Enantiospecific Total Synthesis of the Highly Strained

Communication pubs.acs.org/JACS

Enantiospecific Total Synthesis of the Highly Strained (−)-Presilphiperfolan-8-ol via a Pd-Catalyzed Tandem Cyclization Pengfei Hu†,‡ and Scott A. Snyder*,†,‡ †

Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States Department of Chemistry, University of Chicago, 5735 South Ellis Avenue, Chicago, Illinois 60637, United States

‡

S Supporting Information *

Scheme 1. Strained Natural Products with a 1,2-trans Ring Fusion within a [3.3.0]-Bicycle (Gray Box Highlights) and/or a 1,3-trans Substituent Arrangement (Blue Atoms) on a 5Membered Ring, Features Combined in (−)-Presilphiperfolan-8-ol (5)

ABSTRACT: A rare element of high strain in molecules of natural origin is a 1,2-trans fusion of 5-membered rings within a [3.3.0]-bicycle, a motif present in (−)-presilphiperfolan-8-ol. This molecule also possesses a 1,3-trans stereochemical arrangement of substituents on one of its 5-membered rings, a pattern shared by a number of other terpenes. Herein, we disclose the first total synthesis of this highly strained target in 13 steps. The key operation is a Pd-catalyzed tandem cyclization that directly establishes the requisite 1,3-trans stereochemical arrangement on one ring while concurrently setting the stage for the controlled generation of the highly strained 1,2-trans ring fusion of the final architecture.

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mong the diverse structures of natural products, there are several that possess high strain in the form of bent arene rings,1 anti-Bredt double bonds,2 and medium-sized rings with multiple sites of unsaturation.3 Another form of such strain resides in bicyclo[3.3.0]octanes, wherein the constituent 5membered rings are fused in a 1,2-trans fashion. By calculation and experiment, such systems possess ∼6 and 13 kcal/mol of additional strain energy relative to their 1,2-cis-fused counterparts.4 Perhaps unsurprisingly, these molecules are rare, with only 10 such fusions out of 2000 bicyclo[3.3.0]octane-containing molecules found from a survey of available X-ray crystal structures;5 similarly, only 35 natural products are believed to have this system in an all-carbon format.6 From a synthetic perspective, molecules with this strain element are also hard to synthesize, with only four natural products7 bearing such domains having been prepared to date (1−4, Scheme 1), two with heteroatoms as part of the bicycle7a−g and two with an allcarbon framework.6,7h In the latter cases, both cis- and trans-fused products resulted from the annulation strategy.6 As part of a program seeking to fashion challenging but relatively functionally deficient molecules (i.e., structures largely composed of saturated C−H and C−C bonds with few, if any, additional reactive handles),8 we became interested in a natural product possessing an all-carbon trans-fused bicyclo[3.3.0]octane known as (−)-presilphiperfolan-8-ol (5).9 Isolated from Eriophyllum staechadifolium and Flourensia heterolepis in 1981 by Bohlmann and co-workers,9a this molecule has since been shown biosynthetically to result from water capture of the tertiary carbocation (6), formed as a cyclization product of 7.10 While 6 itself is the progenitor of a number of other frameworks (such as 8−10),11,12 natural product 5 could also potentially serve a © XXXX American Chemical Society

similar role in Nature, as its separate exposure to different acid sources leads to many of these same structures,9b presumably via a strain-relieving ionization of its tertiary alcohol, eliminating its 1,2-trans ring fusion. To date, however, 5 has remained an unsolved synthetic challenge despite several attempts;13 those efforts have been able to generate its full carbon framework, but not with the proper functionalization and/or stereochemical arrangement of substituents at the C-4 and C-8 positions in its most strained form. By contrast, both of its cousins (11 and 12), molecules that possess a 1,2-trans ring fusion element within a slightly larger [4.3.0]nonane framework, have been the subject of successful and creative synthetic campaigns by the groups of Received: February 10, 2017

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DOI: 10.1021/jacs.7b01454 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Communication

