Preparation of the enantiomerically enriched precursor of lamivudine (3TC™) via asymmetric catalysis mediated by Klebsiella oxytoca

Abstract We report the asymmetric catalysis mediated by a newly isolated strain from soil, Klebsiella oxytoca, for the preparation of the chiral intermediate of antiviral agent lamivudine which is proven to be one of most potent medicines for the treatment of human chronic hepatitis B and HIV infection. To improve the efficiency of the transformation, firstly the carbon and nitrogen sources of the medium were screened and the best performance was achieved with glucose (5 g/L) as carbon source and tryptone (5 g/L) as nitrogen source. Secondly, optimization of the reaction condition was carried out. A series of parameters were investigated including temperature, pH, metal ions, surfactant, and substrate concentration. The best outcome [enantiomeric excess (ee) of 99.9% and yield of 24%] of the enantioselective resolution of the racemic substrate catalyzed by whole cell of Klebsiella oxytoca was reached at 30 ℃, pH 7.0, substrate concentration of 1.5 g/L, and no additives. As a comparation to most of the lipase-catalyzed systems for the production of chiral oxathiolane moiety of lamivudine, the reaction occurred in a single-phase aqueous system which meets the golden and stringent criteria of green chemistry. To our knowledge, this is the first study using Klebsiella oxytoca as catalyst for the preparation of the chiral moiety of lamivudine.