The Steroid Ring System

Because the steroid ring system is rigid, functional groups bonded to ring atoms have well-defined positions. Substituents below the plane of the ring are designated as a those above the plane of the ring are P. We recall that down and up in substituted cyclohexane compounds are not synonymous with equatorial and axial. For the same reasons, this method of nomenclature for steroids does not indicate whether the substituent is equatorial or axial. 

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A spectacular example of selective deliydiogenation in the steroid ring system (42) has been attributed to stereoelectronic effects (31) the yield is 80%. Several related steroids also show this chemistry. An extensive review containing many additional examples and a mechanistic discussion is available (23). 

Since the stereochemical course of a catalytic hydrogenation is dependent on several factors, " an understanding of the mechanism of the reaction can help in the selection of optimal reaction conditions more reliably than mere copying of a published recipe . In the first section the factors which can influence the product stereochemistry will be discussed from a mechanistic viewpoint. In subsequent sections the hydrogenation of various functional groups in the steroid ring system will be considered. In these sections both mechanistic and empirical correlations will be utilized with the primary emphasis being placed on selective and stereospecific reactions. 

The same qualitative results based on steric and electronic properties of the steroid ring system are found regardless of the structure of the peracid. Thus, although the generality of stereochemistry can be discussed with regard to all peracids, a quantitative comparison is valuable in some instances. 

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. 

Substituent groups on the steroid ring system can be either axial or equatorial. As with simple cyclohexanes (Section 4.7), equatorial substitution is generally more favorable than axial substitution for steric reasons. The hydroxyl group at C3 of cholesterol, for example, has the more stable equatorial orientation. Unlike what happens with simple cyclohexanes, however, steroids are rigid molecules whose geometry prevents cyclohexane ring-flips. 

The selectivity for two-alkyne annulation can be increased by involving an intramolecular tethering of the carbene complex to both alkynes. This was accomplished by the synthesis of aryl-diynecarbene complexes 115 and 116 from the triynylcarbene complexes 113 and 114, respectively, and Danishefsky s diene in a Diels-Alder reaction [70a]. The diene adds chemoselectively to the triple bond next to the electrophilic carbene carbon. The thermally induced two-alkyne annulation of the complexes 115 and 116 was performed in benzene and yielded the steroid ring systems 117 and 118 (Scheme 51). This tandem Diels-Alder/two-alkyne annulation, which could also be applied in a one-pot procedure, offers new strategies for steroid synthesis in the class O—>ABCD. 

Cholesterol is formed from acetyl-CoA in a complex series of reactions, through the intermediates /3-hydroxy-/3-methylglutaryl-CoA, mevalonate, and two activated isoprenes, dimethylallyl pyrophosphate and isopentenyl pyrophosphate. Condensation of isoprene units produces the noncyclic squalene, which is cyclized to yield the steroid ring system and side chain. 

The steroid hormones (glucocorticoids, mineralocorticoids, and sex hormones) are produced from cholesterol by alteration of the side chain and introduction of oxygen atoms into the steroid ring system. In addition to cholesterol, a wide variety of isoprenoid compounds are derived from mevalonate through condensations of isopentenyl pyrophosphate and dimethylallyl pyrophosphate. 

Exercise 30-16 An ingenious and highly practical synthetic procedure for forming the steroid ring system has been developed by W. S. Johnson that closely mimics the squalene cyclization without the need for enzymes. The cyclizations occur by carbocationic intermediates under rather strictly defined conditions that are designed to prevent the reactants from being diverted to nucleophilic substitution or elimination... 

An alternative sequence from diosgenin to hydrocortisone has been devised, making use of another microbiological hydroxylation, this time a direct 11 p-hydroxylation of the steroid ring system (Figure 5.121). The fungus Curvu-laria lunata is able to 11 p-hydroxylate cortex-olone to hydrocortisone in yields of about 60%. 

Nature often provides excellent suggestions about how to synthesize a compound. After the pathway for the biosynthesis of steroids by cationic cyclization of polyenes was determined, Professor William S. Johnson and coworkers at Stanford University used a very similar reaction to synthesize progesterone. The last part of this synthesis is outlined in the following equations. Alcohol A was prepared in 12 steps with an overall yield of 10%. It was then cyclized to form the steroid ring system. 

Fig. 7 Aliphatic region of a NOESY spectrum of dutasteride in DMSO-d6- Correlations show through space interactions between neighboring nuclei and are used to make relative stereochemical assignments for proton resonances. Correlations between the His methyl group and nearby protons on the same side of the steroid ring system are highlighted. (See Fig. 10 for structure and numbering scheme.)...

FIGURE 15.18. The structure of cholesterol myristate (Ref. 144). Some unit-cell edges are indicated, (a) Chemical formula, and (b) and (c) two views of the molecular packing in the crystal, (b) View onto the steroid ring systems, and (c) view along them. The equilibria, with temperatures, are ... 

The ileal bile acid transporter (IBAT) transports conjugated bile acids in a Na + -dependent manner. Like the peptide transporter, it serves as a target for prodrugs, which consist of drugs being coupled to the hydroxyl group at position 3 of the steroid ring system of a bile acid [25, 26]. 

The flexible hydrocarbon chains in the hydrophobic core (lightly shaded area in the middle) make the membrane fluid. The steroid ring system of cholesterol molecules, positioned in the outer surfaces, stiffens the membrane. (Nitrogen atoms are red, oxygen atoms are blue, and phosphorus atoms are orange.) Cell membranes are about 7 to 9 nm thick. 

Bile salts are structurally similar to soap in that they contain a polar head group (e.g., the charged amino acid residue glycine) and a hydrophobic tail (the steroid ring system). 

Figure 15.11. Overlapping pharmacophore stmc-tuires of corticosteroids, (a) Clobetasol propionate (in gray) and the soft corticosteroid loteprednol eta-bcnate (26) (in black). The view is from the a side, from slightly below the steroid ring system, (b) Loteprednol etabonate (in black) and a 17a-dichlo-roester soft steroid (in gray). This view is from the j8 side, from above the steroid ring system. See color insert.

In 1971, Makino et al. found that considerable amounts of 3jS-hydroxychol-5-en-24-oic acid were excreted in urine of children with extrahepatic biliary atresia [111]. Since then, the unsaturated C24 bile acid has been identified in human meconium [112,113], amniotic fluid [114,115], gallbladder bile from premature and term infants [116], urine from children and adults, both healthy and with liver disease [82,117], and bile and feces from newborn and fetal guinea pigs [118]. The natural occurrence of 3j8-hydroxychol-5-en-24-oic acid suggests that the side chain of cholesterol is degraded before modification of the steroid ring system (Chapter 9). 

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