The metabolism of the isomeric tert.-butylcyclohexanones

Abstract

([plus or minus])-2, ([plus or minus])-3- and 4-tert.-Butylcyclohexanone are reduced in the rabbit to secondary alcohols, which are excreted extensively conjugated with glucuronic acid. The major metabolite of ([plus or minus])-2-tert.-butylcyclohexanone is (+)-cis-2-tert.-butylcyclohexanol, which has been isolated from the urine as [(+)-cis-2-tert.-butylcyclohexyl [beta]-D-glucosid]uronic acid. The minor metabolite is (+)-trans-2-tert.-butylcyclohexanol. ([plus or minus])-3-tert.-Butylcyclohexanone is reduced mainly to ([plus or minus])-cis-3-tert.-butylcyclohexanol, and to a smaller extent to ([plus or minus])-trans-3-tert.-butylcyclohexanol. 4-tert.-Butylcyclohexanone yields mainly the trans-alcohol, which is excreted in conjugated form and has been recovered from the urine as (trans-4-tert.-butylcyclohexyl [beta]-D-glucosid)uronic acid. The cis-alcohol is formed to a minor extent and excreted in conjugated form. The ratios of the amounts of cis- to trans-alcohols produced by the three ketones differed from the relative amounts of cis- and trans-alcohols produced by the corresponding methylcyclohexanones. From these findings the suggestion is made that two orientations of ketone relative to coenzyme occur alcohols with an equatorially orientated hydroxyl group are thought to be produced as a result of a ''face-to-face'' interaction with NADH, and alcohols with axially orientated hydroxyl groups as a results of a "perpendicular" interaction. Which will predominate is thought to depend on steric factors, particularly the size and position of alkyl substituents in the substrate.