Studies on the synthesis of bisindole Aspidosperma alkaloids
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Pinto-tpinto-phd-chemistry-2024-thesis.pdf
Description
Thesis PDF
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13.76 MB
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Adobe PDF
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2e056fc8a60253c36f584b015a31420a
Author(s)
Pinto, Taylor
Advisor(s)
Movassaghi, Mohammad
Date Issued
September 2024
Publisher
Massachusetts Institute of Technology
Abstract
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.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
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