Total Synthesis of (+)-Pleuromutilin

Transcription

1 Communication Total Synthesis of (+)-Pleuromutilin Elliot P Farney, Sean S. Feng, Felix Schäfers, and Sarah E. Reisman Subscriber access provided by Caltech Library J. Am. Chem. Soc., Just Accepted Manuscript DI:./jacs.b0 Publication Date (Web): Jan 0 Downloaded from on January, 0 Just Accepted Just Accepted manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides Just Accepted as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. Just Accepted manuscripts appear in full in PDF format accompanied by an TML abstract. Just Accepted manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital bject Identifier (DI ). Just Accepted is an optional service offered to authors. Therefore, the Just Accepted Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the Just Accepted Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these Just Accepted manuscripts. Journal of the American Chemical Society is published by the American Chemical Society. Sixteenth Street N.W., Washington, DC 00 Published by American Chemical Society. Copyright American Chemical Society. owever, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

2 Page of Journal of the American Chemical Society Total Synthesis of (+)-Pleuromutilin Elliot P. Farney, Sean S. Feng, Felix Schäfers, and Sarah E. Reisman* The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California, United States. Supporting Information Placeholder ABSTRACT: An -step synthesis of the antibiotic (+)- pleuromutilin is disclosed. The key steps of the synthesis include a highly stereoselective SmI -mediated cyclization to establish the eight-membered ring, and a stereospecific transannular [,]-hydrogen atom transfer to set the C stereocenter. This strategy was also used to prepare (+)-- epi-pleuromutilin. The chemistry described here will enable efforts to prepare new mutilin antibiotics. (+)-Pleuromutilin () is a diterpene natural product first isolated from the fungus Clitopilus passeckerianus in (Scheme ). (+)-Pleuromutilin binds to the peptidyl transferase center of bacterial ribosomes, preventing protein synthesis. Semi-synthetic derivatives of in which the C ester is modified have been identified as potent antibiotics; for example, retapamulin is an FDA-approved topical antibiotic. Recently, derivatives of -epi-mutilin have been developed as broad-spectrum antibiotics with efficacy against gramnegative pathogens. Given its promising antibacterial properties, four total syntheses of have been reported to date, the most recent of which was disclosed by erzon and coworkers in 0.,, ere we report an approach that enables the preparation of (+)-pleuromutilin and (+)--epipleuromutilin in steps from (+)-trans-dihydrocarvone. In considering a design plan for a synthesis of (+)-, we targeted a modular approach in which a bifunctional hydrindane fragment (e.g. ) would be annulated to form the eightmembered ring through two sequential C C bond forming steps. In particular, the C C and C C bonds, which each link vicinal stereogenic centers, were identified as strategic points of disconnection. Applying this general plan in a retrosynthesis, (+)- was simplified to, which was further disconnected through the C C bond to aldehyde (Scheme ). In the forward sense, we envisioned forming the eight-membered ring through a late-stage SmI -mediated ketyl radical cyclization of. It is important to distinguish this approach from the SmI -mediated cascade cyclization employed in Procter s synthesis of, c,d which formed the C C bond by a ketyl radical conjugate addition, and the C C bond and - membered ring by intramolecular aldol cyclization. To enable the cascade reaction, Proctor employed an ester as a precursor to the C methyl, and required