Synthesis of Azido and Triazolyl Purine Ribonucleosides

Abstract

Here, we describe detailed synthetic protocols for preparation of 6amino/thio-2-triazolylpurine ribonucleosides. First, 9-(2 ,3 ,5 -tri-O-acetyl-β-D-ribofuranosyl)-2,6-diazido-9H-purine, to be used as a key starting material, is synthesized in an S N Ar reaction with NaN 3 starting from commercially available 9-(2 ,3 ,5 -tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine. Next, 2,6-bis-triazolylpurine ribonucleoside is obtained in a CuAAC reaction between diazidopurine derivative and phenyl acetylene, and used in S N Ar reactions with N-and S-nucleophiles. In these reactions, the triazolyl ring at the purine C6 position acts as a good leaving group. Cleavage of acetyl protecting groups from the ribosyl moiety is achieved in presence of piperidine. In the S N Ar reaction with amino acid derivatives, the acetyl groups remain intact. Moreover, 9-(2 ,3 ,5 -tri-O-acetyl-β-D-ribofuranosyl)-2,6-diazido-9H-purine is selectively reduced at the C6 position using a CuSO 4 •5H 2 O/sodium ascorbate system. This provides a straightforward approach for synthesis of 9-(2 ,3 ,5 -tri-O-acetyl-β-D-ribofuranosyl)-6-amino-2-azido-9H-purine.