Highly reactive and stereoselective (R)- and (S)-3-(N,N-dimethylcarbamoyl)-1,2,4-trimethyl-1,4-dihydropyridines for NADH-NAD+ mimicry

Abstract

NADH model compound 3-(N~-dimethylcarbamoyl)-1,2,4-trimethyl-l,4-dihydrop~idine, 1, has been resolved into its enantiomers.Subsequently these hydride donors were brought into reaction with divergent carbonyl substrates, e.g., methyl benzoylformate, methyl pyruvate, acetone-& and DDQ.Significant asymmetric induction was observed in the corresponding axially chiral NAD+ analogue 3-(N,N-dimethylcarbamoyl)-1,2,4-trimethylpyridinium perchlorate, 2. The absolute configuration and conformation of optically active 1 and 2 respectively were elucidated.Finally, conditions were developed for the hydride transfer from 1,Cdihydropyridine 1 to methyl benzoylformate affording the corresponding pyridinium derivative 2 and methyl mandelate in optical yields exceeding 95%.In all cases studied, a preferential syn orientation of the amide carbonyl dipole and of the leaving C-4 hydrogen accounts for the observed chirality transfer.