Journal of the American Chemical Society Stoltz14 and Weyerstahl.15 Herein, we describe an approach predicated on the use of a tandem Pd-mediated cyclization to establish the 1,3-trans relationship of substituents colored in blue on the structure of 5, a motif shared in varied formats by many other structures such as 11−16.16 This process affords a material from which we could then establish the final trans-fused bicyclo[3.3.0]octane system as a single stereoisomer through a number of carefully orchestrated and highly diastereoselective transformations. Overall, the route proceeded in 13 steps, with the first 10 operations effected on gram scale. As shown in Scheme 2, our hope was that following an enantiospecific preparation of vinyl triflate 18 in a variety of

stereochemistry and functional group patterning hopefully affording the means to install the tertiary alcohol with the necessary stereocontrol to complete the 1,2-trans-fused bicyclo[3.3.0]octane core. Worth noting, as an added argument for pursuing a Pd-based solution to this framework, radical- or Limediated approaches would not appear likely to afford the requisite stereochemical control.19 Although both strategies were actively investigated, the tandem cyclization approach ultimately afforded (−)-presilphiperfolan-8-ol (5), with significant optimization of the cyclization needed from the precedents in Scheme 2 to achieve a high yield. Our synthesis began with a Sakurai allylation of commercial (R)-pulegone20 (17, Scheme 3), using a terminating KOH/

Scheme 2. Potential Formation of a 1,3-trans Stereochemical Relationship (Including a Quaternary Carbon) via a Diastereoselective Pd-Catalyzed Tandem Cyclization

Scheme 3. Development of a 13-Step Asymmetric Total Synthesis of (−)-Presilphiperfolan-8-ol (5)a

a

Reagents and conditions: (a) TiCl4 (0.98 equiv), methallyltrimethylsilane (1.3 equiv), CH2Cl2, −78 to 0 °C, 20 min; KOH (0.8 equiv), MeOH, 23 °C, 4 h, 70%, 4:1 dr; (b) LDA (1.1 equiv), −78 to 0 °C, 1 h; allyl bromide (1.2 equiv), 12 h, 90%, 5:1 dr; (c) KHMDS (1.3 equiv), −78 to 0 °C, 2 h; Comins’ reagent (1.1 equiv), −78 °C, 20 min, 85%, 5:1 rr; (d) Pd(OAc)2 (0.1 equiv), DPEphos (0.2 equiv), Et3N (2 equiv), 90 °C, toluene, 10−12 h, 90 °C; (e) OsO4 (0.14 equiv), NMO (4.3 equiv), acetone/H2O (3/1), 23 °C, 12 h; NaIO4 (4.3 equiv), 23 °C, 30 min; (f) mCPBA (3 equiv), NaHCO3 (8 equiv), CH2Cl2, 23 °C, 15 min; (g) LiHMDS (3 equiv), −78 to 0 °C, 1.5 h; MeOH (5 equiv), −78 to 23 °C, 1 h; Stryker’s reagent (0.4 equiv), 23 °C, 5 h, 28% over 4 steps; (h) TMSOTf (5 equiv), Et3N (6 equiv), CH2Cl2, 23 °C, 10 min; 2 N HCl; (i) p-ABSA (20 equiv), DBU (30 equiv), CH3CN, 12 h, 95% over 2 steps; (j) 125 W Hg-lamp, MeOH, Et3N, 23 °C, 30 min, 83%; (k) DIBAL-H (3 equiv), CH2Cl2, −78 °C, 1 h; t-BuOH (30 equiv); DMP (5 equiv), NaHCO3 (10 equiv), 1 h, 93%; (l) Rh(PPh3)3Cl (1.5 equiv), toluene/PhCN (6/1), 130 °C, 12 h; (m) TBAF (10 equiv), THF, 30 °C, 12 h, 40% over 2 steps.

formats as determined by group R, starting from a readily available chiral source material such as (R)-pulegone (17), its subsequent exposure to an appropriate Pd(0) catalyst could establish the requisite 1,3-arrangement of substituents, as drawn in 19. That result would require that the C-7 center control the orientation of substituents in the rigid 4-membered ring transition state of the migratory insertion step, an outcome that seemed reasonable given precedent from Grigg (24 → 25 → 26, transition state shown)17 on a related molecule and Overman (27 → 28)18 on a different systemthe assumption here being, especially in relation to the Grigg case, that the methyl ester and the other quaternary carbon in 24 are not also required for high selectivity. If formed properly, though, the resulting alkylpalladium intermediate (19) could then hopefully engage in a second Heck-type cyclization18 (if R = allyl) to 20 or be functionalized in a variety of formats17b (when R = H) to afford 22; the quaternary carbon formed in the initial cyclization to 19 precludes the possibility of a competing β-H elimination. Each approach would afford strategically different opportunities to generate 5 (and other scaffolds), with the resident

