Other Reactions of Olefinic Steroids

Other Reactions of Olefinic Steroids.—Reaction of cholest-5-en-3-one with air and acetic acid shows that isomerization to the A -3-oxo-compound is accompanied by autoxidation to the 6a- and 6/8-hydroxy-3-oxo-A -compounds and the 3,6-dioxo-A -compound. The oxidation appears to be controlled by heterolysis of the 4/3-proton and formation of the intermediate ion pair (73). Sitosterol was autoxi-dized at C-7 to give the 7-oxo- and the epimeric 7-hydroxy-derivatives. Oxidation of a 17-methylene steroid with Pb, Tl , and Hg acetates in methanol gave a wide variety of products. The reaction with Pb(OAc)4 gave the rearranged products (74), (75), and (76) whereas the Tl and Hg products retained the 

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Other Reactions of Olefinic Steroids.—[6/3- H]Cholest-4-ene reacts with [Pd(PhCN)2Cl2] to give the a-4-617 and /3-4-6t/ PdCl derivatives with stereospecific syn elimination of the 6-H or 6- H, confirming that in the case of the 3-oxo-A -steroids the high proportion of anti elimination must be attributed to... 

Geometric features of transition states for addition reactions of olefins (Chapter 3), bimolecular substitutions (Si f3 reactions p. 36), bimolecular eliminations (E2 reactions p. loi) and many other reactions have been defined from studies of a variety of steroid systems (e.g. Fig. la). Reactions proceeding through carboniumions (e.g. Fig.Tb seep. 228) are sensitive to... 

Other examples of the successful displacement of tosylates are the preparation of 31 -, 16a-,16j - and27- labeled steroids. This displacement reaction fails, however, with certain C-18 and C-19 alcohol derivatives which give mainly O—S instead of C—O bond cleavage. Unsatisfactory results were also obtained with sterically hindered tosylate esters at C-11, C-12 and C-20, which give considerable amounts of olefinic products in addition to O—S bond cleavage. ... 

The special potential for constructing double bonds stereoselectively, often necessary in natural material syntheses, makes the Wittig reaction a valuable alternative compared to partial hydrogenation of acetylenes. It is used in the synthesis of carotenoids, fragrance and aroma compounds, terpenes, steroides, hormones, prostaglandins, pheromones, fatty acid derivatives, plant substances, and a variety of other olefinic naturally occurring compounds. Because of the considerable volume of this topic we would like to consider only selected paths of the synthesis of natural compounds in the following sections and to restrict it to reactions of phosphoranes (ylides) only. 

Arnold reported a surprising difference between typical primary alkyl bromides and tosylates on being refluxed for extended periods with potassium /-butoxide in (-butanol tosylates undergo displacement to give /-butyl ethers whereas bromides undergo elimination to the olefin (minor products of other reactions may be formed). Wood and Chang" found that, with DMSO as solvent, these reactions proceed in a matter of minutes, and with steroid tosylates and bromides noted the same difference in the nature of the reactions. 

Tosylhydrazones.—The reaction between suitable tosylhydrazones and alkyl-lithium was reported in 1967 to afford high yields of olefins, the less-substituted olefin being favoured where two possibilities exist (Hoffman-type products). In the reviewer s own experience, and that of other workers,this reaction can be unreliable, giving complex mixtures of products, some containing nitrogen. More recently, it was reported that the reaction succeeds when a limited amount of methyl-lithium in hexane is added dropwise to the steroid tosylhydrazone in tetrahydrofuran, under nitrogen e.g. 2-ene, 3-ene, 6-ene, and 1,3-diene, from... 

Chugaev discovered the formation of olefins from the pyrolysis of xanthates in 1899,5 in connection with his studies on the optical properties of xanthates6 and other compounds.7 He subsequently employed the reaction in his structural investigations of terpenes and steroids, demonstrating its utility as an olefin-forming reaction and as a tool for structural determination. For example, he converted cholesterol into methyl cholesteryl xanthate (4)... 

Many steroidal A -olefins have been protected as the dibromide during reactions of other parts of the molecule with ozone [3], chromium trioxide [4-8], potassium permanganate [9], and osmium tetroxide [9]. Other olefins have been protected in this way from oxidation [10-12] addition reactions [13], catalytic reduction [14, 15] and hydrogenolysis [16]. 

The addition proceeds most smoothly with highly functionalized (more polar) steroids as seen in examples by Bernstein and others. The polar reaction conditions pose solubility problems for lipophilic androstane, cholestane and pregnane derivatives. Improved yields can be obtained in some cases by using dimethyl sulfoxide or t-butanol " as solvents and by using sodium A-bromobenzenesulfonamide or l,3-dibromo-5,5-dimethyl hydantoin (available from Arapahoe Chemicals) as a source of positive bromine. The addition of bromo acetate and bromo formate to steroid olefins has been studied to a limited extent. ... 

Iodine azide, on the other hand, forms pure adducts with A -, A - and A -steroids by a mechanism analogous to that proposed for iodine isocyanate additions. Reduction of such adducts can lead to aziridines. However, most reducing agents effect elimination of the elements of iodine azide from the /mwj -diaxial adducts of the A - and A -olefins rather than reduction of the azide function to the iodo amine. Thus, this sequence appears to be of little value for the synthesis of A-, B- or C-ring aziridines. It is worthy to note that based on experience with nonsteroidal systems the application of electrophilic reducing agents such as diborane or lithium aluminum hydride-aluminum chloride may yet prove effective for the desired reduction. Lithium aluminum hydride accomplishes aziridine formation from the A -adducts, Le., 16 -azido-17a-iodoandrostanes (97) in a one-step reaction. The scope of this addition has been considerably enhanced by the recent... 

Some new examples of cyclosteroid formation by homo-allylic participation have appeared recently. Hydrolysis of the A -19-mesylate (4) proceeded with z -electron participation to give the 5j(5,i9-cyclo-6 -ol (5) [6sa] or the related A -olefin (6) [64] according to the reaction conditions. Further studies on these compounds [63,65,66,6 ]] revealed other complicated transformations which must proceed through carbonium ion intermediates. Recent work by Tadanier [66,6]] indicates that two distinct non-classical carbonium ions are involved. Buffered solvolysis of the A -ig-mesylate (4) gives the ion represented by resonance between the canonical structures (A), or by the non-classical structure (B). Stereoelectronic factors of the type discussed for i-steroids ensure 6jS-attachment of a nucleophile in forming the 5jS, 19-cyclosteroid (5). This appears to be the initial product of a kinetically-controlled process, for a further rearrangement occurs in weakly acidic... 

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