Phosphonates Fluorophosphonates

From (IV), chlorosulphonic acid (V) and benzene sulphonic acid (VI) are obtained by the replacement of H by Cl and C6H5 respectively Arguing along similar lines, (VIII) is phosphonic acid and (IX) is fluorophosphonic acid, hence (I) is diethyl chlorophosphonate. Th ... 

Phosphoric acid Phosphonic acid Fluorophosphonic acid... 

S.G. Withers, i.P. Street, M.D. Percivai, Fiuorinated carbohydrates as probes of enzyme specificity and mechanism, ACS Symposium Series 374 (1988) 59-77. W.G. Stirtan, S.G. Withers, Phosphonate and aipha-fluorophosphonate analogue probes of the ionization state of pyridoxai 5 -phosphate (PLP) in glycogen phosphor-ylase. Biochemistry 35 (1996) 15057-15064. 

Methods involving electrophilic fluorination have been used to prepare a number of fluorophosphonates. Examples include benzylic a,a-difluoromethyl-phosphonates, e.g. 157, by the reaction of the carbanion of 156 with N-fluorobenzenesulfonimide (NFBS) (Scheme 10), which is claimed to be superior to DAST, and (a,a-difluoroprop-2-ynyl)phosphonates 159 by the direct di-fluorination of the a-ketophosphonate 158 (Scheme ll). Compound 158 is prepared by Pfitzner-Moffatt oxidation of the corresponding alcohol and it is worth noting that few such oxidations of a-hydroxyalkylphosphonates have been reported. 

Figure 9 Serine hydrolases as targets of ABPP. (a) Catalytic mechanism of peptide substrate cleavage via the action of a catalytic triad, (b) Aryl phosphonate and fluorophosphonate probe scaffolds.

The recent interest in electrophilic fluorination of phosphonates reflects the importance of a-fluorophosphonates as isosteres of biologically important phosphates. However, the use of electrophilic fluorination methods is increasing with the availability of safe and easy to handle fluorine sources. Several reviews of the synthesis and applications of electrophilic fluorination reagents are now available. Here only the most important of these reagents and their use in the electrophilic fluorination of phosphonates are presented. 

Alkylation-Hydrolysis of a-Fluorophosphonate Carbanions. Our initial choice in the proposed scheme was the phosphonate analog, since we expected this carbanion to be more nucleophilic than die phosphonium analog and therefore more applicable to a variety of alkylating types. An initial concern in the reaction of (3)... 

In contrast to the straightforward facile acylation-hydrolysis reaction of the a-fluoro phosphonium ylide, the acylated product from the a-fluoro phosphonate carbanion is cleaved by base in two different ways. When R is a hydrocarbon group, such as CH3 or C5H5CH2, attack at the acyl carbon with bases, such as sodium bicarbonate, sodium carbonate, sodium hydroxide, and potassium silanoate is favored (Path II in equation 13) with resultant elimination of the a-fluorophosphonate anion. Less than 10% of the desired 2-fluoro-3-oxoester is observed. However, when R is a halofluoroalkyl group (CF3, CF2CI, C3F7), attack of the base (aqueous sodium bicarbonate) occurs only at phosphorus (Path I in equation 13) and the 2-fluoro-3-... 

Arguing along similar lines, (VIII) is phosphonic acid and (IX) is fluorophosphonic acid, hence (I) is diethyl chlorophosphonate. The... 

The fluorophosphonates GB and GD hydrolyze first through the loss of fluorine and second, more slowly, through the loss of the alkoxy group (Kingery and Allen 1995 MacNaughton and Brewer 1994). Under acidic conditions, the products of GB hydrolysis are isopropyl methylphosphonic acid and fluoride the former slowly hydrolyzes to methyl phosphonic acid with the loss of isopropanol (Fig. 5). According to Clark (1989), alkaline hydrolysis results in isopro-... 

Figure 2.3 Serine protease and hydrolase ABPs. (A) Reaction of a general serine hydrolase probe containing a fluorophosphonate (FP) reactive electrophile. This class of probes has been used extensively to label various classes of serine hydrolases including proteases, esterases, lipases and others. (B) The peptide diphenyl phosphonate (DPP) reacts with the serine nucleophile in the active site of serine proteases. This probe is much less reactive than the FP class of probes but is more selective towards serine proteases over other types of serine hydrolases.(C) The natural product epoxomicin contains a keto-epoxide that selectively reacts with the catalytic N-terminal threonine of the proteasome P-subunit. This reaction results in the formation of a stable six-membered ring. This class of electrophile has been used in probes of the proteasome.

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