Total Synthesis of Proteasome Inhibitor (−)-Omuralide through

Letter Cite This: Org. Lett. 2018, 20, 4558−4561

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Total Synthesis of Proteasome Inhibitor (−)-Omuralide through Asymmetric Ketene [2 + 2]-Cycloaddition Pauline Rullier̀ e,†,‡ Alexandre Cannillo,†,‡ Julien Grisel,†,‡ Pascale Cividino,†,‡ Seb́ astien Carret,†,‡ and Jean-François Poisson*,†,‡ †

Univ. Grenoble Alpes, DCM, F-38000 Grenoble, France CNRS, DCM, F-38000 Grenoble, France

‡

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ABSTRACT: The total synthesis of (−)-omuralide, a potent specific proteasome inhibitor, has been achieved through an unprecedented route. The C3 and C4 chiral centers of the natural product have been selectively installed by an asymmetric [2 + 2]-cycloaddition between an unusual oxadisilinane ketene and a chiral enol ether, while the γlactam core was prepared by a single-pot two-step Beckmann transposition. The C5 quaternary center was eventually defined by an original selective oxidative desymmetrization of a spiro cyclic oxadisilinane thanks to the anchimeric assistance of a proximal hydroxyl group. solated from the Streptomyces lactacystenaeus strain by Õ mura et al. in 1991, (+)-lactacystin 2 is the first nonpeptidic proteasome inhibitor to be discovered.1 (+)-Lactacystin spontaneously and reversibly forms (−)-omuralide 1 (also known as (−)-clasto-lactacystin β-lactone) in the extracellular medium, which penetrates the cell and acylates a threonine residue, leading to proteasome inhibition.2 Lactacystin 2 and its cell-permeable β-lactone form, omuralide 1, were found to be potent selective and irreversible inhibitors of the 20S unit of proteasome.3 The exploration of their inhibition properties and mechanism of action was key for the overall understanding of the proteasome machinery, and since then, their inhibition ability has found common use in the systematic biological studies of proteasome.4 In 2003, proteasome inhibition proved to be a relevant strategy to target cancer cells,5 and structural analogues of omuralide and lactacystin, such as salinosporamide A 3, are currently under clinical trial for the treatment of multiple myeloma (Figure 1).6 (−)-Omuralide 1 also served as a synthetic precursor to the natural lactacystin 2 (Figure 1).

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Efficient and unified enantioselective synthetic strategies toward such skeletons have thus become a challenge, not only for the synthesis of the natural products but also in paving the way for synthetic analogues of these active substances. The four contiguous stereogenic centers (C3−6)including one quaternary carbonon a small nitrogen heterocycle, with an all-cis configuration of the substituent on a γ-lactam ring (C3−C5), exhibit a structural complexity that renders their total synthesis challenging. Since the pioneering synthesis of lactacystin reported by Corey in 1992, one year after the reported isolation of the natural product, intensive efforts to develop original synthetic approaches have been realized to solve the complex structural characteristics of these natural products with exceptional biological activities, and the need for robust routes to access potentially more active analogues.7,8 Hence, many impressive syntheses have since then been achieved, very often using an early stage aldolization or acylation, for establishing the C5 quaternary center (C4−C5 bond formation).8a−c,e,f,o The formation of the γ-lactam ring was then carried out later in the synthesis: these strategies tackled the somewhat key quaternary center construction at an early stage of the synthesis. Our approach largely differs from previous strategies as we intended to generate the γ-lactam core through ring expansion of a highly substituted all-cis chiral cyclobutanone (Figure 2). Our group has recently reported the [2 + 2]-cycloaddition of chiral enol ethers, bearing the Stericol (StOH) chiral auxiliary, with a variety of ketenes, producing densely substituted cyclobutanones in high diastereoselectivity.9 The asymmetric cycloaddition between a ketene and a chiral enol ether would allow for the direct installation of the C3 and C4 chiral centers, and

Figure 1. Proteasome inhibitors structures: (−)-omuralide 1, (+)-lactacystin 2, and (−)-salinosporamide A 3. © 2018 American Chemical Society

