Steroid 19-methyl groups

Lactones from alcohols Functionalization of steroid 18-methyl groups... 

Oximinoalcohols from nitrous acid esters Functionalization of steroid 18[Pg.98]

The photolysis of nitrite esters has been found to be of considerable synthetic utility, particularly in functionalizing steroid methyl groups. The most spectacular application of this reaction has been a three-step synthesis of aldosterone.<59) Irradiation of corticosterone-11-nitrite (30) followed by nitric acid treatment gave aldosterone (32) in a 15% overall yield ... 

An unactivated methyl group can be functionalized by the cyclopalladation of oximes. The equatorial methyl of geminal methyls in steroids or hexapyr-anosides is selectively aceto.xylated by the reaction of the palladation complex 523 of the 3-oxime with lead tetraacetate[467,468]. 

Allyl aryl ethers are used for allylation under basic conditionsfh], but they can be cleaved under neutral conditions. Formation of the five-membered ring compound 284 based on the cyclization of 283 has been applied to the syntheses of methyl jasmonate (285)[15], and sarkomycin[169]. The trisannulation reagent 286 for steroid synthesis undergoes Pd-catalyzed cyclization and aldol condensation to afford CD rings 287 of steroids with a functionalized 18-methyl group 170]. The 3-vinylcyclopentanonecarboxylate 289, formed from 288, is useful for the synthesis of 18-hydroxyestrone (290)[I7I]. 

Cholesterol was isolated m the eighteenth century but its structure is so complex that Its correct constitution was not determined until 1932 and its stereochemistry not verified until 1955 Steroids are characterized by the tetracyclic ring system shown m Figure 26 9a As shown m Figure 26 9b cholesterol contains this tetracyclic skeleton modified to include an alcohol function at C 3 a double bond at C 5 methyl groups at C 10 and C 13 and a C Hn side chain at C 17 Isoprene units may be discerned m var lous portions of the cholesterol molecule but the overall correspondence with the iso prene rule is far from perfect Indeed cholesterol has only 27 carbon atoms three too few for It to be classed as a tnterpene... 

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... 

Interest in the synthesis of 19-norsteroids as orally active progestins prompted efforts to remove the C19 angular methyl substituent of readily available steroid precursors. Industrial applications include the direct conversion of androsta-l,4-diene-3,17-dione [897-06-3] (92) to estrone [53-16-7] (26) by thermolysis in mineral oil at about 500°C (136), and reductive elimination of the angular methyl group of the 17-ketal of the dione [2398-63-2] (93) with lithium biphenyl radical anion to form the 17-ketal of estrone [900-83-4] (94) (137). 

According to measurements on steroidal diazirines (49) there is also a high field shift of equatorial methyl groups, although their protons are more distant by one position from the diazirine ring. Reported values lie between 0.1 and 0.2 p.p.m., about 0.8 p.p.m. higher than in alkanes (65JA2665). 

Addition of hydride ion from the catalyst gives the adsorbed dianion (15). The reaction is completed and product stereochemistry determined by protonation of these species from the solution prior to or concurrent with desorption. With the heteroannular enolate, (13a), both cis and trans adsorption can occur with nearly equal facility. When an angular methyl group is present trans adsorption (14b) predominates. Protonation of the latter species from the solution gives the cis product. Since the heteroannular enolate is formed by the reaction of A" -3-keto steroids with strong base " this mechanism satisfactorily accounts for the almost exclusive formation of the isomer on hydrogenation of these steroids in basic media. The optimum concentration of hydroxide ion in this reaction is about two to three times that of the substrate. 

In very dilute base or, preferably, in the presence of weak bases, the homoannular enolate (16) is formed which can be adsorbed in either a cis (17) or a trans (18) manner. In this case the presence of a methyl group results in a slight favoring of trans adsorption, thus leading to the formation of a slight excess of the m-product as is observed on hydrogeneration of A" -3-keto steroids in the presence of triethylamine. ... 

Hydrogenation of 19-nor-A -3-keto steroids also gives 5a- and 5 -product mixtures under the usual conditions but with ruthenium oxide at high pressures only the 5j8-isomer is formed.The presence of a 4-methyl group on a A -3-keto steroid increases the amount of a attack as compared to the parent enone. ... 

The most frequently encountered examples of cyclopropyl ring opening reactions in the steroid field are usually associated with angular or side chain methylation sequences. In fact, isotope labeling of the C-19 angular methyl group is the only reported application of this reaction for deuteration or tritiation pui poses. 

An example is the preparation of 18-trideuterio 5a-steroids bearing a side chain at C-17. Labeling of this position with three deuteriums was accomplished by utilizing the Johnson procedure for steroid total synthesis. This synthesis involves, in part, introduction of the 18-angular methyl group by methylation of the D-homo-17a-keto-17-furfurylidene intermediate (243). By substituting d3-methyl iodide in this step, the C/D cis- and ra/J5-18,18,18-d3 labeled ketones [(244) and (245)] are obtained. Conversion of the C/D tra 5-methylation product (245) into 18,18,18-d3-d /-3)8-hydroxy-5a-androstan-17-one (246) provides an intermediate which can be converted into a wide variety of C-18 labeled compounds of high (98%) isotopic... 

Difluorocarbene reacts with A -steroids (19) bearing a 10 -methyl group affording both the 3a,4a- (20) and 5, 6 -adducts (21), an exception being 17a-acetoxypregna-3,5-dien-20-one, which gives only the 3a,4a-product... 

In general, epoxidation of steroids with trans-anti-trans ring fusions leads to exclusive formation of the a-oxirane. Steroid Reactions lists examples of exclusive a-epoxide formation from 2-, 4-, 6-, 7-, 8(9)-, 14-, 16- and 17(20)-unsaturated steroids. Further examples of a-epoxidation of steroid 1-enes, 3-enes, 8-enes, 9(ll)-enes, 8(14)-enes and 16-enes have been reported. The preferred attack by the reagent on the a-side of the steroid nucleus can be attributed to shielding of the -side of the molecules by the two angular methyl groups. 

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