Studies on organocatalytic asymmetric Michael addition reactions

Abstract

The development of organocatalysts for asymmetric synthesis continues to be actively investigated in recent years due to the advantages over conventional metal-based catalysts. Research in our laboratory has focused on the development of organocatalysts for fundamental carbon-carbon bond forming reactions, such as the Michael addition reaction. -- The organocatalytic Michael addition of ketones to nitroalkenes is of special interest since the reaction generates two contiguous stereocenters and the products (γ-nitro ketones) are useful synthetic intermediates. We have observed that this reaction is efficiently catalyzed by pyrrolidine-based chiral, secondary diamines as well as triamines. The use of a protic acid in conjunction with the amine catalyst is beneficial and the Michael addition products (syn diastereomers) are obtained with excellent enantioselectivities (up to 99% ee) and diastereoselectivity (up to 50:1 dr) for cyclic ketones and nitroalkenes derived from aromatic aldehydes. Details regarding the effect of changes in the catalyst and protic acid structure, variation of catalyst/protic acid combinations and the scope of the reaction with respect to structural changes in the ketone and nitroalkenes will be discussed. -- In addition, the application of the chiral triamines in Michael reactions involving iminium ion intermediates has been examined. Preliminary results from these studies will be presented. The attempted synthesis of pyrrolidine-based organocatalysts with guanidine-containing side chains as well as catalysts based on the camphor scaffold will also be presented.