Fluorinated analogues

Metahation of 2-fluoropyridine with lithium diisopropylamide (LDA) gives 2-fluoro-3-hthiopyridine, thereby providing entry to 3-substituted pyridines (388). This technique has been used to make fluorine analogues of the antitumor eUipticines (389). 

A fluorinated analogue, CFCI2SCI, is made in Europe from trichloromethanesulfenyl chloride and is used for production of the fungicides dichlorofluanid [1085-98-9] (3) and tolylfluanid [731-27-1] (4) (69) ... 

The fluorine analogue of chlorosulfuric acid, fluorosulfuric acid [7789-21-1], FSO H, is considerably more stable than chlorosulfuric acid because of the stronger fluorine-sulfur bond (see Fluorine compounds, inorganic-sulfur, fluorosulfuric acid). Bromosulfiiric acid [25275-22-3], BrSO H, decomposes in air at —30°C, and the iodine equivalent has not been synthesized (23). 

These zinc reagents are useful precursors for stereocontrolled palladium-catalyzed cross-coupling reactions, as illustrated in equations 73-80 [100, 101, 102, 103, 104, 105, 106, 107, 108] This methodology has been used to prepare new fluorinated analogues of codlemone [I09. ... 

Dinitrogen tetrafluoride, N2F4, is the fluorine analogue of hydrazine and exists in both the staggered (trans) C2h and gauche C2 conformations... 

Two closely related indoles fused to an additional saturated ring have been described as CNS agents. The first of these is obtained in straightforward manner by Fischer indole condensation of functionalized cyclohexanone 0 with phenyl hydrazine (19). The product, cyclindole (21) shows antidepressant activity. The fluorinated analogue flucindole (26) can be prepared by the same scheme. An alternate route starting from a somewhat more readily available intermediate involves as the first step Fischer condensation of substituted phenyl hydrazine with 4-hydroxycyclohexanone (23). The resulting alcohol (24) is then converted to its tosylate (25). Displacement by means of dimethyl amine leads to the antipsychotic agent flucindole (26). ... 

Cass AEG, DW Ribbons, JT Rossiter, SR Williams (1987) Biotransformation of aromatic compounds. Monitoring fluorinated analogues by NMR. FEBS Lett 220 353-357. 

Genther BRS, GT Townsend, PJ Chapman (1990) Effect of fluorinated analogues of phenol and hydroxyben-zoates on the anaerobic transformation of phenol to benzoate. Biodegradation 1 65-74. 

In contrast, hydrolysis of the methyl derivative, Cp(OC)2Fe-SiMe(H)Cl (Id), yields the corresponding ferrio-silanol, Cp(OC)2Fe-SiMe(H)OH, as a short-lived intermediate identified by means of IR and NMR spectroscopy, which immediately reacts with Id to give the bis(ferrio)disiloxane 6. Conversion of 6 to the fluorine analogue [Cp(0C)2Fe-Si(Me)F]20, characterized by a linear Si-O-Si arrangement [6], is achieved via consecutive H/Cl- and Cl/F-exchange. 

In view of the well-known pharmacological action of aspirin, it was thought that the fluorine analogue, O (fluoroacetyl) salicylic acid, might be of considerable interest. The compound was readily made by acylation of salicylic acid by fluoroacetyl chloride in the presence of pyridine. The l.d. 50 for subcutaneous injection into mice was approximately 15 mg./kg. After injection the mice went into a drugged sleep, and died overnight. 

In this connexion ethyl 2-cyanoethyl ether, EtO-[CH2]2-CN, was tested and found to be relatively non-toxic, showing that the toxicity of the fluorine analogue was caused ultimately by the presence of the fluorine atom (as fluoroethoxyl) and not to any extent by another part of the molecule. 

A. Amone, P. Bravo, A. Donadelli, and G. Resnati, Fluorinated analogues of nojirimycin and mannojirimycin from a non-carbohydrate precursor, Tetrahedron, 52 (1996) 131-142. 

Inhibition of Cell Wall Peroxidases with Ferulic Salts and Fluorinated Analogues... 

Two main anionic groups were present in the xylem and their activity towards ferulic salts and their fluorinated analogues was determined. Whether the two isozymes represent enzymes specifically involved in lignin biosynthesis is discussed. 

Five- to six-month-old tobacco plants (Nicotiana tabacum var. Samsun) grown in a glasshouse at 20°C were used for this study. Commercial synthetic substrates employed both for histochemical and biochemical assays were guaiacol, p-phenylenediamine-pyrocatechol (PPD-PC), 3-3 di-aminobenzidine (DAB), tetramethylbenzidine (TMB) and syringaldazine. Isopropylamine and monosodium salts of ferulic acid were also used as substrates as well as their / -fluorinated analogues substituted with a fluorine atom on the / -carbon (Fig. 1). Histochemical observations were done on hand-made transverse sections of fresh tobacco stems. Biochemical assays were performed separately on bark (inner cortical parenchyma, phloem and fibres) and xylem fractions. Technical data of incubation, enzyme extraction, spectrophotometric and electrophoretic assays were given elsewhere (5-7). Synthesis of fluorinated compounds was performed as previously described (4). 

Oxidation of Salts from Ferulic and / -Fluoroferulic Acids. When stem sections were incubated with ferulic acid, isopropylamine or sodium salts, the cell walls of the youngest xylem or sclerenchyma elements were stained a light pink color. No reaction was observed in other cell walls (Table I). The same result was obtained with fluorinated analogues. The fact that only peroxidases from lignifying cell walls are able to oxidize ferulic compounds and syringaldazine must be emphasized. Absorption spectra of the pink oxidation products of ferulic acid and / -fluoroferulic acid in the presence of hydrogen peroxide and peroxidases extracted from tobacco cell walls ( covalently bound fraction) showed a peak at 520 nm. 

Fig.1. Chemical structures of fluorinated analogues of amino acids naturally occurring in proteins and labelled with fluorine-18.

This present chapter is devoted to the recent advances, for the last decade, in fluorinated analogues of natural products developed as pharmaceuticals and now/ marketed or in development (registered or in clinical development). These mainly concern fluorine-substituted nucleosides, alkaloids, macrolides, steroids, amino acids and prostaglandins. 

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