5a-Androstan

A number of steroids have been regioselectively acylated ia a similar manner (99,104). Chromobactenum viscosum hpase esterifies 5a-androstane-3P,17P-diol [571-20-0] (75) with 2,2,2-triduoroethyl butyrate ia acetone with high selectivity. The hpase acylates exclusively the hydroxy group ia the 3-position giving the 3P-(monobutyryl ester) of (75) ia 83% yield. In contrast, bacillus subtilis protease (subtihsia) displays a marked preference for the C-17 hydroxyl. Candida iylindracea]i 2Lse (CCL) suspended ia anhydrous benzene regioselectively acylates the 3a-hydroxyl group of several bile acid derivatives (104). 

The reaction of 6-amino-5-(l,2-diethoxycarbonylhydrazino)pyrimidines with enamines represents another convenient method for the preparation of pteridines. Fusion of 5-(l,2-diethoxycarbonylhydrazino)-2,4,6-triaminopyrimidine (281) with an excess of mor-pholinocyclohexene leads to 2,4-diaminotetrahydrobenzo[g]pteridine, and with the morpholinoenamine (282) from 17/3-hydroxy-5a-androstan-3-one regioselective condensation to the fused pteridine (283) takes place in almost quantitative yield (equation 101) (71CC83). 6-Amino-5-nitroso- and 6-amino-5-phenylazo-pyrimidines react similarly, imitating the Timmis-type reaction (72CPB1428). 

As first demonstrated by Stork,the metal enolate formed by metal-ammoni reduction of a conjugated enone or a ketol acetate can be alkylated in liquic ammonia. The reductive alkylation reaction is synthetically useful since ii permits alkylation of a ketone at the a-position other than the one at whicf thermodynamically controlled enolate salt formation occurs. Direct methyl-ation of 5a-androstan-17-ol-3-one occurs at C-2 whereas reductive methyl-... 

There is no generally reliable rule of thumb to predict whether an axial or equatorial proton will exchange faster. For instance, in the examples discussed above, the slowest rate of exchange is found for the S -axial proton in 5a-androstan-7-one (1) [see(2)-(4)] and the 2fi-equatorial proton in 5a-androstan-l 1-one (5) [see (6)-(9)]. Furthermore, the results of base-catalyzed exchange cannot necessarily be predicted from the corresponding... 

Deuteration of 3 -Hydroxy-5a-androstan-7-one at C-6 and C-8 by Exchange with Deuterium Oxide-5% Sodium Deuterioxide in Methanol-OD... 

A solution of 3j5-hydroxy-5a-androstan-7-one (10, 50 mg) in methanol-OD (4 ml) is saturated with deuterium oxide containing 5 % sodium deuterioxide (prepared by reacting sodium with deuterium oxide) and heated under reflux for 3 days. (If the heated solution becomes turbid due to supersaturation, a few drops of methanol-OD should be added until a clear solution is obtained. The use of a drying-tube on top of the condenser is advisable to avoid isotope dilution from moisture.)... 

After cooling, the reaction mixture is diluted with ether, the organic phase washed with ice-cold water and dried over anhydrous sodium sulfate. Evaporation of the solvent and crystallization of the residue from ether-hexane gives 6,6,8j5-d3-5a-androstan-3j5-ol-7-one (11) in 84% yield mp 141-142,5° isotopic composition 6% d2,93% da and 1 %... 

Enolizalion of conjugated or /3,y-unsatiirated enones and dienones in O-deiiterated solvents facilitates the introduction of deuterium labels into positions as far as three and five carbon atoms away from a given ketone function. Exchange of the activated hydrogens in androst-4-en-3-one (12) provides a good illustration of the potential of this method. Saturation of the double bond (section V) in the deuterated enone (13) followed by back exchange of the a-deuteriums (section II-B) proves to be an excellent method for the preparation of 6,6-d2-5a-androstan-3-one (15). ... 

Deuteration at C-3 by Reduction of 5a.-Androstan-3-one Oxime with Lithium Aluminum Deuteride... 

A solution of 5a-androstan-3-one oxime (112 0.6 g) in dry ether (40 ml) is added dropwise to a boiling suspension of lithium aluminum deuteride (1.6 g) in dry ether (80 ml). The reaction mixture is heated under reflux for... 

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. ... 

A pertinent example is the reduction of 5a-androst-8-en-l 1-one (154) which yields 8 -di-5a-androstan-l 1-one (155) in 93% isotopic purity. Saturation of A -6-keto steroids gives equally good results for labeling the 8/5-position. ... 

Zinc dust (35 mg) is added to a solution of 9a-bromo-5a-androstan-ll-one (225, 13 mg) in anhydrous ether (2 ml) and acetic acid-OD (0.5 ml, prepared by heating an equimolar mixture of acetic anhydride and deuterium oxide) and the resulting suspension is stirred at room temperature for 4 hr. (The progress of the reaction can be checked by thin layer chromatography.) The... 

An example is the preparation of 18-trideuterio 5a-steroids bearing a side chain at C-17. Labeling of this position with three deuteriums was accomplished by utilizing the Johnson procedure for steroid total synthesis. This synthesis involves, in part, introduction of the 18-angular methyl group by methylation of the D-homo-17a-keto-17-furfurylidene intermediate (243). By substituting d3-methyl iodide in this step, the C/D cis- and ra/J5-18,18,18-d3 labeled ketones [(244) and (245)] are obtained. Conversion of the C/D tra 5-methylation product (245) into 18,18,18-d3-d /-3)8-hydroxy-5a-androstan-17-one (246) provides an intermediate which can be converted into a wide variety of C-18 labeled compounds of high (98%) isotopic... 

The marked influence of solvent and temperature on product composition is illustrated by results obtained with 3 5-hydroxy-5a-androstan-17-one (5), which yields in addition to the 3a-fluoro derivative (6) the elimination... 

TABLE 8-1 Effect of Reaction Conditions on Product Composition in the Treatment of 3)S-Hydroxy-5a-androstan-l7-one (5,6 mmoles) with Diethyl(2-chloro-l,l,2-trifluoroethyl) amine (9 mmoles)... 

The Synthesis of 16, 17 -lmino-5a-androstan-3 -ol via 16 -Azido-17a.-iodo-5oL-androstan-3 -oi Acetate n4,137... 

Reaction of 17j -acetoxy-3,3-ethylenedioxy-5a-androstan-l-one (1) with methylmagnesium bromide followed by treatment with acid and reacetylation affords the 1-methyl-A -3-ketone (3). The configuration of carbon-1 of the intermediate (2) has not been established/ ... 

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