Raclea Robert-Cristian, Mewald Marius, White Kolby L, Movassaghi Mohammad
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
J Am Chem Soc. 2025 Apr 13. doi: 10.1021/jacs.5c01932.
The first total synthesis of the bisindole alkaloids (+)-hazuntiphylline, (-)-anhydrohazuntiphyllidine, and (-)-hazuntiphyllidine is described. We envisioned an efficient synthetic strategy based on a plausible biosynthetic hypothesis for the rapid assembly of these complex alkaloids via successive methylenation of an oxidized variant of the natural product (-)-mehranine. Our concise synthesis of these alkaloids required the development of completely stereoselective double alkylation sequences of transiently formed C3-enamines and precise timing for hydration of intricate intermediates. Whereas homodimerization of a C3-methylene mehranine-derivative exclusively gave (-)-3--anhydrohazuntiphyllidine, an alternative alkylation cascade was developed to afford the natural products (-)-anhydrohazuntiphyllidine and (+)-hazuntiphylline. Insights gained in these studies concerning the intermediacy of hydrated intermediates enabled a completely stereoselective synthesis of (-)-hazuntiphyllidine, the most complex member of the alkaloids. We discuss our hypothesis for the rapid assembly of these intriguing alkaloids, including our completely controlled access to both the natural and epimeric C3-quaternary stereochemistry of anhydrohazuntiphyllidine, and analysis of plausible biosynthetic intermediates including a sensitive methylenebisdesmethylmehranine-derivative, highlighting divergent pathways to each natural alkaloid based on the order of C-C and C-N bond formation and the hydration of putative intermediates.
本文描述了双吲哚生物碱（+）-哈尊替菲林、（-）-脱水哈尊替菲啶和（-）-哈尊替菲啶的首次全合成。我们设想了一种基于合理生物合成假设的高效合成策略，通过对天然产物（-）-梅拉宁的氧化变体进行连续亚甲基化，快速组装这些复杂的生物碱。我们对这些生物碱的简洁合成需要开发瞬态形成的C3-烯胺的完全立体选择性双烷基化序列，以及精确控制复杂中间体水合的时机。虽然C3-亚甲基梅拉宁衍生物的同二聚化仅得到（-）-3-脱水哈尊替菲啶，但我们开发了一种替代烷基化级联反应来合成天然产物（-）-脱水哈尊替菲啶和（+）-哈尊替菲林。这些研究中关于水合中间体中间体的见解使得能够完全立体选择性地合成（-）-哈尊替菲啶，它是这些生物碱中最复杂的成员。我们讨论了我们关于这些有趣生物碱快速组装的假设，包括我们对脱水哈尊替菲啶天然和差向异构C3-季碳立体化学的完全可控合成，以及对可能的生物合成中间体的分析，包括一种敏感的亚甲基双去甲基梅拉宁衍生物，强调了基于C-C和C-N键形成顺序以及假定中间体水合作用的每种天然生物碱的不同合成途径。
