Enzymatic parallel kinetic resolution of mixtures of D/L 2'-deoxy and ribonucleosides: an approach for the isolation of β-L-nucleosides.

We have developed a lipase-catalyzed parallel kinetic resolution of mixtures of β-D/L-nucleosides. The opposite selectivity during acylation exhibited by Pseudomonas cepacia lipase (PSL-C) with β-D- and β-L-nucleosides furnished acylated compounds that have different R(f) values. As a consequence, isolation of both products was achieved by simple column chromatography. Computer modeling of the transition-state analogues during acylation of β-D- and β-L-2'-deoxycytidine with PSL-C was carried out to explain the high selectivity. PSL-C favored the 3'-O-levulination of the β-D enantiomer, whereas the 5'-OH group was acylated in 2'-deoxy-β-L-cytidine. In both cases, the cytosine base was placed in the alternate hydrophobic pocket of PSL's substrate-binding site, where it can form extra hydrogen bonds (in addition to the five essential catalytically relevant hydrogen bonds) that stabilize these intermediates catalyzing the selective acylation of β-D/L-nucleosides.