A practical and scalable synthesis of several base modified 3'-O-methyl ribonucleosides

Abstract

An easy and efficient large-scale synthesis of 1, 2,-di-O-acetyl-5-O-benzoyl-3-O-methyl-d-ribofuranose (8) was accomplished from commercial 1,2:5,6-di-O-isopropylidene-α-d-allofuranose in 7-steps and 30 % overall yield. The utility of protected 8 was demonstrated via synthesis of 9-(3'-O-methyl-β-d-ribofuranosyl)-6-chloropurine (21) and six other nucleoside analogues in good yields. A library of five novel base modified nucleosides were generated starting from purine nucleoside 21 via functional group manipulations. The 3'-O-modified nucleosides are known to act as chain terminator exerting antiviral activity. The synthesis strategy described herein offers direct access to 3'-O-alkylated nucleosides with wide range of applications, including cap analogues for mRNA vaccine production. This protocol provides a route to exclusive synthesis of 3'-O-alkylated nucleosides, devoid of isomeric 2'-O-alkylated products essential for both therapeutic and biological research.

Keywords: Carbohydrate; Glycosylation; Modified Nucleoside; Selective Alkylation.