Organic Chemistry

A General Approach to 2,2-Disubstituted Indoxyls: Total Synthesis of Brevianamide A and Trigonoliimine C

Myles Smith UT Southwestern Medical Center


The indoxyl unit is a common structural motif in alkaloid natural products and bioactive compounds. Here, we report a general method that transforms readily available 2-substituted indoles into 2,2-disubstituted indoxyls via nucleophile coupling with a 2-alkoxyindoxyl intermediate and showcase its utility in short total syntheses of the alkaloids brevianamide A (7 steps) and trigonoliimine C (6 steps). The developed method is operationally simple and demonstrates broad scope in terms of nucleophile identity and indole substitution, tolerating 2-alkyl substituents and free indole N–H groups, elements beyond the scope of most prior approaches. Spirocyclic indoxyl products are also accessible via intramolecular nucleophilic trapping.


Thumbnail image of Indoxyl Paper Pre-template.pdf
download asset Indoxyl Paper Pre-template.pdf 0.67 MB [opens in a new tab]

Supplementary material

Thumbnail image of Indoxyl SI.pdf
download asset Indoxyl SI.pdf 23 MB [opens in a new tab]
Indoxyl SI