Progress toward the Total Synthesis of Gukulenin A: Photochemically

Letter pubs.acs.org/OrgLett

Cite This: Org. Lett. 2018, 20, 4072−4076

Progress toward the Total Synthesis of Gukulenin A: Photochemically Triggered Two-Carbon Ring Expansion Key to α‑Tropolonic Ether Synthesis David Tymann,* Ulf Bednarzick, Ljuba Iovkova-Berends, and Martin Hiersemann Fakultät für Chemie und Chemische Biologie, Technische Universität Dortmund, 44227 Dortmund, Germany

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S Supporting Information *

ABSTRACT: The ex-chiral-pool synthesis of an advanced gukulenin A precursor from (−)-piperitone is revealed. Key C/C connecting maneuvers to the synthesis of a C2 dissymmetric bis(α-tropolonic) ether building block are a ring-contracting Meinwald rearrangement, a photochemically triggered two-carbon ring expansion, and a homodimerization by cross-metathesis.

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ukulenin A (1a) and F (1b) are members of a small family of tetraterpenoids isolated from the sponge Phorbas gukhulensis (Figure 1); biological studies revealed that both 1a and 1b exhibit significant antiproliferative activity against various human cancer cell lines.1,2 The intricate polycyclic architecture of 1a rests on the unprecedented neohomoverrucosane-5,5a′-seco-neohomoverrucosane scaffold 2. The uniquely ornamented α-tropolone C and C′ rings are defining embedded structural elements of the pentacyclic ensemble of gukulenin A.

Figure 2. Biosynthetic considerations.

Studies in support of our biosynthetic proposal would be empowered by access to the 5,5a-seco-gukulenin 1c, and we sought to implement a synthetic strategy that exploits the inherent C2 dissymmetry of the carbon skeleton of 1c (Figure 2). The unique substituent pattern of the α-tropolone C ring guided our retrosynthetic analysis of 1c. The available methodology for α-tropolone synthesis, however, appeared inept to address the architectural challenges of the gukulenins. Herzon recently contributed an ingenious novel strategy for the synthesis of the C2h symmetric α-tropolone homodimer 8 by one-carbon ring expansion (Figure 3).3 Further elaboration of 8 toward 1a would require

Figure 1. Gukulenin A and the underlying tetraterpene architecture.

Biosynthetically, gukulenin F (1b) and A (1a) are (formally) interrelated by enol keto tautomerism and intramolecular hemiacetalization (Figure 2). We further hypothesized that 1b could be biosynthetically derived from the vinylogous ketene hydrate 1c by intramolecular aldolization and subsequent 1,5-prototopy. © 2018 American Chemical Society

Received: May 23, 2018 Published: June 19, 2018 4072

DOI: 10.1021/acs.orglett.8b01629 Org. Lett. 2018, 20, 4072−4076

Letter

Organic Letters Scheme 1. Ring Contraction

Figure 3. Retrosynthesis and literature precedence.

construction of the sterically congested C10a(sp2)/C10b(sp3) bond. To circumvent expected difficulties in this regard, we envisioned merging the C10a/C10b bond formation with the assembling of the C ring by a photochemically triggered twocarbon ring expansion (Figure 3). This retrosynthetic thinking guided us from the C2-dissymmetric α-tropolonic ether 3, which is expected to be amenable to homodimerization by cross-metathesis (CM), to the vinylogous ester 5. The vinylogous ester 5, in turn, was thought to be accessible from (−)-piperitone (6). The ex-chiral-pool synthesis of the A ring building block (+)-20 commenced with the LAH reduction of (−)-piperitone (6) to piperitol and subsequent Prileschajew epoxidation to deliver the epoxy alcohol 9 as a single diastereomer in 49% yield (5.4 g isolated mass) after separation of the minor diastereomer by chromatography (Scheme 1).4 Subsequent silyl ether formation produced the oxirane 10 in 89% yield (21.6 g) and set the stage for a successful Brønsted acid mediated ring-contracting Meinwald rearrangement.5,6 Exposure of the oxirane 10 to Amberlyst-15 in CH2Cl2 at room temperature afforded the corresponding cyclopentane carbaldehyde that is susceptible to oxidation in air. To limit oxidative degradation, the crude aldehyde was immediately subjected to Wittig methylenation to provide the vinylcyclopentanoid 11 as a single diastereomer in 51% yield (15.4 g) from 10. Fluoride-mediated cleavage of the silyl ether proceeded uneventfully and delivered the alcohol 12 in 95% yield (5.6 g). Next, the diastereoface-differentiating dihydroxylation of the C4/C5 double bond was required. However, direct dihydroxylation of 11 or 12 under various conditions proceeded with low diastereoselectivity.7 Alternatively, (presumably) directed Prileschajew epoxidation of 12 delivered the 4R configured oxirane 13 in 64% yield (0.7 g) after separation of the minor diastereomer by chromatography (dr = 84:16).8 The outcome of the subsequent ringopening of the C4/C5 epoxide 13 depended on the modus operandi. Brønsted or Lewis acid promoted procedures

