Steroids side-chain oxidation

The stereocontroUed syntheses of steroid side chains for ecdysone, cmstecdysone, brassinoHde, withanoHde, and vitamin D have been reviewed (185). Also, other manuscripts, including reviews on the partial synthesis of steroids (186), steroid dmgs (187—189), biologically active steroids (190), heterocychc steroids (191), vitamin D (192), novel oxidations of steroids (193), and template-directed functionali2ation of steroids (194), have been pubhshed. 

In 3-oxosteroid A4-steroid 5)3-reductase deficiency, key intermediates for cholic and chenodeoxycholic synthesis, 7a-hydroxy-4-cholesten-3-one and 7a,12a-dihy-droxy-4-cholesten-3-one undergo side-chain oxidation and conjugation to produce... 

The bile acids are 24-carbon steroid derivatives. The two primary bile acids, cholic acid and chenodeoxycholic acid, are synthesized in the hepatocytes from cholesterol by hy-droxylation, reduction, and side chain oxidation. They are conjugated by amide linkage to glycine or taurine before they are secreted into the bile (see cholesterol metabolism. Chapter 19). The mechanism of secretion of bile acids across the canalicular membrane is poorly understood. Bile acids are present as anions at the pH of the bile, and above a certain concentration (critical micellar concentration) they form polyanionic molecular aggregates, or micelles (Chapter 11). The critical micellar concentration for each bile acid and the size of the aggregates are affected by the concentration of Na+ and other electrolytes and of cholesterol and lecithin. Thus, bile consists of mixed micelles of conjugated bile acids, cholesterol, and lecithin. While the excretion of osmotically active bile acids is a primary determinant of water and solute transport across the canalicular membrane, in the canaliculi they contribute relatively little to osmotic activity because their anions aggregate to form micelles. 

Results of various in vivo experiments with labelled bile acid precursors in patients with CTX have been published [185,190,195]. All these experiments show that there is a defect in the oxidation of the steroid side chain in the biosynthesis of cholic acid but are not fully conclusive with respect to the site of defect. Bjorkhem et al. administered a mixture of [ H]7a,26-dihydroxy-4-cholesten-3-one and [ " C]7a-hy-droxy-4-cholesten-3-one to a patient with CTX [195]. The ratio between and C in the cholic acid and the chenodeoxycholic acid isolated was 40 and 60 times higher, respectively, than normal. Similar results were obtained after simultaneous administration of H-labelled 5)3-cholestane-3a,7a,26-triol and 4- C-labelled 5j8-cholestane-3a,7a-diol. The results of these experiments are in consonance with the contention that the basic defect in CTX is the lack of the 26-hydroxylase, but do not per se completely exclude other defects in the oxidation of the side chain. 

Early in vitro studies showed that mitochondria from livers of hyperthyroid rats did not oxidize cholesterol-26- C to C02 at a faster rate than similar preparations from normal animals (12). A more recent study (13) led to the conclusion that the effects of thyroid hormones on bile acid metabolism must take place at a biosynthetic step preceding side-chain oxidation, perhaps involving hydroxylation of the steroid nucleus. However, it must be realized that the normal substrate for side-chain oxidation leading to the formation of cholic acid from cholesterol is not cholesterol itself but presumably 3a,7afl2a-trihydroxy-5/5-cholestane (14,15), and the substrate for the side-chain oxidation leading to chenodeoxycholate is, presumably, 3a,7a-dihydroxy-5/5-cholestane (16). Thus results of in vitro experiments in which cholesterol is employed as the substrate must be interpreted with caution, since mitochondria do not have the enzyme system required for formation of the triol and diol from cholesterol. 

The in comparison to steroids atypical epoxysqualene cychsation, followed by a series of sequential rearrangements within the A,B-ring system, produces first the monocyclic iridal. Addition of a methyl group from S-adenosylmeth-ionine at the terminal double bond of the side-chain initiates the second cyclisa-tion. Cycloiridal results from dehydrogenation of the side-chain. Oxidative cleavage of the central double bond finally produces the desired scent molecule. [57]... 

