Fluoroacetate sources

Despite these great discoveries, for a long time fluorine chemistry remained more oriented toward the field of materials than toward medicinal chemistry. This can be explained by the fact that a traditional source of inspiration often comes from nature, and organofluorine compounds are almost absent as natural products. Moreover, the only one known at that time was fluoroacetic acid, a potent poison. 

Few of these have been found so far, the first not until 1944, in a poisonous South African plant, Gifblaar . The toxic principle of this was identified44 as fluoroacetic acid. A recent summary45 indicates that some 10 fluorinated natural products have now been isolated (in small amounts) largely from other plant sources, their formation being rationalized from the metabolism of fluoroacetate. The exception is nucleocidin (1), an antibiotic from a microbial source (Streptomyces calvus), originating in an Indian soil sample, and which has a ribose moiety carrying fluorine at C4. 

Fluoroacetic acid has been identifled as the toxic component of the South African plant gijblaar (Dichapetalum cymosum) [34]. Its mechanism of action is based on inhibition of the citric acid cycle, the main source of metabolic energy in all animals [35]. In this cyde, fluoroacetate can replace acetate as a substrate of aconi-tase, an enzyme complex which usually forms dtrate by addition of acetate to a-oxoglutarate. The resulting fluorocitrate is binds tightly to the enzyme, but cannot be further converted to ds-aconitate and isocitrate [36], thus inhibiting aconitase. 

Another possible substrate for citrate synthase is /luoroacetyl-CoA. The source of the fluoroacetyl-CoA is fluoroacetate, which is found in the leaves of various types of poisonous plants, including locoweeds. Animals that ingest these plants form fluoroacetyl-CoA, which, in turn, is converted to fluorocitrate by their citrate synthase. Fluorocitrate, in turn, is a potent inhibitor of aconitase, the enzyme that catalyzes the next reaction of the citric acid cycle. These plants are poisonous because they produce a potent inhibitor of life processes. 

The original Pfittner-Moffatt procedure for alcohol oxidation by activated dimethyl sulfoxide utilized dicyclohexylcarbodiimide (DCC) and a source of protons such as polyphosphoric acid or pyridinium tri-fluoroacetate. The use of strong acids such as the common mineral acids must be avoided since, although acidic conditions are initially required, the reaction must readily become basic in the later stages of the process. Mechanistically it is reasonable to suggest that the activation follows the pattern whereby initial attack of the nucleophilic sulfinyl oxygen of dimethyl sulfoxide, with the protonated carbodiimide, forms a sulfonium isourea. This is followed by displacement of dicyclohexylurea by the alcohol to form an alkoxysulfonium salt. Base treatment of this salt forms an ylide, which collapses via the proven cyclic mechanism to the carbonyl compound and dimethyl sulfide (Scheme 4). 

B. I Sources. Fluoroacetate is used to control rodents and predators. Because of its extreme toxicity to a variety of domestic animals and wildlife, it is available only to licensed extern minators for limit applications. 

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