| Abstract
| - Phosphoric esters of secondary alcohols are ubiquitous in biological systems. However, despitethe obvious interest of the corresponding difluoromethylene phosphonates as isopolar mimics, a singleexample of such an analogue featuring this particular substitution pattern has so far been reported in theliterature, due to synthetic problems associated with their preparation. The lithium salt of diethyldifluoromethylphosphonothioate 28d provides a solution to this problem, as demonstrated by an 8-stepsynthesis of all five fully protected analogues of nucleoside 3‘-phosphates in 9−18% overall yield, fromreadily 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 thethree steps of the process requiring stereocontrol. The key conversion of the PS bond into its oxygenatedanalogue is simply achieved by use of m-chloroperoxybenzoic acid. It is noteworthy that the synthesis canbe carried out on large scale: a 31-g batch of compound 26b has been prepared. The deprotectednucleoside 3‘-phosphate analogues can be liberated from their precursors as exemplified by the conversionof 7b, 8b, and 9b into the corresponding difluorophosphonic acids, isolated in the form of their disodiumsalts.
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