Received: June 14, 2018 Published: July 16, 2018 4558

DOI: 10.1021/acs.orglett.8b01851 Org. Lett. 2018, 20, 4558−4561

Letter

Organic Letters

obtained with n-butyllithium, and selective hydrogenation of the intermediate ynol ether (Scheme 1).10 On the other hand, the symmetrical oxadisilinane ketene was prepared from commercially available dichlorodisiloxane 611 and generated in situ by dehydrohalogenation with triethylamine of freshly prepared acid chloride 8. Reaction of the in situ produced ketene with the chiral enol ether eventually afforded cyclobutanone (+)-9 in an almost quantitative yield and with excellent diastereoselectivity (Scheme 1). Notably, on a single batch, more than 12 g of cyclobutanone could be produced with no erosion of the diastereoselectivity (with an even greater yield on large scale, 97% vs 83%). An X-ray analysis of cyclobutanone (+)-9 confirmed the expected relative and absolute configuration.9 The direct one-pot Beckmann transposition of cyclobutanone using Tamura’s reagent (O-mesitylenesulfonylhydroxylamine, MSH)12 has already been used to produce a variety of lactam in high yields.13 The high regioselectivity is the result of a welldefined E-stereochemistry of the initial oxime which upon treatment on basic alumina afforded cyclobutanone through a specific anti bond migration. However, when applied to cyclobutanone 9, a very low 12% yield of regioisomeric lactams was obtained. While the Beckmann transposition14 is a wellestablished method for the formation of lactams from ketones,15 only a few examples of crowded α,α′-trisubstituted ketones are known.16 With highly substituted ketones, the abnormal Beckmann fragmentation has often been reported, leading to the ring-opened nitrile derivative.17 It was found that using pure crystalline MSH was crucial for reproducible yields of lactam formation.12b As Stericol-bearing substrates underwent ring expansion with low yields, we took advantage of the embedded symmetry in 10 to replace the bulky chiral auxiliary by a TBS ether: the diastereoselective DIBAL-H reduction of cyclobutanone 9 followed by TBS protection, Stericol cleavage, and Dess-Martin oxidation of the secondary alcohol afforded cyclobutanone 11, in excellent overall yield (Scheme 2). The

Figure 2. Synthetic strategies toward (−)-omuralide 1.

would require a subsequent desymmetrization of the quaternary center by a regioselective transformation of one of the R1 chains (Figure 2). To generate the acid and the secondary alcohol at C5, the R1 group could be either a protected hydroxyl function or a hydroxymethylene surrogate. A symmetrically disubstituted ketene would then be an ideal precursor to selectively generate the C5 center, but strikingly, no [2 + 2]-cycloaddition with protected bis-hydroxymethylene ketenes (R1 = CH2OR) had been reported. In fact, all those we tested (R1 = CH2OBn, CH2OTBS, CH2OSiMe2OCH2) failed to produce any synthetically useful amount of cyclobutanones (Figure 2). We thus turned our attention to the cyclic oxadisilinane moiety as a potential hydroxymethylene surrogate. The unusual oxadisilinane ketene was chosen because it exhibits stable and “neutral” functionality in the envisioned following steps of the synthesis, with the possibility of unmasking a bis-hydroxyl group when required. Indeed, we envisioned a stereocontrolled desymmetrization of the oxadisilinane, followed by a subsequent selective Tamao and Fleming type oxidation, which would install the quaternary center, en route to omuralide 1 (Figure 2). The asymmetric synthesis of the all-cis cyclobutanone (+)-9, obtained from a chiral enol ether and the oxadisilinane ketene, was therefore undertaken, starting from the R-enantiomer of the chiral auxiliary securing the absolute configuration of the final synthetic target (Scheme 1). The chiral enol ether (R)-5 is easily obtained in three steps on gram scale from the reaction of the (R)-Stericol potassium alkoxide with trichloroethylene, followed by methylation of the lithiated ynol ether intermediate

Scheme 2. Preparation of γ-Lactam Core through Beckmann Transposition and X-ray Crystal Structure of Imidate (±)-13

Scheme 1. Asymmetric [2 + 2]-Cycloaddition between Chiral Enol Ether (R)-5 and Cyclic Oxadisilinane Ketene

a

MSH = O-mesitylenesulfonylhydroxylamine.

MSH-mediated Beckmann transposition on cyclobutanone 11 afforded γ-lactam 12 as a single regioisomer in 58% yield. To prevent any C2 epimerization and in prevision of reactions with basic and nucleophilic organometallics, the lactam moiety was protected as the benzyl imidate 13. This regioselective Oalkylation is the result of the steric hindrance around nitrogen due to the pseudoaxial methyl groups of the chairlike 1,2,6oxadisilinane ring. The X-ray crystal structure of 13 confirmed the O-benzylated imidate function (Scheme 2). 4559

DOI: 10.1021/acs.orglett.8b01851 Org. Lett. 2018, 20, 4558−4561

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Scheme 3. Desymmetrization of spiro-Oxadisilinane via Selective Ring-Opening by Proximal Alcohol: Synthesis Endgame

