Total Synthesis of Oligomeric Cyclotryptamine Alkaloids

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.

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

2023

Author dc:creator

• Scott, Tony Z.

Advisor dc:contributor.advisor

• Movassaghi, Mohammad

Statement dc:rights

• In Copyright - Educational Use Permitted
• Copyright MIT

Licence dc:rights.uri

• http://rightsstatements.org/page/InC-EDU/1.0/

Handle dc:identifier.uri

https://hdl.handle.net/1721.1/150563

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/150563