14-methyl steroids. Part 3. Synthesis of (±)-14α-methyl-9β-estradiol and related 14α-methyl-19-norsteroids

Catalytic hydrogenation of a totally synthetic mixture of (±)-3-methoxy-14-methyl-14α-estra-1,3,5( 10), 9(11)-tetraen-17-one(1) and the corresponding 1,3,5(10),8-tetraen-17-one (2) gives a mixture of 14α-methyl-8β,9β-, -8α,9α-, and -8β,9α-estrones, which is converted into the 17β-hydroxy-mixtures. t-Butylation gives a separable mixture of the three isomers, of which (±)-17β-t-butoxy-3 methoxy-14-methyl-9β,14α-estra-1,3,5(10)-triene(6) is the major component. The corresponding 14α-methylestradiols are prepared. A practical synthesis of (±)-14-methyl-14α-estra-1,3,5(10), 6,8-pentaene-3,17β-diol(25) is described, and it is shown that DDQ dehydrogenation of 1,3,5(10),9(11)-tetraenes in this series leads exclusively to the corresponding 1,3,5(10),6,8,11-hexaenes, whereas that of 1,3,5(10),8-tetraenes gives only 1,3,5(10),6,8-pentaenes.     

Synthesis and molecular structure study of 3-methoxy-7α-methyl-6-oxa-9β,14β-estra-1,3,5(10)-trien-17-one in solution

It was established by NMR spectroscopy that the catalytic hydrogenation of 3-methoxy-7α-methyl-6-oxa-14β-estra-1,3,5(10),8-tetraen-17-one leads to the formation of 3-methoxy-7α-methyl-6-oxa-9β,14β-estra-1,3,5(10)-trien-17-one, the structure of which was investigated in solution. The corresponding analog with a free hydroxyl group at the position 3 possesses an antiradical activity at the absence of uterotropic effect.     

New analogs of steroid estrogens

Aiming at the investigation of the mechanism of functioning of steroid estrogens a series of compounds with unnatural rings junction was synthesized. All investigated compounds exhibit a reduced uterotropic activity. It was established applying the NMR spectroscopy that 7α-methyl-3-methoxy-D-homo-6-oxa-8α,14β-estra-1,3,5(10)-trien-17a-one existed in solution in two conformations distinguished by the structure of the rings B, C, and D simultaneously. The reaction of 17-methylidene-3-methoxy-6-oxa-8α-estra-1,3,5(10)-triene with hydrobromic acid in acetic acid promotes a rearrangement with the migration of a methyl group into the position 17 resulting in the formation of 17,17-dimethyl-6-oxa-8α-gona-1,3,5(10),13(14)-tetraene derivatives.     

Synthesis in the diazasteroid group. III . Syntheses of the 8,16- and 8,17-diazasteroid systems

By using 3-pyrrolidone derivatives as a source of the D ring, the following five diazasteroids were synthesized: 8,16-diaza-2,3-dimethoxy-15,15,16-trimethylgona-1,3,5(10),13-tetraen-12-one (VII), 8,16-diaza-2,3-dimethoxy-16-acetylgona-1,3,5(10),13-tetraen-12-one (X), 8,17-diaza-2,3-dimethoxy-17-acetylgona-1,3,5(10),13-tetracn-12-one (XI), 8,16-diaza-16-acetylgona-1,3,5(10), 13-tetraen-12-one (XII), and 8,17-diaza-17-acetylgona-1,3,5(10),13-tetraen-12-one (XIII).     

The total synthesis and anti-fertility activity of 6-silasteroids

4,4-Dimethyl-6-methoxy-4-sila-1-tetralone (2) was prepared by a modified literature procedure and converted to 3-methoxy-6,6-dimethyl-6-silaestra-1,3,5(10),8,14-pentaen-17β-yl acetate (5c). Catalytic hydrogenation of 5c gave 3-methoxy-6,6-dimethyl-6-silaestra-1,3,5(10),8-tetraen-17β-yl acetate (6b), and its 14-iso- and Δ^{1,3,5(10),8(14)} isomers, the proportions varying with the catalyst and solvent. Reduction of 6b with lithium-liquid ammonia, and O-demethylation, gave 6,6-dimethyl-6-silaestradiol (8b). Reduction of the 3-methyl ether of 8b with lithium-liquid ammonia-t-butanol and hydrolysis afforded 3-keto-6,6-dimethyl-6-silaestr-1(10)-en-17β-ol (15), which was catalytically reduced to its 1,10α-dihydro derivative 17. The 5,6 SiC bond of 8b, 15 and their derivatives was cleaved by boron tribromide, aq. ethanolic hydrogen fluoride, and other reagents, providing a series of 5,6-seco-6,6-dimethyl-6-silasteroids. X-ray crystallographic analysis of 17 and the 17α-ethynyl derivative of 15 confirmed the stereochemical assignments. None of the compounds which were subjected to uterotropic, anti-uterotropic, or post-coital assays, showed significant activity. A partially completed synthesis of 6-silaestradiol (21a) is described.     

