Steroids ester forms

Figure 12.5 Cholesterol ester. Cholesterol is a derivative of the cyclopentanoper-hydrophenanthrene condensed ring system and is therefore a member of the group of compounds called steroids. It often occurs esterified at position 3 with a long chain fatty acid, which may be saturated or unsaturated and commonly contains 16 or 18 carbon atoms. Steroids that form esters in this way are more correctly called sterols.

Among the variety of sulfate esters formed by living cells are the sulfate esters of phenolic and steroid compounds excreted by animals, sulfate polysaccharides, and simple esters, such as choline sulfate. The key intermediate in the formation of all of these compounds lias been shown to be 3 -phosphoadenosine-5/-phosphosulfate (PAPS). This nucleotide also serves as an intermediate in sulfate reduction. 

With inflexible substrates, this photochemical functionalization process showed significant selectivity. As our first example, photolysis of steroid ester 70 led to carbonyl insertion into the C-H bonds at C-7 and C-14 [149,150]. Other steroid esters afforded selective functionalizations in various positions [e.g. 151, 152], and compound 71 directly dehydrogenated the steroid to form the product olefin 72 [150]. 

The gas-chromatographic separation of corticosteroids as cyclic boronates offers considerable promise. Alkyl (or phenyl) boronic acids condense readily with 17a,20-, or 20,21-diols, and also with 17a,21-hydroxy-20-oxo steroids to form cyclic esters [e.g. (557) and (558)] with excellent g.l.c. properties. The mass spectra of these boronates exhibit prominent molecular ions. 

Essentially the same transformation can be conducted on a more highly substituted steroid. The required nitroso ester can in principle be prepared from reaction of DHEA 3-acetate (6-1) with bromine and nitrous acid (Scheme 3.6). The reaction sequence would start by addition of bromine from the open a-side of the steroid to form bromonium ion 6-2. Attack on that ion by the nitroso anion from the [3 side together with the rule of diaxial opening of a three-membered ring will the lead to formation of the nitrite 6-3. Irradiation of a toluene solution of the nitrite ester with a mercury vapor lamp walks the nitro group across the gap, in effect functionalizing C19. Heating the initially formed nitroso dimer in propan-... 

Chlorocarbonylmethoxy)-4-melhylcoumarin is a reagent related to the above mentioned carbonyl azides [499]. It is prepared from 7-hydroxy-4-methylcoumarin and bromoacelic acid. The resulting carboxylic acid is transformed into the carbonyl chloride by refluxing with thionyl chloride. Derivatives (of prostaglandins and steroids) are formed in carefully dried methylene chloride containing 4-dimethylaminopyridine as catalyst. The esters formed are sufficiently stable for chromatographic separation. 

Identification and quantitative determination of different neutral steroid ester sulfates carried out with adrenal and liver tissues from fetuses at 12-17 weeks of gestation establish that tliese tissues form only monosulfates and that in both adrenals and liver pregnenolone sulfate is quantitatively the most important ester sulfate formed (560 fig/100 g of adrenal tissue and 50 gg/100 g of liver). It lias been su ested that the reduction of the ketonic function in Gn or Cso takes place principally in the liver (Huhtaniemi, JjUukkaiiieii, and Vihko, 1970). 

Since in placental tissues there is an important suifata-se activity and since the fetal compartment is very active in the formation of steroid ester sulfates, most of tlie steroids transferred from tlie fetus to the placenta are ester sulfates, and vice versa, most of the steroids which cross from the placenta to the fetus are in unconjugated form. 

The following acid-catalyzed cyclizations leading to steroid hormone precursors exemplify some important facts an acetylenic bond is less nucleophilic than an olelinic bond acetylenic bonds tend to form cyclopentane rather than cyclohexane derivatives, if there is a choice in proton-catalyzed olefin cyclizations the thermodynamically most stable Irons connection of cyclohexane rings is obtained selectively electroneutral nucleophilic agents such as ethylene carbonate can be used to terminate the cationic cyclization process forming stable enol derivatives which can be hydrolyzed to carbonyl compounds without this nucleophile and with trifluoroacetic acid the corresponding enol ester may be obtained (M.B. Gravestock, 1978, A,B P.E. Peterson, 1969). 

