First and efficient synthesis of phosphonodifluoromethylene analogues of nucleoside 3'-phosphates: crucial role played by sulfur in construction of the target molecules.
Phosphoric esters of secondary alcohols are ubiquitous in biological systems. However, despite the obvious interest of the corresponding difluoromethylene phosphonates as isopolar mimics, a single example of such an analogue featuring this particular substitution pattern has so far been reported in the literature, due to synthetic problems associated with their preparation. The lithium salt of diethyl difluoromethylphosphonothioate 28d provides a solution to this problem, as demonstrated by an 8-step synthesis of all five fully protected analogues of nucleoside 3'-phosphates in 9-18% overall yield, from readily available ketones. Sulfur is shown to play a crucial role in the introduction of the phosphorus-substituted difluoromethylene unit onto the furanose ring. Complete diastereoselectivity is observed in the three steps of the process requiring stereocontrol. The key conversion of the P=S bond into its oxygenated analogue is simply achieved by use of m-chloroperoxybenzoic acid. It is noteworthy that the synthesis can be carried out on large scale: a 31-g batch of compound 26b has been prepared. The deprotected nucleoside 3'-phosphate analogues can be liberated from their precursors as exemplified by the conversion of 7b, 8b, and 9b into the corresponding difluorophosphonic acids, isolated in the form of their disodium salts.
Lopin
Chrystel
C
Laboratoire des Fonctions Azotées et Oxygénées Complexes, UMR CNRS 6014, IRCOF-Université de Rouen, Rue Tesnières, F-76821 Mont Saint Aignan, France.
Gautier
Arnaud
A
Gouhier
Géraldine
G
Piettre
Serge R
SR
D006845:Hydrocarbons, Fluorinated / Q000737:chemistry; D009711:Nucleotides / Q000138:chemical synthesis* / Q000737:chemistry; D010755:Organophosphates / Q000138:chemical synthesis* / Q000737:chemistry; D013455:Sulfur / Q000737:chemistry*
D006845:Hydrocarbons, Fluorinated; D009711:Nucleotides; D010755:Organophosphates; D013455:Sulfur