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

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 catalytically active 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 the 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.