The lactam function was then released by hydrogenolysis of imidate 18, and the dimethylphenylsilane was subsequently oxidized under Fleming conditions,18b leading to the primary alcohol in lactam 19. Jones oxidation followed by saponification of the two acetates afforded the intermediate diol 20. Finally, a classical esterification led to the β-lactone ring, providing natural (−)-omuralide 1 in 90% yield over the last three steps. The physical data and optical rotation of the synthetic (−)-omuralide (1) obtained are in agreement with those reported in the original isolation paper.8f A formal synthesis of (+)-lactacystin is also therefore realized, requiring a simple transesterification step with N-acetyl-cysteine.8f In conclusion, the stereocontrolled total synthesis of (−)-omuralide 1 and formal synthesis of (+)-lactacystin 2 have been achieved, involving readily available starting materials. The synthetic strategy features an asymmetric [2 + 2]cycloaddition between a chiral enol ether 5 and an oxadisilinane ketene. A regioselective ring expansion of chiral cyclobutanone 11 afforded a highly functionalized γ-lactam core bearing two of the four stereogenic centers. The uncommon cyclic oxadisilinane revealed itself to be an excellent bis-hydroxylmethylene surrogate, with highly selective stepwise oxidation of each silyl group. This synthesis not only allows access to the naturally occurring substances but also opens the way to potential attractive designed analogues for future investigation as anticancer agents. Application of this synthetic strategy toward a unified synthesis of (−)-salinosporamide A and synthetic analogues is currently underway.

The choice of the cyclic oxadisilinane functionality as masked hydroxyl groups was to be tested next. Surprisingly, the sixmembered ring oxadisilinane in 13 does not undergo direct Tamao−Fleming oxidation under classical conditions,18 unlike reported examples with five-membered ring oxadisilinane.19 It seems that a Thorpe−Ingold effect20 associated with the spiro cyclic nature of the cyclobutane-oxadisilinane leads to an unexpectedly stability of the disiloxane moiety. However, we found that, in the presence of a proximal free alcohol, the oxadisilinane ring could be opened with complete regioselectivity with 2 equiv of phenyllithium, affording a silanol on one side and a dimethylphenylsilane on the other side (Scheme 3). The 2D NMR analysis revealed that the dimethylphenylsilane group ended up on the most hindered face of the γ-lactam 15 (Scheme 3). This unique selective transformation solely occurs in the presence of a proximal free hydroxyl group: the TBS protected imidate 13 did not lead to the oxadisilinane ring opened product, neither did lactam 12. In agreement with the observed stereochemistry, we postulate that the alcohol, obtained after treatment with TBAF, is deprotonated by the first equivalent of phenyllithium and then reacts with the proximal silyl atom, in an intramolecular fashion, forming in situ the five-membered oxasilinane 14. A second equivalent of phenyllithium then reopened the oxasilinane 14 affording 15 bearing a dimethylphenylsilane group on the same face of the lactam ring as the hydroxyl in C4, and a silanol on the other side of the ring. Thereby, this stereoselective addition of phenyllithium allowed for the differentiation of the two silicon atoms of the oxadisilinane: indeed, the dimethylsilanol (in red, Scheme 3) should be oxidized under Tamao oxidation conditions,18a while the dimethylphenylsilane (in blue, Scheme 3) is stable under these conditions but should be oxidized under Fleming oxidation conditions.18b Silanol in 15 was indeed selectively oxidized using potassium fluoride and hydrogen peroxide, affording diol 16, leaving the dimethylphenylsilane moiety untouched. The primary alcohol in 16 was selectively oxidized in the presence of the unprotected secondary alcohol using TEMPO and N-chlorosuccinimide to afford aldehyde 17. Addition of isopropyllithium to aldehyde 17 at low temperature eventually yielded a diol intermediate with a 7:3 dr. Esterification of the crude reaction diol without further purification afforded diacetate 18 isolated as a single diastereomer in 51% yield over two steps (Scheme 3).

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01851. Detailed experimental procedures and full characterization for all new compounds (PDF) Accession Codes

CCDC 1822688 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. 4560

DOI: 10.1021/acs.orglett.8b01851 Org. Lett. 2018, 20, 4558−4561

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Jean-François Poisson: 0000-0002-4982-7098 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Labex ARCANE (ANR-11LABX-0003-01). P.R. thanks the French Ministry of Research for a PhD fellowship (AMX). The authors also thank the ICMG Chemistry Nanobio Platform for technical support and Dr. Christian Philouze (DCM, Grenoble) for X-ray measurements.

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DOI: 10.1021/acs.orglett.8b01851 Org. Lett. 2018, 20, 4558−4561