Total Synthesis of Oligomeric Cyclotryptamine Alkaloids
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scott-tzscott-phd-chemistry-2023-thesis.pdf
Description
Thesis PDF
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11.1 MB
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Adobe PDF
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9812bfd924e953475ef6ad2d6dc55eaa
Author(s)
Scott, Tony Z.
Advisor(s)
Movassaghi, Mohammad
Date Issued
February 2023
Publisher
Massachusetts Institute of Technology
Abstract
I. Total Synthesis and Stereochemical Assignment of (–)-Psychotridine
We report the first enantioselective total synthesis and stereochemical assignment of (–)-psychotridine. The application of our diazene-directed assembly of enantiomerically enriched cyclotryptamines afforded a highly convergent synthesis of the pentameric alkaloid, allowing its detailed structural assignment. Highlights of the synthesis include the introduction of four quaternary stereocenters with complete stereochemical control in a single step via the photoextrusion of three molecules of dinitrogen from an advanced intermediate and metal-catalyzed C–H amination reactions in challenging settings.
II. Iterative, Diazene-Directed Total Synthesis of (+)-Quadrigemine H, (+)-Isopsychotridine C, (+)-Oleoidine, and (+)-Caledonine
We describe the unified enantioselective total synthesis of the polycyclotryptamine natural products (+)-quadrigemine H, (+)-isopsychotridine C, (+)-oleoidine, and (+)-caledonine. Our bioinspired synthesis leverages the modular, diazene-directed assembly of whole cyclotryptmines to iteratively introduce C3a−C7' quaternary linkages on an advanced heterodimeric intermediate with full stereochemical control at each quaternary linkage. We developed a strategy for iterative aryl-alkyl diazene synthesis using increasingly complex oligomeric hydrazide nucleophiles and bifunctional cyclotryptamines bearing a C3a leaving group and a pendant C7 pronucleophile. The utility of our method is demonstrated by the first total synthesis of heptamer (+)-caledonine and hexamer (+)-oleoidine. Additionally, enabled by our fully stereoselective total synthesis and acquisition of expanded characterization data, we provide the first complete stereochemical assignment of pentamer (+)-isopsychotridine C and confirm that tetramer (+)-quadrigemine H is identical to the alkaloid called (+)-quadrigemine I.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
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