Conformational Preferences and Dynamics of 4-Isoxazolyl-1,4-dihydropyridine Calcium Channel Antagonists as Determined by Variable-Temperature NMR and NOE Experiments

Abstract

A series of 14 4-(3′,5′-disubstituted isoxazolyl)-1,4-dihydropyridine calcium channel antagonists were examined using variable-temperature proton nuclear magnetic resonance spectroscopy and nuclear Overhauser effect (NOE) experiments. Two of these compounds, the 1,4-dihydro-2,6-dimethyl-4-[5′-methyl-3′-(4″-fluorophenyl)isoxazol-4′-yl]-3,5-pyridinedicarboxylic acid dimethyl ester (3a) and 1,4-dihydro-2,6-dimethyl-4-[5′-methyl-3′-(4″-bromophenyl)isoxazol-4′-yl]-3,5-pyridinedicarboxylic acid dimethyl ester (5a), were synthesized to assist in the clarification of ambiguities discovered in the low-temperature spectra of 1,4-dihydro-2,6-dimethyl-4-(5′-methyl-3′-phenylisoxazol-4′yl)-3,5-pyridinedicarboxylic acid diethyl ester (2b). The solid-state structure of 3a is also reported. The solution-state rotameric preferences of the 14 compounds are reported and compared with those calculated at the AM1 level. C-4—C-4′ bond rotation barriers were also calculated at the AM1 level for nine of the systems examined. Several species failed to display temperature-dependent signals associated with hindered rotation owing to highly biased rotameric equilibria at the temperatures required to freeze out the rotation. The seven experimental rotation barriers (ΔG≠ from ⩽26 to 40.4 kJ mol−1) reported are 1–6.8 kJ mol−1 higher than ΔH≠ calculated at the AM1 level.