Studies on the synthesis of bisindole Aspidosperma alkaloids

I. Introduction and Background on Aspidosperma Alkaloids A brief overview of monoterpene indole Aspidosperma alkaloids is discussed. The biosynthesis of the characteristic pentacyclic core from tryptamine and secologanin is summarized. Some representative examples of total syntheses of Aspidosperma alkaloids are discussed. Synthetic strategies for the synthesis of bisindole members of the family are also examined. II. Total Synthesis of (–)-Voacinol, (–)-Voacandimine C, and related congener, (−)-methylenebisdeoxoapodine 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. III. Progress Toward the Total Synthesis of Voacandimine A We describe our work toward the total synthesis of bisindole Aspidosperma alkaloid, voacandimine A. Key features of the synthetic progress include two routes for monomer synthesis, two methods for complex fragment assembly to form the bisindole structure, and strategies to address the stereochemistry of the ring fusion.

Name thesis:degree_name

Doctoral

Department dc:contributor.department

Massachusetts Institute of Technology. Department of Chemistry

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2024

Author dc:creator

• Pinto, Taylor

Advisor dc:contributor.advisor

• Movassaghi, Mohammad

Statement dc:rights

• Attribution-ShareAlike 4.0 International (CC BY-SA 4.0)
• Copyright retained by author(s)

Licence dc:rights.uri

• https://creativecommons.org/licenses/by-sa/4.0/

Handle dc:identifier.uri

https://hdl.handle.net/1721.1/157599

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/157599