Asymmetric Michael Reaction of Aldehydes and α‐Cyano α,β‐Unsaturated Esters Catalyzed by Diphenylprolinol Silyl Ether; a Facile Asymmetric Route to 3,4,5‐Trisubstituted Piperidines

A highly enantioselective diphenylprolinol silyl ether‐mediated asymmetric Michael reaction of a variety of aldehydes and β‐substituted α‐cyano α,β‐unsaturated esters was developed. The organocatalytic conjugate addition provided synthetically useful chiral adducts possessing three consecutive stereocenters and suitably oriented functional handles that were readily transformed via a sequence of reductive‐cyclization and subsequent epimerization to furnish single isomers of 3,4,5‐trisubstituted piperidines with high levels of yield and excellent enantiopurity. Asymmetric synthesis: An efficient organocatalytic protocol for the preparation of trisubstituted piperidines with enhanced stereo control was developed. The key asymmetric conjugate addition was accomplished via a highly enantioselective diphenylprolinol silyl ether catalyzed 1,4 addition of aldehydes to α‐cyano α,β‐unsaturated esters which generated a highly functionalized adduct that was transformed under reductive conditions to provide enantiopure 3,4,5‐trisubstituted piperidines.