Biocatalytic route to C-3′-azido/-hydroxy-C-4′-spiro-oxetanoribonucleosides

• Novozyme®-435 catalyzed deacetylation methodology has been optimised for exclusive diastereoselective monodeacetylation of diacetoxy α-D-ribofurano-sugar derivative.
• The developed methodology has been successfully used for the efficient synthesis of 3′-azido-/3′-amino-C-4′-spiro-oxetanoribonucleosides T, U, C and A.
• Further, recently developed enzymatic diastereoselective decaetylation methodology has been used for the synthesis of C-4′-spiro-oxetanoribonucleosides A and C.
• The X-ray crystal data analysis on 3′-O-benzyl-C-4′-spiro-oxetanoribouridine revealed that the presence of spiro carbon restricts the conformational flipping of furanose ring.
• Thus the sugar puckering in C-4′-spiro-oxetanoribonucleosides attains N-type conformation which is in consonance with the literature report.

The lipase, Novozyme®-435, exclusively deacetylates the 5-O-acetyl over 4-C-acetyloxymethyl group of almost identical reactivity in 5-O-acetyl-4-C-acetyloxymethyl-3-azido-3-deoxy-1,2-O-isopropylidene-α-D-ribofuranose that led to the development of first and efficient synthesis of 3′-azido-/3′-amino-C-4′-spiro-oxetanoribonucleosides T, U, C and A in 20–24% overall yields. The X-ray study on the compound obtained by tosylation of lipase-mediated monodeacetylated product unambiguously confirmed the point of diastereoselective monodeacetylation on diacetoxy-azido-ribofuranose derivative. The capability of Novozyme®-435 for selective deacylation of 5-O-acetyl group in 5-O-acetyl-4-C-acetyloxymethyl-3-O-benzyl-1,2-O-isopropylidene-α-D-ribofuranose recently discovered by us has been successfully used for the synthesis of C-4′-spiro-oxetanoribonucleosides A and C in good yields. These results clearly indicate that the broader substrate specificity and highly selective capability of Novozyme®-435 for carrying out acetylation/deacetylation reactions can be utilized for the development of environment friendly selective methodologies in organic synthesis.

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