3-Ketocholanic acid

From the preceding data it can be seen that reduction studies with NaBH4 have not been as extensive as those with Li AIH4. Reduction at the 4-position of the 5a-H series should give a predominance of the -epimer. Reduction of a 2-keto-3j -acetoxy compound gives 84% of the 2, 3)5-diol. ° In the 5J -H series reduction of 7-ketocholanic acid gives a 75% yield of 7a-hydroxy-cholanic acid with only traces of the 7 -ol, but 7-ketocholesterol gives a mixture of the 7a- and 7j8-epimers. ... 

Reduction of ketones. Reduction of ketones with metals in an alcohol is one of the earliest methods for effecting reduction of ketones, and is still useful since it can proceed with stereoselectivity opposite to that obtained with metal hydrides.1 An example is the reduction of the 3a-hydroxy-7-ketocholanic acid 1 to the diols 2 and 3. The former, ursodesoxycholic acid, a rare bile acid found in bear bile, is used in medicine for dissolution of gallstones. The stereochemistry is strongly dependent on the nature of the reducing agent (equation I).2 Sodium dithionite and sodium borohydride reductions result mainly in the 7a-alcohol, whereas reductions with sodium or potassium in an alcohol favor reduction to the 7p-alcohol. More recently3 reduction of 1 to 2 and 3 in the ratio 96 4 has been achieved with K, Rb, and Cs in f-amyl alcohol. Almost the same stereoselectivity can be obtained by addition of potassium, rubidium, or cesium salts to reductions of sodium in t-amyl alcohol. This cation effect has not been observed previously. 

Stereoselective reduction. 12-Ketocholanic acids are reduced by this complex to 12/ - and 12a-hydroxycholanic acids in ratios of 5.0 1.5. 3-Keto- and 7-ketocholanic acids are reduced with some preference to the a-hydroxy acids. 

Hyocholic acid was isolated from pig bile by Haslewood in 1954 (123, 124). It has not been detected in the bile of other species. Hyocholic acid was characterized by Haslewood (125), Ziegler (126,127) and by Hsia et al. (89) as 3a,6a,7a-trihydroxycholanic acid. The acid may be synthesized by NaBH4 reduction of 3a,6a-dihydroxy-7-ketocholanic acid, which in turn is prepared from chenodeoxycholic acid (89). 

The first application of the manifold experiences gained in the field of bioreductions to substances of the cholic acid and sterol series is due to Kim. He showed that dehydrodesoxycholic acid is transformed by bottom yeast to 3-hydroxy-12-ketocholanic acid. Mamoli and Vercel-... 

Common Name Acide dehydrocholique Acidum dehydrocholicum Acidum trioxocholanicum Dehydrocholic acid Dehydrocholsaeure Ketocholanic acid... 

Inversion of 3 -hydroxy steroid. Reduction of the dihydroxy keto cholanate 1 with Raney nickel (no. 28) results in partial epimerization of the axial 3 -hydroxy group (but not the axial 7a-group). This inversion step must be fairly slow because it is not observed when reduction of a 12-ketocholanic acid group is effected within 4 hours. This reaction is the mildest method known for inversion of an axial C,-slcroidal alcohol. ... 

Chem, 80, 287 (1912) Wieland, Boersch, ibid. 106, 193 (1919) Windaus, Neukirchen, Her. 52, 1915 (1919) Wieland, Vocke, Z. Physiol. Chem. 191, 69 (1930). From 3-ketocholanic acid diethyl thioacetal by hydrogenolysis Bernstein/ Dorfman, U.S. pat. 2,440,660 (1948 to Am, Cyanamid). 56-Cholanic acid differs from the thermodynamically more stable 5a-isomer, by being cis at the A/B steroid ring function rather than irons. 

Although the specific oxidation of X to pregnan-3a-ol-ll,20-dione acetate (XI) does not appear to have been described in the literature, this step is carried out in precisely the same manner as described for the corresponding 12-broinide (Fig. 5) from which XI is equally accessible. Alternatively, it is possible to carry out the Meystre-Miescher degradation (Hershberg et al., 1952a) with 3a,12/3-dihydroxy-ll-ketocholanic acid (III) and to treat the resulting diphenyl olefin (VII) with phosphorus tribromide. The 12-bromodiphenyl olefin (VIII) can then be transformed further to XI, as indicated in Fig. 5 (X — XIV). 

To a solution of 5.95 g 3-hydroxy-12-ketocholanic acid in 50 mL methanol was added 2 mL acetyl chloride. The solution was refluxed for 15 min and then allowed to stand at room temperature for 3 h. The ester was obtained in crystalline form by carefully diluting the solution to 175 mL with water, in the amount of 5.10 g (99% yield), m.p., 110-112°C. 

Respective ketocholanic acids, which are absent from bile, can be obtained from C, DC, and LC by oxidation of secondary alcohohc groups (dehydrogenation). Dehydrocholic acid, used both in a free and conjugated form (of sodium salt), is about 10 times less toxic than C. Dehydrocholic acid activates production of bile, speeds up its flow, and facilitates resorption of fat because it intensifies the activity of pancreatic hpase. Bile acids are weU absorbed from the alimentary tract next, they enter the blood stream and then activate hvCT cells to produce bile. However, bile acids are strongly toxic compounds, and their overdose leads to degeneration of... 

Ketocholanic acid has been detected as a fecal bile acid in man (52) but has not been found in other sources. The acid may be prepared by Cr03 oxidation of lithocholic acid (64, 141). 

Dehydrogenation of carbonyl compounds. Introduction of a 9,11-double bond into a 12-keto bile acid by selenium dehydrogenation was discovered by Schwenk and Stahl and became a key step in the commercial production of cortisone. Kendall and co-workers " studied the reaction carefully as applied to methyl 3a-benzoyloxy-12-ketocholanate, using as solvent a 4 1 mixture of chlorobenzene and acetic acid. They found that a trace of hydrochloric acid slowed down the reaction but increased the yield. Thus with no added mineral acid the yield reached a maximum of 67% in a reflux period of 24 hrs. but with the mixture 0.0006 normal in HCl refluxing for 72 hrs. alforded the product in 84% yield. The product was to be isolated after... 

Esters. Under usual conditions of experimentation, carboxylic esters are not reduced by sodium borohydride. Thus 3-keto bile acid esters can be reduced at C3 without disturbance of the ester function. Methyl 4y8-bromo-3-ketocholanate... 

A further advance of major importance in the practical utilization of the bile acids for cortisone syntheses was the replacement of the laborious Barbier-Wieland degradation (cf. Fig. 2) by the Meystre-Miescher degradation. As applied by Wettstein and Meystre (1947) to methyl 3a-acetoxy-ll-ketocholanate (VI, R = Ac R = CH3), this procedure involves reaction with phenylmagnesium bromide and acetylation to produce the diphenyl olefin (IX), which upon bromination with N-bromo-suooinimide and dehydrobromination smoothly yields the diene (X). 

A sample of 7.2 g of the crude 3-hydroxy-12-keto-nor-cholanyldiphenylcarbinol dissolved in 50 mL acetic acid and 25 mL acetic anhydride was refluxed for 2.5 h. The solvent was removed by vacuum distillation, and the gummy residue was dissolved in hot acetone. On standing in the cold room, 1.454 g 3-acetoxy-12-keto-bis-nor-cholanyldiphenylethylene was separated as crystals, in a yield of 24% (based on methyl 3-hydroxy-12-ketocholanate), m.p. 175-178°C... 

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