A5-Steroids

C. Thus, using these reaction conditions, several A5-steroids were converted into the corresponding A5-7-keto-steroids, in good to high yields (Scheme 16). 

Scheme 16 Allylic oxidation of A5-steroids catalyzed by Bi(III) salts, using r-BuOOH...

In patients suspected of congenital adrenal hyperplasia, to identify 21-hydroxylase deficiency, 11- hydroxylase deficiency, and 3l3-hydroxy-A5 steroid dehydrogenase deficiency, based on the steroids that accumulate in response to ACTH administration (see Figure 39-1 and Chapter 39)... 

Griffiths et al. [23] studied the ESI MS of sterols, and while they are not hormonal steroids, similar derivatization methods can be used. He converts 3/5-hydroxy-A5 sterols to - -4-ene sterols using cholesterol oxidase and follows this by preparation of Girard P hydrazones. This increases the sensitivity by 1000 in ESI. This technique would also be applicable to pregnenolone, dehydroepiandrosterone (DHEA) and similar A5 steroids, which can also be oxidized by cholesterol oxidase. 

Infants with salt-losing crisis and adrenal insufficiency in infancy may have adrenal hypoplasia congenita. This can be of two types recessive, for which the cause has not been defined and which affects mostly the fetal zone, and X-linked, which is caused by mutations in the DAX-1 gene, which (with steroidogenic factor-1) controls definitive zone development and steroidogenesis [71]. GC-MS analysis of patients with the disorder show variant patterns from absence of neonatal A5 steroids, appropriate for the recessive form [81], to extremely low cortisol production and transient 11/Lhy-droxylase deficiency, as evidenced through increased THS excretion (Malunowicz, personal communication). 

Hydrogenation of 19-hydroxy-3a- and 3/ -substituted-A5-steroids over platinum or rhodium yields increased amounts of 5/ -products as compared to the corresponding 19-desoxy series160 161 (hydroxyl group effect). In contrast, the A5-19-carboxaldehyde (27) gives only the 5a-product when hydrogenated over either palladium or platinum.162,168... 

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 3/ -hydroxy-A5-steroids, since it gives less side products resulting from double bond migration. Thus, treatment of the 7a-96 or 7j8-bromo87 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 3/ -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. 

Table 2-1 gives the percentage or ratio of the epimers formed in a number of reductions covering a wide variety of steroids. Structures (10), (11) and (12) show typical percentages of the predominant epimer formed at various positions in 5a-, 5/ - and A5-steroids. 

Hydrogenation of unsubstituted" or 3/ -substituted-A5-steroids (25a) over platinum gives, almost exclusively, the 5a-product (26a).121,138 With 3a-substituents (25b) the 5 -product (24b) is formed preferentially.87,121,136 Hydrogenation of A4-steroids (23a or b) gives product mixtures in which the 5a/5/ ratio is dependent on the nature and stereochemistry of the sub-... 

The displacement of homoallylic tosylates follows an entirely different course with a strong tendency for the formation of cyclo steroids. Thus, when the 3/ -tosylate of a A5-steroid (187) is treated with lithium aluminum deuteride, the product consists mainly of a 3j5-drA5-steroid (188) and a 6 -d1-3,5a-cyclo steroid (189).15,51 The incorporation of deuterium at the 3/ position in (188) indicates that this reaction proceeds via a 3,5-cyclo cholesteryl cation instead of the usual SN2 type displacement sequence. This is further substantiated by the formation of the cyclo steroid (189) in which the deuterium at C-6 is probably in the / configuration.51... 

The addition of HF to the 5,6-double bond in 3-hydroxy-A5-steroids has been investigated intensively. Bowers et al.47 prepared the 5a-fluoro derivative (32) from pregnenolone acetate (31) in 10 % yield using methylene dichloride-THF as solvent at 0°. Pregnenolone itself is converted in 30%... 

