Diastereo-Differentiating Hydride Transfer at Bridged NAD(H) Models

Article abstract of DOI:10.1021/ja00325a020

Five NAD(H) models are described which contain the 1-benzyl(dihydro)pyridine-3,5-diamide moiety as a redox center.This redox center is bridged by various CH2CH2ArCH2CH2 groups connecting the amido nitrogens and thereby incorporating the redox center into a cyclophane framework.X-ray structure data as well as 1H NMR studies reveal a profound influence of the nature of the aryl group (Ar) on the molecular and magnetic symmetry of the environment in which the redox center resides.In three of the cyclophanes this leads to a distinct anisochronism of the C(4) hydrogens at the reduced redox center (i.e., the 1,4-dihydropyridine moiety), analogous to the anisochronism observed for the C(4) hydrogens in NAD(P)H.Deuterium isotope exchange studies show that the diastereotopism of the C(4) positions revealed by the NMR data also leads to a distinct diastereo-differentiation in hydride (deuteride) exchange processes at C(4).These systems thereby constitute the first examples of NAD(H) models capable to mimic the diastereo-differentiating course of hydride exchange at pyridine dinucleotides under enzymatic conditions.The degree of diastereo-differentiation amounts to 67percent for Ar=1,4-naphthylene and to more than 90percent for two cyclophanes in which the Ar group is a substituted 1,3-phenylene moiety.From X-ray structure data and from electronic absorption spectra it is concluded that in all reduced cyclophanes the strain exerted by the bridge leads to a boat-shape distortion of the 1,4-dihydropyridine moiety, which places the C(4) hydrogens in axial and equatorial orientations.Interestingly the distortion of the dihydropyridine moiety was found to be most pronounced in the two cyclophanes displaying the highest degree of diastereo-differentiation.Furthermore it could be shown that in all cases hydride exchange preferentially occurs via the axial C(4) position.Kinetic investigation of the hydride-exchange processes suggests that a (partial) boat shape of the pyridine ring also occurs in the transition state.It is therefore concluded that diastereo-differentiating hydride exchange at the cyclophanes may largely be attributed to stereoelectronic effects which favor exchange at an axial site.Since comparison of free and enzyme-bound NAD(P)H fails to reveal a distortion of the dihydronicotinamide chromophore in the latter, such distortion is concluded to be of minor importance in the enzymatic diastereo-differentiation.A model based on "positive-differentiation" is proposed, which links enzymatic diastereo-differentiation to enzymatic catalysis and in which selective catalysis of hydride transfer at one of the diastereotopic C(4) positions leads to a diastereo-differentiation which equals the catalytic effect of the enzyme.This model is in agreement with recent findings concerning the orientation of the nicotinamide ring in enzyme-bound NAD(P)H.