Efficient synthesis of 2′-deoxyzebularine and its α-anomer by the silyl method of N-glycosylation. Crystal structures and conformational study in solution

• Synthesis of α- and β-deoxyzebularine with high stereoselectivity by N-glycosylation.
• Full spectral characterization of α- and β-2′-deoxyzebularine.
• Crystal structure and conformation analysis in solution of α- and β-2′-deoxyzebularine.

2′-Deoxyzebularine and its α-anomer have been efficiently synthesized with relatively high stereoselectivity by a modified procedure of the silyl method of the N-glycosidic bond formation. An SnCl4-catalyzed condensation of silylated pyrimidin-2-one with 1-α-chloro-3,5-di-O-p-toluoyl-2-deoxy-d-ribofuranose under kinetic control condition (−33 °C, 1,2-dichloroethane) led to the mixture of β- and α-anomeric nucleosides in 3:1 ratio. Analogous condensation at +35 °C (thermodynamic control conditions) provided mainly p-toluoyl protected α-2′-deoxyzebularine (α:β = 4:1), easily separated by crystallization from the anomeric mixture. The structures of both 2′-deoxyzebularine anomers were confirmed by X-ray analysis of the crystals and conformational studies in solution performed using an NMR method.

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