delivered mixtures of the C4 epimers of the triol 14. Diastereoselective nucleophilic ring-opening by hydroxide to provide the triol 14 could be accomplished using aqueous NaOH at 80 °C, but only in the presence of DMSO as a cosolvent. On a gram-scale, the crude triol 14 was protected and subsequently oxidized to afford the sterically congested ketone 16 as a single diastereomer in 59% yield (1.5 g) from the oxirane 13. Installment of the strategically important C10b/C10a bond by methylenation of the C10b carbonyl group of the α-chiral ketone 16 required laborious optimization of reagent and conditions.9 After screening various reagents for ketone methylenation, we found that a mixture of the Nysted reagent (6.5 equiv) and TiCl4 (4 equiv) at 80 °C in THF was suitable to accomplish methylenation of 16 to methylenecyclopentanoid 17 in 71% yield (1.7 g).10 Diastereoface-differentiating hydroboration of the C10b/ C10a bond of 17 was targeted next. However, the outcome 4073

DOI: 10.1021/acs.orglett.8b01629 Org. Lett. 2018, 20, 4072−4076

Letter

Organic Letters of the hydroboration was constantly hampered by concomitant reductive cleavage of the isopropylidene acetal to the corresponding isopropyl ether. This intrinsic lack of chemoselectivity forced us to pursue a deprotection−reprotection detour to the desired alcohol 20.11,12 Thus, Brønsted acid mediated cleavage of the isopropylidene acetal afforded the diol 18 and subsequent hydroboration using H3B·THF provided the triol 19 after an oxidative workup with aqueous NaOCl.13 Reprotection of the triol 19 by acetalization finally provided the crystalline alcohol 20 as a single diastereomer in 88% yield (3 g) from the alkene 17. Our next objective was the homologation of the alcohol 20 to the homopropargylic alcohol 23 and the subsequent formation of the vinylogous ester 5 (Scheme 2). IBX-

Scheme 3. Two-Carbon Ring Expansion

Scheme 2. Synthesis of the Vinylogous Ester 5

consisting of a photochemically triggered (2 + 2)-photocycloaddition to deliver the cyclobutene 24 that undergoes a rapid retro-aldol type ring-opening to yield the cyclopentylcycloheptanoid 25. The conversion of the perhydrocyclohepta[b]furanoid 25 into the homometathesis-competent α-tropolone ether 4 was realized, as outlined in Scheme 4. Nucleophilic vinylation and elimination could be accomplished by a one-pot procedure: Scheme 4. C Ring Oxidation and Homometathesis

Oxidation of 20 delivered the cyclopentane carbaldehyde 21 without epimerization in 91% yield (2.6 g). Reductive alkynylation of 21 was accomplished using lithium(trimethylsilyl)diazomethane14 to provide the terminal alkyne 22 in 92% yield (0.9 g).15 Two-carbon chain elongation of 22 was achieved by nucleophilic ring-opening of ethylene oxide to yield the homopropargylic alcohol 23 in 82% yield (0.7 g). Finally, Mitsunobu esterification of 23 with cyclopentane-1,3dione delivered the vinylogous ester 5 in 83% yield (0.1 g).16 The photochemically triggered metal-free two-carbon ring expansion of the vinylogous ester 5 was studied thereon (Scheme 3).17 Gratifyingly, irradiation of a solution of 5 in 2,2,2-trifluoroethanol (TFE) in a sealed tube made of quartz glass using UV−C lamps (254 nm) of a commercially available photoreactor at ambient temperature for 13 h delivered the ring expansion product 25 in 92% yield (519 mg). Extensive NMR studies corroborate the structural assignment of 25. NOE studies suggest the existence of a single axially chiral aR configured atropdiastereomer of 25. Mechanistically, we propose a cascading bond reorganization 4074