MeOH treatment to thermodynamically equilibrate the newly formed chiral center.13a This operation proceeded on multigram scale in a reproducible 70% yield and 4:1 dr favoring 29 as long as sub-stoichiometric amounts of TiCl4 were used. Following chromatographic separation of 29 and its diastereomer (noting that the minor one could again be equilibrated to a 4:1 mixture favoring 29 with KOH/MeOH), an allyl side chain was installed on the other side of the ketone within the core of 29, generating B

DOI: 10.1021/jacs.7b01454 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Communication

Journal of the American Chemical Society 30 in 5:1 dr.13a Our goal now was to differentiate the two tertiary hydrogens adjacent to the core ketone, an operation that proved possible by treating 30 with KHMDS at 0 °C followed by quenching the resultant enolate with Comins’ reagent to afford an inseparable 5:1 mixture of regioisomers in 85% combined yield favoring 31. Lowering the reaction temperature afforded no improvement in selectivity, with other bases such as LDA and LiTMP failing to give commensurate results. The stage was now set to explore the key Pd-catalyzed tandem cyclization. In our initial experiments we were able to generate the desired product using Overman’s conditions18 (27 → 28, cf. Scheme 2), though the yield was low (∼20%) and the product was contaminated with several unidentified byproducts. A quick survey of solvents indicated that toluene was a superior choice, affording 20 in 38% yield irrespective of ligand loading (Table 1,

subsequent enone reduction using Stryker’s reagent. This process afforded 21 in 28% yield over 4 steps from 31 on gram scale as a single diastereomer; X-ray crystallographic analysis confirmed that 21 was formed with a 1,2-trans ring fusion. Based on molecular models, we believe that the exceptional diastereoselectivity in the epoxidation step arises from the fact that the methyl group attached to C-4 (presilphiperfolan-8-ol numbering) is perpendicular to the tetrasubstituted olefin, thereby blocking the α-face; by contrast, the C-9 methyl group is in an equatorial position, exerting minimal steric bias and thus allowing mCPBA to approach from the β-face of the molecule. Of further note, despite these steps forming part of a less strained bicyclo[4.3.0]nonane framework, 32 and 33 are highly acid labile, succumbing to dehydration and/or decomposition even when aluminum oxide is used for chromatographic purification. We now had to effect a ring contraction27 while retaining the seemingly sensitive tertiary alcohol. Initial efforts, such as a Favorskii rearrangement as well as thallium-mediated reactions, failed with 21 and/or its protected analogues. Pleasingly, the Wolff rearrangement28 worked extremely well on a TMSprotected variant of 21 by generating the requisite diazoketone (i.e., 34) using excess p-ABSA in the presence of DBU29 and then irradiating in MeOH at 23 °C for 20 min. This process afforded more than 800 mg of the highly strained 35 when conducted on gram scale. The synthesis of (−)-presilphiperfolan-8-ol (5) was then completed by converting the exocyclic methyl ester into an aldehyde using a one-pot DIBAL-H/Dess−Martin procedure followed by deformylation30 using stoichiometric Wilkinson’s catalyst and final TMS removal.31 Of note in these final steps, separate reduction and oxidation steps proceeded in inferior yield in generating 38 (70% versus 93%), 32 while the Rh(PPh3)3Cl operation proceeded smoothly when conducted on small scale (∼15 mg). In total, the synthesis required 13 steps from commercial 17, and ∼15 mg of 5 has been prepared with spectral properties and optical rotations matching that of the natural isolate.9 In conclusion, we have developed the first enantioselective synthesis of the highly strained natural product (−)-presilphiperfolan-8-ol in 13 steps, the majority of which proceed effectively on gram scale. Key features include (1) a highly diastereoselective Pd-based cascade cyclization which establishes the requisite 1,3-stereochemical patterning at key ring fusions and (2) the installation of functionality from that process which allows for the final generation of the highly strained and reactive 1,2-trans-bicyclo[3.3.0]octane core through the use of a less strained trans-indane system and appropriate ring contraction strategies. The application of elements of this overall sequence to other unique terpenes is the subject of current endeavors and will be reported in due course.

