A generic parallel combinatorial approach to Chiral Lewis acid catalyst discovery: application to the aza-Diels-Alder reaction

Abstract

A generic parallel combinatorial method was used in order to attempt to develop new asymmetric processes for the aza-Diels-Alder reaction. Initially, an N-para-methoxyphenyl glyoxylate derived imine and its reactions with a variety of dienes was examined. Several new adducts were obtained, which included both "normal" "inverse" electron-demand aza-Diels-Alder products, and an acyclic product. These results strongly suggested the intervention of a stepwise addition-cyclisation mode of the reaction of diene with the imine. Later, new W-phosphorus imines were examined as dienophile substrates for aza-Diels-Alder reactions. The results of the reactions between these imines and a variety of dienes showed a reduced level of imine reactivity when compared to the N-para-methoxyphenyl C-carboxylate-derived system. Several new products were obtained and the results indicated a stepwise reaction process was in operation, due to the formation of other di-dehydro-piperidinone or acyclic ketone or aldehyde derivatives, hi this study, the first apparent N-phosphonyl imino-Diels-Alder reaction on such systems has been recorded. Screening reactions with different Lewis acids and chiral ligands produced no asymmetric induction, however, this system proved to be unreliable for monitoring by HPLC due to the presence of both cyclic and acyclic products.