3-Keto-5a-steroids

The isotopic purity of the products from a lithium aluminum deuteride reduction is usually equivalent to that of the reagent. The presence of moisture has little effect on the isotope composition of the products, causing only the decomposition of some of the reagent. For the best results, however, it is advisable to distill the solvent— usually ether, tetrahydrofuran or dioxane depending on the desired reaction temperature—from lithium aluminum hydride directly into the reaction flask. In this manner the reduction of 3-keto-5a-steroids (60), for example, gives the corresponding 3a-di alcohols (61) in 98% isotopic purity. ... 

In the presence of an axial la-hydroxyl group methylmagnesium iodide reacts with 3-keto-5a-steroids from the j5-side exclusively to yield the 3f -methyl isomer. ... 

A -3-Ketosteroids are converted into 2 -nitro-A -3-ketones, 3-keto-5a-steroids give 2a-nitro-3-ketones, and 3-keto-5/8-steroids give 4/S-nitro-3-ketones. 17-Ketones give 16-nitro derivatives. ... 

The Ben May workers found that enol ethers also serve as intermediates. Thus the enol ethers of three 3-keto-5a-steroids on reaction with FCIO3 in pyridine at room temperature for 2 min., with subsequent acidification, afforded 2c -fluoro-3-ketones in yields of 75-90%. The enol ether of A -cholestene-3-one, namely 3-... 

Purification of 3-keto- -steroids. - Brominatiun of ti 3-keto-5a-steroid and dehydrobromination to the 3-keto-A -derivative (3) is accompanied by the following... 

Dimethylsulfonium methylide also reacts predominantly with 3-keto-5a-steroids (dihydrotestosterone) by a-side attack.130 However, the isomer formed by (1-attack (3) is the exclusive product when dimethyloxosulfonium methylide is used. Analogous results were obtained with cholestanone-3. 

Henbest reduction. Under Henbest s conditions (1. 131-132), 3-ketosteroids are reduced predominantly to the axial alcohols that is, 3-keto-5a-steroids are... 

Butenandt, Dannenberg, and Suranyi (B-80) reported the reduction of A -3-keto-5a-steroids to 3/3-hydroxysteroids with yeast. 

The method of Chakravarti, Chakravarti, and Mitra (84) for the transformation,of 3-hydroxy-5 steroids to 3-keto-5a steroids has been utilized by Danielsson et al. (34) for the preparation of methyl 12a-hydroxy-3-keto-5a-cholanoate from the corresponding 5 3 derivative, and by Anderson and Haslewood (69) for the preparation of ethyl 3 3,7 ,r2 -trihydroxy-5a-chol-anoate from ethyl 7a,12a-dihydroxy-3-keto-5a-cholanoate in boiling cymene. The latter authors have commented on the poor and capricious yields obtained by this procedure (25). 

Compounds with the following side chain at C-17 have been used as starting materials (5),153 (6),168,169 (7),17O(8),171(9)172and(10).173,174 The procedure is conveniently carried out with 6a- and 9a-fluoro steroids as well as substituted 3-keto-5a-H-steroids. 

In the 19-nor series the results of methylenation of A1-3-keto-5a-H and 5/ -H steroids are analogous to those observed in the corresponding 10-methylated series.239... 

In bestimmten Fallen kann die Darstellung auch anderer Derivate zur Lokalisierung der Carbonylgruppe von Vorteil sein So lassen sich bei-spielsweise aus 3-Keto-5a-steroiden A2-Enolacetate herstellen, die dann in der fur A2-Steroide typischen Weise unter Dienspaltung (siehe unten) zerfalien 12). Ahnlich charakteristisch verlauft der Zerfall der ent-sprechenden Enolather 12>. 

I-Methyl-2-pyrrolidone [I, 696, before references]. Henbest5 used this solvent to advantage for the reaction of 3-keto-A4-steroids with sodium cyanide to give 5a- and 5/3-cyano-3-ketosteroids. The steric course of the addition is not strongly affected by the 17-substituent. 

From 3-keto-A steroids the partial reduction leads to A -steroids with the same advantages of short times and regioselectivity.i24 However, mixtures of 5a and 5P epimers are obtained. An acetyl or acetoxyl group on carbon 17 resists reduction (p.337). 

Mosbach and colleagues have contributed extensively to a better understanding of the mechanism of biosynthesis of cholestanol. After intracardial administration of mevalonate- C to guinea pigs, radioactive cholestanol was isolated from liver, intestinal wall, and adrenals (117). With rat liver homogenates the incorporation of C-mevalonate or C-cholesteroI into C-cholestanol of the order of 0.05% in 4 hr (118).t The 5a-reductase of rat liver and adrenal localized (119) in the microsomal fraction, was shown to require NADPH, exhibited product inhibition, and was more active in preparations from female than male rats. The enzyme was considered distinct from the Cjg- and C2i-5a reductases, since it was inhibited by Cjg-3-keto-/I steroids. 

