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

Abstract

We describe the first total synthesis of complex aspidosperma alkaloids (–)-voacinol and (–)-voacandimine C via a late-stage C7-methylenation strategy inspired by a biogenetic hypothesis. We envisioned rapid access to these natural alkaloids from a common, symmetrical precursor assembled by methylenation of a D-ring-oxidized variant of the structurally related natural product (–)-deoxoapodine. Chemoselective N9-oxidation of a pentacyclic deoxoapodine precursor enabled the synthesis of the corresponding hexacyclic C8-aminonitrile. Stereocontrolled methylenation of a C8-enamine derivative of deoxoapodine, accessed by ionization of the C8-aminonitrile, afforded a symmetrical dodecacyclic bisaminonitrile as a versatile precursor to these bisindole alkaloids. Final-stage, biosynthesis-inspired, controlled reductive 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 (–)-methylenebisdeoxoapodine.

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

“…This approach provided the first synthetic samples of bisindole alkaloids (−)- 1 and (−)- 2 , along with the corresponding enantiomers and derivatives of interest, including (−)-methylenebisdeoxoapodine ( 3 ), for detailed structural analysis and characterization. Furthermore, we demonstrate the viability of the dodecacyclic bisenamine (−)- 7 as a plausible biosynthetic precursor to (−)-voacinol ( 1 ) and (−)-voacandimine C ( 2 , Scheme ) and highlight factors that influence the control of stereochemistry in these D-ring-methylene-adjoined bisindole aspidosperma alkaloids …”

“…Furthermore, we demonstrate the viability of the dodecacyclic bisenamine (−)-7 as a plausible biosynthetic precursor to (−)-voacinol (1) and (−)-voacandimine C (2, Scheme 1) and highlight factors that influence the control of stereochemistry in these D-ring-methylene-adjoined bisindole aspidosperma alkaloids. 48 ■ ASSOCIATED CONTENT * sı Supporting Information…”