Alkynes undergo stoichiometric oxidative reactions with Pd(II). A useful reaction is oxidative carboiiyiation. Two types of the oxidative carbonyla-tion of alkynes are known. The first is a synthesis of the alkynic carbox-ylates 524 by oxidative carbonylation of terminal alkynes using PdCN and CuCh in the presence of a base[469], Dropwise addition of alkynes is recommended as a preparative-scale procedure of this reation in order to minimize the oxidative dimerization of alkynes as a competitive reaction[470]. Also efficient carbonylation of terminal alkynes using PdCU, CuCI and LiCi under CO-O2 (1 I) was reported[471]. The reaction has been applied to the synthesis of the carbapenem intermediate 525[472], The steroidal acetylenic ester 526 formed by this reaction undergoes the hydroarylalion of the triple bond (see Chapter 4, Section 1) with aryl iodide and formic acid to give the lactone 527(473],... 

Another synthesis of the cortisol side chain from a C17-keto-steroid is shown in Figure 20. Treatment of a C3-protected steroid 3,3-ethanedyidimercapto-androst-4-ene-ll,17-dione [112743-82-5] (144) with a tnhaloacetate, 2inc, and a Lewis acid produces (145). Addition of a phenol and potassium carbonate to (145) in refluxing butanone yields the aryl vinyl ether (146). Concomitant reduction of the C20-ester and the Cll-ketone of (146) with lithium aluminum hydride forms (147). Deprotection of the C3-thioketal, followed by treatment of (148) with y /(7-chlotopetben2oic acid, produces epoxide (149). Hydrolysis of (149) under acidic conditions yields cortisol (29) (181). 

Catalytic hydrogenation of the 14—15 double bond from the face opposite to the C18 substituent yields (196). Compound (196) contains the natural steroid stereochemistry around the D-ring. A metal-ammonia reduction of (196) forms the most stable product (197) thermodynamically. When R is equal to methyl, this process comprises an efficient total synthesis of estradiol methyl ester. Birch reduction of the A-ring of (197) followed by acid hydrolysis of the resultant enol ether allows access into the 19-norsteroids (198) (204). 

The 7 a-bromo steroid (9) can also be treated with sodium phenyl selenolate (41). The resultant 7 P-phenyl selenide (13) can be oxidized and the corresponding phenyl selenoxide elirninated to form the 7-dehydtocholesteryl ester (11). 

The reactivity of various steroid alcohols decreases in the order primary > secondary (equatorial) > secondary (axial) > tertiary. The only systematic investigation relating to the selective protection of steroidal hydroxyl functions has been carried out with the cathylate (ethyl carbonate) group. Since only equatorial hydroxyl groups form cathylates this ester has been used as a diagnostic tool to elucidate the configuration of secondary alcohols. 

Extension of this reaction to other substrates, however, revealed that it is more complex, and that side products are formed depending on (1) the nature of the substrate, (2) the reaction conditions, e.g. temperature and solvent,and (3) the method of work-up." Thus, in addition to the desired substitution products, primary and secondary hydroxy steroids generally yield esters and ethers and undergo simple dehydration as well as dehydration accompanied by rearrangement. 

The required nitrite esters 1 can easily be obtained by reaction of an appropriate alcohol with nitrosyl chloride (NOCl). The 3-nitroso alcohols 2 formed by the Barton reaction are useful intermediates for further synthetic transformations, and might for example be converted into carbonyl compounds or amines. The most important application for the Barton reaction is its use for the transformation of a non-activated C-H group into a functional group. This has for example been applied for the functionalisation of the non-activated methyl groups C-18 and C-19 in the synthesis of certain steroids. ... 

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