Synthesis of Natural and Sugar-Modified Nucleosides Using the Iodine/Triethylsilane System as N-Glycosidation Promoter

Abstract

The reagent system based on the combined use of Et₃SiH/I₂ acts as an efficient N-glycosidation promoter for the synthesis of natural and sugar-modified nucleosides. An analysis of reaction stereoselectivity in the absence of C2-positioned stereodirecting groups revealed high selectivity with six-membered substrates, depending on the nucleophilic character of the nucleobase or based on anomerization reactions. The synthetic utility of the Et₃SiH/I₂-mediated N-glycosidation reaction was highlighted by its use in the synthesis of the investigational drug apricitabine.

Keywords: N-glycosidation; anomerization; apricitabine; glycosyl iodide; iodine/triethylsilane; nucleosides; stereoselectivity.

Scheme 1

General scheme of the N-glycosidation reaction.

Scheme 2

Silane/I₂-mediated N-glycosidation reactions.

Scheme 3

Et₃SiI and HI as activating agents of glycoside acetates.

Scheme 4

Et₃SiH/I₂-mediated N-glycosidation: preliminary screening. α:β ratios were assigned by comparative ¹H NMR analysis with literature data (see Supplementary Materials for details).

Scheme 5

(a) Effect of temperature, time, nucleobase and eq. of activating reagents on the stereoselectivity of the N-glycosidation of hexopyranosides 5 and 6. (b) Substrate-dependent effect of the temperature of step 2 on the stereoselective outcome of the N-glycosidations due to anomerization reactions. α:β ratios were assigned by comparative ¹H NMR analyses with the literature data (see Supplementary Materials for details). ^a If a non-anhydrous reaction solvent was used, up to 90% of disaccharide 16 was recovered (see Supplementary Materials).

Scheme 6

Stereoselectivity of the N-glycosidation reaction: mechanistic hypotheses.

Scheme 7

N-Glycosidation reactions of five-membered substrates.

Scheme 8

The use of the Et₃SiH/I₂-mediated N-glycosidation reaction in the synthesis of antiretroviral nucleoside apricitabine.