STEREOSPECIFICITY IN THE TRANSFER OF HYDROGEN TO ALICYCLIC KETONES

Abstract

The in vitro reduction and oxidation of the isomeric methylcyclohexanones and methylcyclohexanols by horse liver alcohol dehydrogenase, in the presence of reduced nicotinamide adenine dinucleotide (NADH2) or nicotinamide adenine dinucleotide (NAD), has been studied. Whereas (±)-2-methylcyclohexanone give (+)-trans-, and (+)-cis-2-methylcyclohexanol, (+)-2-methylcyclohexanone gives (+)-trans-2-methylcyclohexanol and (-)-2-methylcyclohexanone gives (+)-cis-2-methylcyclohexanol. (±)-3-methylcyclohexanone affords racemic cis-and trans-3-methylcyclohexanol, while the optically active (+)-3-methylcyclohexanone gives (-)-cis- and (-)-trans-3-methylcyclohexanol, and (-)-3-methylcyclohexanone give (+)-cis- and (+)-trans-3-methylcyclohexanol. The alcohols were isolated by ether extraction and were characterised by gas chromatography, thin layer chromatography, infrared analysis and their optical rotations. These results closely resemble the in vivo metabolic conversions observed for the 2-, and 3-methylcyclohexanones, and suggest that the oxido-reductase in the animal body, responsible for the observed changes, is either liver alcohol dehydrogenase or an enzyme with properties remarkably similar to those of LADH. The findings are discussed in terms of the conformations and the established absolute configurations of alcohols and ketones, and a correlation of the observed rates and Km values and the steric specificity lends support to a general hypothesis on the stereospecific nature of LADH The results from the in vitro oxidation of the isomeric methylcyclohexanols together with the results from the in vitro reductions of the ketones, help to validate the hypothesis that the observed in vivo inversion of the thermodynamically less stable (±)-cis-2-methylcyclohexanol and the (±)-trans-3-methylcyclohexanol occurs through a ketone intermediate.