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

Scheme 5

Synthesis of 𝜈₂,ε,ζ-Dioxaphosphorinane-Constrained Nucleic Acid dinucleotides (𝜈₂,ε,ζ-D-CNA). Reagents and conditions: (i) PDC, Ac₂O, DCM, 80°C, 87%; (ii) nBuLi, Ph₃PMeBr, THF, 83%; (iii) BH₃Me₂S, THF, 0°C then H₂O₂ 25%, NaOH 2 N, H₂O/THF (1/1), 81%; (iv) BzCl, pyr, DMAP, rt, 61%; (v) HCl 0.06 N, MeOH, 55°C, 2 h, 81%; (vi) BzCl, pyr, 0°C, 2 h, 54%; (vii) AcOH 80%, 80°C, 46%; (viii) KIO₄, EtOH/H₂O (1/1), rt, 18 h, 90%; (ix) Ac₂O, pyr, 94%; (x) TMSOTf 0.55 M in toluene, bis(trimethylsilyl)thymine, acetonitrile reflux, 56%; (xi) NH₄OH 28%, rt, quant; (xii) 3′-O-t-butyldiphenylsilylthymidine-5′-O-phosphoramidite, 1H-tetrazole, acetonitrile, then collidine, I₂/H₂O, 75%; (xiii) K₂CO₃, MeOH/H₂O (4/1), rt, 6 h, 45%; (xiv) 1-(mesitylene-2-sulfonyl)-3-nitro-1,2,4-triazole (MSNT), pyr, rt, 60–75%.