The first general synthesis of 2-C-(β-d-glycopyranosyl)pyrimidines and their evaluation as inhibitors of some glycoenzymes

Abstract

A systematic study was performed on the preparation of unknown 2-C-(β-D-glucopyranosyl)pyrimidines. Pinner type cyclisation of O-perbenzylated C-(β-D-glucopyranosyl)formamidine with β-ketoesters, dimethyl malonate, and β-diketone derived α,β-unsaturated β-chloroketones followed by catalytic hydrogenation resulted in various substituted 2-C-(β-D-glucopyranosyl)-pyrimidin-4(3H)-ones, and 2-C-(β-D-glucopyranosyl)-4,6-disubstituted-pyrimidines, respectively, in moderate to good yields. The above pyrimidine derivatives were also obtained by ring closure of the unprotected C-(β-D-glucopyranosyl)formamidine with the same 1,3-dielectrophiles. In addition, a continuous one-pot three-step procedure starting from O-peracylated D-glycopyranosyl cyanides was also elaborated to give representatives of the aforementioned pyrimidines with various sugar configurations in acceptable to excellent overall yields (25–94%). Due to the versatility of the applied 1,3-dielectrophiles, these synthetic routes represent the first expansible method to obtain the target compounds. The new C-glycopyranosyl pyrimidines showed moderate inhibition against α-glucosidase and β-galactosidase enzymes, had, however, no activity against glycogen phosphorylase. The obtained molecule library is ready for further biological testing.