Synthesis of Ribonucleosidic Dimers with an Amide Linkage from d-Xylose

Abstract

An original and efficient stereocontrolled synthesis of ribonucleosidic homo- and heterodimers has been achieved from inexpensive d-xylose. This successful strategy involved the sequential introduction of nucleobases, using two stereocontrolled N-glycosidation reactions, from a common two-furanoside amide-linked scaffold offering the possibility of obtaining any given base sequence. The pertinence of this approach is illustrated through the preparation of the homodimers UU-34 and TT-35 in 18 steps with an excellent overall yield of more than 10% from d-xylose, while the heterodimer route led to UT-39 in 19 steps with around 10% overall yield.

An LNA-amide modification that enhances the cell uptake and activity of phosphorothioate exon-skipping oligonucleotides

“…This stereoselectivity was predicted because the 1,2- O -isopropylidene groups on the α-face of furanosyl carbohydrate derivatives direct incoming H 2 to the β-face 44 . Key intermediate 5 was then converted to the 1,2-di- O -acetate glycosyl donor 6 following a procedure reported by Arzel et al 45 , avoiding the formation of a lactone which occurred when the acetonide was cleaved in the presence of water.

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Second Generation Synthesis of Modified Dinucleotide Analogues Featuring a Difluorophosphin(othio)yl Linkage

“…However, reports of application of the same process on dinucleotides have been scarce. In a recent paper published during the course of this work, a substrate featuring a single nucleobase (T) and an amide linking the two furanosyl units was reported as cleanly reacting at room temperature with uracil under the Vorbrüggen conditions to deliver the desired heterodinucleotide (T−U) in good yield [21] . Expectedly, attempts to perform the same experiment with substrate 16 a under strictly identical conditions (uracil, rt, 24 h) was unsuccessful, and unconsumed 16 a was recovered.…”

“…In a recent paper published during the course of this work, a substrate featuring a single nucleobase (T) and an amide linking the two furanosyl units was reported as cleanly reacting at room temperature with uracil under the Vorbrüggen conditions to deliver the desired heterodinucleotide (TÀ U) in good yield. [21] Expectedly, attempts to perform the same experiment with substrate 16 a under strictly identical conditions (uracil, rt, 24 h) was unsuccessful, and unconsumed 16 a was recovered. This lack of reactivity may be due to the higher stabilization of the intermediate oxonium ion, the result of the documented anchimeric assistance of the phosphonothioyl unit.…”

From Oxygen to Sulfur and Back: Difluoro-H-phosphinothioates as a Turning Point in the Preparation of Difluorinated Phosphinates: Application to the Synthesis of Modified Dinucleotides

“…To a solution of oxalyl chloride (0.38 mL, 4.49 mmol) in dry CH 2 Cl 2 (8 mL) was added a solution of DMSO (0.33 mL, 4.65 mmol) in CH 2 Cl 2 (1 mL) at −78 °C under inert atmosphere. After 10 min stirring at −78 °C, a solution of the requisite alcohol 28 (1.04 g, 3.71 mmol) in CH 2 Cl 2 (6 mL) was added, and the reaction mixture was kept under stirring at −78 °C for 15 min. Then, DIPEA (3.0 mL, 18.15 mmol) was added dropwise to the reaction and stirring was continued at −78 °C for additional 30 min.…”