Steroids nucleus

Early work in vitro on the sequence of reactions in the conversion of cholesterol into bile acids was carried out with mitochondrial preparations from rat and mouse liver (11). These preparations were found to catalyze predominantly reactions involving the oxidation of the side chain of C27-steroids. No evidence for the formation of 12a-hydroxylated metabolites was obtained. In 1963, Mendelsohn and Staple (12) reported the conversion of cholesterol into 5/ -cholestane-3a,7a-12a-triol in the presence of a 20,000 supernatant fluid of rat liver homogenate. This finding provided the first experimental evidence for the long surmised role of 5/ -cholestane-3a,7a,12a-triol as an intermediate in the conversion of cholesterol into cholic acid. Subsequent work with this enzyme preparation and subfractions of it has led to the elucidation of the sequences of reactions in the conversion of cholesterol into 5/ -cholestane-3a,7a,12a-triol (Fig. 1). 

The presence of esters of 5-cholestene-3/5,7a-diol in rat liver has been shown by Boyd (26), who suggested that 7a-hydroxylation might occur with cholesterol esters rather than cholesterol. It appears, however, that esters of 5-cholestene-3/5,7a-diol are formed predominantly by esterification of 5-cholestene-3/5,7a-diol. Hutton and Boyd (27) have found that the 100,000g supernatant fluid of rat liver homogenate catalyzes the esterification of 5-choIestene-3/5,7a-diol, and Katayama and Yamasaki (28) have reported that in vitro there is no significant 7a-hydroxylation of cholesterol esters under conditions of efficient 7a-hydroxylation of cholesterol. 

The role of the 7a-hydroxylation of cholesterol as a rate-limiting step in the biosynthesis of bile acids will be discussed in Section VI. 

Conversion of 5-Cholestene-S, 7a-diol into 7a-Hydroxy 4 cholesten-3-one 

In the apparently major pathway for the conversion of cholesterol into 5 -cholestane-3a,7a,12a-triol, the step following the formation of 7a-hydroxy-4-cholesten-3-one is a 12a-hydroxylation yielding 7a,12a-dihydroxy-4-cholesten-3-one (Fig. 1). The reaction is catalyzed by the microsomal fraction fortified with NADPH (15,37). The conversion of 5-cholestene-3, 7a-diol into 5-cholestene-3/5,7a,12a-triol, which is a reaction in another pathway for the formation of 5/5-cholestane-3a,7a,12a-triol, is also catalyzed by the microsomal fraction fortified with NADPH (30,37), as is the 12a-hydroxylation of 5/5-cholestane-3a,7a-diol and 7a-hydroxy-5)5-cholestan-3-one (37). The rates of 12a-hydroxylation of these C27-steroids differ considerably the rate with 5-cholestene-3/5,7a-diol is about one-tenth and with 5 -cholestane-3a,7a-diol about half of that with 7a-hydroxy-4-cholesten-3-one (37). Einarsson (37) and Suzuki et al. (38) have studied some properties of the 12a-hydroxylase system with special reference to the possible participation of electron carriers such as NADPH-cytochrome c reductase and cytochrome P-450. The 12a-hydroxylation of 7a-hydroxy-4-cholesten-3-one was inhibited by cytochrome c, indicating that NADPH-cytochrome c reductase might be involved. However, no direct evidence for the participation of flavins was obtained. If NADPH-cytochrome c reductase participates, it is not rate-limiting, since the activity of this enzyme increases upon treatment with thyroxine whereas the activity of the 12a-hydroxylase decreases (39). Suzuki et al. (38) found no inhibition of 12a-hydroxylation by carbon monoxide, whereas Einarsson (37) obtained some inhibition. The 12a-hydroxylase activity was unaffected by methylcholanthrene treatment (40) and lowered by phenobarbital treatment (37,38). These observations indicate that the cytochrome(s) P-450 induced by methylcholanthrene and 

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Many stereoselective reactions have been most thoroughly studied with steroid examples because the rigidity of the steroid nucleus prevents conformational changes and because enormous experience with analytical procedures has been gathered with this particular class of natural products (J. Fried, 1972). The name steroids (stereos (gr.) = solid, rigid) has indeed been selected very well, if one considers stereochemical problems. We shall now briefly point to some other interesting, more steroid-specific reactions. 

