Androstane 4,4-dimethyl

A solution of 4,4-dimethyl-5a-androst-l-en-3-one (128, 14 mg) in cyclohexane (3 ml) is stirred in a microhydrogenation apparatus in the presence of 10 % palladium-on-charcoal (15 mg) at atmospheric pressure and room temperature. The uptake of one eq of deuterium (1.15 ml) is complete in about 1 min and no more deuterium is consumed. After 5 min the catalyst is removed by filtration, and the solvent evaporated under reduced pressure. The resulting l<, 2< -d2-4,4-dimethyl-5a-androstan-3-one (129, 13 mg, 93%), mp 120-122°, exhibits 87% isotopic purity and 13% d species. ... 

When the l<, 2( -d2-labeled product (129) is subjected to alkaline equilibration to back exchange the 2i -label (for experimental conditions see section IT-B), the crystalline l< -di-4,4-dimethyl-5a-androstan-3-one (130) exhibits 6% do and 94% d isotopic composition. ... 

The addition proceeds most smoothly with highly functionalized (more polar) steroids as seen in examples by Bernstein and others. The polar reaction conditions pose solubility problems for lipophilic androstane, cholestane and pregnane derivatives. Improved yields can be obtained in some cases by using dimethyl sulfoxide or t-butanol " as solvents and by using sodium A-bromobenzenesulfonamide or l,3-dibromo-5,5-dimethyl hydantoin (available from Arapahoe Chemicals) as a source of positive bromine. The addition of bromo acetate and bromo formate to steroid olefins has been studied to a limited extent. ... 

The 11-keto group is relatively difficult to attack, due to steric hindrance. However, reaction of 3j -hydroxy-5a-androstane-l 1,17-dione (37) with methylmagnesium bromide at 25° unexpectedly gives a 30% yield of 1 la,17a-dimethyl-5a-androstane-3j5,lljS,17i -triol (38) in addition to the 17-monomethyl product (39). 

Ethynylation of 3j -hydroxy-16a-methyl-5a-androstan-17-one in a mixture of diethylene glycol dimethyl ether and diethylene glycol monoethyl ether in the presence of potassium hydroxide produces two isomeric 17-ethynyl derivatives. This result is not unexpected since molecular models suggest that the steric influence of the 13/ -methyl group is nearly offset by the 16a-methyl group. The presence of a 16a-acetoxy group in the estrone series also leads to the formation of epimeric 17-ethynyl compounds (61) and (62) on reaction with acetylenedimagnesium bromide. 

An ethereal solution approximately 2.5 molar in methyllithium is prepared from 17 ml of methyl iodide and 4 g of lithium metal in 200 ml of anhydrous ether. A mixture consisting of 150 ml anhydrous ether, 3 g (10 mmoles) of 3jS-hydroxy-5a-androstane-ll,17-dione and 60 ml (0.15 moles) of the above methyllithium solution are stirred at room temperature for 40 hr. The reaction mixture is diluted with 100 ml of water and the ether is removed by distillation. Filtration of the chilled aqueous phase yields 2.6 g (77%) of 1 la,17a-dimethyl-5a-androstane-3a,l l/ ,17j5-triol mp 149-154°. Recrystallization from acetone-hexane yields pure material mp 164-166° [a] —5° (CHCI3). 

A mixture of 3.18 g (10 mmoles) of 17 -hydroxy-2-hydroxymethylene-5a-androstan-3-one, 20 ml dry dimethyl formamide and 0.3 g (13 mmoles) of sodium hydride is stirred for 0.5 hr at room temperature under nitrogen. A total of 1.51 g (12.5 mmoles) of redistilled allyl bromide is added and the mixture is stirred for 1 hr on the steam bath. Aqueous potassium hydroxide (2 g in 5 ml of water) is added and stirring is continued for 1 hr on the steam bath. The reaction mixture is diluted with 50 ml of methylene dichloride followed by careful addition of 300 ml of water. The organic phase is separated and the aqueous phase is again extracted with 50 ml of methylene dichloride. The combined extracts are washed with water, dried over sodium sulfate, filtered and chromatographed on 200 g of silica gel. Elution with pentane-ether (4 1) provides 2a-allyl-17j -hydroxy-5a-androstan-3-one 0.85 g (26%) mp 118-119° [aj 14° (CHCI3), after crystallization from ether-hexane. 

Treatment of 4-methyltestosterone under the same conditions affords 17 -hydroxy-4,4-dimethyl-5a-androstan-3 One in about 60% yield while 17jS-hydroxyandrosta-4,6-dien-3-one gives only a low yield of 17 -hydroxy-4,4-dimethylandrost-5-en-3-one. ... 

The deformed-chair conformation of ring A in a 4,4-dimethyl-3-oxo-5or-steroid has been confirmed by an X-ray study of a 17 -benzoyloxyandrostane derivative. The results agree with those of an earlier study of the 17-iodoacetate, and with the geometry indicated by force-field calculations. Dipole moments calculated by the application of molecular mechanics to 5a-androstane-3,17-dione and its distorted 4,4-dimethyl derivative are larger than those observed the reasons for these deviations are not yet clear. 

The synthesis of 4,4-dimethyl-5a-androstan-17j8-ol-3-one and its 19-nor-analogue employed methylation of the 2,2-trimethylenedithian derivatives and subsequent desulphurization. It was confirmed that catalytic hydrogenation of... 

N1 - ANDROSTANE-2-alpha-CARBONITRILE, 4-alpha. 5-alpha-EP0XY-17-beta-HYDR0XY-4,17-DIMETHYL-3-0X0-... 

When the dienolate of 17/ -methoxycarbonyl-5/ -androstan-3-one (3) is treated with two equivalents of dimethyl disulfide at room temperature for 1 hour, only one isomer of the mono-sulfenylated product 4 is isolated, and in a quantitative yield36. 

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