Chemoenzymatic synthesis of bridged homolyxofuranosyl pyrimidine nucleosides: Bicyclic AZT analogues.

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-ß-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-ß-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.

Chemo-enzymatic route to bridged homolyxofuranosyl-pyrimidines.

Synthesis of 2'-O,5'-C-bridged-ß-d-homolyxofuranosyl nucleosides U and T have been achieved starting from diacetone-d-glucose in overall yields 55.7 and 57.1%, respectively. Quantitative regioselective monoacetylation of the lone primary hydroxyl group in trihydroxy nucleoside intermediate, i.e. 3'-O-benzyl-ß-d-glucofuranosyl nucleosides mediated by Novozyme®-435 has been utilized as the key step in the synthesis of homolyxofuranosyl nucleosides. The structure of the synthesized 2'-O,5'-C-bridged-ß-d-homolyxofuranosyl uracil and -thymine has been established on the basis of their spectral (IR, 1H, 13C NMR and HRMS) data analysis and the structure of earlier nucleoside was confirmed by its X-rays diffraction analysis which revealed that these 2'-O,5'-C-bridged homo-nucleosides are locked into S-type sugar puckering.

Synthesis and Photophysical Studies on N1-(2'-O,4'-C-Methyleneribofurano-nucleoside-3'-yl)-C4-(coumarin-7-oxymethyl)-1,2,3-triazoles.

A series of eight N1-(2'-O,4'-C-methylene-ß-D-ribofuranonucleoside-3'-yl)-C4-(coumarin-7-oxymethyl)-1,2,3-triazoles have been synthesized by Cu(I)-catalyzed azide-alkyne cycloaddition reaction of 3'-azido-3'-deoxy-2'-O,4'-C-methyleneuridine and 3'-azido-3'-deoxy-2'-O,4'-C-methylene-5-methyluridine with 7-propargyloxy coumarins in 82-88% yields. The synthesized coumarintriazolyl-bicyclonucleoside conjugates possess an extra bridge between 2'-O and 4'-C in the nucleoside moiety, which facilitates its pre-organization into N-type sugar puckering. This was confirmed by X-ray crystal structure studies on one of the conjugates, i.e. on N1-(3'-deoxy-2'-O,4'-C-methylene-5-methyluridin-3'-yl)-C4-(4-phenylcoumarin-7-oxymethyl)-1,2,3-triazole. Photophysical studies carried out on the synthesized compounds demonstrate that they possess useful level of fluorescence with Stokes shift of approximately 70 nm.