Chemoenzymatic synthesis of bridged homolyxofuranosyl pyrimidine nucleosides: Bicyclic AZT analogues

Abstract

A greener chemo-enzymatic methodology has been developed for the synthesis of conformationally restricted diastereomeric homolyxofuranosyl pyrimidines (AZT analogue), i.e., (5'R)-3'-azido-3'-deoxy-2'-O,5'-C-bridged-β-d-homolyxofuranosyl-uracil and thymine starting from inexpensive diacetone-d-glucofuranose in 18% and 21% overall yields, respectively. In one of the key steps in multistep synthesis of bicyclic AZT analogues, the primary hydroxyl group of 3'-azido-3'-deoxy-β-d-glucofuranosyl pyrimidines has been acetylated using Novozyme® 435 in THF in 92% and 97% yields, respectively. The monoacetylated nucleoside was converted to desired bicyclic AZT analogue in two steps in an overall yield of 82% and 83%, respectively.

Keywords: Bicyclic AZT analogues; Chemoenzymatic route; Diacetone-d-glucose; Novozyme® 435; Nucleosides.