Substrate Enantioselection in the Microsomal Epoxide Hydrolase Catalyzed Hydrolysis of Monosubstituted Oxiranes. Effects of Branching of Alkyl Chains

Article abstract of DOI:10.1021/jo00286a034

The hydrolysis of racemic 1,2-epoxyhexane (1a), 1,2-epoxydecane (1b), 4,4-dimethyl-1,2-epoxypentane (1c), and 3,3-dimethyl-1,2-epoxybutane (1d) catalyzed by rabbit liver microsomal epoxide hydrolase (MEH) has been investigated in order to further clarify the enantioselecting ability of this enzyme.Both enantiomers of all four epoxides were good substrates.The alkyl chain showed, however, a remarkable effect on the enantiomeric excess of the diols 2 produced during the course of the hydrolysis under enzyme saturation conditions.Linear-chain epoxides gave diols with very low enantiomeric excesses even at very low conversions, whereas branched-chain epoxides gave enantiomerically enriched diols.Furthermore, the ee obtained with the latter epoxides increased with increasing ratio of substrate to microsomal protein.R configurations were demonstrated for the excess enantiomers of diols 2c and 2d by CD and NMR measurements of their dibenzoate esters.In the case of 1c nucleophilic attack by water was proved using 18OH2 followed by MS analysis of the produced diol to occur <*> 95percent at the unsubstituted oxirane carbon.A markedly biphasic profile was found for the time course of the hydrolysis of (+/-)-1d.A mechanistic explanation for the observed substrate enantioselection is proposed.