Bicyclic β-lactones via intramolecular NCAL reactions with cinchona alkaloids: Effect of the C9-substituent on enantioselectivity and catalyst conformation

Abstract

C9-Acylated cinchona alkaloids promote an intramolecular, nucleophile-catalyzed aldol-lactonization (NCAL) reaction leading to optically active bicyclic β-lactones. A mechanistic scheme is proposed for this catalytic, asymmetric process. Only small variations in enantioselectivity were observed for a variety of esters, a carbamate, and a carbonate at the C9 position of quinidine. A combination of coupling constants (3JH8,H9) and nOe data was used to assign predominant solution conformations for these derivatives. Interestingly, a more rigid quinidine derivative gave a complete reversal in the sense of enantioselection.