Stereocontrolled Generation of C-Arylated Carbon Center α to Nitrogen Atom in Six-membered Azaheterocycles. Alternative Strategies

Abstract

Piperidin(on)es represent the core unit of a wide range of alkaloids and biologically active compounds and in particular, 6-(het)aryl substituted compounds play an important role as key targets for the pharmaceutical industry. The stereocontrol of carbon centers embedded in the azaheterocycle is a permanent synthetic task for organic chemists. In this regard we have developed two alternative and conceptually new synthetic approaches to a variety of 6-arylated piperidinones that is based upon the asymmetric reduction of endocyclic enamides readily accessible from imides, as the key step. The stereoselectivity of the reduction process could be controlled either by the use of a (S)-methylprolinol chiral auxiliary (Z = SMP, path a) or by ligand/catalyst chirality transfer (Z = Bn, path b). Varying degrees of success were observed for these conceptually different approaches.