Synthesis of novel 6-substituted thymine ribonucleosides and their 3′-fluorinated analogues

Nine novel 6-fluorothymine nucleoside analogues of both N(1)-alpha/beta and N(3)-beta-ribo series were prepared by the Vorbruggen method starting from persilylated 6-fluorothymine and 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D-ribofuranose, 1-O-acetyl-2,5-di-O-benzoy1-3-deoxy-3-fluoro-alpha,beta-D-ribofuranose or 1,2,3,5-tetra-O-benzoyl-beta-D-ribofuranose and its alpha-anomer. Protected N(3)-beta-D-ribofuranosides were prepared as sole products in high yields at room temperature. A mixture of benzoylated N(1)-beta- and alpha-anomeric ribonucleosides was obtained at lower temperatures. Yields of beta-anomers and stereoselectivities (beta:alpha=2.2/4.5:1) of the condensation reactions depended on reaction conditions and the structure of the glycosylating agent. Debenzoylation of 6-fluorothymine N(1)- or N(3)-beta-D-ribofuranosides and their 3'-fluorodeoxy analogues by LiOH monohydrate in MeCN/H2O resulted in the corresponding fluorinated nucleosides in good yields, whereas the deprotection of N(1)-alpha-ribofuranosides under the same conditions unexpectedly yielded 6,2'-O-alpha-D-anhydronucleosides. 6-Substituted (OMe, NH2) thymine beta-ribonucleosides were prepared by the treatment of protected N(1)-beta-D-ribosides with nucleophilic agents. (C) 2016 Elsevier Ltd. All rights reserved.