36 -Hydroxy-12-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. ... 

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-... 

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. 

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. ... 

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. 

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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