Theoretical study of stereoselective reduction controlled by NADH analogs

The potential energy surfaces (PES) of 2-methyl-4-(R)-methyl-1,4-dihydropyridine-3-carboxamide (4R-DM, 1), 2-methyl-4-(S)-methyl-1,4-dihydropyridine-3-carboxamide (4S-DM, 2) and 2-methyl-1,4-dihydropyridine-3-carboxamide (MM, 3) have been explored with ab initio calculations at the RHF/6-311G** and MP2/6-311G** levels of theory. In agreement with previous experimental and computational results, the PES provides three minima for each of the above molecules. The calculations reported herein indicate that the cisoid conformation is most favorable in gas phase and hydrophobic environments. Nevertheless, the preference of the cis conformation can be controlled by different solvents. The most favorable conformation in methanol, water, and probably in the polar (or water medicated) enzyme active sites, however, would be the one in which the carbonyl group is in a transoid position and is syn to Hsyn. In addition, our calculations suggest that the carbonyl group in the syn, rather than anti, position relative to Hsyn is preferred. These observations are in very good agreement with previous computational and experimental results. Our computational studies have provided an explanation as to why the transoid conformation is preferred in enzyme active sites as well as in many other NADH mimics. Furthermore, these new data imply that the stereoselectivity of NADH analogs can be controlled by means of changing solvents in which the reaction is carried out.