Enantioselective Ring Opening of Azetidines via Charge Recognition in Hydrogen-Bond-Donor Catalysis

We report the highly enantioselective ring-opening of 3-substituted azetidines by alkyl and acyl halides promoted by a chiral squaramide hydrogen-bond donor catalyst. Broad scope is achieved across a variety of substrate combinations possessing disparate steric features. The same catalyst had been identified previously to promote enantioselective opening of oxetanes via both Lewis and Brønsted acid mechanisms. This remarkable generality is interpreted to arise from catalyst recognition of the conserved electrostatic features of the dipolar enantioselectivity-determining transition states in the ring-opening S_N2 mechanisms with simultaneous tolerance of variation of the specific functional group and steric features of the reactions. Specific experimental and computational evidence is provided for a network of electrostatic interactions that forms a shared basis for enantioinduction across these transformations. This work provides a framework for designing catalysts that achieve high enantioselectivity across diverse reactions unified by conserved polar mechanisms.