Catalytic Intramolecular Conjugate Additions of Aldehyde-Derived Enamines to α,β-Unsaturated Esters

We report a pairing of known catalysts that enables intramolecular conjugate additions of aldehyde-derived enamines to α,β-unsaturated esters. Despite extensive prior exploration of conjugate additions of aldehyde-derived enamines, catalytic conjugate additions to unactivated enoate esters are unprecedented. Achieving enantioselective and diastereoselective six-membered ring formation requires the coordinated action of a chiral pyrrolidine, for nucleophilic activation of the aldehyde via enamine formation, and a hydrogen bond donor, for electrophilic activation of the enoate ester. Proper selection of the hydrogen bond donor is essential for chemoselectivity, which requires minimizing competition from homoaldol reaction. Utility is demonstrated in a six-step synthesis of (-)-yohimbane from cycloheptene.