A significant fraction of the body s cholesterol is used to form bile acids Oxidation m the liver removes a portion of the CsHi7 side chain and additional hydroxyl groups are intro duced at various positions on the steroid nucleus Cholic acid is the most abundant of the bile acids In the form of certain amide derivatives called bile salts, of which sodium tau rocholate is one example bile acids act as emulsifying agents to aid the digestion of fats... 

Although many sterols and bile acids were isolated in the nineteenth century, it was not until the twentieth century that the stmcture of the steroid nucleus was first elucidated (5). X-ray crystallographic data first suggested that the steroid nucleus was a thin, lath-shaped stmcture (6). This perhydro-l,2-cyclopentenophenanthrene ring system was eventually confirmed by the identification of the Diels hydrocarbon [549-88-2] (4) and by the total synthesis of equilenin [517-09-9] (5) (7). 

In the 1970s and 1980s, potent antiprogestins were discovered and used as contragestational agents, with possible appHcations for the treatment of various cancers. The synthesis of the antiprogestin RU-486 demonstrated a versatile way to functionalize the 11-position of a steroid nucleus. 

Deuterium labeling of certain positions in the steroid nucleus can be a serious problem if suitably functionalized starting materials are not available or if a particular part of the molecule to be labeled is unsuitable for the various reactions described previously in this chapter. In these cases, the only practical solution to this problem is to incorporate the appropriately labeled carbon fragment by synthesis of the desired skeleton. 

L. Tokes, Insertion of Hetero Atoms into the Steroid Nucleus in Steroid Reactions, C. Djerassi, ed., Holden-Day, Inc., San Francisco, 1963, Chapter 12. 

Other Vicinal or 1 3-Dihydroxy Groups in the Steroid Nucleus... 

As a result, the intervening 15 years have witnessed the development of procedures for the introduction of fluorine in practically every available position of the steroid nucleus. Moreover, fluorine-containing groups such as CF2 and CF3 have been substituted at various positions. A number of recent books and reviews deal extensively with this subject. ... 

The high degree of stereoselectivity associated with most syntheses and reactions of oxiranes accounts for the enormous utility of these systems in steroid syntheses. Individual selectivity at various positions in the steroid nucleus necessitates the discussion of a collection of uniquely specific reactions used in the synthesis of steroidal epoxides. The most convenient and generally applicable methods involve the peracid, the alkaline hydrogen peroxide and the halohydrin reactions. Several additional but more limited techniques are also available. 

In general, epoxidation of steroids with trans-anti-trans ring fusions leads to exclusive formation of the a-oxirane. Steroid Reactions lists examples of exclusive a-epoxide formation from 2-, 4-, 6-, 7-, 8(9)-, 14-, 16- and 17(20)-unsaturated steroids. Further examples of a-epoxidation of steroid 1-enes, 3-enes, 8-enes, 9(ll)-enes, 8(14)-enes and 16-enes have been reported. The preferred attack by the reagent on the a-side of the steroid nucleus can be attributed to shielding of the -side of the molecules by the two angular methyl groups. 

The presence of functional groups on the steroid nucleus can affect the course of the epoxidation reaction thus epoxidation of 3/ -chlorocholest-4-ene (11) gives the 4a,5a-epoxide in 97 % yield, whereas the 3a-chloro group hinders (presumably sterically) attack on the 4,5-double bond towards the a-face of the molecule. The 3a-acetoxy function similarly influences the selectivity of the epoxidation of cholest-4-enes, a 53 47 mixture of the respective 4 , 5a- and 4jS, 5jS-epoxides being obtained after exposure of the 3a-acetoxy-4-ene (13) to perbenzoic acid. 

