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

Abstract

A simple, two-step procedure to convert α,αdifluorinated H-phosphinic acids into the corresponding Hphosphinothioates is described. The usefulness of these species is demonstrated by their transformation into difluorinated phosphinothioyl radicals and their addition onto alkenes. Additionally, sequential treatment of Hphosphinothioates by a strong base and a primary alkyl iodide constitutes an alternate route to the formation of the C−P bond. Both methods efficiently deliver difluorinated phosphinothioates. Similar reactions carried out with the fully oxygenated counterparts clearly indicate the superiority of the sulfur-based species and emphasize the crucial role played by sulfur in the construction of the second C−P bond. Oxidation easily transforms the thereby obtained phosphinothioates into the corresponding phosphinates. The whole strategy is applied to the stereoselective preparation of dinucleotide analogues featuring either a difluorophosphinothioyl or a difluorophosphinyl unit linking the two furanosyl rings.

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

“…TEBAC: benzyltriethylammonium Chloride; BSA: bis(trimethylsilyl)amide. [8] Scheme 2. Controlled introduction of one or two thymine(s) onto bisfuranosylphosphinothioate 15. i: 15 (1 equiv); Thymine (6.6 equiv); BSA (12.9 equiv); TMSOTf (3.4 equiv); MeCN, 80 °C, 25 h. ii: 15 (1 equiv); Thymine (2.9 equiv); BSA (5.7 equiv); TMSOTf (1.6 equiv); MeCN, 40 °C, 17 h, then 60 °C, 4 h. iii: 16 a (1 equiv); Thymine (2.9 equiv); BSA (5.7 equiv); TMSOTf (1.6 equiv); MeCN, 80 °C, 5 h. under the Vorbrüggen conditions would deliver any of the sixteen possible homo-and heterodinucleotides.…”

“…), TEBAC, CH 2 Cl 2 , 40 °C) generated the desired C−P bond and product 20 a was isolated in 47 % yield (Scheme 8). [8] The analogous iodonucleoside 31 bearing a PMB protecting group on the nucleobase furnished product 20 e (69 % isolated yield) under similar conditions. This yield increase may indicate a competition between the acidic hydrogens present in 9 and 19 a .…”

“…[7] Our own work aiming at the preparation of new isosters of phosphoric acid diesters 1 led us to introduce difluorinated Hphosphinates 2 and H-phosphinothioates 3, and to develop their use as synthetic tools to prepare the corresponding fluorinated phosphinates 4 and phosphinothioates 5. [8] Indeed the presence of two PÀ C bonds makes these functional groups essentially inert towards the action of nucleases. [9] In addition and by analogy to the corresponding phosphonic acids 6, the presence of the two fluorine atoms is expected to increase both the structural and electronic similarities with the parent phosphoric acid diesters 1 (Figure 1).…”

“…The residue was purified by column chromatography on silica and elution with CH 2 Cl 2 /MeOH (120/1 to100/1) to give compound 16 a (21.0 mg, 58 %) as a colorless solid. 8 A solution of thymine (11 mg, 84.6 μmol, 3 equiv.) and N,O-bis(trimethylsilyl)acetamide (45 μL, 183.3 μmol, 6.5 equiv.)…”

“… Previous work: first preparation of fully protected dinucleotide analogues featuring either a difluorophosphinothioate ( 13 a ) or difluorophosphinate unit ( 14 a ). TEBAC: benzyltriethylammonium Chloride; BSA: bis(trimethylsilyl)amide [8] …”