Synthesis of Triazole-linked LNA-based Non-ionic Nucleoside Dimers Using Cu(I)-Catalyzed 'Click' Reaction

Three benzylated triazole-linked nonionic locked nucleoside dimers T-L-t-T-L, T-L-t-A(BzL) and T-L-t-C-BzL have been synthesized by Cu(I) catalyzed Huisgen-Sharpless-Meldal [3+2] cycloaddition reaction of 3'-azido-3'-deoxy-2'-O,4'-C-methylenethymidine with 3'-O-benzyl-5'-deoxy-5'-C-ethynyl-2'-O,4'-C-methylenethymidine, 3'-O-benzyl-5'-deoxy-5'-C-ethynyl-2'-O,4'-C-methylene-6-N-benzoyladenosine and 3'-O-benzyl-5'-deoxy-5'-C-ethynyl-2'-O,4'-C-methylene-4-N-benzoylcytidine, which on debenzylation afforded the corresponding hydroxy analogs T-L-t-T-L and T-L-t-A(BzL) in 69% and 63% overall yields. An effort to debenzylate T-L-t-C-BzL failed. Hydroxy T-L-t-T-L, T-L-t-A(BzL) have alternatively been synthesized by the reaction of azidonucleoside with 5'-deoxy-5'-C-ethynyl-2'-O,4'-C-methylenethymidine and 5'-deoxy-5'-C-ethynyl-2'-O,4'-C-methylene-6-N-benzoyladenosine in 79% and 76% overall yields, respectively. Among the two Cu(I) reagents used for cycloaddition (click) reaction, CuSO4 center dot 5H(2)O-sodium ascorbate in THF:(BuOH)-Bu-t:H2O (1:1:1) was found to be better yielding than CuBr center dot SMe2 in THF.