Conformational Preferences and Dynamics of 4-Isoxazolyl-1,4-dihydropyridine Calcium Channel Antagonists as Determined by Variable-Temperature NMR and NOE Experiments
✍ Scribed by Robert B. Palmer; Tina M. Andro; Nicholas R. Natale; Niels H. Andersen
- Publisher
- John Wiley and Sons
- Year
- 1996
- Tongue
- English
- Weight
- 1011 KB
- Volume
- 34
- Category
- Article
- ISSN
- 0749-1581
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✦ Synopsis
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-[ S-methyl-3'-(4''-fluorophenyl)isoxazoI-4'yl]-3,5-pyridinedicarboxylic acid dimethyl ester (3a) and 1,4-dihydro-2,6-dimethyl-4-[S-methyl-3'-(4''bromophenyl)isoxazol-4'-yl] -3,s-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-(S-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-4-4-4' 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 rotarneric equilibria at the temperatures required to freeze out the rotation. The seven experimental rotation barriers (AC' from <26 to 40.4 kJ mol-I) reported are 1-6.8 kJ mol-' higher than AHf calculated at the AM1 level).