Difluorophosphonic acid

Smyth, M. S., Ford, H. Jr., and Burke, T. R. Jr. (1992) A general method for the preparation of benzylic alpha, alpha-difluorophosphonic acids non-hydrolyzable mimetics of phosphotyrosine. Tetrahedron Lett. 33, 4137-4140. 

Since this discovery, several carba analogs of cyclic phosphatidic acid have been developed. In 2006, Prestwich and coworkers replaced the phosphate ring by cychc mono- and difluorophosphonic acids 3a and 3b... 

Considering the acidity, the monofluorophosphonate is the closest compound to the parent phosphate (Fig. 19). The better results in inhibition obtained with monofluorophosphonates with regard to difluorophosphonates can thus be explained (Fig. 19). Conversely, concerning bond angles, a difluorophosphonate... 

Starting from Halogenodifluoroacetic Acids Ethyl chloro-, bromo-, and iododifluoroacetates, as well as the corresponding difluorophosphonates, are powerful reagents for difluoromethylenation through radical, anionic, and elec-trophihc pathways. 

Bis(difluorophosphonates), mimics of 1,3-diphosphoglycerate, have been suggested as PGK inhibitors. Some of these compounds have millimolar Ki values. The presence of a polar function at the molecule center is indispensable. On the other hand, studies on the dissociation constants of the enzyme complexes with dipho-sphonates have shown that the relative values of pKa of both phosphonic acids are important for the affinity. This explains the interest in the incorporation of fluorine (Figure 7.13). ... 

The CHF and CF2 groups are superior to CH2 as isosteres of oxygen and this has led to extensive interest in their chemistry. The a-difluorophosphonate analogues of the phosphates of L-serine (219), L-threonine (220), and L-allothreonine (221) have been prepared by highly enantioselective reactions of difluoromethylpho-sphonate carbanion with chiral esters. Lipase PS catalysed acetylation of prochiral 1,3-propandiol alkylphosphonates 222 is reported to be highly enantioselective and the resulting monoacetate enantiomers 223 have been used to synthesise a series of (o-phosphono-a-amino acids, 224 and 225.Other routes to 225, one of... 

Kawamoto, A.M., and Campbell, M.M., A new method for the synthesis of a phosphonic acid analogue of phosphoserine via a novel 1,1-difluorophosphonate intermediate, J. Fluorine Chem.. 81, 181, 1997. Burton, D.J., Naae. D.G., Flynn, R.M., Smart, B.E., and Brittelli, D.R.. Phosphine- and phosphite-mediated difluorocarbene exchange reactions of (bromodifluoromethyl)phosphonium salts. Evidence for facile dissociation of (difluoromethylene)triphenylphosphorane. J. Org. Chem.. 48. 3616, 1983. Li, A.-R., and Chen. Q.-Y., Diethyl iododifluoromethylphosphonate. A new synthetic method and its reaction with alkynes. Synthesis, 606, 1996. 

Halogenoalkyl and Related Acids. In view of their extensive applications as, for example, phosphate mimics, new routes to a-mono- and -di-fluoroalkylphos-phonates are always welcome and during the period of this review a substantial number have been reported. A variety of functionalised examples of such compounds have been prepared from the readily available difluorophosphonate (188). ° For example, the monofluoro analogue (191) of serine phosphate has been synthesised by the reaction of (188) with organocopper reagents to give (190) followed by reduction and further functionalisation (Scheme 28). The... 

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