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Progress towards the total synthesis of hamigerans C and D: a direct approach to an elaborated 6-7-5 carbocyclic core

Abstract

The hamigeran family of natural products has been the target of numerous synthetic efforts because of its biological activity and interesting structural properties. Herein, we disclose our efforts toward the synthesis of hamigerans C and D, unique among the initially isolated members because of their 6-7-5 carbocyclic core. Our approach directly targets this tricyclic motif by sequential Negishi and Heck coupling reactions, yielding an advanced intermediate with all necessary carbons and sufficient functionality poised for completion of the synthesis of these two natural products.

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References

  1. Wellington, K. D., Cambie, R. C., Rutledge, P. S. & Bergquist, P. R. Chemistry of sponges. 19. Novel bioactive metabolites from Hamigera tarangaensis. J. Nat. Prod. 63, 79–85 (2000).

    CAS  Article  Google Scholar 

  2. Nicolaou, K. C., Gray, D. & Tae, J. Total synthesis of hamigerans: Part 1. Development of synthetic technology for the construction of benzannulated polycyclic systems by the intramolecular trapping of photogenerated hydroxy-o-quinodimethanes and synthesis of key building blocks. Angew. Chem. Int. Ed. 40, 3675–3678 (2001).

    CAS  Article  Google Scholar 

  3. Nicolaou, K. C., Gray, D. & Tae, J. Total synthesis of hamigerans: Part 2. Implementation of the intramolecular Diels–Alder trapping of photochemically generated hydroxy-o-quinodimethanes; strategy and completion of the synthesis. Angew. Chem. Int. Ed. 40, 3679–3683 (2001).

    CAS  Article  Google Scholar 

  4. Mehta, G. & Shinde, H. M. Enantiospecific total synthesis of 6-epi-(–)-hamigeran B. Intramolecular Heck reaction in a sterically constrained environment. Tetrahedron Lett. 44, 7049–7053 (2003).

    CAS  Article  Google Scholar 

  5. Clive, D. L. J. & Wang, J. Synthesis of (±)-hamigeran B, (–)-hamigeran B and (±)-1-epi-hamigeran B: use of bulky silyl groups to protect a benzylic carbon–oxygen bond from hydrogenolysis. J. Org. Chem. 69, 2773–2784 (2004).

    CAS  Article  Google Scholar 

  6. Sperry, J. B. & Wright, D. L. Synthesis of the hamigeran skeleton through an electro-oxidative coupling reaction. Tetrahedron Lett. 46, 411–414 (2005).

    CAS  Article  Google Scholar 

  7. Trost, B. M., Pissot-Soldermann, C. & Chen, I. A short and concise asymmetric synthesis of hamigeran B. Chem. Eur. J. 11, 951–959 (2005).

    CAS  Article  Google Scholar 

  8. Taber, D. F. & Tian, W. Synthesis of (–)-hamigeran B. J. Org. Chem. 73, 7560–7564 (2008).

    CAS  Article  Google Scholar 

  9. Miesch, L., Welsch, T., Rietsch, V. & Miesch, M. Intramolecular Alknylogous mukaiyama aldol reaction starting from bicyclic alkanones tethered to alkynyl esters: formal total synthesis of (±)-hamigeran B. Chem. Eur. J 15, 4394–4401 (2009).

    CAS  Article  Google Scholar 

  10. Cai, Z. & Harmata, M. Studies directed toward the synthesis of hamigeran b: a catalytic oxidative cyclization. Org. Lett. 12, 5668–5670 (2010).

    CAS  Article  Google Scholar 

  11. Lau, S. Y. W. Concise and protective group-free synthesis of (±)-hamigeran B and (±)-4-bromohamigeran B. Org. Lett. 13, 347–349 (2011).

    CAS  Article  Google Scholar 

  12. Mukherjee, H., McDougal, N. T., Virgil, S. & Stoltz, B. M. A catalytic, asymmetric formal synthesis of (+)-hamigeran B. Org. Lett. 13, 825–827 (2011).

    CAS  Article  Google Scholar 

  13. Lin, H. et al. Enantioselective approach to (–)-hamigeran B and (–)-4-bromohamigeran B via Catalytic asymmetric hydrogenation of racemic ketone to assemble the chiral core framework. Org. Lett. 18, 1434–1437 (2016).

    CAS  Article  Google Scholar 

  14. Jiang, B., Li, M.-M., Xing, P. & Huang, Z.-G. A concise formal synthesis of (–)-hamigeran B. Org. Lett. 15, 871–873 (2013).

    CAS  Article  Google Scholar 

  15. Li, X., Xue, D., Wang, C. & Gao, S. Total synthesis of the hamigerans. Angew. Chem. Int. Ed. 55, 9942–9946 (2016).

    CAS  Article  Google Scholar 

  16. Hong, A. Y. et al. Ring-contraction strategy for the practical, scalable, catalytic asymmetric synthesis of versatile γ-quaternary acylcyclopentenes. Angew. Chem. Int. Ed. 50, 2756–2760 (2011).

    CAS  Article  Google Scholar 

  17. Mirrington, R. N. & Feutrill, G. I. Orcinol monomethyl ether. Org. Synth. 53, 90–93 (1973).

    CAS  Article  Google Scholar 

  18. Stork, G. & Zhao, K. A stereoselective synthesis of (Z)-1-iodo-1-alkenes. Tetrahedron Lett. 30, 2173–2174 (1989).

    CAS  Article  Google Scholar 

  19. Balamurugan, R., Kothapalli, R. B. & Thota, G. K. Gold-catalysed activation of epoxides: application in the synthesis of bicyclic ketals. Eur. J. Org. Chem. 2011, 1557–1569 (2011).

    Article  Google Scholar 

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Acknowledgements

Dedicated to Prof K. C. Nicolaou for his tremendous scientific contributions to the total synthesis of highly complex and biologically important natural products. We thank NIH-NIGMS (R01GM080269) for supporting this research. DCD would like to thank the NSF (predoctoral research fellowship, No. DGE-1144469) and Caltech for financial support. Dr David VanderVelde (Caltech) is thanked for aid in NMR structural determination. Dr Allen Hong and Dr Scott Virgil are thanked for helpful discussions.

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Correspondence to Brian Mark Stoltz.

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Dedicated to Professor KC Nicolaou for his tremendous scientific contributions to the total synthesis of highly complex and biologically important natural products.

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The authors declare no conflict of interest.

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Supplementary Information accompanies the paper on The Journal of Antibiotics website

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Duquette, D., Jensen, T. & Stoltz, B. Progress towards the total synthesis of hamigerans C and D: a direct approach to an elaborated 6-7-5 carbocyclic core. J Antibiot 71, 263–267 (2018). https://doi.org/10.1038/ja.2017.96

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