Table 1. Screening of Conditions for the Pd-Catalyzed Tandem Cyclization

a Yields determined by 1H NMR using 1,3,5-trimethoxybenzene as the internal standard. b40 mol % Ph3P was used. cThis reaction was performed at 90 °C.

entries 1 and 2). While other more electron-rich monodentate ligands failed to improve upon this initial lead (not shown), we did observe that bidentate ligands also promoted the reaction, affording higher yields and cleaner crude product samples (entries 3−8). Ultimately, DPEphos proved to be the best ligand, affording 20 in 75% yield, even when the process was conducted at a lower reaction temperature (entries 9 and 10). Of note, the cyclization could be conducted on 10 mmol scale to deliver nearly 2 g of 20 in a single batch; interestingly, cyclization products from the other alkenyl triflate isomer were never observed. Having established the key 1,3-trans relationship of substituents on one 5-membered ring, our goal next was to forge the final 1,2-trans-bicyclo[3.3.0]octane framework, a task which required installation of a tertiary alcohol and ring contraction of one 6-membered system. As a start toward those ends, we sought to convert the exocyclic alkene into a carbonyl and then functionalize the internal alkene. First, we found that Upjohn dihydroxylation21 of 20, followed by in situ oxidative cleavage, could afford the desired ketone. All other dihydroxylation conditions probed, such as the Sharpless asymmetric protocol22 as well as Os-free23 metal-catalyzed variants, led to either recovery of starting material or decomposition. Next, efforts to directly install the tertiary hydroxyl, and thus generate 21, were undertaken. However, despite many trials, such Mukaiyama-type hydrations24 were unsuccessful. Pleasingly, a two-step alternative rose to the occasion based on mCPBA-mediated epoxidation25 followed by a one-pot base-promoted epoxide opening26 and

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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/jacs.7b01454.

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Detailed experimental procedures, spectral data, X-ray data, and full characterization (PDF) X-ray crystallographic data for 21 (CIF)

AUTHOR INFORMATION

Corresponding Author

*[email protected] C

DOI: 10.1021/jacs.7b01454 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Communication