several additional steps to adjust the oxidation states at C and C. In contrast, a SmI cyclization of was expected to provide with C, C, and C in the correct oxidation states for advancement to. Aldehyde was anticipated to arise from enone, which, depending on the targeted stereochemistry at C, could be prepared by crotylation of enal with either Z- or E-boronic Scheme. Retrosynthetic analysis. pleuromutilin () R R : R =, R = vinyl -epi-: R = vinyl, R = R PR R SmI strategy: modular fragment coupling to prepare or -epi- R R crotylation R Trt + () B R Z-: R =, R = C C Trt E-: R = C C Trt, R = Comparison of SmI Approaches to Pleuromutilin Framework Piv Procter et al.: -membered ring formed by aldol Cyclization product has C Sm III and C at incorrect δ + δ oxidation states C δ δ + Sm III P mutilin: R = retapamulin: R = S N PR R This Work: -membered ring formed by ketyl addition Cyclization product has C and C at correct oxidation states

3 Journal of the American Chemical Society Page of Scheme. Synthesis of a cyclization substrate. MgBr ) CuCN LiCl, TMSCl MgBr ) CuI, TF TF, C; then C to 0 C ) Cl (aq), TF, 0 C ) Pd(Ac) ( mol %).: dr.: dr DMS,, rt % yield % yield % yield, steps Trt Z- MM ) MMCl, i Pr NEt () B ) C, Et ) (R)-, -Br -BINL (0 mol %) ) K P, NaI 0% yield, steps ) [Cu(CN) ]Tf Trt + Trt t Bu, Å MS DMS, ºC Ph, 0 C % yield NMI, CN 0% yield % yield b % brsm a desired,-bis-epi.: a:b -bpy, ABN acid. Thus, through appropriate design of the crotylation reaction, either or -epi- would be accessible through this route. ydrindanone enal was mapped back to enone via sequential conjugate addition reactions and functional group interconversions. The synthesis began with the preparation of enone in one step from (+)-trans-dihydrocarvone. Conjugate addition of the cuprate derived from, followed by Pd-catalyzed desaturation furnished (Scheme ). A second conjugate addition furnished the C-quaternary stereocenter; however, attempts to promote an intramolecular aldol condensation under Brønsted- or Lewis-acid catalysis resulted in the formation of undesired Prins-type products. ypothesizing that electronic deactivation of the isopropenyl group would mitigate this non-productive reactivity, was converted to the allylic chloride using trichloroisocyanuric acid (TCCA). Indeed, treatment of the ketal with Cl at 0 C provided enone as a.: mixture of diastereomers at C; the major diastereomer was isolated in % yield.,-addition of methylmagnesium chloride was achieved with the aid of CeCl LiCl and the diastereomeric mixture was submitted to pyridinium chlorochromate (PCC) to effect an oxidative transposition. Kornblum oxidation of delivered enal in steps from. With enal in hand, the first of two key C C bond constructions required to form the bridging eight-membered ring was investigated. Reaction of with boronic acid Z- under the conditions developed by Szabó and coworkers provided a mixture of diastereomers a and b (Scheme ). b While the reaction proceeded with excellent selectivity for syn crotylation consistent with a closed transition state the catalyst did not discriminate between the diasterofaces of the aldehyde during the nucleophilic attack. Use of the S catalyst provides a :. mixture of a and b. A brief investigation of alternative catalytic asymmetric crotylation conditions proved unfruitful. Separation of the diastereomers by column chromatography, followed by protection of a as the methoxymethyl (MM) ether, cleavage of the trityl ether, and oxidation under the conditions developed by Stahl delivered aldehyde. ) TCCA, EtAc, 0 C % yield At this stage, attention turned to the second key C C bond construction: a SmI -mediated cyclization to form the eightmembered ring (Scheme ). When was treated with a freshly-prepared solution