Cyclization of 3-methoxy-8, 14-seco-D-homoestra-1, 3, 5(10), 9(11)-tetraene-14, 17a-dione into D-homoestrone derivatives

Conclusions In the cyclization of 3-methoxy-8, 14-seco-D-homoestra-1,3,5,(10),9(11)-tetraene-14, 17a-dione (I) the stereoisomeric 14-hydroxy-3-methoxy-D-homoestra-1,3,5(10),9(11)-tetraen-17a-ones (III) and (IV) are formed at first, and after dehydration and isomerization these are converted into 3-methoxy-D-homoestra-1,3,5(10),8,14-pentaen-17a-one (II). The ketol (IV) is much more readily dehydrated than the ketol (III) and is probably themain intermediate product in the cyclization of the diketone (I).Translated from Izvestiya Akadeemii Nauk SSSR, Seriya Khimicheskaya, No. 8, pp. 1413–1416, August, 1965 Original article submitted June 24, 1963     

Synthesis and unusual beckmann fragmentation reaction of syn-3-Methoxy-6α,17β-Dihydroxyestra-1,3,5(10)-trien-7-one oxime

Sodium borohydride reduction of anti-3-methoxy-17β-hydroxyestra-1,3,5(10)-trien-6,7-dione 7-oxime (4a) afforded syn-3-methoxy-6α,17β-dihydroxyestra-1,3,5(10)-trien-7-one oxime (5), which in thionyl chloride at −18 °C undenvent Beckmann fragmentation reaction to the unexpected 3-methoxy-6-oxo-17β-hydroxy-6.7-secoestra-1.3.5(10)-trien-7-nitrile (6). A mechanism of this fragmentation process was proposed.     

An efficient synthesis of 3-methoxy-19-norpregna-1,3,5(10),16-tetraen-20-one

Russian Chemical Bulletin - An efficient preparative method for the synthesis of 3-methoxy-19-norpregna-1,3,5(10), 16-tetraen-20-one was suggested. This compound is a key intermediate product in...     

Conformational Studies of Marine Polyhalogenated α-Chamigrenes Using Temperature-Dependent NMR Spectra. Cyclohexene-ring flipping and rigid-chair cyclohexane ring in the presence of equatorial halogen atoms at C(8) and C(9)

Temperature-dependent NMR spectra indicate that the α-chamigren-3-ones (?) -11 , (+) -12 , (+) -14 (?) -15 , (+) -16, 18 , and 19 bearing equatorial halogen atoms at C(8) and C(9) undergo slow conformational flipping of the envelope-shaped enone ring, while the cyclohexane ring is maintained in the chair conformation. The α-chamigren-3-ols (+) -20 and (+) -21 , obtained by hydride reduction of (+) -12 , behave similarly, with slow half-chair inversion of the cyclohexenol ring. In each case, both conformers are about equally populated and detectable by NMR, except in the case of (+) -15 , where repulsive interactions between Br? C(2) and H_eq?C(7) make the population of the conformer 15b with Me—C(5) faced to H_ax?C(10) so low that it escapes direct ¹H-NMR detection. The energy barriers to these conformational motions are viewed to arise mainly from repulsive interactions between Me—C(5) and the axial H-atoms at C(8) and C(10), while, contrary to previous beliefs, no twist-boat conformations of the cyclohexane ring intervene. Similar conclusions hold for the 4,5-epoxides of both (?) -6 and (+) -7 . Clean Jones oxidatio of (?) -2 to 17 , where the CH₂?C(5) bond is maintained, and acid dehydration-isomerization of the α-chamigrene (+) -21 to the β-chamigrene (+) -24 , reflect the special stability of β-chamigrenes, providing a reason for their frequent occurrence in nature.     