DOI: 10.1021/acs.orglett.8b01629 Org. Lett. 2018, 20, 4072−4076

Organic Letters Subjecting 25 to vinylmagnesium bromide in the presence of CeCl3·2LiCl18 and subsequent addition of the Burgess reagent19 afforded the labile tetraene 26.20 An E1-type elimination via the π-resonance-stabilized oxocarbenium ion A is assumed to account for the initially unexpected doublebond positioning in 26. Regioselective dihydroxylation of the crude 26 by SAD21 yielded a putative α-hydroxy hemiacetal that was subjected to the conditions of a Swern oxidation22 to deliver the α-tropolone ether 4 in 51% yield (95 mg) from 25,23 proposedly via the π-resonance stabilized oxocarbenium ion B. Following our initial planning, the 5,5a-seco-neohomoverrucosanoid building block 4 was subjected to an olefin homometathesis to deliver the fragile C2-dissymmetric homodimer 3 in 83% yield (48 mg).24 In our hands, using the second-generation Hoveyda−Grubbs precatalyst 27 (0.13 equiv) in hexafluorobenzene at 80 °C maximized conversion and minimized decomposition.25 Detailed NMR studies and mass spectroscopy support our assignment of the constitution of the homodimer 3; however, the configuration of the linking double bond could not be deduced from NMR data and was thus assigned on the grounds of mechanistic plausibility. In summary, we have accomplished the symmetry-guided ex-chiral-pool synthesis of the C2-dissymmetric gukulenin A (1a) A−C−C′−A′ building block 3 featuring the complete carbon scaffold of the tetraterpenoid and cyclic ether-capped α-tropolone moieties. The cornerstone of our synthesis was a photochemically triggered two-carbon ring expansion for the atropdiastereoselective construction of the highly substituted cyclopentylcycloheptane moiety. The present efforts are devoted to the conversion of the homodimer 3 into 5,5aseco-gukulenin F (1c), thus enabling investigation of the proposed biomimetic endgame of the total synthesis of gukulenin A (1a).

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ACKNOWLEDGMENTS

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REFERENCES

Financial support by the Beilstein Stiftung (graduate fellowship to D.T.), the DFG (HI628/13-1), as well as the TU Dortmund is gratefully acknowledged.

