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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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).
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).
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).
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).
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).
Sperry, J. B. & Wright, D. L. Synthesis of the hamigeran skeleton through an electro-oxidative coupling reaction. Tetrahedron Lett. 46, 411–414 (2005).
Trost, B. M., Pissot-Soldermann, C. & Chen, I. A short and concise asymmetric synthesis of hamigeran B. Chem. Eur. J. 11, 951–959 (2005).
Taber, D. F. & Tian, W. Synthesis of (–)-hamigeran B. J. Org. Chem. 73, 7560–7564 (2008).
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).
Cai, Z. & Harmata, M. Studies directed toward the synthesis of hamigeran b: a catalytic oxidative cyclization. Org. Lett. 12, 5668–5670 (2010).
Lau, S. Y. W. Concise and protective group-free synthesis of (±)-hamigeran B and (±)-4-bromohamigeran B. Org. Lett. 13, 347–349 (2011).
Mukherjee, H., McDougal, N. T., Virgil, S. & Stoltz, B. M. A catalytic, asymmetric formal synthesis of (+)-hamigeran B. Org. Lett. 13, 825–827 (2011).
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).
Jiang, B., Li, M.-M., Xing, P. & Huang, Z.-G. A concise formal synthesis of (–)-hamigeran B. Org. Lett. 15, 871–873 (2013).
Li, X., Xue, D., Wang, C. & Gao, S. Total synthesis of the hamigerans. Angew. Chem. Int. Ed. 55, 9942–9946 (2016).
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).
Mirrington, R. N. & Feutrill, G. I. Orcinol monomethyl ether. Org. Synth. 53, 90–93 (1973).
Stork, G. & Zhao, K. A stereoselective synthesis of (Z)-1-iodo-1-alkenes. Tetrahedron Lett. 30, 2173–2174 (1989).
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).
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.
Dedicated to Professor KC Nicolaou for his tremendous scientific contributions to the total synthesis of highly complex and biologically important natural products.
The authors declare no conflict of interest.
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
Molecular Diversity (2022)
Molecular Diversity (2022)