A new diastereo- and enantioselective strategy for the functionalization of 2-acetyl-pyridine with α,β-unsaturated aldehydes has been investigated through synergistic catalysis. In particular, the aim of the work was to use cinnamaldehydes bearing different substituents on the phenyl group and to study its effect on the yield, conversion and stereoselectivity of the reaction. The reaction mechanism involves combined iminium ion and transition metal catalysis in a synergistic fashion and proceeds with two consecutives Michael additions, followed by final intramolecular aldol condensation to yield the formation of three new stereogenic carbons, with high to excellent stereoselectivities. The structures of the molecules obtained were fully characterized by NMR spectroscopy. After having assigned the relative configuration by NOE-NMR and 2D-COSY experiments, conformational analysis was performed by DFT calculations to find the most stable molecular conformations. The absolute configuration of each diastereoisomer was then eventually assigned by quantum mechanical simulations of the Electronic and Vibrational Circular Dichroism spectra
