Synthesis of 6,6′-(S)-cyclo-2′-deoxyuridine featuring a unique Barbier-style cyclization

Abstract

Here we present the synthesis of the novel nucleoside 6,6′-(S)-cyclo-2′-deoxyuridine (1). This efficient synthesis is carried out starting from 2′-deoxyuridine and reaches the deprotected product in few steps and high yield. Crystal structures of the product indicate that it is a very good structural mimic of thymidine as found in DNA duplexes. This rigidified nucleoside locks the uracil base in the anti conformation, positioning the nucleobase for Watson–Crick duplex formation at significant entropic savings. The structure of 6,6′-(S)-cyclo-2′-deoxyuridine maps more favorably onto naturally occurring nucleosides than previous cyclo nucleosides. The synthesis features a unique Barbier-style cyclization, expanding on Luche and Sarandeses allyl zinc additions, to create a 7-membered ring in good yield.