Methyl group angular

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). 

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. 

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. 

Cleavage of cyclopropyl rings in the presence of an acid or base is illustrated by tlie tritiation of the 19-angular methyl group in 5, 19-cycloandrostane-3, 17-dione [(239) (240) R = T]. This reaction is carried out by heating... 

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... 

Severe nonbonded interactions with the angular methyl groups at C-10 and C-13 and the 8/ -hydrogen strongly hinder formation of tetrahedral derivatives of the 11-ketone. The formation of protecting groups is therefore difficult to achieve. 

SELECTIVE FUNCTIONALIZATION OF THE ANGULAR METHYL GROUP AND FURTHER TRANSFORMATION TO 19-NORSTEROIDS... 

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. 

The following diagram illustrates the positions from which attack at the angular methyl groups has been realized. 

The oxidation of alcohols with lead tetraacetate was the first reaction used for oxygenation of an angular methyl group in steroids. It is a simple and efficient method and produces tetrahydrofuran derivatives directly from alcohols. 

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. 

Ethers have been prepared by the thermal lead tetraaeetate method in 60-71% ° yield. Introduction of an axial 3a-acetoxy function into 5a-H steroids, however, seems to change the conformation of ring A in such a way that the distance of the 2/ -oxygen from the angular methyl group is considerably increased. Consequently the 2/5,19-ether is formed in only 0.7% to 24% yield. " 02... 

The thermal lead tetraaeetate method has no practical value for the substitution of the angular methyl groups from 11/5-hydroxy steroids. The major product is either the 11-ketone" or the lla,l-ether formed by rearrangement if ketone formation is suppressed. " ... 

N-chloroamine functionalization of the angular methyl group preparation of 3/3-hydroxy-18-chloro-20a-methylamino-5a-pregnan-l l-one trifluoroacetate, 259... 

Lead tetraacetate functionalization of the angular methyl group... 

Oxygenation of angular methyl groups, 240 Ozone, 17, 161 Ozonolysis, 158, 431... 

This procedure has been used to introduce angular methyl groups (methyl groups at the bridgeheads of fused rings). ... 

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