Diastereoselective Synthesis of Conformationally Restricted Dinucleotides Featuring Canonical and Noncanonical α/β Torsion Angle Combinations(α,β‐D‐CNA)

Abstract

The synthesis of the four possible diastereoisomers of α,β‐D‐CNA 5′‐XT (X = A, T, G and C) building units of nucleic acids, in which the α and β torsional angles are stereocontrolled by a dioxaphosphorinane ring structure (D‐CNA family) is described. The crystal structure analysis of the (RC5′,SP)‐configured α,β‐D‐CNA TT dimer demonstrates that the α and β torsional angles are restricted to the canonical {gauche(–),trans} conformation typically observed in DNA duplexes. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Synthesis and Structure of an α,β‐D‐CNA Featuring a Noncanonical α/β Torsion Angle Combination within a Tetranucleotide

“…Whereas an X-ray crystal structure determination was available for the (R C5Ј ,S P ) α,β-D-CNA TT featuring a canonical value of the torsional angles, [12] the relative spatial arrangement of the three cycles of the (S C5Ј ,R P ) α,β-D-CNA was determined by means of NMR spectroscopy and circular dichroism to gain better insight of the relation between the α,β-D-CNA structure and the single stranded oligonucleotide conformation in which it could be introduced.…”

“…The determination of the impact that a neutral phosphotriester linkage would display in the conformational north/south equilibrium is particularly important as it is well recognized that this conformational state is of major importance for the DNA structure formation ability. Like that of the dioxaphosphorinane (R C5Ј ,S P ) isomer, [12] the chair conformation is clearly established from the 1 H and 1 H-{ 31 P} NMR spectra, with no detectable coupling constant between the 5Јb-H involved in the dioxaphosphorinane system and phosphorus ( 3 J 5Јb-H/P Ͻ 1 Hz), which is characteristic of an axial position of this proton.…”

“…We reasoned that the resulting constrained nucleic acids (termed D-CNAs) could locally adopt either a helical or nonhelical conformation depending on the spatial arrangement of the dioxaphosphorinane system and which backbone bonds are included in its ring structure. [12,13] As a first result in this field, we already reported the synthesis of a covalently constrained (S C5Ј ,R P ) α,β-D-CNA TT building unit in which α and β torsions are locked in a noncanonical [gauche(+), trans] conformation that frequently occurs in protein-DNA complexes and in bulged or loop regions of nucleic acids. [14] This approach was usefully applied to prepare α,β-D-CNA with exceptional binding properties [15] and dinucleotide units with α,β,γ and δ,ε,ζ featuring noncanonical values (α,β,γ-D-CNA and δ,ε,ζ-D-CNA).…”

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

“…We previously reported the synthesis of α,β-D-CNA (dioxaphosphorinane-constrained nucleic acid) featuring canonical or noncanonical values of the α and β torsional angles, [16,17] and subsequently, on their properties within Figure 1. Left: the six backbone torsion angles (labeled α a to ζ a for the upper nucleotide and α b to ζ b for the lower nucleotide) of nucleic acids; middle: ν 2 ,ε,ζ-D-CNA dinucleotide, in which ν 2a , ε a , and ζ a are stereocontrolled to canonical or noncanonical values by a dioxaphosphorinane ring structure exhibiting two new asymmetric centers; right: (2Ј,5Ј)-ν 2 ,εЈ,ζЈ-D-CNA dinucleotide, in which ν 2a , εЈ, and ζЈ are stereocontrolled by a dioxaphosphorinane ring structure exhibiting an asymmetric phosphorus center.…”

Synthesis of Phostone‐Constrained Nucleic Acid (P‐CNA) Dinucleotides Through Intramolecular Arbuzov's Reaction

“…[5] Our general strategy is based on the introduction of the 1,3,2-dioxaphosphorinane ring structure at key positions along the phosphate backbone. We have already reported on the diastereoselective synthesis of a dioxaphosphorinane-CNA (D-CNA) dinucleotide building unit in which the α and β torsion angles are locked in a (g + ,t) conformation (Scheme 1).…”