Steroids, 21-bromo

The 7 a-bromo steroid (9) can also be treated with sodium phenyl selenolate (41). The resultant 7 P-phenyl selenide (13) can be oxidized and the corresponding phenyl selenoxide elirninated to form the 7-dehydtocholesteryl ester (11). 

Reduction of a 16a-bromo-17-ketone (but not the 16 -epimer) is a little less stereospecific than reduction of the 17-keto compound. When a 2a-bromo-3-keto steroid is reduced, at least 78 % of the 3/ -alcohol is obtained. 

Displacement of an allylic halide is complicated by side reactions involving migration of the double bond. A good example is the reaction of 7a-bromo-3 -acetoxy-A -steroids (201) which gives, besides the expected... 

Replacement of halides with deuterium gas in the presence of a surface catalyst is a less useful reaction, due mainly to the poor isotopic purity of the products. This reaction has been used, however, for the insertion of a deuterium atom at C-7 in various esters of 3j -hydroxy-A -steroids, since it gives less side products resulting from double bond migration. Thus, treatment of the 7a- or 7j5-bromo derivatives (206) with deuterium gas in the presence of 5% palladium-on-calcium carbonate, or Raney nickel catalyst, followed by alkaline hydrolysis, gives the corresponding 3j3-hydroxy-7( -di derivatives (207), the isotope content of which varies from 0.64 to 1.18 atoms of deuterium per mole. The isotope composition and the stereochemistry of the deuterium have not been rigorously established. 

Deuteration at C-9 by Treatment of a 9a-Bromo-11 -keto Steroid with Zinc in Acetic Acid-OD... 

Deuteration at C-9 by treatment of a 9a-bromo-ll-keto steroid with zinc in acetic acid-OD, 204... 

In analogy with the peracid attack on steroidal double bonds, the formation of the bromonium ion, e.g., (81a), occurs from the less hindered side (usually the a-side of the steroid nucleus) to give in the case of the olefin (81) the 9a-bromo-l l -ol (82). Base treatment of (82) provides the 9 5,1 l S-oxide (83). Similarly, reaction of 17/3-hydroxyestr-5(10)-en-3-one (9) with A -bromosuccinimide-perchloric acid followed by treatment with sodium hydroxide and sodium borohydride furnishes the 3, 17 5-dihydroxy-5a,l0a-oxirane. As mentioned previously, epoxidation of (9) with MPA gives the 5, 10 -oxirane. °... 

The addition proceeds most smoothly with highly functionalized (more polar) steroids as seen in examples by Bernstein and others. The polar reaction conditions pose solubility problems for lipophilic androstane, cholestane and pregnane derivatives. Improved yields can be obtained in some cases by using dimethyl sulfoxide or t-butanol " as solvents and by using sodium A-bromobenzenesulfonamide or l,3-dibromo-5,5-dimethyl hydantoin (available from Arapahoe Chemicals) as a source of positive bromine. The addition of bromo acetate and bromo formate to steroid olefins has been studied to a limited extent. ... 

A variety of conditions has been used to prepare oxiranes from trans-hxomo-hydrins. In general, bromohydrins are heated in a solution of 5-10% methanolic potassium hydroxide for 30 min to 8 hr. Longer reflux times are required for bromohydrins which are not anti-coplanar, e.g., diequatorial bromohydrins. A 5 % solution of potassium acetate in boiling ethanol can be used to cyclize steroidal bromohydrins containing base sensitive groups. The use of 1.1 equivalents of sodium methoxide per equivalent of steroid in methanol solution is especially recommended for 9a-bromo-l lj5-hydroxy steroids. 

Addition of dimethylsulfoxonium methylide to the a-face of A -20-ketones, A -5a-H-ketones and A " -3-ketones results in the formation of the corresponding 16a,17a-methylene (1), la,2a-methylene-5a-H (2) and la,2a-methylene-A" steroids (3), respectively. Smooth reaction is also observed in the presence of 2-chloro and 2-bromo substituents in the A -5a-H-3-ketone series.Yields of 90% are obtained within a reaction period of 5 hr at room temperature. A A -3-keto system in (1) is not attacked under these conditions. 

