Dioxaphosphorinane-Constrained Nucleic Acid Dinucleotides as Tools for Structural Tuning of Nucleic Acids

Scheme 1

Synthesis of α,β-Dioxaphosphorinane-Constrained Nucleic Acid dinucleotides (α,β-D-CNA). Reagents and conditions: (i) TBDMSiCl, pyr, 95%; (ii) TBDPSiCl, imid, DMF, 97%; (iii) PTSA, MeOH, 95%; (iv) DCC, Cl₂HCCOOH, DMSO then oxalic acid, 90%; (v) cat BiCl₃, ZnI₂, methyl acetate silylketene, DCM, 90%; (vi) NaBH₄, EtOH, 85%; (vii) TsCl, CHCl₃, pyr, 90; (viii) 5′-O-DMT-3′-O-diisopropylamino-cyanoethoxyphosphite thymidine, 1H-tetrazole, acetonitrile, then I₂/H₂O, 89%; (ix) Et₃N, DMF, 90°C, 95%; (x) 3% TFA/DCM, 95%; (xi) TBAF, THF, 90%; (xii) (a) ω-t-butyldimethyl-silyloxy-allyltrimethylsilane, Et₂O:BF₃, DCM, (b) TiCl₄, DCM, 60%; (xiii) (a) OsO₄ cat, N-methylmorpholine N-oxide, H₂O, (b) NaIO₄, MeOH, (c) NaBH₄, EtOH. 64%.