Oxidation studies on steroid hormone analogues
In Part I, a short introduction describes the chemistry and properties of quinonemethides and of the styrene, 178-hydroxy-5-methoxy-de-A-oestra-5,7,9,14-tetraene, with emphasis on possible routes of its transformation into the extended quinones, de-Aoestra-6,8(14),9,l5-tetraene-5,17-dione and de-A-oestra-6,8(14) 9,16-tetraene-5,15dione. In Chapter 1 the attempted peracid epoxidation of the h 4-bond of the styrene which afforded the ketols, 14a- and 148,178-dihydroxy-5-methoxy-de A-oestra-5,7,9triene-l5-one, is described. The difficult configurational assignment at C14 ofthe ketols was made from comparison of spectral data (particularly 1H-NMR and CD) with that of related steroids. A mechanism of formation of the ketols is proposed, in which the initially formed 14,15-epoxide undergoes ring opening under the influenceof the electron release of the 5-methoxyl substituent, and thus explains why the 14,15- cepoxide of the styrene could not be isolated even from peracid oxidation under talkaline conditions. The 15,178-dihydroxy-5-methoxy-de-A-oestra-5,7,9,14-tetraene E derived from ring opening of the 14,15-epoxide of the styrene, is suggested to undergoepoxidation at the A34-bond more rapidly than initial epoxidation of the A14-bond of i the styrene thus accounting for ketol isolation on oxidation of the styrene with one equivalent of oxidant. The A16-15-ketone obtained by elimination of acetic acid during acetylation of the 148-ketol, as compared with the 14a-ketol, is explained by conformational differences between these two epimers. The A16-15-ketone underwent rearrangement to a lactone. The 13C NMR spectra of 14a,178-dihydroxy-5-methoxy-deA-oestra-5,7,9-triene-15-one and its analogues were also of value during structural elucidation.The use of chromium(VI) rea*ents for the oxidation of 178-hydroxy-5-methoxy-deA-oestra-5,7,9-triene and its AI -analogue to their 17-ketone derivatives is discussed in Chapter 2. Mechanisms are presented for the formation of 148-hydroxy-5-methoxyde-A-oestra-5,7,9,15-tetraene-l7-one from DDQ oxidation of 5-methoxy-de-A-oestra5,7,9-triene-l7-one and from chromium trioxide-pyridine oxidation of 178-hydroxy-5methoxy-de-A-oestra-5,7,9,14-tetraene, with evidence in support of the involvement of 5-methoxy-de-A-oestra-5,7,9,14-tetraene-l7-one. A16-15-Ketones were formed from 14a,178-dihydroxy-5-methoxy-de-A-oestra-5,7,9-triene-15-one during demethylation and deoxygenation.The formation of the acetal 6-methoxy-2-methyl-2-(3',3'-dimethoxy-1'-hydroxy propyl)-l-tetralone, from photo-oxidative cleavage of the styrene, 178-hydroxy-5methoxy-de-A-oestra-5,7,9,l4-tetraene, is described in Chapter 3. The proposed mechanism for the formation of this acetal involves reaction of the styrene with singlet molecular oxygen (102). The electron releasing effect of the 5-methoxyl substituent initiates cleavage of the intermediate dioxetane to two carbonyl fragments which undergo solvent addition. The 6-methoxy-2-methyl-l-tetralone isolated as a minor component, from photo-oxygenation of the styrene, is formed by a retro-Aldol cleavage of the photoproduct. Clear evidence is given to show that the photooxygenation of the styrene can be autosensitized.Part II deals with the unexpected formation of substituted 2-methyl-l-naphthols, and their coupling to binaphthyl dimers, during catalytic transfer hydrogenation of the corresponding 2-benzoyloxymethylene-l-tetralones. Evidence is presented to show that a methoxyl substituent, substituted in the aromatic ring of the 1-tetralone derivative, is required for coupling to occur and that the coupling reaction involves aerial oxidation of the corresponding-l-naphthols. The site of methoxyl substitution in the aromatic ring of the 2-benzoyloxymethylene-l-tetralone derivatives was also shown to be an important factor in determining the reaction products. The mechanism of formation of the 2-methyl-l-naphthols is rationalised as tautomerisation of an intermediate 2-methylene-l-tetralone and involves dehydrogenation via the catalyst (10% Pd/C). Reaction temperature and hydrogen donating ability of the solvent were shown to be important factors since reaction of 2-benzoyloxymethylene-l-tetralone with 102 palladium on charcoal in toluene (a poor hydrogen donor) gave coupled products together with a thermally rearranged product of the 1-tetralone derivative, 1-naphthyl benzoate. The formation of 2-acetoxy-6-methoxy-2-methyl-l-tetralone during enol-acetylation of 6-methoxy-2-methyl-l-tetralone has been shown to involve aerial oxidation of the initially formed enol-acetate (which also undergoes thermal rearrangement to 6-methoxy2-methyl-l-naphthyl acetate). The 13C NMR spectra of 2-acetoxy-6-methoxy-2-methyl-ltetralone and related compounds are discussed.