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--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.