Other Fluorinated Steroids

While in these laboratories the oxygen flask combustion method has been used without any difficulty for the determination of fluorine in triamcinolone and other fluorinated steroids use of the Pregl-Roth distillation method has also been recommended . 

Fluoropyridinium triflate (la) exhibits high selectivity in fluorinations. In a steroid 8 with two reaction sites, a conjugated and a nonconjugated vinyl acetate moiety, 1-fluoropyridinium triflate (la) reacts at the conjugated site only. On the other hand, steroid 9 with a silyl enol ether and a conjugated acetate moiety affords the product resulting from reaction at the former site only.44,52... 

The fluorination of 12, easily prepared from the corresponding triketo steroid, with an equimolar amount of 1 (Scheme 2) shows the remarkable ability of 1 to distinguish di-substituted from tri-substituted enol silyl ethers. The 9a-fluoro steroid 13 is produced in 51% yield (78% based on recovered triketo steroid) and the combined yield of the other fluorinated products is only 4.6%.17 it thus is apparent that 1 reacts almost exclusively with the trisubstituted enol ether moiety. The new, selective direct fluorination at the 9a-position holds considerable promise as a means to prepare biologically important 9a-fiuoro steroids.18... 

Fluorinated Steroids. The fluorination of steroids has been known to have profound effects on biological activity since the early work of Fried (40). Fluorinated steroids have been described in other reviews (111). The use of fluorination as a tool to enhance biological selectivity and to improve the utility of a biologically active material has been clearly demonstrated in studies of vitamin D. ... 

By comparison to the other chlorine oxyfluorides, perchlo-ryl fluoride is a mild fluorinating agent and has been used for the preparation of fluorinated steroids. FCIO3 also reacts with phenyl lithium to form the unstable perchloryl benzene, C6H5CIO3, and lithium fluoride. 

In other work Rozen added molecular fluorine to a steroidal ene-one dissolved in ethanol at low temperatures to produce a vicinal difluonde in a cleaner, better yield reaction than previously obtainable [55] Although the reaction was not general, the stereoselectivity was very high, and contrary to addition of other halogens, addition was r>ii, characteristic of an electrophilic addition pathway... 

Iodine fluoride is a more versatile reagent than molecular fluorine in geminal fluorination of other hydrazones and related compounds under milder reaction conditions [55] Substrates fluorinated include hydrazones of simple cyclic or steroidal ketones (e g, 4 tert butylcyclohexanone, 70%, 3 cholestanone, 70%), W methyl and A/N dimethylhydrazones [R2C=NNH(CH3) 70%, R2C=NNC(CH3)2, 50%], semicarbazones (R2C=NNHCONH2, 25-50%), and 2,4-dinitrophenylhy-drazones [R2C==NNH-C6H3-2,4(N02)2, 25-50%]... 

Bromo [ F]fluoride is different from the other electrophilic radiolabelling agents discussed so far in the sense that the electrophilic part of the molecule is not fluorine but bromine. This is reflected by its synthesis from nucleophilic p F]fluoride and it can be obtained in high specific radioactivity. Bromo p F]fluoride was developed for fluorine-18 labelling of steroids (see Section 3.2) [64-66]. It was prepared (Scheme 11) in situ by reaction of dried p Fjfluoride with 1,3-dibromo-5,5-dimethylhydantoin and sulphuric acid in dichloromethane containing also the substrate. 

It is interesting to note that a number of researchers have attempted, more or less successfully, to construct reliable mathematical models which combine structural elements and experimental data to predict the toxicities of new substances not yet experimentally tested for humans and other species.110152 Furthermore pharmacology, toxicity, metabolism and enzyme-inhibiting effects of fluorine-containing aromatic systems (e.g., anilines, ben-zothiadiazines, butyrophenones, corticoids, phenothiazines, steroids, uracils) have been discussed in depth in the literature.153-156... 

Another steric factor becomes important when working with bile acids or other A/B cis-(5p)-steroids 14. Despite the fact that the C9 —H bond is the most electronically favored for electrophilic substitution, ring A which is perpendicular to the steroidal plane blocks the access to it. The fluorine, which has to approach with a solvent molecule, attacks the other tertiary sites at C5, Cl 4 and C17.42... 

Steroids with enone units in ring A64 or ring D72 were successfully fluorinated forming the corresponding vicinal ra-difluorides without affecting other parts of the molecules, e.g. 12 -> 13 and 14 -> 15. 

Trimethylsilyl ethers of several steroidal ketones were a-fluorinated by 4-(difluoroiodo)toluene, in moderate yield because of concomitant elimination, accompanied by the formation of other by-products from nucleophilic substitution to a phenyliodonium intermediate. The analogous reaction with xenon difluoride resulted in much better yields but different stereochemistry [50],... 

Other side reactions during fluorinations with DAST are skeletal rearrangements, which arc frequently observed in steroid chemistry. For example, treatment of 19-hydroxycholest-4-en-3-one (12) with DAST in refluxing acetonitrile gives the rearranged product 13. Further examples of similar rearrangements are cited in ref 38. 

Other examples of efficient fluorinations in the steroid field are the syntheses of 16-fluoro-cstrogens, 162-ethyl-21-[ F]fluoro-19-norprogesterone, and 11/i-(2-fluoroethyl)estra-1,3.5(10)-trienc-3,17/3-diol." ... 

Such is the versatility of DAST and related reagents that many fluorinated derivatives of natural products, including steroids, carbohydrates, nucleosides, prostaglandins and vitamin D analogues, amongst others, have been successfully synthesised [10, 16, 17] (Table 3.5). 

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