Oestrone 3-methyl ether

The 1,11 -etheno-derivative (8) of oestrone methyl ether has an unusually flat structure, as a consequence of the presence of the extra aromatic ring." X-Ray analysis has established the geometry of 3a, 17a-dihydroxy-4,4,14a-trimethyl-19-nor-10a-pregn-5-ene-l 1,20-dione (9)" and the configuration of the S=0 bond in 2a,3a-epithio-5a-androstan-17/3-ol (R) S-oxide (10)."... 

Details have been published of the pyridine-type molecule approach for the construction of carbocyclic compounds,11 in particular ( )-D-homo-oestrone. Treatment of (39) with toluene-p-sulphonic acid in hot benzene for one minute gave12 compound (40) of the elusive A8(9)-structure further reaction led to the expected oestrapentaene (41) from which by suitable reduction procedures 8aH-, 9 8H,14j3H-, 8aH,14 3H-, and 9/3H-oestrone methyl ethers were obtained. The well known compound (42) on electrocatalytic reduction13 (palladinized platinium... 

The trienone (74), either by reaction with diazomethane and pyrolysis of the derived pyrazoline or by treatment with dimethylsulphoxonium methylide anion, yielded28 the 1 a,2 -methylene derivative (75). Epoxidation followed by the action of hydrogen chloride gave (77). The methylene bridge was re-formed by the reaction of collidine, the product being (76). Halogenated steroids of use in determining the metabolic fate of 16-chloro-oestrone methyl ethers and of chlormadinone acetate have been synthesized.29... 

Although known for almost forty years, and in spite of a total synthesis of its racemate, the stereochemistry of doisynolic acid has remained in doubt. This problem has now been settled by a stepwise chemical conversion (Scheme 23) of 14)5-oestrone methyl ether (339), prepared from natural oestrone (114a), into c/s-doisynolic acid methyl ether (342). Osmium tetroxide oxidation of the enol acetate corresponding to (339) provided 16a-hydroxy-14)S-oestrone methyl ether. Subsequent periodic acid oxidation afforded the lactol (340), which upon treatment with diazomethane gave the aldehydo-ester (341). Electrochemical reduction of the aldehyde (341) afforded a methyl ester which by alkaline hydrolysis provided (-f )-ds-doisynolic acid 3-methyl ether (342), thus defining its complete stereochemistry. ... 

The 9(10-> l9)-abeo analogue (6) of oestrone methyl ether has been shown by X-ray crystallography to have the normal 9a -configuration, but because of the chair conformation of the enlarged ring b the molecule differs considerably in shape from oestrone methyl ether. X-Ray, n.m.r., and o.r.d. data establish the structures and absolute configurations of a series of insect-repellent steroids isolated from Nicandra physaloides. The structure and conformation of the 6-sila-steroid (7) have been determined. ... 

Oestrone methyl ether reacts at the 17-oxo-group with methoxyvinyl-lithium, giving the 17a-adduct (162). Hydrolysis afforded the 20-oxo-derivative (163), whereas oxidation (OSO4) generated the dihydroxyacetone system (164), albeit in the wrong configuration at C-17 for a corticosteroid synthesis. ... 

Vicinal phenylthio-alcohols are cleaved by lead tetra-acetate with insertion of oxygen. The 16/3-phenylthio-derivative (255) of oestrone methyl ether, for example, was reduced to the thio-alcohol (256) treatment with lead tetra-acetate then gave the cyclic hemithioacetal acetate (257), which could be methanolysed to give the derivative (258). Similar reaction after methylation at C-16 (259) gave the product (260), which was hydrolysed and cyclized (KOH-MeOH) to give the D-homo-17-en-16-one (261). ... 

Ethyl-19-nortestosterone, an anti-androgen, has been synthesized by a route which includes C-acetylation of oestrone methyl ether (EtOAc-NaOMe) to give the 16-acetyl derivative (510), conversion into a mixture of enol acetates (511) and... 

The aromatic ring of oestradiol or oestrone methyl ether readily forms a tricarbonyl chromium (0) complex in which the 13C signals from the aromatic ring are shifted strongly upheld (by ca. 14—34 p.p.m.). Smaller upheld shifts for other carbon atoms close to the aromatic ring (e.g. 2 p.p.m. for C-6) have been used to settle uncertainties in the earlier literature concerning the assignments of individual 18C resonances.69 13C N.m.r. spectra discriminate between A4- and A5-isomers of spiro-3-steroidal ketone derivatives thiazolidine formation results only in the (3i )-isomer (12), whereas hemithioacetals are mixtures of the (3R)- and (35)-forms.80... 

Methylation of the ethyleneketal of 11-oxo-oestrone methyl ether with methyl magnesium bromide gives the 1 la-methyl compound which has been further transformed into the 11 -methyl-19-nor steroids (356 = O, R = H) and... 

