Bio- and Organocatalytic routes in the synthesis of novel acyclic nucleosides

PALAZZOLO, M. A.; PÉREZ-SÁNCHEZ, M.; IRIBARREN, A. M.; LEWKOWICZ, E. S.; DOMÍNGUEZ DE MARÍA, P.

Hamburgo

Congreso; 6th International Congress on Biocatalysis (Biocat 2012); 2012

Bio- and Organocatalytic routes in the synthesis of novel acyclic nucleosides   M. A. Palazzolo1,3, M. Pérez-Sánchez3, A. M. Iribarren1,2, P. Domínguez de María3, E.S. Lewkowicz1 1Biocatalysis & Biotransformations Laboratory, Universidad Nacional de Quilmes, Roque Sáenz Peña 352, 1876 Bernal, Buenos Aires, Argentina. 2Chemistry of Nucleic Acids Laboratory, INGEBI-CONICET, Vuelta de Obligado 2490, 1428 Ciudad Autónoma de Buenos Aires, Argentina. 3Institute of Technical and Macromolecular Chemistry, RWTH Aachen University. Worringerweg 1, D-52074 Aachen, Germany.   elewko@unq.edu.ar   The use of nucleoside-based compounds as antiviral drugs is widely established. Their mechanisms of action lie either on the specific inhibition of constitutive enzymes or as blocking agents within the viral RNA or DNA biosynthesis. Nucleoside derivatives in which the sugar moiety is replaced by an acyclic, functionalized chain are of high interest since they mimic natural nucleosides, thus acting on viral target enzymes [1]. Acyclovir, the main representative molecule, is extensively used against herpes virus. Although the biocatalyzed synthesis of nucleosides has been extensively studied [2], the preparation of acyclic derivatives has not been explored so far. The use of aldolases, like rabbit muscle aldolase (RAMA), that catalyze the aldol reaction between aldehydes and ketones to afford 1,3-hydroxy-ketones, provides a promising framework for the development of new nucleoside-based acyclic antiviral drugs [3]. Organocatalysis has emerged in the last decade as a mild and powerful alternative to carry out key organic reactions with high yields and low wastes [4]. The use of organocatalysts able to perform aldol additions, like pyrrolidine [5], may confer a complementary strategy to the aldolase-catalyzed route. In this context, the study of both aldolase-based and organocatalyst-based paths may provide a broader scope of green technologies for the synthesis of acyclic nucleosides. To this end, N-9 and N-1 aldehydes of adenine and thymine, respectively, were selected as model substrates 1. Remarkably, reactions biocatalyzed by RAMA using dihydroxyacetone phosphate as donor afforded products 2 in high yields. In addition, when pyrrolidine was used as organocatalyst and acetone and diethyl-2-oxopropylphosphonate were evaluated as donors, acyclic nucleosides analogues 3 were obtained in 100% yield (Figure 1).     Figure 1. Bio- and organocatalytic complementary strategies for the production of acyclic nucleoside analogues.   [1] De Clercq, E.; Holý, A. Nature Rev., 2005, 4, 928-940. [2] a) Lewkowicz, E. S.; Iribarren, A. M. Curr. Org. Chem., 2006, 10, 1197-1215. b) Valino, A. L.; Palazzolo, M. A.; Iribarren, A. M.; Lewkowicz, E. S. Appl. Biochem. Biotechnol, 2012, 166, 300–308. [3] Palazzolo, M. A.; Iribarren, A. M.; Lewkowicz, E. S. 2012, manuscript under preparation. [4] Domínguez de María, P.; Bracco, P.; Castelhano, L. F.; Bargeman, G. ACS Catalysis, 2011, 1, 70-75. [5] P. Renzi, M. Bella, Chem. Commun. 2012, DOI: 10.1039/C2CC31599H.