Base-dependent stereodivergent intramolecular aza-michael reaction: Asymmetric synthesis of 1,3-disubstituted isoindolines

Abstract

The nucleophilic addition (AN) / intramolecular aza-Michael reaction (IMAMR) process on Ellman's tert-butylsulfinyl imines, bearing a Michael acceptor in the ortho position, is studied. This reaction affords 1,3-disubstituted isoindolines with a wide range of substituents in good yields and diastereoselectivities. Interestingly, careful choice of the base for the aza-Michael step allows either the cis or the trans diastereoisomers to be exclusively obtained. This stereodivergent cyclization has enabled the synthesis of C2-symmetric bisacetate-substituted isoindolines. In addition, bisacetate isoindolines bearing two well-differentiated ester moieties are also noteworthy because they may allow for the orthogonal synthesis of β,β'-dipeptides using a single nitrogen atom as a linchpin. Asymmetry and amines: A series of 1,3-disubstituted isoindolines with a wide range of substituents has been prepared in good yields and diastereoselectivities from Ellman's imines bearing a Michael acceptor in the ortho position. The careful choice of the base for the aza-Michael step exclusively allows either the cis or trans diastereomer to be obtained (see scheme; DBU=1,8-diazobicycloundec-7-ene, TBAF=tetrabutylammonium fluoride). Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.