First and Efficient Synthesis of Phosphonodifluoromethylene Analogues of Nucleoside 3‘-Phosphates:  Crucial Role Played by Sulfur in Construction of the Target Molecules

Abstract

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.

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

“…Thus, sequentially treating 40a-c with 6 Eq. of trimethylsilylbromide at 80 8C for 1 h, and water delivered phosphonic acid 41a-c, which were converted to the final nucleotide analogues 42 by the action of ammonia in methanol; the target molecules were conveniently isolated as sodium salts by standard purification with Dowex 50X-2 resin [27][28][29].…”

“…However, all attempts to react this substrate with phosphonyl or phosphonothioyl radicals failed to deliver the expected adducts 25 or 52, respectively, the starting material being recovered in each case (Scheme 12) [27].…”

Synthesis of α-brominated phosphonates and their application as phosphate bioisosteres

“…98 Carbocyclic dinucleoside polyphosphonates have shown activity against HIV reverse transcriptase-catalyzed DNA synthesis and hence demonstrate antiviral activity. 59, 101 60, 102 61, 103 62,104 and 63, 105 Fig. 99 It is important to note here that synthetic access to biologically interesting cyclic and acyclic a-uorophosphonate and a,a-diuorophosphonate nucleoside(-tide) analogs has been well studied and reviewed (e.g.…”

Medicinal Chemistry of Fluorinated Cyclic and Acyclic Nucleoside Phosphonates

“…A synthesis of 3′‐deoxyribofuranose nucleoside analogues 31–33 (Fig. ) bearing the α,α ‐(difluoromethylene)phosphonate group at the position 3 of the tetrahydrofurane ring was developed with an attempt to prepare new potential antivirals, but no data were published . Later, a synthesis of the compound 34 (Fig.…”