Base-Dependent Stereodivergent Intramolecular Aza-Michael Reaction: Asymmetric Synthesis of 1,3-Disubstituted Isoindolines

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).