Many selective epoxidations are possible with polyunsaturated steroids. In general, oc, -unsaturated ketones are not attacked by peracid, although linear dienones react slowly at the y,5-double bond. Aw-Chloroperbenzoic acid is the reagent of choice for this reaction.When two isolated double bonds are present in the steroid nucleus, e.g. (27) and (30), the most highly substituted double bond reacts preferentially with the peracid. Selective epoxidation of the nuclear double bond of stigmasterol can likewise be achieved.However, one exception to this general rule has been reported [See (33) (34)]. ... 

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. °... 

Few procedures are available for the synthesis of steroid thiiranes because the rigidity of the steroid nucleus prohibits the application of many methods of thiirane synthesis. The only general methods involve the con-... 

The solvated phosphorane adds to the polarized carbonyl with the incipient C-21 methyl group pointing away from the bulk of the steroid nucleus. The newly formed carbon-carbon bond must then rotate in order for the tri-phenylphosphine group and oxygen atom to have the proper orientation for the elimination of triphenylphosphine oxide. This places the C-21 methyl in the CIS configuration. 

Concomitantly, additional transformations may occur at other parts of the steroid nucleus, e.g., 1,2-dehydrogenation, 6 - or 9a-hydroxylation. ... 

Although all the main classes of steroids have now been attained by total synthesis, most drugs are in fact, as noted above, prepared by partial synthesis from natural products that contain the steroid nucleus. The bulk of the world s supply of steroid starting material is derived by differing chemical routes from only two species of plants the Mexican yam, a species of... 

As noted above, the steroid nucleus has been a favorite for the design for site directed alkylating antitumor drugs. Thus reaction of prednisolone (62) with anhydride 63 affords the 21 acylated derivative, prednimustine (64). ... 

The Robinson annelation reaction has classically been employed for the building up of the six-membered ring components of the steroid nucleus (18). In the original method, the enolate is treated with the methiodide of )9-diethylaminoethyl methyl... 

The homology of the tricyclic products in Scheme 6 to the ABC-ring portion of the steroid nucleus is obvious. In fact, the facility with which these tricyclic materials can be constructed from simple building blocks provided the impetus for the development of an exceedingly efficient synthesis of the female sex hormone, estrone (1). This important biomolecule has stimulated the development of numerous synthetic strategies and these have been amply reviewed.16 The remainder of this chapter is devoted to the brilliant synthesis of racemic estrone by K. P. C. Vollhardt et al.i2 17... 

An important stage in the synthesis has been reached. It was anticipated that cleavage of the trimethylsilyl enol ether in 18 using the procedure of Binkley and Heathcock18 would regiospecifically furnish the thermodynamic (more substituted) cyclopentanone enolate, a nucleophilic species that could then be alkylated with iodo-diyne 17. To secure what is to become the trans CD ring junction of the steroid nucleus, the diastereoisomer in which the vinyl and methyl substituents have a cis relationship must be formed. In the... 

Epoxides are often encountered in nature, both as intermediates in key biosynthetic pathways and as secondary metabolites. The selective epoxidation of squa-lene, resulting in 2,3-squalene oxide, for example, is the prelude to the remarkable olefin oligomerization cascade that creates the steroid nucleus [7]. Tetrahydrodiols, the ultimate products of metabolism of polycyclic aromatic hydrocarbons, bind to the nucleic acids of mammalian cells and are implicated in carcinogenesis [8], In organic synthesis, epoxides are invaluable building blocks for introduction of diverse functionality into the hydrocarbon backbone in a 1,2-fashion. It is therefore not surprising that chemistry of epoxides has received much attention [9]. 

Substituents are designated as in die a configuration if they are below the plane of the steroidal nucleus, and as P if above the plane ... 

The key questions are can hydroxylations be carried out in vitro at desirable positions on the steroid nucleus, and can this be done to achieve the desired configuration ... 

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