Concise Total Syntheses of (+)-Haplocidine and (+)-Haplocine via Late-Stage Oxidation of (+)-Fendleridine Derivatives
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Author(s)
White, Kolby L.
Movassaghi, Mohammad
Date Issued
September 2016
Journal
Journal of the American Chemical Society
Publisher
American Chemical Society (ACS)
Citation
White, Kolby L., and Mohammad Movassaghi. “Concise Total Syntheses of (+)-Haplocidine and (+)-Haplocine via Late-Stage Oxidation of (+)-Fendleridine Derivatives.” Journal of the American Chemical Society 138, no. 35 (August 26, 2016): 11383–11389.
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Author's final manuscript
Abstract
We report the first total syntheses of (+)-haplocidine and its N1-amide congener (+)-haplocine. Our concise synthesis of these alkaloids required the development of a late-stage and highly selective C-H oxidation of complex aspidosperma alkaloid derivatives. A versatile, amide-directed ortho-acetoxylation of indoline amides enabled our implementation of a unified strategy for late-stage diversification of hexacyclic C19-hemiaminal ether structures via oxidation of the corresponding pentacyclic C19-iminium ions. An electrophilic amide activation of a readily available C21-oxygenated lactam, followed by transannular cyclization and in situ trapping of a transiently formed C19-iminium ion, expediently provided access to hexacyclic C19-hemiaminal ether alkaloids (+)-fendleridine, (+)-acetylaspidoalbidine, and (+)-propionylaspidoalbidine. A highly effective enzymatic resolution of a non-β-branched primary alcohol (E = 22) allowed rapid preparation of both enantiomeric forms of a C21-oxygenated precursor for synthesis of these aspidosperma alkaloids. Our synthetic strategy provides succinct access to hexacyclic aspidosperma derivatives, including the antiproliferative alkaloid (+)-haplocidine.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
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DOI of Published Version
https://doi.org/10.1021/JACS.6B07623
