The synthesis of derivatives of the boar taint steroid
In chapter one the literature of androst-16-enes is reviewed, showing how the economic importance of these steroids is due to both porcine physiology and human sensibilities. Their biosynthesis and physiological function in the pig are discussed showing their relationship to meat producting potential. Their effects upon meat and consumer opinion are detailed together with a discussion of the drawbacks of conventional methods of taint elimination. The chemical generation of Δ¹⁶ bonds is also reviewed with a discussion of the limitations of various methods. Lastly the idea of auto-immunization is explained showing how it may have an important role to play in the solution of the boar taint problem. In chapter two a ring C derivative of androstenone, its llα hemisuccinate, was synthesised from adrenosterone in seven steps. The catalytic hydrogenation and selective ketalization procedures used in the first two steps were optimised. Conversion of the 17-ketone to a Δ¹⁶ bond by Barton's reaction of hydrazones requires sodium reduction of a vinyl iodide to yield the olefin and these conditions caused the reduction of the 11-carbonyl to an llα-hydroxyl group. This was esterified with succinic acid, and after hydrolysis of the 3-ketal, gave the desired hemisuccinate. In chapter 3 a ring B substituted androstenone, its 7-carboxymethoxyloxime, was synthesised from DHEA (androst-5-ene-3β-ol-l7-one) in eleven steps. Ring B was functionalized by allylic oxidation of the Δ⁵ bond to an unsaturated ketone. Removal of the Δ⁵ bond by catalytic hydrogenation and protection of the 7-carbonyl allowed the selective conversion of the 17-ketone to a Δ¹⁶ bond. Deprotection of the 7-ketone, its condensation with carboxymethoxylamine, and oxidation of the 3-hydroxyl to a carbonyl group yielded the product. The use of MS and ¹³C NMR data in differentiating between the ketones and ketals produced is demonstrated. In chapter 4 an isomer of androstenone with inverted configuration at C₁₄ (14β) was synthesised from 5α,14α-androstan-3β-ol-17-one using various synthetic strategies. The final route chosen allows for high yield inversion at C₁₄ in five simple steps. Unsaturation is introduced by bromination and dehydrobromination, but the spontaneous isomerisation of the initial product requires conversion of the isomers produced to a common product, the Δ¹⁴ -7 ketal, before catalytic hydrogenation is used to give the inverted configuration Hydrolysis of the ketal allows the conversion of the 17-carbonyl group to a Δ¹⁶ bond by Barton's reaction of hydrazones. The 3β-hydroxyl was oxidised to a carbonyl group with chromic acid to give 5α,14β-androst-l6-ene-3-one. In chapter five an interesting epoxidation observed during work on ring B functionalization is examined further. Under the same conditions as a Δ⁵ bond is allylically oxidised a Δ¹⁶ bond is epoxidised. Studies with simple analogues and analysis of the by-products of earlier oxidations suggest that an explanation more complicated than ring size or simple steric hindrance is required. This is confirmed by the relationships between the differences in reaction products and molecular conformation observed upon inversion of configuration at C₁₄. The results are explained in terms of a recent theory on the mechanism of oxidations by metal oxides. This requires consideration of the relationship between the orientation of the axial allylic proton and the hindrance at the olefinic bond. In chapter six an unexpected reduction led to the proposal that under certain conditions hydroxylamine can condense to form diazene, a known reductant. A recent paper upon a similar system contained a mechanism that would only explain both sets of results if modified substantially. The reasoning behind these modifications is given, along with a possible explanation for other anomalous results in this chapter.