Recent syntheses of steroids apply efficient strategies in which open-chain or monocyclic educts with appropiate side-chains are stereoselectively cyclized in one step to a tri- or tetracyclic steroid precursor. These procedures mimic the biochemical synthesis scheme where acyclic, achiral squalene is first oxidized to a 2,3-epoxide containing one chiral carbon atom and then enzymatically cyclized to lanostetol with no less than seven asymmetric centres (W.S. Johnson, 1%8, 1976 E.E. van Tamden, 1968). 

The most abundant natural steroid is cholesterol. It can be obtained in large quantides from wool fat (15%) or from brain or spinal chord tissues of fat stock (2-4%) by extraction with chlorinated hydrocarbons. Its saturated side-chain can be removed by chromium trioxide oxidation, but the yield of such reactions could never be raised above 8% (see page 118f.). 

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... 

Steroids (1) are members of a large class of lipid compounds called terpenes that are biogenicaHy derived from the same parent compound, isoprene, C Hg Steroids contain or are derived from the perhydro-l,2-cyclopentenophenanthrene ring system (1) and are found in a variety of different marine, terrestrial, and synthetic sources. The vast diversity of the natural and synthetic members of this class depends on variations in side-chain substitution (primarily at C17), degree of unsaturation, degree and nature of oxidation, and the stereochemical relationships at the ring junctions. 

Other stmctural variations in both series are the stereochemistry at C3 and the degree of oxidation on the nucleus and side chains. Cardiac steroids probably exert their inotropic effects by acting as specific, noncompetitive inhibitors of — ATPases, known as sodium pumps, and thus... 

Oxidation of the 3-hydroxy-A systenli with manganese dioxide in refluxing benzene affords a moderate yield of the corresponding 4,6-dien-3-one. These vigorous conditions also suffice to cleave the corticoid side chain (17a,21-dihydroxy-20-ketones) to give 17-keto steroids. ... 

Steroids possessing an epoxide grouping in the side chain have likewise been converted to fluorohydrins. Thus, 20-cyano-17,20-epoxides of structure (19) furnish the 17a-fluoro-20-ketones (20) after treatment of the intermediate cyanohydrins with boiling collidine. The epimeric 5a,6a 20,21-oxides (21) afford the expected bis-fluorohydrins (22). The reaction of the allylic... 

In the early 1930 s, when the prime research aim was the commercial synthesis of the sex hormones (whose structures had just been elucidated), the principal raw material available was cholesterol extracted from the spinal cord or brain of cattle or from sheep wool grease. This sterol (as its 3-acetate 5,6-dibromide) was subjected to a rather drastic chromic acid oxidation, which produced a variety of acidic, ketonic and hydroxylated products derived mainly by attack on the alkyl side-chain. The principal ketonic material, 3j -hydroxyandrost-5-en-17-one, was obtained in yields of only about 7% another useful ketone, 3 -hydroxypregn-5-en-20-one (pregnenolone) was obtained in much lower yield. The chief acidic product was 3j -hydroxy-androst-5-ene-17j -carboxylic acid. All three of these materials were then further converted by various chemical transformations into steroid hormones and synthetic analogs ... 

Sib CJ, KC Wang, HH Tai (1968) Mechanisms of steroid oxidation by microorganisms XIII. C22 acid intermediates in the degradation of the cholesterol side chain. Biochemistry 7 796-807. 

A total synthesis of functionalized 8,14-seco steroids with five- and six-membered D rings has been developed (467). The synthesis is based on the transformation of (S)-carvone into a steroidal AB ring moiety with a side chain at C(9), which allows the creation of a nitrile oxide at this position. The nitrile oxides are coupled with cyclic enones or enol derivatives of 1,3-diketones, and reductive cleavage of the obtained cycloadducts give the desired products. The formation of a twelve-membered ring compound has been reported in the cycloaddition of one of the nitrile oxides with cyclopentenone and as the result of an intramolecular ene reaction, followed by retro-aldol reaction. 

---