Metal-ammonia reductions and synthesis of steroid hormone analogues

Abstract

The thesis entitled "METAL-AMMONIA REDUCTIONS AND SYNTHESIS OF STEROID HORMONE ANALOGUES" consists of three chapters.

Chapter I has been divided into four sections.

Section I is a brief review on the hydrogenation of unsaturated systems with metal-ammonia solutions.

Section II describes the metal-ammonia reductions and reductive methylations of 1-acetylnaphthalene, 2-acetylnaphthalene, and 6-methoxy-2-acetylnaphthalene. Reduction of 1-acetylnaphthalene with lithium, sodium, or potassium (2 atoms or excess), followed by quenching the reaction with ammonium chloride, sodium benzoate, or ethanol, gave 1-acetyl-3,4-dihydronaphthalene. Reductive methylation of 1-acetylnaphthalene with lithium (2 atoms or excess) or with sodium and potassium (2 atoms) gave 1-acetyl-1-methyl-1,4-dihydronaphthalene; with excess sodium or potassium, a mixture of 1-propionyl-1-methyl-1,4-dihydronaphthalene and 1-acetyl-1-methyl-1,4-dihydronaphthalene was obtained. A possible mechanism has been discussed.

Reduction of 2-acetylnaphthalene with 4 atoms of lithium or sodium, followed by quenching with ammonium chloride or sodium benzoate, gave an equimolecular mixture of 2-acetyl-1,2,3,4-tetrahydronaphthalene and the corresponding alcohol; reduction of 2-acetylnaphthalene with 4 atoms of potassium gave exclusively 1,4-dihydro-2-acetylnaphthalene. Reduction in the presence of a trace of anhydrous ferric chloride gave only 1,4-dihydro-2-acetylnaphthalene. Reductive methylation of 2-acetylnaphthalene with 4 atoms or excess lithium gave 2-methyl-2-acetyl-1,2,3,4-tetrahydronaphthalene; with lithium in the presence of anhydrous ferric chloride, it gave 2-methyl-2-acetyl-1,2-dihydronaphthalene. Using 4 atoms of sodium, a mixture of 2-acetyl-2-methyl-1,2,3,4-tetrahydronaphthalene and 2-propionyl-2-methyl-1,2,3,4-tetrahydronaphthalene was obtained; with excess sodium, only 2-propionyl-2-methyl-1,2-dihydronaphthalene was obtained. With potassium (4 atoms), a mixture of 2-methyl-2-acetyl-1,2-dihydronaphthalene and 2-propionyl-2-methyl-1,2-dihydronaphthalene was obtained; with 2 atoms of potassium, a mixture of the starting material and 2-methyl-2-acetyl-1,2-dihydronaphthalene was obtained; with excess potassium, only 2-propionyl-2-methyl-1,2-dihydronaphthalene was obtained.

Similar results were obtained in the reduction and reductive methylation of 6-methoxy-2-acetylnaphthalene with lithium, sodium, or potassium in ammonia. The mechanisms of the reduction and reductive methylation of 2-acetylnaphthalene and 6-methoxy-2-acetylnaphthalene are discussed.

Section III describes the reduction and reductive methylation of 4-keto- and 1-keto-7-methoxy-1,2,3,4-tetrahydrophenanthrene and a modified method for the preparation of 4-keto-7-methoxy-1,2,3,4-tetrahydrophenanthrene. 4-Keto-7-methoxy-1,2,3,4-tetrahydrophenanthrene was prepared earlier starting from 2-methoxynaphthalene in poor yields. Succinoylation of 2-methoxynaphthalene gives a mixture of 5- and 1-substituted naphthoic acids, depending on the solvent and reaction conditions. Maximum yield (25%) of the desired 6-substituted derivative is obtained in nitrobenzene. Our modified method starts from 2-methoxy-1-bromonaphthalene. Succinoylation of 2-methoxy-1-bromonaphthalene in nitrobenzene, carbondisulphide, or methylene chloride gave p-(2-methoxy-1-bromo-6-naphthoyl)-propionic acid in good yield. Clemmensen reduction of this ester gave unexpectedly Y-(2-methoxy-6-naphthyl)-butyric acid, which on cyclisation with polyphosphoric acid–phosphorus oxychloride gave the required ketone in good yields.

Reduction of 4-keto-7-methoxy-1,2,3,4-tetrahydrophenanthrene with lithium, sodium, or potassium (2 atoms or excess), followed by quenching with ammonium chloride, sodium benzoate, or ethanol, gave 4-keto-7-methoxy-1,2,3,4,9,10-hexahydrophenanthrene in good yields. Reductive methylation of the same compound gave only 4-keto-7-methoxy-11-methyl-1,2,3,4,9,12-hexahydrophenanthrene. Reduction of 1-keto-7-methoxy-1,2,3,4-tetrahydrophenanthrene with lithium, sodium, or potassium (4 atoms or excess) followed by quenching gave the cis-1-keto-7-methoxy-1,2,3,4,9,10,11,12-octahydrophenanthrene in good yield. Similar reductions in the presence of anhydrous ferric chloride gave exclusively the octahydro derivative. Reductive methylation of 1-keto-7-methoxy-1,2,3,4-tetrahydrophenanthrene with lithium (4 atoms or excess) afforded a cis-trans mixture of l-keto-7-methoxy-11-methyl-1,2,3,4,9,10,11,12-octahydrophenanthrene in a 4:1 ratio; with sodium (4 atoms), a mixture of cis-trans l-keto-7-methoxy-11-methyl-octahydro derivative and l-keto-7-methoxy-2,11-dimethyl-octahydro derivative was obtained; with excess sodium only the 2,11-dimethyl derivative was obtained; with potassium (4 atoms) a similar mixture was obtained; with excess potassium only the 2,11-dimethyl derivative was obtained. The mechanism of reduction and reductive methylation is discussed.

