A New Straightforward Synthesis of 2', 3'-Didehydro-2', 3'-dideoxy-2'-(2"-(trimethylsilyl)ethylthio)thymidine, Key Intermediate for the Synthesis of 2'-Substituted Thionucleosides

Maralise P Oliveira,Cláudia M O Simões,Maria C A Lima,Ricardo J Alves,Jean-Luc Décout,Suely L Galdino,Lucas L Franco,Ivan R Pitta

doi:10.5935/0103-5053.20150025

Abstract

We describe herein a straightforward and efficient preparation of 2',3'-dideoxy-2'-(2''- (trimethylsilyl)ethylthio)thymidine, which allows the preparation of diverse potentially antiviral and/or anticancer nucleosides (disulfides, thiols, sulfides, thiocyanates).

Highlights

We describe a straightforward and efficient preparation of 2’,3’-dideoxy-2’-(2’’(trimethylsilyl)ethylthio)thymidine, which allows the preparation of diverse potentially antiviral and/or anticancer nucleosides
In the search for new bioactive agents and tools for biological studies, many sulfur containing nucleosides, nucleotides and oligonucleotides have been synthesized over 50 years.[8,9,10,11,12,13,14,15]
In the search for antiviral and antitumour nucleosides, one or more hydroxyl functions carried by the ribose and 2’-deoxyribose can be replaced by a thiol function or the corresponding mixed disulfide functions that can be reduced in vivo.[20,21,26,27]

Summary

Introduction

Chemical modifications of natural occurring nucleosides and nucleotides have led to a large number of drugs especially antiviral and antitumour agents.[1,2,3,4,5,6,7]In the search for new bioactive agents and tools for biological studies, many sulfur containing nucleosides, nucleotides and oligonucleotides have been synthesized over 50 years.[8,9,10,11,12,13,14,15]The explosion of interest in thionucleosides was ignited by discovery in early 1990’s that L-isomer of 2’-deoxy3’-thiacytidine [(-)-b-L-3TC, lamivudine)] (1) (3TC, Figure 1) is a potent inhibitor of HIV and HBV viruses. 2’,3’-didehydro-2’,3’-dideoxy-2’-(2”-(trimethylsilyl) ethylthio)thymidine (9) was previously synthesized from the corresponding saturated TMSE sulfide (5) in four steps (64% overall yield): (i) 4,4’-dimethoxytritylation of the 5’-hydroxyl function, (ii) mesylation at the 3’-position, (iii) removal of the trityl group under acidic conditions, and (iv) elimination in the presence potassium carbonate in acetonitrile under reflux (Scheme 1).[29] In this synthesis, the good mesyl leaving group has been introduced after selective protection of the 5’-hydroxyl group by tritylation.

Results

Conclusion