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 1 f (10 mol %), (CuOTf)2⋅C7H8 (5 mol %), and 4 Å 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. A variety of aromatic, heteroaromatic, enal, and aliphatic aldehydes have been found to be suitable substrates for a novel asymmetric Henry reaction, which employs a new chiral CuI–[H4]salen catalyst. Products from this reaction are obtained in moderate to high yields with excellent enantioselectivities (see scheme). This protocol is air‐tolerant and has been successfully extended to the synthesis of (S)‐norphenylephrine.