Condensation of the isothiouronium salt, obtained from the vinyl alcohol (413), with 2-methyl-cyclopentane-1,3-dione has led to a series of A-nor-3-oxa-steroids and similar condensation of the thia-analogue (408) with 2-methyl-cyclopentane-1,3-dione afforded the thia-oestrane (410), which was reduced catalytically to a mixture of 14a- and 14/S-H-dihydro-epimers. Reduction of the remaining conjugated 8,9-unsaturation was less easy than in the carbocyclic analogue metal-ammonia afforded thiols, and catalytic reduction was slow and led to a mixture of, presumably, 8a,9a- and 8, 9jS-epimers. The former isomer (416) which has its 9 -H favourably disposed for hydride abstraction with DDQ readily dehydrogenated to the 9(ll)-olefin which, on subsequent catalytic reduction, gave 6-thia-oestrone methyl ether. Condensation of the same thia-... 

A total synthesis of d/-oestrone methyl ether (18) starting with Michael addition of the vinyl ketone (15) to (4a) has been reported. The method is similar to previously described procedures. ... 

Another synthesis of oestrone methyl ether (18) used eugenol (19a) as starting material. This was converted into m-methoxyallylbenzene (19c) by treatment of the phosphate (19b) with sodium in liquid ammonia in presence of an excess of ethanol. The Grignard derivative (20a) was prepared by reaction of (19c) with... 

Further reductions of 17-hydroxy-17-alkynyl-steroids with LiAlH4-AlCl3 to give the 17(20),20-dienes (allenes) confirmed that the reactions proceeded by a stereospecific c/5-5n2 mechanism. Aromatic fluorides were prepared in high yield by treatment of aryl-triazenes with 70% HF in pyridine and 4-fluoro-oestrone methyl ether was prepared by this method. ... 

Other Reactions.—Reaction of 17-oxo-steroids with allyl or methallyl phos-phorodiamidates and two equivalents of butyl-lithium gave the spirolactones (30a) or (30b) respectively. Trimethylsilylallylzinc chloride reacted with the 17-oxo-steroids to give the hydroxyvinylsilanes (31), which were converted into the spirolactone (30a). Oestrone methyl ether and 5a-cholestan-3-one reacted with the sodium salt of dimethyl-Mtoluene-p-sulphonyl)sulphoximine (32) to give the oxetans (33) and (34) respectively. Reaction of 5a-androstan-17/S-ol-3-one with 2,4,6-tri-isopropylbenzenesulphonylhydrazine followed by treatment... 

Norethisterone is more elegantly prepared from oestrone methyl ether by a sequence of Birch reduction, Oppenauer oxidation and ethynylation. [39,40]... 

In one of the first production processes, after a Birch reduction of oestrone methyl ether, methanol was added to the A-ring the hydroxy-group at C-17 was then oxidised with pyridinium chlorochromate in presence of sodium acetate,... 

Aromatic Compounds.—Regioselective mercuration at position 2 was reported for oestradiyl 3-methyl ether 17-acetate with Hg(OAc)2-CH3CN and allowed the preparation of the 2-chloro-, -bromo-, and -iodo-derivatives.54 The major product (41 %) of the reaction between oestrone and Ph5Bi was reported to be the 2,4-... 

Chlorosulphonation of the 3-methyl ether of oestradiol 17-acetate, and subsequent treatment with various amines, has given rise to a series of 2-sulph-amoyl oestratrienes, and a number of /V-substituted sulphamoyl derivatives of 17a-ethynyl-oestradiol have also been made. Methane- and butane-sulphonamido-oestra-l,3,5(10)-trienes prepared from the 3-amino-analogue of oestrone have shown poor biological activity. 

A convenient synthesis of ll, 17 -dihydroxyoestra-4,9-dien-3-one starting from 17jS-hydroxyoestra-4,9-dien-3-one has been described, as have the preparations of oestr-5- and -5(10)-en-17-ones and their 7a-methyl analogues. The methyl ethers of 16a- and 16) -bromo-13a-oestrone and both 17a- and 17)S-bromo-16-ones have been prepared for conformational analysis studies and a new synthesis of 3-methoxyoestr-16-ene and its two epoxy-derivatives has... 

Attempts to obtain the analogous C-10 methyl compound by a similar cyclisation were unsuccessful. Optimum conditions have been sought for catalytic reduction (to 9/5, lOa-dihydro-compound) of tricyclic ketones related to (456 R = Me or Et n = 1 or 2). Eugenol has been used to prepare oestrone via the allyl methoxybenzene (457) and oestradiol 3-methyl ether has been resolved by means of the cinchonine salt of the 17-hemiphthalate. ... 

Catalytic hydrogenation of 8,9-didehydro-14/ -oestrone gave the products of both 8a,9a- and 8, 9)S-addition. Birch reduction of 8a-methyloestradiol 3-methyl ether, followed by hydrolysis, gives mainly the non-conjugated 5(10)-en-3-one, which appears to be more stable in the 8a-methyl series than the conjugated 4-en-3-one. ... 

Nortestosterone and 19-norprogesterone were considerably easier to obtain as soon as Arthur John Birch (1915-1995) had discovered the reduction of aromatics. [36] While the reactivity of deprotonated oestrone is too low for a direct Birch reduction, the methyl ethers were used in particular, because electron donors lower the reaction rate. The donor substituent is always attached at the remaining double bond, and the product is, on account of the principle of least motion, a 1,4-cyclohexadiene, in this case the 2,A -doubly unsaturated steroid skeleton. The second conceivable isomer, with double bonds at the 3,6-positions, is for steric reasons thermodynamically less favoured (Bredt s Rule). [37]... 

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