17-Acetyl steroids

Some deviations from this normal route which involves an oxirane intermediate occurred in sterically hindered ketones. For example, 2,2,6,6-tetramethyl-4-piper-idine underwent a-methoxylation (20%) [19], whereas cholestanone yielded a product of Favorski-type rearrangement [21], In 17-acetylated steroids the reaction with DIB-MeOH-KOH was normal but in 17-hydroxy-17-acetyl-steroids intramolecular cyclization occurred with formation of oxetanones [22] ... 

Limited studies have been done on template-directed chlorination on the -face of steroids. Compound (15 Scheme 19) was designed so that die template could curve around the angular C-18 methyl group and direct chlorination to C-20. Reaction with an excess of PhICh led to ca. 40% chlorination of C-20 with 25% unftmctionalized steroid. The 20-chloro steroid was converted in part to the which was ozonized to form the 17-acetyl steroid (15). A similar result was observed with the i-steroid derivative (17). The selectivities and yields are not yet up to those of other examples of the radical relay reaction. 

Acetyl steroids. 17-Keto steroids can be converted into 17-acetyl steroids by reaction with tosylmethyl isocyanide. The resulting nitriles are obtained as epimeric mixtures in which the 17)3-epimer predominates. The mixtures can be separated by crystallization or chromatography. The 17-carbonitriles are converted into 17-acetyl steroids in satisfactory yield by brief treatment with methyllithium. ... 

Like in Chapt. 7, we begin the discussion with acetates, since acetic acid is the simplest nontoxic acyl group, formic acid being less innocuous. An informative study was carried out to compare the kinetics of hydrolysis of two types of corticosteroid esters, namely methyl steroid-21-oates (which are active per se) and acetyl steroid-21-ols (which are prodrugs), as exemplified by methyl prednisolonate (8.69) and prednisolone-21-acetate (8.70), respectively [89]. In the presence of rat liver microsomes, the rate of hydrolytic inactivation of methyl steroid-21-oates was much slower than the rate of hydrolytic activation of acetyl steroid-21-ols. Thus, while the Km values were ca. 0.1 -0.3 mM for all substrates, the acetic acid ester prodrugs and the methyl ester drugs had Vmax values of ca. 20 and 0.15 nmol min-1 mg-1, respectively. It can be postulated that the observed rates of hydrolysis were determined by the acyl moiety, in other words by the liberation of the carboxylic acid from the acyl-enzyme intermediate (see Chapt. 3). 

D. Kumari, H. J. Lee, Hydrolysis of Methyl Steroid-21-oates and Acetyl Steroid-21-ols by Rat Liver Microsomes , Drug Metab. Dispos. 1985, 13, 627-629. 

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. 

Methyl group (Section 2 7) The group —CH3 Mevalonic acid (Section 26 10) An intermediate in the biosyn thesis of steroids from acetyl coenzyme A Micelle (Section 19 5) A sphencal aggregate of species such as carboxylate salts of fatty acids that contain a lipophilic end and a hydrophilic end Micelles containing 50-100 car boxylate salts of fatty acids are soaps Michael addition (Sections 18 13 and 21 9) The conjugate ad dition of a carbanion (usually an enolate) to an a 3 unsatu rated carbonyl compound... 

CH2=C=0- r-BuOK, THF. The 17Q -hydroxy group of a steroid was acetylated by this method. 

The enolization of 5a-3-ketones appears to be cleanly directed to C-2, whereas that of 5j5-3-ketones is less selective. Remote substituents can have a significant effect on the kinetic and thermodynamic enol acetylation of 5j3-steroids. ... 

Iodine azide is a highly selective reagent addition to the 16-double bond of androsta-4,16-diene-3-ones is possible and some selectivity in addition to the 16-double bond of A -dienes has been observed.Hydroxy groups in the steroid should be protected, e.g., by acetylation, since in some instances oxidized side products are formed. 

