Atropisomeric Flavoenzyme Models with a Modified Pyrimidine Ring:  Syntheses, Physical Properties, and Stereochemistry in the Reactions with NAD(P)H Analogs

• Published in: Journal of organic chemistry 1996-12, Vol.61 (26), p.9344-9355
• Main Authors: Ohno, Atsuyoshi, Kunitomo, Jun, Kawai, Yasushi, Kawamoto, Tetsuji, Tomishima, Masaki, Yoneda, Fumio
• Format: Article
• Language: English
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo961799t

Optically active 5-deazaflavin derivatives (3-aryl-10-(4-tert-butylphenyl)pyrimido[4,5-b]quinoline-2,4(3H,10H)-dione) with an axial chirality at the pyrimidine ring have been synthesized, and the kinetics of enantiomerization have been measured for some of them. The absolute configurations of these compounds have been determined by X-ray crystallographic analysis and chemical reactions for the first time in atropisomeric flavoenzyme models. Enantioface-differentiating (net) hydride-transfer reactions with 1-benzyl-1,4-dihydronicotinamide (BNAH) have revealed that the selectivity of the reacting face of the 3-[2-(hydroxymethyl)phenyl] derivative 1 changes depending on the presence or absence of Mg2+; the hydroxymethyl group of 1 exerts steric inhibition in the absence of Mg2+, whereas it facilitates the approach of BNAH in the presence of Mg2+. Asymmetric (net) hydride-transfer reactions with chiral 1,4-dihydro-2,4-dimethyl-N-(α-methylbenzyl)-1-propylnicotinamide (Me2PNPH) predict that the most favorable intermolecular arrangement of these two molecules at the transition state is the one in which the pyrimidine ring of 1 and the carbamoyl group of Me2PNPH tend to face each other and the maximum overlap of their molecular planes is achieved regardless of the presence or absence of Mg2+. The arrangement mimics that of FAD and NADPH in the active site of a flavoenzyme. The present result indicates an energetically favorable overlap of the molecular planes of a flavin and an NAD(P)H coenzyme, as well as a significant influence of functional groups from an apoenzyme in proximity to a flavin coenzyme on the stereochemistry of biological redox reactions.