A -Fluorophosphonates

Reaction of a fluorophosphonate with an aldehyde that provides F-a-fluoro-a, jS-esters. 

The a-fluorophosphonate moiety has previously been introduced utilizing thermally unstable organolithium reagents166,167 and fluorinating agents such as DAST168. (EtO)2P(0)CFHZnBr is thermally stable, scalable and avoids the use of expensive and hazardous fluorination reagents. 

Many gene products are uncharacterized enzymes that lack a specific class assignment. As discussed in Sect. 2.3, ABPP probes can be used to identify structurally disparate members of enzyme families based on their reactivity with mechanism-based inhibitors. To date, many uncharacterized enzymes have been classified upon their identification via ABPP. For example, the use of a fluorophosphonate probe by Jessani et al. led to the characterization of sialyl acetylesterase - expressed... 

Fluoro-2, 3 -unsaturated L-nucleosides have been prepared by condensing the reagent with a fluorophosphonate ester. The resulting vinyl fluoride was then transformed into the 2-fluorobute-nolide, from which a variety of L-nucleosides could be prepared (eq 6). ... 

Analogously, ethyl 4-fluoro-3-methylcrotonate is brominated with NBS in the presence of AIBN and then reacted with triethyl phosphite to produce good yields (72-78%) of a-fluorophosphonate, a key intermediate in the synthesis of fluorinated vitamin A esters (Scheme 3.3)7 Following a similar procedure (radical bromination and Michaelis-Arbuzov rearrangement), ( )-l-fluoro-3-(l-trityl-l,2,4-triazol-3-yl)-2-propenylphosphonate, a good inhibitor of imidazoleglycerol phosphate dehydratase, has been prepared in 25% overall yield. ... 

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. 

The fluorinated diastereomers are separated by silica gel chromatography. Removal of the ephedrine auxiliary by TMSBr and TFA provides a racemization-free procedure for liberating the desired a-fluorophosphonic acids. ... 

Stirtan, W.G.. and Withers, S.G., Phosphonate and a-fluorophosphonate analogue of the ionization state of pyridoxal 5 -phosphate (PLP) in glycogen phosphorylase. Biochemistry, 35, 15057, 1996. 

Esters with one or two fluorines at the a-carbon are useful building blocks for construction of interesting and novel biologically active substrates. Alkylation of a-fluorocarboethoxy phosphonium ylides followed by hydrolysis of the resultant phosphonium salt with 5% aqueous sodium bicarbonate provides a useful preparative route to a-fluoroesters. Similarly, acylation/hydrolysis of either a-fluoro phosphonium ylides or a-fluorophosphonate anions gives a general route to 2-fluoro-3-oxo-esters. The a,a-difluoroesters can be prepared by Cu° catalyzed addition of iododifluoroacetates to olefins followed by reduction of the iodo addition adduct. Both terminal and internal olefins participate equally well in the addition reaction. 

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)... 

As noted earlier in the alkylation study of a-fluoro phosphorus ylides, hydrolysis of the resultant a-fluoro phosphonium salts and a-fluorophosphonates do not necessarily parallel each other. This difference is again exhibited in the hydrolysis of the acylated products of the a-fluoro ylides. For example, the acylation product (10) is readily hydrolyzed at room temperature to give the desired a-fluoro-p-ketoester. The results of the acylation-hydrolysis of (4) with a variety of alkyl, cycloalkyl and aryl acyl halides are summarized in Table HI. 

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-... 

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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