Enantioselective enzymatic desymmetrization of the prochiral pyrimidine acyclonucleoside

The effect of the solvent and the acyl group donor on the selectivity of the transesterification reaction of 1-{[(1,3-dihydroxypropan-2-yl)oxy]methyl}-5-methylpyrimidine-2,4(1H,3H)-dione was examined. Lipase (EC 3.1.1.3) Amano PS from Burkholderia cepacia (BCL) enabled desymmetrization of prochiral hydroxyl groups and gave the (R)-monoester in high enantiomeric excess (ee 88–99%). The best selectivity was obtained for the transesterification reaction with vinyl benzoate as the acylating agent (only monoester, 99% ee). The absolute configuration of the newly formed stereogenic center was determined with a high degree of confidence on the basis of the combined experimental and theoretical electronic circular dichroic (ECD) studies. The hydrolysis of prochiral diesters formed during the transesterification reaction in the presence of BCL provided the opposite enantiomer, that is, the (S)-monoester.

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3-Hydroxy-2-((5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methoxy)propyl acetateC11H16N2O6[α]D25=-45.2 (c 0.20, CHCl3)Source of chirality: enzymatic reactionAbsolute configuration: (R)

3-Hydroxy-2-((5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methoxy)propyl butyrateC13H20N2O6[α]D25=-30.2 (c 0.20, CHCl3)Source of chirality: enzymatic reactionAbsolute configuration: (R)

3-Hydroxy-2-((5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methoxy)propyl benzoateC16H18N2O6[α]D25=-14.5 (c 0.20, CHCl3)Source of chirality: enzymatic reactionAbsolute configuration: (R)

3-Hydroxy-2-((5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methoxy)propyl decanoateC21H36N2O6[α]D25=-18.3 (c 0.20, CHCl3)Source of chirality: enzymatic reactionAbsolute configuration: (R)