Fluorophosphonates, synthesis

The power of the pooled GST fusion protein approach will increase as new biochemical reagents and assays become available. The development of chemical probes for biological processes, termed chemical biology, is a rapidly advancing field. For example, the chemical synthesis of an active site directed probe for identification of members of the serine hydrolase enzyme family has recently been described (Liu et al., 1999). The activity of the probe is based on the potent and irreversible inhibition of serine hydrolases by fluorophosphate (FP) derivatives such as diisopropyl fluorophosphate. The probe consists of a biotinylated long-chain fluorophosphonate, called FP-biotin (Liu et al., 1999). The FP-biotin was tested on crude tissue extracts from various organs of the rat. These experiments showed that the reagent can react with numerous serine hydrolases in crude extracts and can detect enzymes at subnanomolar... 

Insects are very sensitive to fluorophosphonates, so that the compound parathion was synthesised and used as an insecticide soon after the Second World War. However, it entered the food chain and eventually found its way into mammals and caused death. An important breakthrough occurred with the synthesis of malathion, an insecticide which has high toxicity to insects, where it is converted to malaoxon, a potent acetylcholinesterase inhibitor. However, malathion is much less toxic to mammals, since it is readily detoxified (Appendix 3.8). 

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. 

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