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. The 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.

Construction of Chiral Cyclobutanone-Fused 4-Aminoquinolines via Sequential Chiral Phosphoric Acid and Palladium Catalysis

“…Nitrogen-heterocyclic ring, such as indole and quinoline, fused polycyclic structures are privileged motifs and key frameworks of many natural products and bioactive compounds. 1 Therefore, the identification of an efficient synthetic route for these polycyclic structures has attracted continuing interests, especially in an enantioselective fashion. 2 Among the documented methods, the asymmetric carbonyl-amine condensation-based cascade reactions are one of the most commonly used.…”

“…On the other hand, transition-metal-catalyzed cyclization of 2haloaniline-derived enaminones has been proved as an effective method to synthesize N-heterocyclic rings. The directed intramolecular coupling reaction of N-2-haloaryl enaminones could afford indole derivatives or multisubstituted benzo [b]- [1,4]oxazepines, 6 whereas the intramolecular coupling reaction of enaminones with another component could give rise to a series of 6-membered benzo rings. 7 For example, Ji and coworkers reported a Pd-catalyzed cascade reaction of isocyanides with enaminones for the synthesis of 4-aminoquinoline derivatives in 2014 (Scheme 1a).…”