Movassaghi Paper Published in the Journal of the American Chemical Society

Danielle Randall
August 11, 2016

Concise Total Syntheses of (+)-Haplocidine and (+)-Haplocine Via Late-Stage Oxidation of (+)-Fendleridine Derivatives.

Kolby L. White and Mohammad Movassaghi
 
DOI: 10.1021/jacs.6b07623 
 

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 orthoacetoxylation 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.