Chloride-Mediated Alkene Activation Drives Enantioselective Thiourea and Hydrogen Chloride Co-Catalyzed Prins Cyclizations

Abstract

The mechanism of chiral hydrogen-bond donor (HBD) and hydrogen chloride (HCl) co-catalyzed Prins cyclizations was analyzed through a combination of experimental and computational methods and revealed to involve an unexpected and previously unrecognized mode of alkene activation. Kinetic and spectroscopic studies support the participation of a HCl•HBD complex that displays reduced Brønsted acidity relative to HCl alone. Nevertheless, rate acceleration relative to the HCl-catalyzed background reaction as well as high levels of enantioselectivity are achieved. This inverse Brønsted correlation is ascribed to chloride-mediated substrate activation in the rate-limiting and enantiodetermining cyclization transition state. Density-functional theory (DFT) calculations, distortion–interaction analysis, and quasiclassical dynamics simulations support a stepwise mechanism in which rate acceleration and enantioselectivity are achieved through precise positioning of the chloride anion within the active site of the chiral thiourea to enhance the nucleophilicity of the alkene and provide transition state stabilization through local electric field effects. This mode of selective catalysis through anion positioning likely has general implications for the design of enantioselective Brønsted acid catalyzed reactions involving π-nucleophiles.