement. Eur. J. Org. Chem. 2009, 2009, 371−377. (17) Taunton, J.; Collins, J. L.; Schreiber, S. L. Synthesis of natural and modified trapoxins, useful reagents for exploring histone deacetylase function. J. Am. Chem. Soc. 1996, 118, 10412−10422. (18) (a) Ullrich, A.; Chai, Y.; Pistorius, D.; Elnakady, Y. A.; Herrmann, J.; Weissman, K. J.; Kazmaier, U.; Müller, R. Pretubulysin, a potent and chemically accessible tubulysin precursor from Angiococcus disciformis. Angew. Chem., Int. Ed. 2009, 48, 4422−4425. (b) Ullrich, A.; Herrmann, J.; Müller, R.; Kazmaier, U. Synthesis and biological evaluation of pretubulysin and derivatives. Eur. J. Org. Chem. 2009, 2009, 6367−6378. (19) (a) Karmann, L.; Schultz, K.; Herrmann, J.; Müller, R.; Kazmaier, U. Total syntheses and biological evaluation of miuraenamides. Angew. Chem., Int. Ed. 2015, 54, 4502−4507. (b) Becker, D.; Kazmaier, U. Synthesis of simplified halogenated chondramide derivatives with strong cytostatic properties. Eur. J. Org. Chem. 2015, 2015, 2591−2602. (20) Servatius, P.; Kazmaier, U. Total synthesis of the natural HDAC inhibitor Cyl-1. Org. Biomol. Chem. 2018, 16, 3464−3472. (21) Kazmaier, U.; Deska, J. Peptide backbone modifications. Curr. Org. Chem. 2008, 12, 355−385. (22) Seebach, D.; Beck, A. K.; Studer, A. In Modern Synthetic Methods; Ernst, B., Leumann, C., Eds.; VCH, Weinheim, 1995; Vol. 7, pp 1−178. (23) Seebach, D.; Beck, A. K.; Bossler, H. G.; Gerber, C.; Ko, S. Y.; Murtiashaw, C. W.; Naef, R.; Shoda, S.-I.; Thaler, A.; Krieger, M.; Wenger, R. Modification of cyclosporin A (CS): Generation of an enolate at the sarcosine residue and reactions with electrophiles. Helv. Chim. Acta 1993, 76, 1564−1590. (24) (a) Seebach, D.; Bossler, H.; Gründler, H.; Shoda, S.-I.; Wenger, R. C-Alkylation of peptides through polylithiated and LiClsolvated derivatives containing sarcosine Li-enolate units. Helv. Chim. Acta 1991, 74, 197−224. (b) Miller, S. A.; Griffiths, S. L.; Seebach, D. C-Alkylation of sarcosine residues in cyclic tetrapeptides via lithium enolates. Helv. Chim. Acta 1993, 76, 563−595. (c) Bossler, H. G.; Seebach, D. Peptide enolates. C-Alkylation of glycine residues in linear tri-, tetra-, and pentapeptides via dilithium azadienediolates. Helv. Chim. Acta 1994, 77, 1124−1165. (25) (a) Deska, J.; Kazmaier, U. Stereoselective syntheses and reactions of stannylated peptides. Angew. Chem., Int. Ed. 2007, 46, 4570−4573. (b) Deska, J.; Kazmaier, U. Highly stereoselective peptide modifications through Pd-catalyzed allylic alkylations of chelated peptide enolates. Chem. - Eur. J. 2007, 13, 6204−6211. (26) Kazmaier, U.; Maier, S. Stereoselective backbone modifications of peptides via chelate enolate Claisen rearrangement. J. Org. Chem. 1999, 64, 4574−4575. 11348

DOI: 10.1021/acs.joc.8b01569 J. Org. Chem. 2018, 83, 11341−11349

Note

The Journal of Organic Chemistry (27) (a) Kazmaier, U.; Deska, J.; Watzke, A. Highly stereoselective allylic alkylations of peptides. Angew. Chem., Int. Ed. 2006, 45, 4855− 4858. (b) Datta, S.; Bayer, A.; Kazmaier, U. Highly stereoselective modifications of peptides via Pd-catalyzed allylic alkylation of internal peptide amide enolates. Org. Biomol. Chem. 2012, 10, 8268−8275. (c) Kazmaier, U. Non-stabilized enolates − versatile nucleophiles in transition metal-catalyzed allylic alkylations. Org. Chem. Front. 2016, 3, 1541−1560. (28) (a) Kazmaier, U.; Schneider, C. Application of the asymmetric chelate-enolate Claisen rearrangement to the synthesis of 5-epiisofagomine. Tetrahedron Lett. 1998, 39, 817−818. (b) Kazmaier, U.; Schneider, C. Application of the asymmetric chelate enolate Claisen rearrangement to the synthesis of unsaturated polyhydroxylated amino acids. Synthesis 1998, 1998, 1321−1326. (29) Schneider, C.; Kazmaier, U. Asymmetric syntheses of chiral allylic alcohols. Synthesis 1998, 1998, 1314−1320. (30) Schmidt, U.; Beutler, U.; Lieberknecht, A. Total synthesis of the antitumor antibiotic WF-3161. Angew. Chem., Int. Ed. Engl. 1989, 28, 333−334. (31) Neises, B.; Steglich, W. Simple method for the esterification of carboxylic acids. Angew. Chem., Int. Ed. Engl. 1978, 17, 522−524. (32) Weygand, F.; Frauendorfer, E. Reduktive Entfernung des NTrifluoracetyl- und N-Trichloracetylrestes durch Natriumborhydrid mit Anwendungen in der Peptidchemie. Chem. Ber. 1970, 103, 2437− 2449. (33) Schnurrenberger, P.; Hungerbuehler, E.; Seebach, D. Total synthesis of (+)-colletodiol from (S,S)-tartrate and (R)-3-hydroxybutanoate. Liebigs Annalen der Chemie 1987, 1987, 733−744.

11349

DOI: 10.1021/acs.joc.8b01569 J. Org. Chem. 2018, 83, 11341−11349