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

Abstract

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 nu-

Recombinant lipase fromCandida rugosafor regioselective hydrolysis of peracetylated nucleosides. A comparison with commercial non-recombinant lipases

“…In agreement with previous results reported for CRL Sigma immobilized on octyl-agarose versus peracetylated uridine (1) and cytidine (3) (Bavaro et al 2009), the hydrolysis proceeded with a very high regioselectivity for the 5 -position. The conversion percentage of 1 and 3 to the 5 -monodeprotected derivatives 1a and 3a was 85% and 77%, respectively (Table IV).…”

“…Analytical data of compounds 1a and 3a were consistent with those previously reported (Bavaro et al 2009 …”

“…Wild-type and mutant enzymes Roncaglia et al 2001). A process for the preparation of the 5 -modified nucleosides doxifluridine and uridine 5 -monophosphate from peracetylated nucleosides based on regioselective deacylation catalyzed by immobilized lipases has been described recently (Bavaro et al 2009). Doxifluridine and uridine 5 -monophosphate are used as an antineoplastic drug and a food additive, respectively (Jyonouchi 1994;Longley et al 2003).…”

“…Compounds 1, 3 and 4 were synthesized by following the procedure previously described (Bavaro et al 2009). Analytical data of 1 and 3 were consistent with those reported.…”

Biocatalytic approaches applied to the synthesis of nucleoside prodrugs

“…DFUR, which was previously developed for the treatment of breast, colorectal and other cancers, shows a tumour-selective activity as a result of its selective conversion to 5-FU by human TP, an enzyme with higher activity in tumour than in normal tissues (Shimma et al, 2000). In a first chemo-enzymatic approach to prepare DFUR (Scheme 9), Bavaro et al (2009) employed 2′,3′,5′-tri-O-acetyluridine (1, Scheme 9) as starting material and two biocatalysed steps were involved. In the initial one, the substrate was regioselectively hydrolysed by Pseudomonas fluorescens lipase and after four chemical steps, 5′-deoxyuridine (2) was obtained.…”