Synthesis and Structure of Dinucleotides with S‐Type Sugar Puckering and Noncanonical ϵ and ζ Torsion Angle Combination (ν₂,ϵ,ζ‐D‐CNA)

Abstract

The synthesis of the diastereoisomers of ν2,ϵ,ζ‐D‐CNA dinucleotide building units of nucleic acids and their (2′,5′)‐ν2,ϵ′,ζ′‐D‐CNA analogues, in which the ϵ and ζ torsional angles are stereocontrolled by a dioxaphosphorinane ring structure (D‐CNA family) is described from a common 3‐deoxy‐3‐(hydroxymethyl)‐D‐allofuranose intermediate. NMR spectroscopic and circular dichroism structure analysis of ν2,ϵ,ζ‐D‐CNA shows that the sugar puckering is fixed in the C‐2′‐endo conformation and that these D‐CNA structuralelements allow stabilization of the ϵ/ζ torsion angle combinations, which are significantly different from the typical combinations observed in canonical A‐ or B‐form duplexes. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

The Medicinal Chemistry of Therapeutic Oligonucleotides

“…222 The α,β-D-CNA analogue (S configuration at C5′, Figure 17), in which α is constrained in the +sc range (as opposed to −sc in canonical Bform duplexes), was used to stabilize ssDNA hairpin structures because of its ability to induce a bend in the sugar−phosphate backbone. 223 In addition, α,β-D-CNA was also used as a chain terminator for proof reading DNA polymerases. 224 Synthesis of constrained nucleic acid analogues which restrict torsion angles α, β, and γ (α,β,γ−D-CNA) or δ, ε, and ξ (δ,ε,ξ-D-CNA) by tethering a C4′-hydroxymethyl substituent to the nonbridging oxygen in the phosphodiester backbone has also been reported.…”

“…Incorporation of the epimeric α,β-CNA analogues into the gap region of RNaseH ASOs targeting SNPs linked to the CAG expansion in mutant huntingtin transcripts, showed differential ability to modulate allele selective silencing . The α,β-D-CNA analogue ( S configuration at C5′, Figure ), in which α is constrained in the +sc range (as opposed to –sc in canonical B-form duplexes), was used to stabilize ssDNA hairpin structures because of its ability to induce a bend in the sugar–phosphate backbone . In addition, α,β-D-CNA was also used as a chain terminator for proof reading DNA polymerases …”

Convertible and Constrained Nucleotides: The 2’-Deoxyribose 5’-C-Functionalization Approach, a French Touch

“…For the purpose of expanding the set of covalently constrained nucleic acids (CNA) with specific canonical or non-canonical backbone conformations, we have extended the approach proposed for α,β- D -CNA to the control of five other sets of torsional angles [ 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 ]. Firstly, we connected the phosphate, either to the 4′-C carbon of the lower sugar moiety to generate α,β- D -CNA, or to the upper sugar to obtain δ,ε,ζ- D -CNA.…”

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

“…The synthesis of ν 2 , ε , ζ -D-CNA implied the connection of the phosphate to the 2′- C -carbon of the sugar moiety through a methylene link [49]. To achieve this goal, instead of starting from a nucleoside precursor, we choose to reproduce a protocol previously described by Marquez and Coll.…”