Direct asymmetric vinylogous Michael addition of cyclic enones to nitroalkenes via dienamine catalysis

In spite of the many catalytic methodologies available for the asymmetric functionalization of carbonyl compounds at their alpha and beta positions, little progress has been achieved in the enantioselective carbon-carbon bond formation gamma to a carbonyl group. Here, we show that primary amine catalysis provides an efficient way to address this synthetic issue, promoting vinylogous nucleophilicity upon selective activation of unmodified cyclic alpha,beta-unsaturated ketones. Specifically, we document the development of the unprecedented direct and vinylogous Michael addition of beta-substituted cyclohexenone derivatives to nitroalkenes proceeding under dienamine catalysis. Besides enforcing high levels of diastereo- and enantioselectivity, chiral primary amine catalysts derived from natural cinchona alkaloids ensure complete gamma-site selectivity: The resulting, highly functionalized vinylogous Michael adducts, having two stereocenters at the gamma and delta positions, are synthesized with very high fidelity. Finally, we describe the extension of the dienamine catalysis-induced vinylogous nucleophilicity to the asymmetric gamma-amination of cyclohexene carbaldehyde.