A new copper(I)-tetrahydrosalen-catalyzed asymmetric Henry reaction and its extension to the synthesis of (S)-norphenylephrine

A new chiral hydrogenated salen catalyst has been developed for the asymmetric Henry reaction which produces the expected products in moderate to high yields (up to 98%) with excellent enantioselectivities (up to 96% ee). A variety of aromatic, heteroaromatic, enal, and aliphatic aldehydes were found to be suitable substrates in the presence of hydrogenated salen If (10 mol %), (CuOTf)(2)center dot C7H8 (5 mol %), and 4 angstrom molecular sieves. This process is air-tolerant and easily manipulated with readily available reagents, and has been successfully extended to the synthesis of (S)-norphenylephrine in 67% overall yield, starting from commercially available m-hydroxybenzaldehyde. Based on experimental investigations and MM+ calculations, a possible catalytic cycle including a transition state (8 or A) has been proposed to explain the origin of reactivity and asymmetric inductivity.