Analogues of nucleotides and oligonucleotides featuring difluorophosphonate, difluorophosphonothioate and difluorophosphinate functional groups

Efforts to stereoselectively install difluorophosphonyl, difluorophosphonothioyl and difluorophosphinyl groups in place of the phosphate linking positions 3′ and 5′ of two furanoses are reviewed. Two equally efficient approaches have been worked out based on either the ionic addition of difluorophosphonothioate reagents 17 or 33 onto a ketone, or on the addition of phosphorus-centered radicals onto gem-difluoroalkenes. These methodologies resulted in the successful preparation of 3′-phosphonodifluoromethyl analogues to nucleosides-3′-phosphates, and of key intermediate 83, featuring two ribofuranosyl nuclei linked by a difluorinated phosphonothioyl unit on positions 3′ and 5′. In addition, the groundwork for the synthesis of H-difluorophosphinates and difluorophosphinates has been laid.