Total Synthesis of (+)-Hazuntiphylline, (−)-Anhydrohazuntiphyllidine, and (−)-Hazuntiphyllidine

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-<i>epi</i>-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 <i>Hazunta</i> 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.