Journal of the American Chemical Society ORCID

2008, 3, 791. (e) Wang, C.-M.; Hopson, R.; Lin, X.; Cane, D. E. J. Am. Chem. Soc. 2009, 131, 8360. (11) (a) Bohlmann, F.; Jakupovic, J. Phytochemistry 1980, 19, 259. (b) Klobus, M.; Zhu, L.; Coates, R. M. J. Org. Chem. 1992, 57, 4327. (c) Fitjer, L.; Monzó-Oltra, H. J. Org. Chem. 1993, 58, 6171. (d) Weyerstahl, P.; Marschall, H.; Seelmann, I.; Jakupovic, J. Eur. J. Org. Chem. 1998, 1998, 1205. (12) For an excellent review discussing the biosynthesis and chemical synthesis of the presilphiperfolanol family, see: Hong, A. Y.; Stoltz, B. M. Angew. Chem., Int. Ed. 2014, 53, 5248. (13) (a) Kobayashi, T.; Shiroi, H.; Abe, H.; Ito, H. Chem. Lett. 2013, 42, 975. (b) Zhang, Z.; Li, Y.; Zhao, D.; He, Y.; Gong, J.; Yang, Z. Chem. Eur. J. 2017, 23, 1258. (14) Hong, A. Y.; Stoltz, B. M. Angew. Chem., Int. Ed. 2012, 51, 9674. (15) Weyerstahl, P.; Marschall, H.; Schulze, M.; Schwope, I. Liebigs Ann. 1996, 1996, 799. (16) For a review describing many terpenes bearing 1,3-trans stereochemical arrangement, see: (a) Mehta, G.; Srikrishna, A. Chem. Rev. 1997, 97, 671. For the isolation of penifulvin A, see: (b) Shim, S. H.; Swenson, D. C.; Gloer, J. B.; Dowd, P. F.; Wicklow, D. T. Org. Lett. 2006, 8, 1225. For isolation of quiannulatic acid, see: (c) Okada, M.; Matsuda, Y.; Mitsuhashi, T.; Hoshino, S.; Mori, T.; Nakagawa, K.; Quan, Z.; Qin, B.; Zhang, H.; Hayashi, F.; Kawaide, H.; Abe, I. J. Am. Chem. Soc. 2016, 138, 10011. (17) (a) Grigg, R.; Sansano, J. M.; Santhakumar, V.; Sridharan, V.; Thangavelanthum, R.; Thornton-Pett, M.; Wilson, D. Tetrahedron 1997, 53, 11803. For a review, see: (b) Grigg, R.; Sridharan, V. J. Organomet. Chem. 1999, 576, 65. (18) Overman, L. E.; Abelman, M. M.; Kucera, D. J.; Tran, V. D.; Ricca, D. J. Pure Appl. Chem. 1992, 64, 1813. (19) Chamberlin, A. R.; Bloom, S. H.; Cervini, L. A.; Fotsch, C. H. J. Am. Chem. Soc. 1988, 110, 4788. (20) Miles, R. B.; Davis, C. E.; Coates, R. M. J. Org. Chem. 2006, 71, 1493. (21) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 17, 1973. (22) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung, J.; Jeong, K. S.; Kwong, H. L.; Morikawa, K.; Wang, Z.-M.; Xu, D.; Zhang, X.-L. J. Org. Chem. 1992, 57, 2768. (23) For a review, see: (a) Bataille, C. J. R.; Donohoe, T. J. Chem. Soc. Rev. 2011, 40, 114. For a typical procedure of Ru-catalyzed dihydroxylation, see: (b) Plietker, B.; Niggemann, M. Org. Lett. 2003, 5, 3353. (24) For a representative procedure, see: Renata, H.; Zhou, Q.; Baran, P. S. Science 2013, 339, 59. (25) While we were not able to fully characterize this compound, 1H and 13C NMR of crude 32 indicated that one diastereomer was formed in the epoxidation step. See SI for details. (26) Applying common epoxide isomerization conditions such as Al2O3 or Et3N/MeOH led to the formation of a diene compound. (27) Silva, L. F. Tetrahedron 2002, 58, 9137. (28) For selected uses in synthesis, see: (a) Snyder, S. A.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 740. (b) Mascitti, V.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 3118. (29) We initially attempted Regitz diazotization; however, αformylation was never observed. Reactions with less than 20 equiv of p-ABSA led to slow conversion and byproducts. (30) Ohno, K.; Tsuji, J. J. Am. Chem. Soc. 1968, 90, 99. (31) Efforts to convert the methyl ester into the corresponding carboxylic acid, in an effort to deploy radical-based decarboxylations to reach the final target, failed under a variety of conditions, including basic hydrolysis and milder and sometimes uniquely selective approaches such as the use Me3SnOH: Nicolaou, K. C.; Estrada, A. A.; Zak, M.; Lee, S. H.; Safina, B. S. Angew. Chem., Int. Ed. 2005, 44, 1378. (32) The alcohol intermediate is acid-labile and decomposed even with NaHCO3 buffering during the oxidation. The basic residue resulting from the t-BuOH quench of the DIBAL-H seemingly prevents the decomposition of the alcohol intermediate in the oxidation.

Pengfei Hu: 0000-0003-2915-4102 Scott A. Snyder: 0000-0003-3594-8769 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Dr. Alexander Filatov (University of Chicago) for obtaining the X-ray crystal structure of 21 and Mr. Tyler J. Poore (Columbia University) for some preliminary explorations of alternate routes to 5. We also thank Dr. Xiangming Kong (TSRI) and Dr. Antony Jurkiewicz (University of Chicago) for assistance with NMR and Dr. C. Jin Qin (University of Chicago) for help with mass spectrometry. Financial support for this work came from The Scripps Research Institute and the University of Chicago.

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DOI: 10.1021/jacs.7b01454 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX