biostudies-literatureXu FUniversity of Texas Southwestern Medical CenterWelch Foundation13756-13763https://www.ebi.ac.uk/biostudies/studies/S-EPMC8549782biostudies-literatureUnknown12(41)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.Chemical scienceA general approach to 2,2-disubstituted indoxyls: total synthesis of brevianamide A and trigonoliimine C.PMC8549782I-2045Xu FSmith MWfalseA general approach to 2,2-disubstituted indoxyls: total synthesis of brevianamide A and trigonoliimine C.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.2021-01-01T00:00:00Z2021 Oct2026-05-09T10:01:22.944Z2022-02-11T12:42:18.761ZS-EPMC85497823476016010.1039/d1sc03533a