General Methods as Applied to Allocholic Acid

The initial studies of Anderson and Haslewood on the identification of Ohta s acid (79) sparked efforts to synthesize allocholic acid. Early attempts to reduce catalytically methyl 3a,12a-diaceto. y-7-ketochol-5-enoate to the 

5(r derivative produced a mixture of 5 3and 5a compounds in which the latter predominated. Separation of cholic acid from its 5a-epimer by crystallization was not feasible. Ample evidence exists for a-attack of the Cj double bond to provide the allo-acid, e.g., catalytic reduction of 3,5-acetoxy-7-ketocholest-5-ene provided the 5a-cholestane derivative (80). However, Anderson and Haslewood (19) successfully prepared allocholic acid as outlined in Fig. 6. Ethyl cholate was oxidized at C7 and the product (II) acetylated at C3 and C,2. The ketone (III) was brominated at Cg and the product (IV) was allo-merized to the important alloketol, (V). The Cg carbonyl group of V was eliminated by desulfurization of the derived thioketal (VI) with Raney nickel to provide 3a,7/3,12a-trihydroxy-5a-cholanoic acid (VII). Oxidation of the ethyl ester of VII with NBS provided the ketone, (VIII), which was reduced catalytically to the desired 7a,ol hydrolysis afforded allocholic acid, (1). The procedure was duplicated with minor variations by Karavolas et al. (28). 

Because of the low yields attendant with this somewhat lengthy method, other procedures were investigated. Two general methods for the preparation of allo-acids have resulted. 

Reduction of 3-keto-d -acids with Li-NH and Trimethylphosphite-iridiiim (IV) Chloride 

Kallner (66) studied the stereospecific formation of 5a steroids by the reduction of 3-keto- -derivatives with Li in liquid ammonia (Fig. 7). Oppenauer oxidation of methyl cholate provided the 3-dehydro derivative IX which was hydrolyzed to the free acid (X) and the product dehydrogenated with Se02 to the dihydroxy-3-ketochol-4-enoic acid (XI). The unsaturated acid (XI) was reduced with Li in liquid ammonia, and the product methylated to provide a mixture from which XII was separated from the desired ketone 

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