Electrostatic Basis for Enantioselective Brønsted-Acid-Catalyzed Asymmetric Ring Openings of meso-Epoxides

Computational studies of three chiral phosphoric-acid-catalyzed asymmetric ring-openings of meso -epoxides show that the enantioselectivity of these reactions stems from favorable electrostatic interactions of the preferred transition state with the phosphoryl oxygen of the catalyst. The 3,3′-aryl substituents of the catalysts, which are vital for enantioselectivity, serve primarily to create a narrow binding groove that restricts the substrate orientations within the chiral electrostatic environment of the phosphoric acid. This electrostatic, enzyme-like mode of stereoinduction appears to be general for these reactions and suggests a complementary means of achieving stereoinduction in chiral phosphoric acid catalysis. Finally, examination of the mechanism for subsequent reactions in List’s organocatalytic cascade for the synthesis of β-hydroxythiols (Monaco, M. R.; Prévost, S.; List, B. J. Am. Chem. Soc . 2014, 136, 16982) explains the requirement for elevated temperatures for the latter steps in the cascade sequence, as well as the lack of reactivity of five-membered cyclic epoxides in this transformation.