Steroidal 5,7-dienes

The double bond migration in steroid hydrocarbons catalyzed by acids or noble metals (see, for example, ref. 185) will not be discussed here. A general review of nonsteroid olefin isomerization has recently been published. Iron carbonyl has been used to isomerize steroidal dienes. 

Enolate trapping, 97 Epoxidation of steroidal dienes, 7 Epoxidation of steroidal monoenes, 2 4, 5/3-Epoxycholestan-3 -ol, 27 5a,6a-Epoxy-5a-cholestan-3 -ol, 82 5a,6a-Epoxy- 17-cy anoandr ost-16-en-3 jS-ol acetate, 20... 

The reaction of benzyne with cyclohexadiene has been known for some time 4>, but although a number of steroidal cis-dienes are readily available no reactions with arynes had been reported prior to our beginning such investigations 145>. This was somewhat surprising in view of the number of reports concerning the modification of steroids by means of reactions with carbenes 146 i49) and the known Diels-Alder reactions of steroidal dienes and trienes iso.isi). 

Interaction, in presence of diluent below 0°C, with isopropylamine or isobuty-lamine caused separation of explosive liquids, and with aniline, phenylhydrazine and 1,2-diphenylhydrazine, explosive solids [1], In absence of diluents, contact with most aliphatic or non-aromatic heterocyclic amines often leads to uncontrolled oxidation and/or explosions [2], During oxidation of two steroidal dienes in dry pyridine at —35 to —40°C, on one occasion each of the reactions was accompanied by violent explosions [3],... 

The fact that PTAD readily reacts with 5,7-steroidal dienes to form the Diels-Alder adducts, whereas the isomeric 4,6-diene remains unchanged can be used for their separation. Owing to the significant differences in the polarity of these compounds, they can be separated sometimes by simple crystallization <2004JOC8529>. Similarly, the reaction can be used for purification of the 5,7-dienes from other impurities <2005H(65)2107>. 

Novel steroidal pyridazines are readily prepared from ADC compounds and steroidal A2,4-dienes,163 A14,1 -dienes,164 and A16,20-dienes.165 ADC compounds are also commonly used in the protection of the steroid 5,7-diene system (see Section V,A). These Diels-Alder adducts of steroidal dienes and azo dienophiles should not be confused with the so-called azasteroids, which are also prepared from ADC compounds. Cyclic ADC compounds such as the pyrazole-3,5-diones (7), and the diazaquinones 12 and 13 readily add to dienes to give bicyclic pyridazine derivatives,166168 and these reactions have been adapted to the synthesis of 5,10-diazasteroids (106).42 Similarly, the 13,14-diaza- (107) and 13,14,16-triazasteroid (108) ring systems have been prepared.169... 

Microwave-assisted Heck reactions have also been carried out with triflates as coupling partners, involving some very complex molecules. Winterfeld and coworkers have reported a multigram synthesis of a complex non-symmetrical bis-steroidal diene by microwave-promoted coupling of the corresponding alkene and triflate steroidal moieties (Scheme 6.8) [27]. 

The iron carbonyl complex [Fe(CO)5] in basic media hydrogenated steroidal dienes selectively (equations 10-12)30. 

However, too few examples are available to allow a general prediction of the position for hydrogen attachment. Electrochemical reduction of 1,4-diphenylbutadiene gives products from both 1,2- and 1,4-attachment of hydrogen [6], The 1,2-addition product predominates in absence of a good proton donor because electro-chemically generated base catalyses isomerisation of the 1,4-addition product. Reduction of a steroid diene 4 gives the 1,4-addition product [17],... 

Although epoxidation reactions are treated in detail elsewhere in these volumes, it should be mentioned here that a template ester attached to a steroid alkene can direct epoxidation to remote double bonds using the general concepts of remote functionalization. Steroidal diene (5) underwent the epoxidation shown (Scheme 13) with excellent regiochemical and stereochemical control. The product was formed in quantitative yield, although the reaction was carried through to only 25% conversion. 

STEROID DIENES 4,Phenyl-l,2,4-t riazo line-3,5-dione. 