Section IV deals with the reduction of a few cyclic, p-unsaturated ketones using an improved method and the reduction of a few cyclic styrenoid derivatives. Reduction of carvone with lithium or sodium in the presence of catalytic amounts of anhydrous ferric chloride afforded dihydro-carvone in 90% yield, whereas reduction in the absence of ferric chloride gave 60% yield. Reduction of 3,5-dimethylcyclohexen-1-one with lithium or sodium in the presence of ferric chloride gave 3,5-dimethylcyclohexanone in 80% yield; in the absence of ferric chloride, yield was 50%. Reduction of 1-keto-7-methoxy-1,2,3,4,9,10-hexahydrophenanthrene in the presence of ferric chloride gave cis-1-keto-7-methoxy-octahydro derivative in 90% yield, versus 70% without ferric chloride. Reduction of 1-keto-7-methoxy-11-methyl-1,2,3,9,10,11-hexahydro derivative with lithium or sodium in ammonia, followed by oxidation with Jones reagent, afforded an equimolecular mixture of cis- and trans-1-keto-7-methoxy-11-methyl-octahydrophenanthrene. Reduction of 9(11)-dehydroestradiol-3-methyl ether with lithium or sodium in ammonia, followed by oxidation, gave a mixture of oestrone-3-methyl ether (66%) and 9?-oestrone-3-methyl ether (34%). The formation of the less stable isomer during metal-ammonia reduction is discussed.

Chapter II consists of two sections:

Section I is a brief review of the chemistry of 9-methyl steroids, with special emphasis on their syntheses.

Section II describes the attempted synthesis of 9-methyl-18-nor-steroid hormone analogues starting from 18-nor-14?,17?-iceto-equilenin-3-methyl ether and the corresponding 3-deoxy derivative, based on the results of metal-ammonia reduction and reductive methylation of 1-acetylnaphthalene and 4-keto-7-methoxy-1,2,3,4-tetrahydrophenanthrene.

Chapter III is divided into two sections:

Section I is a brief review of the chemistry of B-nor-steroids with special emphasis on total syntheses and biological activities.

Section II describes the total syntheses of 18-homo-B-nor-oestrone and its 8?- and 9?-iso isomers, and 18-homo-B-nor-19-nor-8?,10?- and 9?,10?-testosterones, starting from 5-methoxy-indan-1-one following Torgov’s method.

Grignard reaction of 5-methoxy-indan-1-one with vinyl magnesium bromide gave 5-methoxy-vinyl-indan-1-ol, which on condensation with 2-ethylcyclopentane-1,3-dione gave a mixture of 18-homo-3-methoxy-B-nor-oestra-1,3,5(10),9(11)-tetraene-8,14-seco-14,17-dione and a new dimeric material. The structure of the dimer was deduced from spectral data and its isomerisation to the known dimer. Cyclodehydration of the 8,14-secodione with methanolic hydrochloric acid gave 18-homo-3-methoxy-B-nor-oestra-1,3,5(10),8-pentaen-17-one. Reduction of the pentaenone with sodium borohydride in methanol afforded the 17?-alcohol. Stereoselective hydrogenation of the 17?-alcohol in the presence of 5% Pd-C gave 18-homo-3-methoxy-B-nor-oestra-1,3,5(10),8-tetraen-17?-ol. Metal-ammonia reduction of the tetraenol afforded 18-homo-B-nor-9?-oestradiol-3-methyl ether, which on oxidation with Jones reagent gave 18-homo-B-nor-9?-oestrone-3-methyl ether. Metal-ammonia reduction of the tetraenol in the presence of aniline afforded a mixture of two isomers, which was directly oxidised with Jones reagent. The structure 18-homo-B-nor-9?-oestrone-3-methyl ether was assigned to the major product and 18-homo-B-nor-oestrone-5-methyl ether to the minor product. Catalytic hydrogenation of the pentaenol or tetraenol with 10% Pd-C gave a single isomer, which on oxidation with Jones reagent gave 18-homo-B-nor-8?-oestrone-3-methyl ether. Metal-ammonia reduction of 18-homo-B-nor-8?-oestradiol-3-methyl ether with lithium in the presence of tertiary butanol, followed by hydrolysis, gave 18-homo-19-nor-B-nor-8?,10?-testosterone. Similar reduction of 18-homo-B-nor-9?-oestradiol-3-methyl ether or 18-homo-B-nor-oestra-1,3,5(10),8-tetraen-17?-ol-3-methyl ether, followed by hydrolysis, afforded 18-homo-B-nor-19-nor-9?,10?-testosterone.