1.2- Fluorohydrins

Steroids possessing an epoxide grouping in the side chain have likewise been converted to fluorohydrins. Thus, 20-cyano-17,20-epoxides of structure (19) furnish the 17a-fluoro-20-ketones (20) after treatment of the intermediate cyanohydrins with boiling collidine. The epimeric 5a,6a 20,21-oxides (21) afford the expected bis-fluorohydrins (22). The reaction of the allylic... 

An alternative to fluorohydrin formation is observed with the 6/ -methyl-5a,6a-epoxide (30), which rearranges, possibly in a concerted reaction, to the A-homo-B-norsteroid (31) (cf, chapter 14, Vol. II). 

The influence of the conformational factors, which play a decisive role in directing oxide fission in the above cases is no longer operative in the case of 3-keto-5a,6a-epoxides and their 3-ethylene ketals. With these substrates the —I effect of the BFs-complexed 3-keto or 3-ketal grouping predominates leading to the fluorohydrins. Thus, treatment of both 5a,6a-oxidopregnane-3,20-dione (35) and its 3,20-bisethylene ketal with BFg-etherate in benzene-ether affords in 45% yield the 6jff-fluoro-5a-hydroxy-derivative (36) and its 3-ethylene ketal, respectively. which are converted into the 6a-fluoro-A -CH3... 

Keto-5) , lOjff-epoxides (38) undergo diaxial opening with BF3-etherate in benzene to form the fluorohydrins (39). ... 

Fluorohydrin formation by epoxide opening with hydrogen fluoride in chloroform-ethanol, 433... 

There is continuous interest in cleavage of epoxides as a general method lor the preparation of fluorohydrins Epoxides are effectively cleaved under mild conditions by a 70% hydrogen fluoride-pyridine complex (Olah s reagent). The... 

Reeently, new fluorinating agents, tetrabutylphosphonium fluoride and its mono- and dihydrofluoride, were used for preparation of fluorohydrins from epoxides [14] (equation 13). 

The combination of alkali metal acid fluorides and porous aluminum fluoride IS a stable, solid, and efficient substitute for anhydrous hydrogen fluoride for promoting the ring-opening reactions of simple aliphatic oxiranes to give the fluorohydrins under sonication [/5] (equations 14 and 15)... 

Epoxides are regio- and stereoselectively transformed into fluorohydrins by silicon tetrafluoride m the presence of a Lewis base, such as diisopropyleth-ylamme and, m certain instances, water or tetrabutylammonium fluoride The reactions proceed under very mild conditions (0 to 20 C in 1,2-diohloroethane or diethyl ether) and are highly chemoselective alkenes, ethers, long-chain internal oxiranes, and carbon-silicon bonds remain intact The stereochemical outcome of the epoxide ring opening with silicon tetrafluoride depends on an additive used, without addition of water or a quaternary ammonium fluoride, as fluorohydrins are formed, whereas m the presence of these additives, only anti opening leading to trans isomers is observed [17, 18] (Table 2)... 

Dehydration of 221 affords the corresponding 9,11 olefin, 223. When this compound is subjected to the series of reactions for introduction of the 9,11 fluorohydrin, there is obtained the antiinflammatory steroid flumethasone (224).° As might be expected from the incorporation of a group in almost every posi-tion known to increase potency 224 is an extremely active agent. 

Incorporation of a vinylic bromide at the 2 position also gives a compound with good activity. Bromination of fluorohydrin under carefully controlled conditions... 

The reaction can be applied to simple epoxides if polyhydrogen fluoride-pyridine is the reagent. The epoxide-to-fluorohydrin conversion has also been carried out with Sip4 and a tertiary amine.Chloro-, bromo-, and iodohydrins can also be... 

The biological activity of a compound can often be affected dramatically by the presence of even a single fluorine substituent that is placed in a particular position within the molecule. There are diverse reasons for this, which have been discussed briefly in the preface and introduction of this book. A few illustrative examples of bioactive compounds containing a single fluorine substituent are given in Fig. 3.1. These include what is probably the first example of enhanced bioactivity due to fluorine substitution, that of the corticosteroid 3-1 below wherein Fried discovered, in 1954, that the enhanced acidity of the fluorohydrin enhanced the activity of the compound.1 Also pictured are the antibacterial (3-fluoro amino acid, FA (3-2), which acts as a suicide substrate enzyme inactivator, and the well-known anti-anthrax drug, CIPRO (3-3). 

Fluorohydrins.1 Both this reagent (1) and Olah s pyridinium poly (hydrogen fluoride) (2) serve as an attenuated source of hydrogen fluoride, and both convert simple epoxides into fluorohydrins, but reactions with 1 require higher temperatures than those with 2. The two reagents can differ in the regioselectivity, with steric factors being more important in reactions of 1 than those of 2. 

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