Direct, enantioselective synthesis of pyrroloindolines and indolines from simple indole derivatives

The (R)-BINOL-SnCl4-catalyzed formal (3+2) cydoaddition between 3-substituted indoles and benzyl 2-trifluoroacetamidoacrylate is a direct, enantioselective method to prepare pyrroloindolines from simple starting materials. However, under the originally disclosed conditions, the pyrroloindolines are formed as mixtures of diastereomers, typically in the range of 3:1 to 5:1 favoring the exo-product. The poor diastereoselectivity detracts from the synthetic utility of the reaction. We report here that use of methyl 2-trifluoroacetamidoacrylate in conjunction with (R)-3,3'-dichloro-BINOL-SnCl4 provides the corresponding pyrroloindolines with improved diastereoselectivity (typically >= 10:1). Guided by mechanistic studies, a one-flask synthesis of enantioenriched indolines by in situ reduction of a persistent iminium ion is also described. (C) 2013 Elsevier Ltd. All rights reserved.