Conformational preferences and dynamics of 4-isoxazolyl-1,4-dihydropyridine calcium channel antagonists as determined by variable-temperature NMR and NOE experiments

Robert B. Palmer, Tina M. Andro, Nicholas R. Natale, Niels H. Andersen

Research output: Contribution to journalArticlepeer-review

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).

Original languageEnglish
Pages (from-to)495-504
Number of pages10
JournalMagnetic Resonance in Chemistry
Volume34
Issue number7
DOIs
StatePublished - Jul 1996

Keywords

  • 4-isoxazolyl-l,4-dihydropyridine calcium channel antagonists
  • Conformation
  • Dynamics
  • NOE
  • Variable-temperature NMR

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