of SmI in TF at 0 C, then quenched with aqueous ammonium chloride, carboxylic acid was obtained as a single diastereomer. Presumably arises from exposure of Sm III -enolate to oxygen, resulting in formation of an a-peroxyketone and subsequent oxidative ring scission. Although the ring scission was deleterious, it nonetheless confirmed that C C bond formation occurred with high diastereoselectivity. In an effort to prevent the unwanted formation of, a variety of conditions were evaluated. After substantial optimization, it was found that dropwise addition of SmI ( equiv) to and equiv as a solution in TF at 0 C, under rigorously anaerobic conditions, followed by quenching first with trimethylsilyl chloride (TMSCl), then aqueous workup delivered tricycle in % yield as a separable : mixture of diastereomers (Scheme ). The addition of was found to be critical to minimize undesired side-product formation and achieve high diastereoselectivity; reactions conducted in the absence of afforded with : dr at C. To complete the synthesis of (+)-, chemoselective reduction of the C C exocyclic olefin and installation of the glycolate ester were required. Unfortunately, standard hydrogenation conditions employing cationic transition metal complexes gave rapid and exclusive reduction of the more sterically-accessible C C0 vinyl group. Instead, we turned to hydrogen-atom transfer (AT) reactions, seeking to leverage the thermodynamic preference for formation of a carbon-centered radical. Indeed, use of tris(,,,- tetramethyl-,-heptanedionato)manganese (III) (Mn(dpm) ) in the presence of phenylsilane and tert-butyl hydroperoxide (TBP) in degassed, anhydrous isopropanol resulted in highly diastereoselective reduction of the C C olefin (Scheme ). We were surprised to discover, however, that alkene reduction was accompanied by oxidation of the C alcohol. This redox relay process delivered diketone in % yield as a single diastereomer. nly Cl ) CeCl LiCl MgCl, 0 C ) PCC, C Cl % yield, steps Cl

4 Page of Journal of the American Chemical Society Scheme. Completion of the synthesis of (+)-pleuromutilin (). MM C SmI conditions MM Sm III MM SmI ( equiv) TF, 0 C, min then N Cl (aq) % yield Sm III rigorously deoxygenated ) SmI ( equiv) ( equiv) TF, 0 C, min Scheme. Redox relay by transannular [,]-AT. MM trace products arising from competing C-C0 vinyl reduction were observed. Substrates in which the C alcohol is protected gave only % conversion after h, and the resulting C stereocenter was formed as a mixture of diastereomers. To test if this reaction proceeds by a transannular [,]-AT process, 0 deuterium-labeled substrate -d was prepared and exposed to the optimized reaction conditions (Scheme ). Tricycle -d was formed as a single diastereomer with complete transfer of the deuterium label. The observation that substrates in which the C alcohol is protected perform poorly under the AT conditions suggests that cleavage of the bond to form the C ketone serves as a driving force for this transformation. aving solved the problem of chemoselective alkene reduction, the selective reduction the C ketone in the presence of the C ketone was now required. Ultimately, selective reduction of diketone proved untenable. Instead, triisopropylsilyl (TIPS) enol ether was prepared and submitted to radical reduction to obtain ketone as a single diastereomer (Scheme ). To complete the total synthesis, was submitted to excess lithium in ammonia, which furnished alcohol 0 as a separable : mixture of diastereomers. Subsequent one-pot acylation with -(,,- trifluoroacetoxy)acetic acid followed by trifluoroacetate methanolysis, then acidic hydrolysis effected global deprotection to deliver (+)-. A key design aspect of our strategy was the ability to easily vary the stereochemistry