A Versatile Synthesis of 5′-Functionalized Nucleosides Through Regioselective Enzymatic Hydrolysis of Their Peracetylated Precursors

We describe a chemo‐enzymatic synthesis of modified nucleosides through lipase‐catalyzed hydrolysis of their peracetylated precursors. It was found from screening of a large number of substrates that these enzymes' regioselectivities were affected by the sugar and the nucleobase structures. By selecting the best enzyme for each substrate in terms of activity and regioselectivity, we prepared a small library of differently monodeprotected purine and pyrimidine nucleosides useful as intermediates for the synthesis of high‐value nucleosides and mononucleotides. By this approach, the chemo‐enzymatic preparation of doxifluridine (14) anduridine 5′‐monophosphate (5′‐UMP, 15) from peracetylated uridine 1 was carried out. Elimination of many of the processing stages associated with existing methods was achieved, and higher yields and products of increased purity were generated. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009) Screening of immobilized lipases against natural and modified peracetylated nucleosides provided a set of biocatalysts with different regioselectivities. Selectively deprotected nucleosides were prepared with theselipases by enzymatic reaction and were then used for the chemo‐enzymatic synthesis of 5′‐functionalized nucleosides and mononucleotides in high yields andpurities.