Steroid 5,6-oxides

Cholesterol epoxide hydrolase, which is expressed in the endoplasmic reticulum and catalyzes the trans-addition of H20 to cholesterol 5,6a-ox-ide and cholesterol 5,6/3-oxide, as well as to a number of other steroid 5,6-oxides. The products are the corresponding vicinal diols [54][55],... 

A second unique microsomal epoxide hydrolases has been described. This enzyme appears to have a narrow substrate specificity, being specific for cholesterol 5,6-oxides and related steroid 5,6-oxides. 

A facile method for the stereospecific labeling of carbon atoms adjacent to an oxygenated position is the reductive opening of oxides. The stereospecificity of this reaction is due to virtually exclusive diaxial opening of steroidal oxides when treated with lithium aluminum hydride or deuteride. The resulting /ra/w-diaxial labeled alcohols are of high stereochemical and isotopic purity, with the latter property depending almost solely on the quality of the metal deuteride used. (For the preparation of m-labeled alcohols, see section V-D.)... 

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. 

Maintenance of adrenal cortex Promotes secretion of steroids, oxidative phosphorylation in adrenal cortex Mobilizes and increases oxidation of free fatty acid in adipose tissue Increases gluconeogenesis in liver increases cyclic adenosine monophosphate (AMP) in adrenal cortex Decreases urea formation in liver... 

Electrophilic Addition Other Addition Reactions Reduction of Unsaturated Steroids Oxidation and Dehydrogenation Miscellaneous Reactions... 

Oxidations by dioxygenases cw-hydroxylation of aromatic double bonds. Oxidations catalyzed by oxidases regio- and stereoselective oxidations of polyols oxidations of carbohydrates oxidations of hydroxy steroids oxidations of alkyl phenols to form chiral /7-hydroxybenzylic alcohols hydroxylation of phenols oxidation of amino acids to keto acids. 

Disproportionation [1, 729-730]. In the absence of a hydrogen acceptor/donor, Raney nickel in boiling p-cymene brings about four different types of reactions on steroids oxidation of a 3-hydroxyl group, hydrogenation of a 5,6-double bond, isomerization of a 5)3-hydrogen to a 5a-hydrogen, and dimerization.453... 

Preparation (2,182, ref. 1). The procedure has now been published.1 Reaction with steroid oxides. 2-Lithio-l,3-dithiane reacts with 5a-cholestane-2a,3a-oxide (1) to give the 2/3-dithianyl-3 -hydroxy derivative (2). Desulfuriza-... 

Microbiological conversions, microbiological iranrformaiions conversions of materials occurring in one or more stages, and catalysed by microorganisms. M.c. are the result of microbiological enzyme action, and often have no importance for the microbial cell. Several M.c. are important in the pharmaceutical industry. Examples are the stereospecific conversions of steroids, oxidation of sorbitol to sorbose by Acetobacter suboxydans (in the production of vitamin C), and the addition of acetaldehyde to benzalde-hyde by Saccharomyces cerevisiae. The product of this last reaction is phenylacetylcarbinol, a precursor for D-ephedrine synthesis. 

Some of the steroid-oxidizing P450s are regulated by adrenocorticotropic hormone (ACTH) and cyclic adenosine monophosphate (AMP) pathways [181],... 

P450 2C19 can also catalyze steroid oxidations, including progesterone 21-hydroxylation and testosterone 17-hydroxylations [825], The organophosphate insecticide diazinon is activated in human liver by P450 2C19 [826],... 

Lynn jr., W. S., and R. Brown Mechanism of in vitro steroid oxidation. BiocWm. biophys. Acta (Amst.) 21, 403 (1956). 

Acetone in conjunction with benzene as a solvent is widely employed. With cyclohexanone as the hydrogen acceptor, coupled with toluene or xylene as solvent, the use of higher reaction temperatures is possible and consequently the reaction time is considerably reduced furthermore, the excess of cyclohexanone can be easily separated from the reaction product by steam distillation. At least 0 25 mol of alkoxide per mol of alcohol is used however, since an excess of alkoxide has no detrimental effect 1 to 3 mols of aluminium alkoxide is recommended, particularly as water, either present in the reagents or formed during secondary reactions, will remove an equivalent quantity of the reagent. In the oxidation of steroids 50-200 mols of acetone or 10-20 mols of cyclohexanone are generally employed. 

Open-chain 1,5-polyenes (e.g. squalene) and some oxygenated derivatives are the biochemical precursors of cyclic terpenoids (e.g. steroids, carotenoids). The enzymic cyclization of squalene 2,3-oxide, which has one chiral carbon atom, to produce lanosterol introduces seven chiral centres in one totally stereoselective reaction. As a result, organic chemists have tried to ascertain, whether squalene or related olefinic systems could be induced to undergo similar stereoselective cyclizations in the absence of enzymes (W.S. Johnson, 1968, 1976). 

Oxidation of olefins and dienes provides the classic means for syntheses of 1,2- and 1,4-difunctional carbon compounds. The related cleavage of cyclohexene rings to produce 1,6-dioxo compounds has already been discussed in section 1.14. Many regio- and stereoselective oxidations have been developed within the enormously productive field of steroid syntheses. Our examples for regio- and stereoselective C C double bond oxidations as well as the examples for C C double bond cleavages (see p. 87f.) are largely selected from this area. 

We shall describe a specific synthetic example for each protective group given above. Regiosdective proteaion is generally only possible if there are hydroxyl groups of different sterical hindrance (prim < sec < tert equatorial < axial). Acetylation has usually been effected with acetic anhydride. The acetylation of less reactive hydroxyl groups is catalyzed by DMAP (see p.l44f.). Acetates are stable toward oxidation with chromium trioxide in pyridine and have been used, for example, for protection of steroids (H.J.E. Loewenthal, 1959), carbohydrates (M.L. Wolfrom, 1963 J.M. Williams, 1967), and nucleosides (A.M. Micbelson, 1963). The most common deacetylation procedures are ammonolysis with NH in CH OH and methanolysis with KjCO, or sodium methoxide. 

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.). 

The most difflcult pharmaceutically relevant oxidation of steroids is the introduction of a 14 -hydroxyl group. This functional group is found in heart-active steroids (cardenolides) such as digitoxigenin, which also contain a 17/J-butenolide substituent. The 14/ -hydroxyl group is easily cleaved off by dehydration and must therefore not be treated with Lewis or... 

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