of the cyclization substrates at C then TMSCl ( equiv) % yield, : dr pleuromutilin () 0 Mn(dpm) MM MM MM ( mol %) [Mn] PhSi X X (. equiv) X [,]-AT TBP ( equiv) single i Pr, rt diastereomer X =, % yield X = D, % yield >% D transfer 0 ) EDCI, DMAP C Cl, rt, h then Et N; then Cl/TF, 0 C 0% yield TIPS 0 ) Li/N Et Et, C % yield : dr ) LiMDS TIPSTf TF to 0 C % yield TIPS transannular redox relay TFA C MM MM TIPS ) Mn(dpm) ( mol %) PhSi, TBP i Pr, rt % yield single diastereomer and C. In particular, given the recent interest in derivatives of C-epi-mutilin as broad-spectrum antibiotics, we sought to demonstrate that the -epi-mutilin framework could be prepared. To this end, enal was subjected to crotylation with E- under the previously developed conditions, to deliver c and d as a : mixture in % combined yield (Scheme, a). Elaboration of c to -epi- proceeded without difficulty. Exposure of -epi- to the optimal conditions for the SmI cyclization furnished -epi- in Scheme. Reactivity of diastereomeric cyclization substrates. (a) Synthesis of -epi-. -epi- MM,-bis-epi SmI SET Sm III MM () B (R)-, -Br -BINL (0 mol %) SmI ( equiv) ( equiv) TF, 0 C, min then TMSCl ( equiv) % yield, : dr (b) Cyclization of a,-bis-epi substrate. E- t Bu, Å MS Ph, 0 C % yield : c:d SmI ( equiv) ( equiv) TF, 0 C, min then TMSCl ( equiv) 0% yield MM MM steps -epi- MM Dowd-Beckwith rearrangement MM MM MM Sm III Trt + Trt c -epi SmI SET Sm III d -epi Trt -epi-

5 Journal of the American Chemical Society Page of % yield and : dr. -epi- was smoothly advanced four steps to complete the synthesis of -epi-. In contrast, attempts to cyclize aldehyde, prepared from crotylation product b, revealed that the C stereochemistry exerts a pronounced effect on reactivity (Scheme, b). Subjection of to the SmI -mediated cyclization conditions provided tricycle as the major product in 0% yield. It is proposed that conformational gearing to minimize A, strain at C reverses the regioselectivity of the Sm-ketyl addition to the enone, producing radical. Subsequent Dowd- Beckwith rearrangement proceeding through cyclopropane delivers the product bearing a bridgehead olefin. In summary, the total syntheses of (+)-pleuromutilin and (+)--epi-pleuromutilin were each completed in steps (longest linear sequence) from (+)-trans-dihydrocarvone. These syntheses were enabled by a modular approach, which employed a highly diastereoselective SmI -mediated radical cyclization to form the eight-membered ring. In addition, we uncovered a transannular [,]-AT that effects a stereospecific redox relay to set the C stereocenter. The brevity and modularity of the route will enable the design and synthesis of new fully synthetic variants of mutilin antibiotics. ASSCIATED CNTENT Supporting Information. The Supporting Information is available free of charge on the ACS Publications website at DI: xx.xxxx/jacs.xxxxxxxxx. Crystallographic data for,, and (CIF) Experimental procedures and characterization and spectral data for all compounds (PDF) AUTR INFRMATIN Corresponding Author *reisman@caltech.edu Author Contributions These authors contributed equally to this work. ACKNWLEDGMENT We thank Dr. Michael Takase and Larry enling for X-ray data collection, Ms. Julie ofstra for X-ray data refinement, Dr. David VanderVelde for assistance with NMR structure determination, Dr. Scott Virgil for assistance with crystallization of, and the Caltech CS for access to analytical equipment. Fellowship support was provided by the NI (E.P.F., Grant FGM) and NSF (S.S.F., DGE-). Financial support from the eritage dical Research Institute is gratefully acknowledged. REFERENCES. (a) Kavanagh, F.; ervey, A.; Robbins, W. J. Proc. Natl. Acad. Sci. U.S.A.,, 0. (b) Birch, A. J.; olzapfel, C. W.; Rickards, R. W. Tetrahedron, Suppl., Part II,.. Poulsen, S. M.; Karlsson, M.; Johansson, L. B.; Vester, B. Mol. Microbiol. 