Mechanisms of Carbonyl Activation by BINOL N-Triflylphosphoramides: Enantioselective Nazarov Cyclizations

Abstract

BINOL N-triflylphosphoramides are versatile organocatalysts for reactions of carbonyl compounds. Upon activation by BINOL N-triflylphosphoramides, divinyl ketones undergo rapid and highly enantioselective (torquoselective) Nazarov cyclizations, making BINOL N-triflylphosphoramides one of the most important classes of catalysts for the Nazarov cyclization. However, the activation mechanism and the factors that determine enantioselectivity have not been established until now. Theoretical calculations with ONIOM and M06-2X are reported which examine how BINOL N-triflylphosphoramides activate divinyl ketones and control the torquoselectivity of the cyclization. Unexpectedly, the computations reveal that the traditionally accepted mechanisms for these catalysts (i.e., NH···O═C hydrogen bonding or proton transfer) are not the dominant activation mechanisms. Instead, the active catalyst is a less-stable tautomer of the phosphoramide containing a P(═NTf)OH group. Proton transfer from the catalyst to the substrate...