Total Synthesis of (-)-Voacinol and (-)-Voacandimine C

We describe thefirst total synthesis of complexaspidosperma alkaloids (-)-voacinol and (-)-voacandimine C via alate-stage C7-methylenation strategy inspired by a biogenetichypothesis. We envisioned rapid access to these natural alkaloidsfrom a common, symmetrical precursor assembled by methylena-tion of a D-ring-oxidized variant of the structurally related naturalproduct (-)-deoxoapodine. Chemoselective N9-oxidation of apentacyclic deoxoapodine precursor enabled the synthesis of thecorresponding hexacyclic C8-aminonitrile. Stereocontrolled meth-ylenation of a C8-enamine derivative of deoxoapodine, accessed byionization of the C8-aminonitrile, afforded a symmetricaldodecacyclic bisaminonitrile as a versatile precursor to thesebisindole alkaloids. Thefinal-stage, biosynthesis-inspired, controlledreductive opening of the oxolane substructures of this dodecacyclic intermediate provided a unified approach to (-)-voacinol and(-)-voacandimine C, while direct reduction of the same intermediate afforded the structurally related (-)-methylenebisdeox-oapodine.

Automated summary

We report the total synthesis of complex aspidosperma alkaloids (-)-voacinol and (-)-voacandimine C using a biogenetic hypothesis-inspired synthetic strategy. By chemoselective oxidation and methylenation reactions, we synthesized a versatile precursor that enabled the access to these natural alkaloids. The final-stage controlled reductive opening of a dodecacyclic intermediate led to a unified approach for the synthesis of (-)-voacinol and (-)-voacandimine C.