Total Synthesis of Seco (+)- and<i>ent</i>-(−)-Oxaduocarmycin SA: Construction of the (Chloromethyl)indoline Alkylating Subunit by a Novel Intramolecular Aryl Radical Cyclization onto a Vinyl Chloride

Abstract

A practical, total synthesis of seco-(+)-oxaduocarmycin 3a, an analogue of the highly cytotoxic natural product, duocarmycin SA (1), is described. The 13-step synthesis features a novel and efficient intramolecular aryl radical cyclization onto a vinyl chloride as a direct entry to the (chloromethyl)indoline alkylating subunit 14. Subsequent resolution, utilizing a preparative Chiralpak AD column, provided enantiomerically pure alkylating subunits 14a and 14b which were elaborated to seco-(+) and ent-(−)-oxaduocarmycins, 3a and 3b, respectively. The natural enantiomer 3a was active at pM concentrations and exhibited 7−50-fold higher potentcy than its enantiomer 3b in in vitro cytotoxicity assays.