Syntheses of derivatives of oestrane and 19-norsteroids from 6-methoxytetralone and 6-hydroxytetralone

The corresponding derivatives of Δ^{1,3,5(10),9,(11)}-8,14-seco- -homo-oestratetraen-3-ol-14,17a-dione(VII, VIII, IX) have been obtained by the condensation of 3-methoxy-, 3-hydroxy-, and 3-tetrahydropyranyloxy-1-vinyltetralols (IV, V, VI) with methyldihydroresorcinol. The diketones VIII and IX cyclize to form Δ^{1,3,5(10),8,14}- -homo-oestrapentaen-3-ol-17a-one (XIII), and the diketone (VII) may be converted, according to conditions, into 3-methoxy-Δ^{1,3,5(10),8,14}- -homo-oestrapentaen-17a-one (X), 3-methoxy-Δ_{1,3,5(10),9,(11)}- -homo-oestratetraen-14-ol-17a-one (XIV), and -homoequilenin (XI). Hydrogenation of the ketones X and XIII leads to the dihydroketones XV and XVI with a trans junction of the C and D rings. Reduction or hydrogen of XV gives the methyl ethers of -homo-oestrone and 8-iso- -homo-oestrone XIX and XVII which have been converted into the methyl ethers of (±)-oestrone and 8-iso-oestrone (XX and XXI). 19-Nor- -homotestosterone (XXV) and its methyl and ethyl analogues, which possess anabolic activity, have been obtained by a series of reactions from the ketones X and XV.     

△^9^(^1^1^)-雌甾四烯类化合物的硼氢化-铬酸氧化 II

雌甾-11-酮化合物是合成具有强效抗生育活性11-烃基取代在甾体化合物的关键中间体。本文对13β-乙基-3-甲氧基-甾-1,3,5(10), 9(11)-四烯-17β-醇的硼氢化-铬酸氧化反应进行研究, 结果发现产物比较复杂, 在温和条件下, 主要产物为13β-乙基-3-甲氧基-甾-1,3,5(10)-三烯-17-酮-112-硼酸, 增加氧化剂用量, 延长反应时间则得到11,17-二酮。     

New analogs of D-homoequilenine with substituents in the D ring

Stereoselectivity of reaction with Raney nickel of D-homoestra-1,3,5(10),8,14-pentaenes containing one or two methyl groups in position 16 was investigated. The reaction direction is governed by the orientation of the substituent at C^17a. The signals in the ¹H and ¹³C NMR spectra of four synthesized compounds were completely assigned. Criteria for evaluation of the character of rings junction in analogs of D-homoequilenine were suggested. 16,16-Dimethyl-3-methoxy-D-homo-13α-estra-1,3,5(10),6,8-pentaen-17a-one was subjected to X-ray diffraction analysis.     

Conformational design for 13alpha-steroids

The diastereomeric 16-bromo- and 16-azido-17-alcohols 5-8, 11, 12, 16, and 17 and 17-ketones 3, 4, 9, and 10 of the 13alpha-estra-1,3, 5(10)-triene series were synthesized as precursors for biologically active compounds and chiral ligands for metal complexation. Conformational investigations of these and some other compounds via X-ray analysis and (1)H NMR spectroscopy show the existence of compounds with the classical steroid conformation (ring C chair, restricted conformation of ring D) and such with an atypical ring C twist-boat and a flexible ring D conformation. It could be shown that 17beta-substituents or flattening of the D-ring are responsible for the twist-boat conformation, whereas compounds containing a 17alpha-substituent or 17-keto group possess the classical conformation. By varying the substituents, compounds with either of these conformations can be intentionally synthesized. MO calculations confirmed the relative stability of the twist-boat conformation.     

Some new ring-D seco steroids

The Beckmann fragmentation product, 3-methoxy-17-oxo-16,17-secoestra-1,3,5(10)-trien-16-nitrile (2) has been reduced by LAH giving the expected 3-methoxy-17-hydroxy-16,17-secoestra-1,3,5(10-trien-16-amine hydrochloride (3) and 3-methoxy-17-oxa-D-homoestra-1,3,5(10)-trien-16-ol (4), by a presumed neighbouring group participation of 17-OH group in the intermediary formed 16-imino derivative (A). The structure of 4 has been proved by an alternative synthetic route by reducing 3-methoxy-17-oxa-D-homoestra-1,3,5(10)-trien-16-one (7) with di-iso-butylaluminium hydride.     

