Fluorinated compounds 4-fluorothreonine

Trifluorothreonine is one of the rare fluorinated compounds found in nature (cf. Chapter 4). The best method for the synthesis of fluorothreonines is the acylation of an equivalent of glycinate anion by a fluoroacetic derivative. The four stereoisomers of monofluorothreonine have been prepared. A completely stereoselective chiral approach involves the alkylation of the Seebach imidazolidinone by fluoroacetyl chloride (Figure 5.16). ... 

Fluorothreonine. In 1986 a second Streptomyces species capable of the biosynthesis of fluorinated compounds was identified (24). In the course of studies with Streptomyces cattleya to improve the yield of the 6-lactam antibiotic, thienamycin, it was discovered that when fluoride was present in tiie culture medium both fluoroacetate 1 and 4-fluorothreonine 6 accumulated in millimolar concentrations during fermentation. 4-fluorothreonine is the only naturally ocurring fluorinated amino acid known. When 4-fluorothreonine was initially isolated (24) the absolute stereochemistry of 4-fluorothreonine was predicted to be analogous to L-threonine. We have recently confirmed this by asymmetric synthesis (25) and demonstrated that natural 4-fluorothreonine has the (25, 3S) configuration. The... 

So far only a few dozen organofluorine compounds have been isolated from living organisms, for example fluoroacetic acid, 4-fluorothreonine and rw-fluoro-oleic acid [244-246], The reason that nature has not invested in fluorine chemistry could be a combination of low availability of water-dissolved fluoride in the environment due to its tendency to form insoluble fluoride salts, and the low reactivity of water-solvated fluoride ion. However, in 2002, O Hagan and collaborators [247] published the discovery of a biochemical fluorination reaction in a bacterial protein extract from Streptomyces cattleya converting S-adenosyl-L-methionine (SAM) to 5 -fluoro-5 deoxyadenosine (5 -FDA). The same protein extract contained also the necessary enzymatic activity to convert 5 -FDA into fluoroacetic acid. In 2004, the same authors published the crystal structure of the enzyme and demonstrated a nucleophilic mechanism of fluorination [248,249]. 

Organofluorines play an important role in medicinal chemistry, and estimates indicate that 20-30% of the pharmaceutical products on the market contain at least one fluorine atom [57, 58], However, natural organofluorine compounds are exceedingly rare, and the pharmaceutical industry has not yet benefited from a microbial source of such compounds. The soil bacterium Streptomyces cattleya was found to produce fluoro-acetate and 4-fluorothreonine, but the biological scope is limited to a single biological pathway that produces fluoroace-tate [58, 59], Identification of the fluorination enzyme FIA, responsible for C-F bond formation in S. cattleya, enabled the directed manipulation of biosynthetic pathways for the formation of fluorinated natural products. 

We have traced the metabolic pathways channelling metabolites towards the fluorometabolites in S. cattleya and an overview of these relationships is shown in Figure 13. We believe that the substrate for the fluorination process is either a C3 phosphorylated glycolytic intermediate such as dihydroxyacetone phosphate or glyceraldehyde-3-phosphate, or alternatively a C2 metabolite such glycoaldehyde phosphate, derived from these compounds. Fluoroacetaldehyde appears to be a strong candidate for the role of common intermediate to both fluoroacetate and 4-fluorothreonine. 

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