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Conformational Preferences and Dynamics of 4‐Isoxazolyl‐1,4‐dihydropyridine Calcium Channel Antagonists as Determined by Variable‐Temperature NMR and NOE Experiments
Author(s) -
Palmer Robert B.,
Andro Tina M.,
Natale Nicholas R.,
Andersen Niels H.
Publication year - 1996
Publication title -
magnetic resonance in chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.483
H-Index - 72
eISSN - 1097-458X
pISSN - 0749-1581
DOI - 10.1002/(sici)1097-458x(199607)34:7<495::aid-omr899>3.0.co;2-5
Subject(s) - chemistry , dihydropyridine , nuclear magnetic resonance spectroscopy , proton nmr , stereochemistry , crystallography , nuclear magnetic resonance , calcium , organic chemistry , physics
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 (Δ G ≠ from ⩽26 to 40.4 kJ mol −1 ) reported are 1–6.8 kJ mol −1 higher than Δ H ≠ calculated at the AM1 level.