Stereoselective Reformatskii-Claisen rearrangement: synthesis of 2',3'-dideoxy-6',6'-difluoro-2'-thionucleosides

摘要

A new approach for the stereoselective synthesis of 2',3'-dideoxy-6',6'-difluoro-2'-thionucleosides, analogues of highly bioactive L-OddC and 3TC, has been developed via TMSCl/pyridine induced stereoselective Reformatskii-Claisen rearragement of secondary allyl chlorodilluoroacetale and then a regioselective Pummerer reaction to introduce bases.rnNucleoside analogues are effective in the clinical treatment of human cancer or viral diseases. However, the toxicities associated with these compounds, as well as the development of resistant viral strains upon prolonged treatment, indicate that there is still a great demand for novel therapeutic agents. One plausible approach is to replace the carbohydrate moiety of naturally occurring nucleosides with other five membered rings." It has been demonstrated that such modifications of these rings have a profound effect on the biological activity of the resulting nucleoside analogues as displayed by (-)-2'-deoxy-3'-thiacytidine (3TC) and ( + )-2'-deoxy-3'-oxacytidine (L-OddC). Recently, a number of difluoromethylene-containing nucleosides and thionucleosides have been prepared, such as: 2'-deoxy-2',2'-difluorocytidine (Gemcitabine), 2'-deoxy-2',2'-difluoro-4'-thiocytidine, 2',3'-dideoxy-6',6'-difluoro-3'-thionucleoside and 2',3'-dideoxy-6'-carba-2'-thionucleosides. Among them, Gemcitabine has been approved as a drug for solid tumor treatment. As part of an ongoing search for new antiviral and antitumor leads, we designed our target molecules 1 and 2, difluoromethylene-containing analogues of L-OddC and 3TC (Fig. 1).