Conformational dynamics of 4-aryl-1,4-dihydropyridine calcium channel antagonists. 1. Quantitation of C4-C1' bond rotational barriers

Article abstract of DOI:10.1016/0040-4020(96)00500-5

The solution state dynamics of six substituted 4-aryl-1,4- dihydropyridine calcium channel antagonist analogs were studied using saturation transfer, difference NOE and variable temperature NMR spectroscopy. Thermodynamic activation parameters for aryl ring rotation were determined for all six compounds from linear Eyring plots which span four orders of magnitude. The barrier to rotation about the ring juncture was also calculated at the AM1 level and these calculations correctly predict the general magnitude, though not the specific barriers, to rotation. The asymmetrically substituted compound, 1,4-dihydro-2,6-dimethyl- 4-(2'-chloro-6'-methylphenyl)-3,5-pyridine-dicarboxylic acid dimethyl ester (2a), showed a rotameric preference of 17:1 by NMR for having the aryl methyl group syn to the C4H of the dihydropyridine ring; AM1 correctly predicts this preference but overestimates its magnitude. In the crystal state, the rotameric ratio appears to be nearer 1:1.