CONFORMATIONAL DYNAMICS OF 4-ARYL-1,4-DIHYDROPYRIDINE CALCIUM-CHANNELANTAGONISTS .1. QUANTITATION OF C4-C1' BOND ROTATIONAL BARRIERS

The solution state dynamics of six substituted 4-aryl-1,4-dihydropyrid ine calcium channel antagonist analogs were studied using saturation t ransfer, difference NOE and variable temperature NMR spectroscopy. The rmodynamic activation parameters for aryl ring rotation were determine d for all six compounds from linear Eyring plots which span four order s of magnitude. The barrier to rotation about the ring juncture was al so calculated at the AM1 level and these calculations correctly predic t the general magnitude, though not the specific barriers, to rotation . The asymmetrically substituted compound, ro-2,6-dimethyl-4-(2'-chlor o-6'-methylphenyl)-3,5- pyridine-dicsrboxylic acid dimethyl ester (2a) , showed a rotameric preference of 1.7:1 by NMR for having the aryl me thyl group syn to the C4H of the dihydropyridine ring; AMI correctly p redicts this preference but overestimates its magnitude. In the crysta l state, the rotameric ratio appears to be nearer 1:1. Copyright (C) 1 996 Elsevier Science Ltd.