Steroids, halo

Today, it is well known that the introduction of a chlorine or fluorine atom at the C-9 position of the natural adrenal substances cortisone and hydrocortisone (and of their dehydro-analogues) markedly enhances the anti-inflammatory activity of these agents, and is accompanied by a striking increase in both salt and water retention [14]. These undesirable side effects, which are manifested generally by 9-halo-steroids, preclude their use systemically in the management of disorders that are normally responsive to adrenocortical steroid therapy. 

Biological studies on 16a-hydroxy-hydrocortisone [15] have demonstrated that this type of corticoid derivative still maintains a considerable activity in the usual types of assays (glycogen deposition, thymus involution and anti-inflammatory tests). It was therefore of interest to prepare the 16a-hydroxy derivatives of the more potent 9a-halo steroids. 

In terms of synthetic utility these rearrangements fall into two major classes (i) reactions of halo steroids and related systems and (ii) reactions that yield cage-like structures. Reactions of the first type are exemplified by the rearrangements illustrated in Scheme 38. ... 

The optical rotatory dispersion curves of steroidal ketones permit a distinction to be made between the conformations, and assignment of configuration is possible without resorting to chemical methods (see, e.g. ref. 36) which are often tedious. The axial halo ketone rule and, in the more general form, the octant rule summarize this principle and have revealed examples inconsistent with the theory of invariable axial attack in ketone bromination. 2-Methyl-3-ketones have been subjected to a particularly detailed analysis. There are a considerable number of examples where the products isolated from kinetically controlled brominations have the equatorial orientation. These results have been interpreted in terms of direct equatorial attack rather than initial formation of the axial boat form. 

While the dehydrohalogenation of 3-halo-5a-steroids gives the A -olefin selectively, it has been shown that in the 5j5-series dehydrochlorination of 3j5-chloro compounds with quinoline gives a mixture of A - and A -olefins in a 45 55 ratio. 

A third type of reduction of a-substituted ketones is typified by the expulsion of the substituent and the reduction of the keto function to form an olefin. Wolff-Kishner reductions of a-hydroxy, a-acetoxy, " a-halo, °° and a-epoxy (see below) ketones are the most frequently encountered steroid examples of this general class. ... 

The synthesis of epoxides proceeds in the presence of a variety of functional groups and is also applicable to cyclo steroids. Halo epoxides, e.g, (45), can... 

Formation of oxiranes on the sterically more hindered side of the steroid ring system is usually carried out via /raw -halohydrins which afford oxiranes on treatment with base (c -Halohydrins yield ketones on exposure to base). Two general methods are available for the synthesis of tm s-halohydrins (1) the reduction of a-halo ketones and (2) the addition of a hypohalous acid to unsaturated steroids. 

The procedure involving a-halo ketone intermediates has been used for the synthesis of 11, 12 - and oxiranes of 5a-steroids... 

Rearrangement of a,/B-epoxy ketones to ftdicarbonyl isomers, 307 Reductive alkylation, 97 Reductive cleavage of halo ethers, 264 Reductive degradation of 19-substitutional steroids, 277, 278 Reformatsky reaction, 139 Removal of the C-10 substituent in steroids. 272... 

The rearrangement with ring contraction probably is the most important synthetic application of the Favorskii reaction it is for example used in the synthesis of steroids. Yields can vary from good to moderate. As solvents diethyl ether or alcohols are often used. With acyclic a-halo ketones bearing voluminous substituents in a -position, yields can be low a tcrt-butyl substituent will prevent the rearrangement. 

Halogenation of steroid 3-ketones can lead to complicated mixtures by virtue of the fact that the kinetic enol leads to 3 halo products, whereas the thermodynamic product is that halogenated at the 4 position. Carefully controlled reaction of the 5a-androstanolone with chlorine thus leads to the 2a-chloro derivative (29). Reaction of that intermediate with O(p-nitrophenyl)-hydroxylamine affords the androgenic agent ni stremine acetate (30). ... 

Propiolaldehyde diethyl acetal has found numerous synthetic applications in the literature which may be briefly summarized. The compound has been utilized in the synthesis of unsaturated and polyunsaturated acetals and aldehydes by alkylation of metal-lated derivatives, " by Cadiot-Chodkiewicz coupling with halo acetylenes, " and by reaction with organocuprates. Syntheses of heterocyclic compounds including pyrazoles, isoxazoles, triazoles, and pyrimidines have employed this three-carbon building block. Propiolaldehyde diethyl acetal has also been put to use in the synthesis of such natural products as polyacetylenes " and steroids. ... 

ORGANIC REACTIONS IN STEROID CHEMISTRY H. Vinylogous a-Halo Ketones... 

Halo Nitro Compounds Reaction of Steroid-5-enes with Nitrosyl Chloride... 

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