Mechanistic insights into the origin of enantioselectivity of the organocatalytic asymmetric chlorolactonization

Mechanistic studies of the (DHQD)2PHAL catalyzed asymmetric chlorolactonization reaction of alkenoic acids have led to some surprising conclusions. Deuterium labeling studies of the catalyzed reaction have revealed that the face selectivity of the delivery of the chlorenium ion to olefins is neither a necessary nor a sufficient condition to deliver the product lactones with high enantioselectivities. The reaction likely proceeds via a carbocation intermediate with the enantioselectivity originating as a result of "templation" of the cyclization of the acid nucleophile by the chiral catalyst. Reaction progress kinetic analysis (RPKA) competition studies revealed that the rate-determining step is the formation of the chloronium ion. Taken together, these results suggest that the rate determining step and the enantioselectivity determining step are segregated. Moreover, NMR studies lead us to a plausible resting state of the asymmetric chlorolactonization.