Some new ring- seco steroids

The Beckmann fragmentation product, 3-methoxy-17-oxo-16,17-secoestra-1,3,5(10)-trien-16-nitrile (2) has been reduced by LAH giving the expected 3-methoxy-17-hydroxy-16,17-secoestra-1,3,5(10-trien-16-amine hydrochloride (3) and 3-methoxy-17-oxa- -homoestra-1,3,5(10)-trien-16-ol (4), by a presumed neighbouring group participation of 17-OH group in the intermediary formed 16-imino derivative (A). The structure of 4 has been proved by an alternative synthetic route by reducing 3-methoxy-17-oxa- -homoestra-1,3,5(10)-trien-16-one (7) with di-iso-butylaluminium hydride.     

Photo-oxygenation of Styrenic Estrogens: Product characterization and kinetics of the dye-sensitized photo-oxygenation of 9,11-didehydroestrone derivatives

The dye-sensitized photo-oxygenation of 3-hydroxyestra-1,3,5(10), 9(11)-tetraen-17-one ( 8 ) gives a complex mixture from which only the 1,4-endo-peroxide 10 can be isolated in low yield. In contrast, the 3-methoxy derivative 9 yields the C-seco-aldehyde 11 as a major product, suggesting that 1,2-dioxetane is a primary photo-oxygenation intermediate. As the electron-donating character of the substituent at C(3) decreases in the sequence 12 (R = PhCO), 13 (R = Ac), and 14 (R = Ts), the rate constant in substrate disappearance becomes drastically smaller as compared with 8 and 9 , and no photoproducts are detected. The results are rationalized by means of electronic and conformational factors.     

Molecular structure and biological properties of some 16,16-dimethyl-D-homo-B-nor-9β analogs of steroid estrogens

The interproton distances in the molecule of 17aβ-acetoxy-16,16-dimethyl-3-methoxy-D-homo-Bnor-9β-estra-1,3,5(10)-triene, determined from the X-ray diffraction data and by ¹H NMR spectroscopy, were consistent with those calculated ab initio and by the PM3 and MM+ methods. Therefore, MM+ calculations were used to perform docking of a series of D-homo-B-nor-9β-estra-1,3,5(10)-trienes to hormone-binding pocket of estrogen α-receptors, and 16,16-dimethyl-D-homo-B-nor-9-estrone was selected for studying its biological properties. This compound was found to possess cardioprotective activity and no uterotropic effect.     

A convergent approach to huperzine A and analogues

We describe a concise and convergent synthesis of (rac)-5-methoxy-6-azatricyclco[7.3.1.0(2,7)]trideca-2(7),3,5,11-tetraen-13-ol, which has the basic ring system of huperzine A, a potent inhibitor of acetylcholinesterase. We also describe the synthesis of the novel system 5-methoxy-6-azatricyclo[7.2.2.0(2,7)]trideca-2(7),3,5-trien-10-one and a series of related systems.     

Mass spectra of dihydroxy stereoisomers of 3-methoxy-1,3,5(10)-estratrienes

Electron impact mass spectral data for each of the four isomeric 16,17-, 15,17- and 14,17-diols of 3-methoxy-1,3,5(10)-estratriene and the 15,17-diols of 3-methoxy-14β-1,3,5(10)-estratriene are reported. The mass spectra of the diols show very similar fragmentation patterns except for differences in the relative abundances of particular ions. The different [M ? H₂O]⁺˙/[M] ⁺˙ and [M ? 2H₂O] ⁺˙ [M] ⁺˙ ratios can be used for distinguishing between the four isomeric 3-methoxy-1,3,5(10)-estratriene-14,17-diols as well as between the four isomeric 3-methoxy-14β-1,3,5(10)-estratriene-15,17-diols. No significant differences could be detected in the spectra of the epimeric 16,17-and 15,17-diols of 3-methoxy-1,3,5(10)-estratriene.     

13β-乙基-3-甲氧基-甾-1,3,5(10),9(11)-四烯-17β-醇的间氯过氧苯甲酸氧化反应

研究了13β-乙基-3-甲氧基-甾-1,3,5(10),9(11)-四烯-17β-醇与间氯过氧苯甲酸的氧化反应, 得到了9β-羟基-11酮化合物和一个未知化合物9α-过氧甲氧基-11-酮化合物。推测了反应机理, 讨论了未知物的化学结构和构型。