00,, -.. (a) Rittenhouse, S.; Biswas, S.; Broskey, J.; McCloskey, L.; Moore, T.; Vasey, S.; West, J.; Zalacain, M.; Zonis, R.; Payne, D. Antimicrob. Agents. Chemother. 00, 0,. (b) Fazakerley, N. J.; Procter, D. J. Tetrahedron, 0, 0,.. Thirring, K.; eilmayer, W.; Riedl, R.; Kollmann,.; Ivezic-Schoenfeld; Wicha, W.; Paukner, S.; Strickmann, D. W0A, 0 July 0.. (a) Gibbons, E. G. J. Am. Chem. Soc.,,. (b) Boeckman Jr., R. K.; Springer, D. M.; Alessi, T. R. J. Am. Chem. Soc.,,. (c) elm, M. D.; Da Silva, M.; Sucunza, D.; Findley, T. J. K.; Procter, D. J. Angew. Chem. Int. Ed. 00,,. (d) Fazakerley, N. J.; elm, M. D.; Procter, D. J. Chem. Eur. J. 0,,. (e)murphy, S. K.; Zeng, M.; erzon, S. B. Science 0,,. (f) Zeng, M.; Murphy, S. K.; erzon, S. B. J. Am. Chem. Soc. 0,,.. Synthetic studies toward pleuromutilin: (a) Paquette, L. A.; Wiedeman, P. E.; Bulman-Page, P. C. J. rg. Chem.,,. (b) Bacque, E.; Pautrat, F.; Zard, S. rg. Lett. 00,,. (c) Loresta, S. D.; Liu, J.; Yates, E. V.; Krieger, I.; Sacchettini, J. C.; Freundlich, J. S.; Sorensen, E. J. Chem. Sci. 0,,.. For a review of the role of synthesis in antibacterial drug discovery: Wright, P. M; Seiple, I. B.; Myers, A. G. Angew. Chem. Int. Ed. 0,, 0.. For examples of medium size ring construction using SmI, see: (a) Molander, G. A.; McKie, J. J. rg. Chem.,,. (b) Enholm, E. J.; Satici,.; Trivellas, A. J. rg. Chem.,,. (c) Matsuda, F.; Sakai, T.; kada, N.; Miyashita, M. Tetrahedron Lett.,,. (d) Molander, G. A.; George, K. M.; Monovich, L. G. J. rg. Chem. 00,,. Blot, V.; Reibig,.-U. Eur. J. rg. Chem. 00,. For a review: (e) Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem. Rev. 00,,.. (a) Lou, S.; Moquist, P. N.; Schaus, S. E. J. Am. Chem. Soc. 00,, 0. (b) Alam, R.; Vollgraff, T.; Eriksson, L.; Szabó, K. L. J. Am. Chem. Soc. 0,,.. White, J. D.; Grether, U. M.; Lee, C-S. rg. Synth. 00,,. Commercially available (+)-dihydrocarvone is supplied as : mixture of trans and cis isomers, which can be chromatographically separated to give pure trans.. Singh, D.; McPhee, D.; Paddon, C. J.; Cherry, J.; Maurya, G.; Mahale, G.; Patel, Y. Kumar, N.; Singh, S.; Sharma, B.; Kushwaha, L.; Singh, S.; Kumar, A. rg. Process Res. Dev. 0,,.. Krasovskiy, A.; Kopp, F.; Knochel, P. Angew. Chem. Int. Ed. 00,,.. Dauben, W. G.; Michno, D. M. J. rg. Chem.,,.. See the Supporting Information for the synthesis of Z- and E-.. See Supporting Information.. Steves, J. E.; Stahl, S. S. J. Am. Chem. Soc. 0,,.. This type of oxidative ring scission has previously been observed: Spring, D. M.; Bunker, A.; Luh, B. Y.; Sorenson, M. E.; Goodrich, J. T.; Bronson, J. J.; DenBleyker, K.; Dougherty, T. J.; Fung-Tomc, J. Eur. J. d. Chem. 00,,.. (a) Ma, X.; erzon, S. Chem. Sci. 0,, 0. (b) Crossely, S. W. M.; bradors, C.; Martinez, R. M.; Shenvi, R. A. Chem. Rev. 0,,.. Conditions were adapted from: Iwasaki, K.; Wan, K. K.; ppedisano, A.; Crossley, S. W. M.; Shenvi, R. A. J. Am. Chem. Soc. 0,, 0.

6 Page of Journal of the American Chemical Society For examples of transannular [,]-AT on a medium-sized ring, see: (a) Winkler, J. D.; Sridar, V.; Rubo, L.; ey, J. P.; addad, N. J. rg. Chem.,, 00. (b) Boivin, J.; da Silva, E.; urisson, G.; Zard, S. Z. Tetrahedron Lett. 0,, 0.. Intermolecular hydrogen-bonding with an acceptor molecule, such as isopropanol solvent, may be responsible for polarizing the bond, leading to weakening of the C carbinol hydrogen atom. See: (a) Gawlita, E.; Lantz, M.; Paneth, P.; Bell, A. F.; Tonge, P. J.; Anderson, V. E. J. Am. Chem. Soc. 000,, 0. (b) Jeffrey, J. L.; Terrett, J. A.; MacMillan, D. W. C. Science 0,,.. The aldehyde derived from d underwent the analogous cyclization. TC graphic: (+)-pleuromutilin steps