The properties of chlorine azide resemble those of bromine azide. Pon-sold has taken advantage of the stronger carbon-chlorine bond, i.e., the resistance to elimination, in the chloro azide adducts and thus synthesized several steroidal aziridines. 5a-Chloro-6 -azidocholestan-3 -ol (101) can be converted into 5, 6 -iminocholestan-3l -ol (102) in almost quantitative yield with lithium aluminum hydride. It is noteworthy that this aziridine cannot be synthesized by the more general mesyloxyazide route. Addition of chlorine azide to testosterone followed by acetylation gives both a cis- and a trans-2iddMct from which 4/S-chloro-17/S-hydroxy-5a-azidoandrostan-3-one acetate (104) is obtained by fractional crystallization. In this case, sodium borohydride is used for the stereoselective reduction of the 3-ketone... 

A methyl group at C-16 hinders addition to the double bond and the reaction then proceeds normally and in good yield to the 16-methyl-17-acetyl-amino steroid, which gives the 16j9-methyl-17-ketone on hydrolysis. 

Since many steroidal double bonds will react with peracids, these must be protected before the enol acetylation step. Chlorination is generally satisfactory for this purpose. ... 

Esters and acetylated hydroxyl groups are completely stable under the experimental conditions, but with ketals 10 29,110,112 yields are generally observed in the thermal reaction. Double bonds do not seem to interfere seriously with the course of the reaction provided that the geometric relationship of the free hydroxyl group to the angular methyl group is not changed drastically. In some cases allylic acetoxylation occurs, e.g., at C-7 of A -steroids. ° Ketones are usually stable (especially under photo-lytic conditions) but occasionally a-acetoxylation has been observed. 

With saturated 6/ -hydroxy compounds containing only acetylated hydroxyl groups, 6/5,19-ethers are formed in 70-90% yield. " In the case of 5a-chloro-6a-hydroxy steroids up to 67% yield of 6/ ,19-ethers have been obtained, whereas with 6/5-hydroxy-3,20-diketals, yields are in the order of 10-20%. 6/5,19-Ethers are only formed in low yield from 6a-methyl-6/5-hydroxy steroids because of extensive eleavage of the 5,6-bond. In one case at 46% yield of crude ether was claimed. ... 

A considerable extension of the synthetic utility of the hypoiodite reaction is achieved if the steroid hypoiodite (2) is generated from the alcohol and acetyl hypoiodite and then decomposed in a nonpolar solvent. In this case ionic hydrogen iodide elimination in the 1,5-iodohydrin intermediate (3) is slow, thereby allowing (3) to be converted into an iodo hypoiodite (5). 

Lead tetraacetate fragmentation has not been applied to the 20-hydroxy-18, 20-cyclo steroids. However, preferential cleavage of the 17,20-bond would be expected, as was observed in the chromic acid oxidation of a saturated 20-hydroxy-18,20-cyclo steroid in hot acetic acid which affords the 18-acetyl-17-ketone in 50-60% yield. 

Mevalonic acid (Section 26.10) An intermediate in the biosynthesis of steroids from acetyl coenzyme A. 

N-acyl enaminc (104, R = CHjCHj) gave an unstable enamine (106) which decomposed readily to 3-cholestanone. The steroidal N-acetyl enamines (107 and 108, R = C HjCHj) can be reduced by lithium aluminum hydride in tctrahydrofuran to the corresponding enamines (109, R = CJH5CH2) in 90 and 68% yield, respectively 100). Attempts to reduce the enamide (107, R = CH3) led to the formation of the impure enamine (109, R = CHj), which decomposed to the hydroxy ketone (110). 

Conversion of A -3-ketosteroids or their trimethylsilyl or acetyl derivatives in fluorescent components, whereby the detection limits were improved by 65% for the acetates. A -3-keto- and A -3-OH-steroids also react with the same sensitivity. 

Acetyl-CoA is also used as the precursor for biosynthesis of long-chain fatty acids steroids, including cholesterol and ketone bodies. 

Figure 26-3. Biosynthesis of cholesterol. The numbered positions are those of the steroid nucleus and the open and solid circles indicate the fate of each of the carbons in the acetyl moiety of acetyl-CoA. Asterisks Refer to labeling of squalene in Figure 26-2.

Cholesterol is synthesized in the body entirely from acetyl-CoA. Three molecules of acetyl-CoA form mevalonate via the important regulatory reaction for the pathway, catalyzed by HMG-CoA reductase. Next, a five-carbon isoprenoid unit is formed, and six of these condense to form squalene. Squalene undergoes cychzation to form the parent steroid lanos-terol, which, after the loss of three methyl groups, forms cholesterol. 

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