(1) Park, S. Y.; Choi, H.; Hwang, H.; Kang, H.; Rho, J.-R. J. Nat. Prod. 2010, 73, 734−737. (2) Jeon, J.-E.; Liao, L.; Kim, H.; Sim, C. J.; Oh, D.-C.; Oh, K.-B.; Shin, J. J. Nat. Prod. 2013, 76, 1679−1685. (3) Kats-Kagan, R.; Herzon, S. B. Org. Lett. 2015, 17, 2030−2033. (4) Macbeth, K. A.; Milligan, B.; Shannon, J. S. J. Chem. Soc. 1953, 0, 901−902. (5) Notably, Yamamoto and co-workers observed the opposite stereochemical outcome in the case of the MABR-mediated ringcontraction of (+)-10: (a) Maruoka, K.; Ooi, T.; Yamamoto, H. J. Am. Chem. Soc. 1989, 111, 6431−6432. (b) Maruoka, K.; Ooi, T.; Nagahara, S.; Yamamoto, H. Tetrahedron 1991, 47, 6983−6998. (c) For an efficient ring-contraction of a related epoxide using catalytic amounts of HOTf, see: Li, X.; Xue, D.; Wang, C.; Gao, S. Angew. Chem. 2016, 128, 10096−10100. (6) Deploying our established conditions to the ring-contraction of (+)-9 led only to the formation of a complex mixture. (7) While dihydroxylation of 11 favored the formation of the undesired 4S configuration (SAD using AD-mix-β, dr = 40:60; Upjohn dihydroxylation, dr = 35:65), 12 in turn was dihydroxylated with low diastereoselectivity in favor of the desired 4R configuration (SAD using AD-mix-β, dr = 2:1; Upjohn dihydroxylation, dr = 55:45). IBX oxidation of 12 delivered the corresponding ketone, which under various dihydroxylation conditions (Upjohn dihydroxylation; SAD using AD-mix-α or AD-mix-β) gave the undesired 4Sconfigured diol with high diastereoselectivity (dr = 1:9). (8) Diastereomeric ratio of the crude reaction mixture. (9) While Wittig olefination (Ph3PMeBr (3 equiv), KOt-Bu (2.8 equiv), and PhMe, 100 °C) gave a 1:1 mixture of the C1 epimers of 17, Petasis olefination (Cp2TiMe2 (5 equiv), PhMe, 70 °C) resulted in recovery of epimerized 16. Peterson olefination failed due to unreactivity of 16 toward various Grignard reagents or organolithium reagents. (10) (a) Nysted, L. N. U.S. Patent 3,865,848, Feb 11, 1975; Chem. Abstr. 1975, 83, 10406q. (b) Matsubara, S.; Sugihara, M.; Utimoto, K. Synlett 1998, 1998, 313−315. (11) Exposure of 17 to 9-BBN, thexylborane, or dicyclohexylborane led to recovery of the starting material. (12) For an alternative approach to (+)-20, see: Kats-Kagan, R. Studies Toward the Synthesis of Gukulenins A and B And Development of a Method for the Synthesis of Highly Substituted α-Tropolones. Ph.D. Thesis, Yale University, New Haven, CT, 2015. (13) No product isolation after oxidative workup using H2O2 or NaBO3. For oxidations of organoboron compounds using sodium hypochlorite, see: Brown, H. C. U.S. Patent 3,439,046, Apr 15, 1969. (14) (a) Colvin, E. W.; Hamill, B. J. J. Chem. Soc., Chem. Commun. 1973, 151−152. (b) Colvin, E. W.; Hamill, B. J. J. Chem. Soc., Perkin Trans. 1 1977, 1, 869−874. (c) Miwa, K.; Aoyama, T.; Shioiri, T. Synlett 1994, 1994, 107−108. (15) Attempts to convert 21 to the alkyne 22 in a two-step procedure (e.g., Corey−Fuchs reaction or vinyl chloride formation followed by elimination) gave no satisfactory results. While Corey− Fuchs conditions (CBr4 (2 equiv), Ph3P (4 equiv), CH2Cl2, 0 °C) resulted in decomposition, vinyl chloride formation via Wittig olefination (Ph3PCHCl (3.3 equiv), THF, rt) resulted in incomplete starting material consumption. Ohira−Bestmann conditions (dimethyl 1-diazoacetonylphosphonate (1.5 equiv), K2CO3 (2 equiv), MeOH, rt) led to the isolation of the epimerized alkyne 10bS-22. (16) For gram-scale preparation of 5, see the Supporting Information.

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01629. NMR spectra (PDF) HPLC, elemental analyses, and IR spectra (PDF) Experimental procedures (PDF) Accession Codes

CCDC 1841771 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 [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Martin Hiersemann: 0000-0003-4743-5733 Notes

The authors declare no competing financial interest. 4075

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Organic Letters (17) For a two-carbon ring expansion deploying acetylene and 3methoxycyclopent-2-en-l-one, see: Cavazza, M.; Pietra, F. J. Chem. Soc., Chem. Commun. 1986, 1480−1481. (18) Krasovskiy, A.; Kopp, F.; Knochel, P. Angew. Chem., Int. Ed. 2006, 45, 497−500. (19) Atkins, G. M., Jr.; Burgess, E. M. J. Am. Chem. Soc. 1968, 90, 4744−4745. (20) Incomplete addition in the absence of CeCl3·2LiCl, presumably due to enolate formation. (21) 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, 2768−2771. (22) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651−1660. (23) Other oxidizing agents, including IBX, DMP, PCC, or CuSO4 gave lower yields. (24) Contaminated with 5−10% of an inseparable NMR-visible impurity of unknown constitution. (25) Performing the CM in 1,2-dichloroethane or lower temperatures led to incomplete conversion.

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DOI: 10.1021/acs.orglett.8b01629 Org. Lett. 2018, 20, 4072−4076