Hydrogenation of 19-nor-A -3-keto steroids also gives 5a- and 5 -product mixtures under the usual conditions but with ruthenium oxide at high pressures only the 5j8-isomer is formed.The presence of a 4-methyl group on a A -3-keto steroid increases the amount of a attack as compared to the parent enone. ... 

With the recently developed [py3RhCl3]-NaBH4 catalyst the double bonds of A -3-keto steroids are reduced quite readily but mixtures of 5a- and 5j9-products are obtained. ... 

A recent modification of this technique utilizes A,A-d2-propylamine as the solvent for the lithium reduction, thereby eliminating the inconveniences associated with the preparation and handling of liquid deuterioammonia. Under these conditions the reaction can be carried out at room temperature and less overreduction of the carbonyl group is observed. For example, the reduction of A" -3-keto steroids (159) under these conditions, followed by back exchange in protic media, leads to the corresponding 5a-di-3-ketones (160) which exhibit good isotopic purity. ... 

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 reaction of 9(1 l)-dehydro steroids with nitrosyl fluoride was studied by Grantz and Rosenthal in pursuit of an alternate source for the important 9a-fluoro-11-oxygenated steroids. As expected, reaction at the more hindered 9(1 l)-double bond proceeds more slowly than at either the 4- or 5-double bonds. After 10 days at 3°, 3 -acetoxy-5a-pregn-9(l l)-en-20-one (50) affords a 45% yield of the 9a-fluoro-ll-nitrimine (51). Other 9a-fluoro-ll-nitrimines were prepared and it was found that the presence of additional keto groups, particularly the 3-keto group gives rise to side products with a concomitant reduction in yield of the desired 9a-fluoro-ll-nitrimines. In the case of the A" -3-ketones the yield is reduced to 10 %. The steric hindrance... 

Spero and Cooley have reported an alternate route to 6-methyl-A -3-keto steroids by using 3,3-ethyIenedioxy-5a,6a-epoxides (6). In contrast... 

Mazur " obtained 2a-alkyl-5a-H (3) or 4 -alkyl-5 -H products (6) by direct alkylation of either 5a-H (1) or 5 -H-3-keto steroids (4) with alkyl halides under basic conditions. In general, formation and alkylation of the more stable enolate ion is observed in this procedure. 

The methylenation of A -3 -hydroxy-5a-H steroids (5) proceeds analogously to give 1 ) ,2i3-methylene steroids in solvent mixtures of glyme and diethyl ether at reflux. The yields for various examples incorporating additional functionality, i.e., 17j -acetoxy, 17-keto, 20j9-hydroxy, 1-methyl-17j5-acetoxy-19-nor and 17j5-acetoxy-17a-ethynyl-19-nor are about 25 to 60... 

Addition of dimethylsulfoxonium methylide to the a-face of A -20-ketones, A -5a-H-ketones and A " -3-ketones results in the formation of the corresponding 16a,17a-methylene (1), la,2a-methylene-5a-H (2) and la,2a-methylene-A" steroids (3), respectively. Smooth reaction is also observed in the presence of 2-chloro and 2-bromo substituents in the A -5a-H-3-ketone series.Yields of 90% are obtained within a reaction period of 5 hr at room temperature. A A -3-keto system in (1) is not attacked under these conditions. 

Levisalles and co-workers have prepared A-homo-5a-cholestan-4-one by the dibromocarbene procedure starting with 3-methoxy-5a-cholest-2-ene. Wieland and Anner have converted 19-mesyloxy-A -3-keto steroids into... 

Cyanogen azide is a useful reagent for conversion of pyrrolidine enamines of 3-keto steroids to A-norsteroids. " Ring contractions can be carried out in the presence of 17j5-hydroxy, 17j -acetoxy, 20-keto groups and isolated double bonds. In a typical procedure, 17j -hydroxy-5a-androstan-3-one (partial formula 8) is converted into the enamine (9) by pyrrolidine in benzene... 

The synthetic value of this reaction should be mentioned. Thus, current production of 5p-steroids from As-3(i-ols, readily available and cheap starting materials, requires a preliminary Oppenauer oxidation or fermentation to the A4-3-keto derivative followed by catalytic hydrogenation under alkaline conditions, as direct catalytic hydrogenation with both heterogeneous and homogeneous systems gives only the 5a isomer. 

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