Application of enzyme-mediated esterifications to the resolution of chiral alcohols and phosphines
Jennings, Lee D.
Doctor of Philosophy
Optically active allylic, propargylic, and aliphatic alcohols (33 examples) were obtained by kinetic resolution using transesterification catalyzed by an enzyme from Pseudomonas sp. (Amano Enzyme Co., AK). In every case for which the absolute configuration of the resolved alcohol was determined, the R-enantiomer of the substrate was esterified. In comparison with other methods for resolving chiral allylic alcohols, this methodology is applicable in some cases where other methods do not work well. Kinetic resolutions of two substrates (allenol 18 and dienol 13) by Sharpless asymmetric epoxidations were performed for comparison with the methodology presented in this paper. This method is also widely applicable and extremely convenient for the resolution of alkynols and allenic alcohols. The combined data collected in this work gave an indication of what structural features of the substrates could be correlated with high enantioselectivites in the resolution of chiral secondary alcohols. Molecular modeling and energy minimization programs were used to refine our observation that the lipase catalyzed the esterification of the R-enantiomer of a substrate and a space filling model of the lipase active-site was produced from these results. This model is useful for rationalizing the results of other published resolutions of chiral secondary alcohols by transesterification catalyzed by lipase from Pseudomonas sp. Furthermore, the results account for the apparent reversal of enantioselectivity previously observed in resolutions of $\gamma$-hydroxy-$\alpha,\beta$-unsaturated esters. Enzyme-mediated acylations were also used to resolve $\alpha$-methylene-$\beta$-hydroxy ester and ketones, a useful class of compounds for which no effective asymmetric synthesis has been reported. This methodology was complementary to, and much more convenient than, kinetic resolution by chiral transition-metal complex catalyzed hydrogenation. An asymmetric synthesis of a chiral phosphine by enzyme-mediated enantiogroup selective acylation of a phosphine diol is also reported. This is the first reported use of enzymes to prepare optically active phosphines chiral at phosphorous. The synthesis and partial resolution of other chiral phosphines is also reported.