Attempts to extend this reaction to the preparation of iodofluorides were unsuccessful with compounds (14), as well as with the A9(11)- and A16-derivatives discussed earlier. A5-Steroids (e.g., pregnenolone84 and cholesterol51), on the other hand, furnish good yields of iodofluorides, which, contrary to expectation, must be formulated as 5oc-fluoro-6/ -iodides (16)... 

Mechanism90 The reaction of A4- and A5-steroids with nitrosyl fluoride to form ni trimines is best discussed in conjunction with the nitrosyl chloride reaction leading to the 5a-chloro-6/ -nitro steroids (33). Since nitroso alkanes are oxidized with nitrosyl chloride to nitro alkanes it is believed that 5a-chloro-6/S-nitro steroids are formed in this way from an initially formed 5a-chloro-6/ -nitroso adduct. The same is true for nitrosyl fluoride up to the stage of the nitroso fluoride (56). Since NOF is a weaker oxidizing agent than NOC1 the nitroso fluoride tautomerizes to the fluoro oxime (57) at a rate... 

Subsequent reaction of (7) with the iodomethylzinc iodide reagent gives l/ ,2/l-methylene-3/l-hydroxy-A5-steroids which are readily transformed to the important 3-keto-A4 analogs.219,220... 

Ring contraction by ozonization of A5- steroids—cyclization of keto aldehydes... 

Chromium trioxide oxidation of A5-steroids / 429 Ozonization of A5-steroids / 431... 

However, suitably located hydroxyl and acetoxyl functions can assist the cisoid approach of the peracid reagent. While 4/J-acetoxycholest-5-ene gives a 9 1 ratio of the a- and j8-epoxides, the 4a-acetoxy-5-ene yields the a-epoxide233 exclusively. The directive effect can be used to prepare a-22,23 and / -oxiranes24 from A5-steroids as illustrated by the epoxidation of (16) and (18). 

No satisfactory explanation has been advanced for the reductive removal of one iodine atom. The di-iodination procedure does not appear to be useful with 3/ -hydroxy-A5-steroids, but 3-keto-A4 systems do not interfere. 

A promising general method for preparing B-homo-19-norsteroids has been reported by Tadanier and Cole32a in a study of the homallylic rearrangements of 19-substituted-A5-steroids. The ready availability of 19-hydroxy-A5-steroids33 (c/ chapter 12) makes this approach particularly attractive. 

Ozonization of A5-steroids usually gives complex mixtures (however, see ref. 48). Ozonolysis became a practical step in the general synthesis of B-norsteroids with the discovery that added methanol49,50 (or formaldehyde49) improves yields significantly. Thus, Tanabe and Morisawa50 prepared 5/ -hydroxy-6/ -formyl-B-norsteroids (74) from cholesterol acetate, dehydroepiandrosterone acetate and pregnenolone acetate in overall yields of 64-74 % by the reaction sequence represented below. 

Schenck GO, Neumuller O-A, Eisfeld W (1958) Zur photosensibilisierten Autoxydation der Steroide. A5- Steroid-7a-hydroperoxyde und 7-Ketone durch Allylumlagerung von As-Steroid-5a-hydro-peroxyden. Liebigs Ann Chem 618 202-210... 

There have been known many examples that the hydrogenation of 3p-substituted A5-steroids yields mainly or exclusively saturated steroids of 5a series.166 Lewis and Shoppee studied the influence of various 3 a substituents on the stereochemical course of the hydrogenation of A5-steroids, and found that the 3a substituents lead to the preferential and sometimes exclusive formation of 5P-cholestane derivatives.166 The hydrogenations over platinum oxide were effectuated in methanol or ethyl acetate in the presence of traces of strong acids such as perchloric acid, sulfuric acid or hydrobromic acid. The results summarized by Lewis and Shoppee (eq. 3.34), which also include those by Haworth et al.,167 suggest that the bulkier the axial 3a substituent, the larger is the proportion of 5P steroid formed. The hydrogenation of A4-steroids usually leads to a mixture of 5a and 5P compounds and the stereochemical influence of 3a and 3P substituents is less marked than in the cases of A5-steroids.168... 

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