Functionalization steroid methyl group

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 ... 

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]. 

Alkoxy radicals are also the active hydrogen-abstracting species in a procedure that involves photolysis of nitrite esters. This reaction was originally developed as a method for functionalization of methyl groups in steroids.379... 

The Barton reaction" has been applied successfully to functionalize the methyl group C(18) in a D-homo-c-nor-steroid." (see Part II, Chapter 1, ref. 304). 

There are a variety of photochemical reactions involving free nitrous oxide (NO) as persistent radical. Often there is an initial fragmentation, as presented in Scheme 6 for TV, 7V-dimethyl-/V-nitro-samine. One example is the Barton reaction of nitrite esters (Scheme 15). It allows the functionalization of methyl groups in steroids and utilizes an intermediate 1,5-hydrogen atom migration, which converts the initially formed oxygen-centered radical to a carbon-centered species.69... 

Section 12.5. in Part A describes some additional reactions that are of synthetic value and involve intramolecular hydrogen abstraction at unactivated groups. Of particular value is the nitrite photolysis method developed by Barton, which has been important in the functionalization of methyl groups in steroids. 

This reaction was originally developed as a method for functionalization of methyl groups in steroids. 

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]. 

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... 

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 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. ... 

Synthetic Applications of the Diels-Alder Reaction. Diels-Alder reactions have long played an important role in synthetic organic chemistry.74 The reaction of a substituted benzoquinone and 1,3-butadiene, for example, was the first step in one of the early syntheses of steroids. The angular methyl group was introduced by the methyl group on the quinone and the other functional groups were used for further elaboration. 

Functionalization of the methyl groups in the photolysis of the nitrites of 6-hydroxy-4,4-dimethyl steroids is used as a probe for conformational analysis. It is confirmed that in the 4,4-dimethyl-19-nor-series ring A has the normal chair... 

It was shown by Barton et al. that the photolysis of steroidal nitrites 50 proceeding by formation of alkoxy radicals could result in hydrogen abstrae-tion from suitably situated methyl groups forming earbon-centered radicals, which then reacted with the NO generated to give oximes (equation 79). This permitted the functionalization of the unaetivated centers. 

Ketones have an acyl group with another alkyl or aryl group connected to the carbonyl carbon. Many steroid hormones contain ketone functionality, e.g. testosterone and progesterone. The simplest ketone is acetone (CH3COCH3), where the carbonyl carbon is bonded to two methyl groups. 

In the steroid series photochemical rearrangement of hypochlorites of the type A - B (X = halogen) were first used successfully at the Institute to functionalize the 18- and 19-methyl groups.51-63 Thus the hypochlorite (5) on irradiation gave the corresponding chlorohydrin which was smoothly cyclized to the ether (6, X = H2) oxidation of the ether to the lactone (6, X = O) constituted a formal proof of its structure. 

The y-effect is also evidenced by steroid epoxides. (55) Thus, the a-epoxide of 17/7-acetoxy-5cr-androst-2-ene shows a 5-3 ppm shielding at C-5 compared with the /7-epoxide. A variety of other epoxides have also been studied. When a methyl group is adjacent to the epoxy function rather unusual effects are noted due to deformations of the half chair conformations of the steroid ring bearing the epoxide. (56)... 

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