Unified, Biosynthesis-Inspired, Completely Stereocontrolled Total Synthesis of All Highest-Order [n + 1] Oligocyclotryptamine Alkaloids
Name
nihms-2020824.pdf
Description
Accepted version
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1.28 MB
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Adobe PDF
Checksum (MD5)
070844d5ebda65545d860a0de2204f09
Author(s)
Scott, Tony Z
Movassaghi, Mohammad
Date Issued
August 21, 2024
Journal
Journal of the American Chemical Society
Publisher
American Chemical Society
Citation
Tony Z. Scott, Mohammad Movassaghi; Unified, Biosynthesis-Inspired, Completely Stereocontrolled Total Synthesis of All Highest-Order [n + 1] Oligocyclotryptamine Alkaloids. Journal American Chemical Society 21 August 2024; 146 (33): 23574–23581.
Version
Author's final manuscript
Abstract
We describe the unified enantioselective total synthesis of the polycyclotryptamine natural products (+)-quadrigemine H, (+)-isopsychotridine C, (+)-oleoidine, and (+)-caledonine. Inspired by our hypothesis for the biogenesis of these alkaloids via an iterative concatenative addition of homochiral cyclotryptamines to a meso-chimonanthine headcap, we leverage the modular, diazene-directed assembly of stereodefined cyclotryptamines to introduce successive C3a–C7’ quaternary stereocenters on a heterodimeric meso-chimonanthine surrogate with full stereochemical control at each quaternary linkage. We developed a new strategy for iterative aryl-alkyl diazene synthesis using increasingly complex oligomeric hydrazide nucleophiles and a bifunctional cyclotryptamine bearing a C3a leaving group and a pendant C7 pronucleophile. The utility of this strategy is demonstrated by the first total synthesis of heptamer (+)-caledonine and hexamer (+)-oleoidine. Enabled by our completely stereoselective total syntheses and expanded characterization data sets, we provide the first complete stereochemical assignment of pentamer (+)-isopsychotridine C, provide evidence that it is identical to the alkaloid known as (+)-isopsychotridine B, and report that tetramer (+)-quadrigemine H is identical to the alkaloid called (+)-quadrigemine I, resolving longstanding questions about the structures of the highest-order [n + 1] oligocyclotryptamine alkaloids.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
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DOI of Published Version
https://doi.org/10.1021/jacs.4c07705