In Situ Preparation of 5H-1,2,4-THazole-3,5(4//)-diones and Their Cycloaddition to Steroidal Dienes General Procedure101 ... 

Comparison of 17a-methyl-17)8-hydroxy-5a -androstano[3,2-r] pyrazole (D-l 1), 17a-methyl-17)8-hydroxyandrost-4-eno[3,2-c]pyrazole (A-157), and 17a-methyl-17/3-hydroxyandrost-4,6-dieno[3,2-c]pyrazole (A-168) showed that as the degree of unsaturation is increased there is a corresponding decrease in the anabolic and androgenic activities, with the last compound (A-168) having complete loss of these activities. It was suggested [124] that the anabolic and androgenic properties of this compound were lost due to the flattening imposed by the steroidal diene system. It was also found that introduction of an additional double bond between carbons 6 and 7 in 4-chlorotestosterone acetate (S-I48) results in the complete loss of activity (compare with S-146). 

A number of steroidal dienes have been selectively hydrogenated at the sterically less-hindered position using various catalysts. Raney nickel and PtOa are the most commonly used heterogeneous catalysts for this purpose. Several examples of selectivity in heterogeneous catalytic hydrogenation of dienes are illustrated in Scheme 88. ... 

A very interesting way to control alkene epoxidation was introduced by Breslow and Meresca. In the steroid diene, 77, epoxidation takes place exclusively at the 4,5 double bond using Mo(CO)6 and TBHP. However, by attaching a template, as in 78, to the alcohol, the regioselectivity could be inverted so that epoxidation takes place only at the 17,20 double bond. It was concluded that the appendage did not act as a steric shield, but the remote tertiary alcohol moiety was transformed in situ to a hydroperoxide resulting in the observed selectivity by intramolecular epoxidation. This approach was then extended to other functionalized polyenes, such as famesol and geranylgeraniol. ... 

Steroidal A2-4- and A5 7-dienes form tricarbonyliron complexes in 30-70% yielt when treated with iron pentacarbonyl. Transoid A3 5- and A4-6-diencs under the same conditions give the complex of A2-4-dienes. The cisoid A2,4-diene can be recovered by treatment with ferric chloride. It is thus possible to convert heteroannular steroidal dienes into the less stable homoannular isomer.7... 

Diels-Alder dienes Benzene, see Dicyanoacetylene. Cyclooctatetraene, see 4-Phenyl-l,2,4-triazoline-3,5-dione. Cyclopentadiene ketals. cis-7,8-Dichlorobicyclo[4.2.0]octadiene-2,4, see cis-3,4-Dichlorocyclobutene. 5,5-Dimethoxy-l,2,3,4-tetrachlorocyclopentadiene. Hexa-chlorocyclopentadiene. Methyl tra .rl2,4-pentadienoate. A 4 l6-Steroid dienes, see 4-Phenyl-l,2,4-triazoline-3,5-dione. Tetrachlorocyclopentadienone ethylene ketal ... 

The classic Diels-Alder reaction continues to be applied to steroidal dienes and has been used to prepare benzene-fused compounds (277) (from 6-methylene testosterone ), and (278) and (279) [from the furano-steroid (217) ] and adducts between A -dienes and methyl acrylate, hexafluorobut-2-yne, dimethylacetylene dicarboxylate, and methyl propiolate have been obtained. In this last reaction the mono-adduct (280) was accompanied by a diadduct, assigned the structure (281), which arises from homo-conjugate Diels-Alder addition and which appears to be the first example of homo-conjugate addition to a substituted bicyclo[2,2,l]heptadiene. The diadduct was also obtained in good yield by treatment of the mono-adduct with more methyl propiolate. 

The structurally related steroidal diene 3 was hydrogenated in pyridine to the c/.v-fused product 4, but under these reaction conditions the benzylic double bond was not affected6. 

An empirical method of calculating the position of the long wavelength absorption maximum of any steroid diene has been proposed by Fieser, Fieser and Rajagopalan17. The method is described in Table 7.1. 

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