Preparation of 19-norsteroids from 19-substituted steroids by transformations of 6/3, 19-ethers reductive cleavage of 5o -bromo-6/3,19-ethers, 266... 

The halogenation of enamines is formally analogous to protonation with salt formation. Thus the steroidal enamine (164) undergoes bromination (7/5) to give the j8-bromo iminium bromide (165), which is readily hydrolyzed to the /5-bromo aldehyde (166). 

Allylic bromination of pregnenolone acetate with dibromodi-methylhydantoin affords the 7-bromo compound (155) of undefined stereochemistry. Dehydrobromination by means of collidine followed by saponification affords the 5,7 endocyclic cis,cis-diene, 156. This compound contains the same chromophore as ergosterol, a steroid used as a vitamin D precursor. The latter displays a complex series of photochemical reactions among the known products is lumisterol, in which the stereochemistry at both C9 and Cio is inverted. Indeed, irradiation of 156 proceeds to give just such a product (158). This reaction can be rationalized by... 

This system is the only osmotic system developed commercially at this time that is suitable for the oral administration of insoluble drugs to humans. It has been utilized in the development of several other drugs including isradipine, doxazosin, diltiazem, contraceptive steroids, glipizide, and verapamil [48-53], The system has also been utilized to codeliver the free bases of compounds normally administered as water-soluble salts such as pseudoephedrine and bromo-pheniramine [54], The latter system includes both a loading dose and a controlled release dose and is intended for applications in the over-the-counter market. 

The carbonylation of the same substrates (138-144) with several A-substituted hydrox-ylamines proceeds with the same order of substrate reactivity (Scheme 67). In particular, with steroidal alkenyl iodides 138-141 and enol triflates 142 and 143 complete conversion of the substrates could be achieved, in the latter cases (142 and 143) with long reaction times. The analogue bromo derivative 144 is completely unreactive. 

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. 

Bromo [ F]fluoride (Section 3.9.1) addition across a double bond was used in the synthesis of fluorine-18-labelled steroids of high specific radioactivity. After addition, the bromine is removed by reduction or by dehydrobromination. [ F]Fluoro-5a-dihydrotestosterone was obtained in about 3% radiochemical yield (Scheme 17) [64] and 6a-p F]fluoroprogesterone in only 0.3% [65]. The yields were quite low but sufficient to allow for animal studies. These reactions had been tested out successfully with simpler model alkenes [66]. 

A review of neighbouring-group effects in natural products includes steroidal examples. The 19-acetoxy-5a-bromo-6-oxo-steroids (228) fragment with base to give the 6-oxo-A -compounds (229) which are regarded as potentially useful intermediates in prostanoid synthesis.The preparation and properties of the 6-spirocyclopropane (230) have been reported. Attempts to cleave the cyclopropane symmetrically were unsuccessful although other cleavages are discussed. ... 

A typical example is alkylation of the steroid ester 11. Treatment of 1 with LDA in tetrahydrofuran at —78 °C for 1 hour followed by addition of 4-bromo-2-methyl-2-butene in the presence of HMPA at —78 °C to —20 °C furnished an 87 13 mixture of the monoalkylated esters 3a and 3b. The potassium enolate 2 (KHMDS, THF, —78 °C, 1 h) has been hydroxylated with an oxaziridine reagent in 70% yield to give a 3 1 mixture of a-hydroxy derivatives. 

Careful investigation of the bromination reaction of 3 keto steroids, which leads ultimately to 2,4-dibromo derivatives (see, for example, S-2-5-3), revealed that the sequence starts with the formation of a 2a bromo derivative, a futher demonstration of the preferred enolization of the carbonyl group toward the 2 position. 

The addition of halogen fluorides to C = C bonds in steroids is affected by steric crowding to a greater extent than by electronic factors so that the products may be of the anti-Mar-kovnikov type. In several instances the orientation of the bromine monofluoride addition was shown to depend on reaction conditions resulting cither in 6/ -bromo-5a-fluoro- or 5a-bromo-6/i-fluorosteroids.33... 

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