Allocholic acid preparation

In a study by Ali and Elliott it was shown that 5a-cholestane-3 ,7a-diol was an even better substrate for the 12a-hydroxylase in rabbit liver microsomes than 7a-hydroxy-4-cholesten-3-one (156%) [104]. This reaction is probably of importance in the formation of allocholic add. The high specificity of the 12 -hydroxylase towards the coplanar 5a-sterol nucleus is also evident from the finding that allochenodeoxycholic acid can be converted into allocholic acid in rats, both in vivo and in vitro [105,106, Chapter 11]. Based on the known structural requirements of the 12a-hydroxylase, Shaw and Elliott prepared competitive inhibitors with different substitutions in the C,2 position [107]. The best inhibitor of those tested was found to be 5a-cholest-ll-ene-3a,7 ,26-triol. Theoretically, such inhibitors may be used to increase the endogenous formation of chenodeoxycholic acid in connection with dissolution of gallstones. 

Noma et al. found 2 keto bile alcohols in unconjugated form in bullfrog bile [42]. Their structures were determined as 24-dehydro-26-deoxy-5a-ranol and its 5 isomer by comparison with synthetic 3a,7a,12a-trihydroxy-27-nor-5a- and 5/8-choles-tan-24-ones, prepared from allocholic acid and chohc acid, respectively [41]. 

In the 5a series allochenodeoxycholate is 12a-hydroxylated to allocholate in the bile fistula rat [131] or with a hepatic microsomal preparation from rat, rabbit or human liver fortified with NADPH [152,153]. Kallner [133] noted that small amounts of more polar derivatives were present in rat bile, with largely unchanged allochenodeoxycholate. AUohyocholate was identified as a minor metabolite [154]. With rabbit liver microsomal preparations, allochenodeoxycholate is a competitive inhibitor for 12a-hydroxylation of 7a-hydroxy-cholest-4-en-3-one and 5a-choles-tane-3a,7a-diol, precursor of cholic and allocholic acids, respectively [155]. Allo-cholic acid has also been characterized as a metabolite of 3 8,7a-dihydroxy-5-cholenic acid after intraperitoneal injection into carp [156]. 

A method for the preparation of allochenodeoxycholic and allocholic acids from the corresponding cholic acids has been reported. The key step in the synthesis is the oxidation-dehydrogenation of 3a-hydroxy-5p-bile acid formyl esters 816 to give oxodienes 817 (Scheme 3.322) [1115]. 

Until recent years, bile salts were considered to be exclusively 5 8 steroids. The first recognition of the occurrence of 5a or alio bile salts came from the studies of Anderson and Haslewood (165) who synthetized allocholic acid and identified it as a previously unidentified naturally occurring acid from fish bile. The earliest isolation of allocholic acid appears to have been that by Ohta from the bile of the Gigi fish (166). Since that time allocholic acid has been isolated from the bile of a large number of fishes, birds, and, to a smaller extent, mammals (4). It has also been detected in human feces (121). Allocholic acid may be prepared from cholic acid by allomerization of the 6,7-ketol in hot alkali (165) or by treatment of the 3-keto acid with Raney nickel in boiling isopropyl benzene (167). 

The natural occurrence of the 5a-epimer of deoxycholic acid was first demonstrated by Danielsson, Kallner, and Sjovall (62). The original isolation of this compound was probably by Kishi (61) who named the unidentified acid lagodeoxycholic acid from rabbit bile. In addition to its occurrence in rabbit bile, allodeoxycholic acid is present in rabbit feces (62) and accumulates as the glycine conjugate in gallstones of rabbits fed cholestanol (168). Allodeoxycholic acid may be synthesized from cholic acid by reactions similar to the preparation of allocholic acid (62,168). 

Goto (88) obtained an allo-acid designated as 3a,7 -dihydroxy-5a-cholanoic acid in a manner somewhat analogous to the procedure of Anderson and Haslewood for the preparation of allocholic acid. Methyl 3 -cathyl-7,12-diketo-6a-bromo-5/3-cholanoate was allomerized with alkali to provide three ketolic acids. One of these designated as 3a,7/3-dihydroxy-6,12-diketo-5a-cholanoic acid, m.p. 235 °C, was reduced by the Wolff-Kishner procedure to provide equal quantities of allocholanic acid and alloursodeoxycholic acid, m.p. 223-224°C. 

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