Cholic acid, cleavage

Additional activation of the 3-OH group by an allylic double bond increases the selectivity and leads to 50% testosterone (27). Cholic acid is oxidized exclusively at the 3a-position without any attack at the 7a- and 12a-hydroxy groups. Comparable selectivities have been reported for oxidations by silver carbonate on celite and by molecular oxygen with a platinum catalyst The yield of 23 is however lowered by a competing reaction to the lactone 24 this is formed by oxidative cleavage of the C3—C4 bond, followed by lactonization during work-up. 

The occurrence of bile alcohols hydroxylated at position 25 in CTX patients indicated the presence of an alternate pathway of bile acid synthesis from cholesterol (via 25-hydroxylated intermediates ). In particular, the identification of 5P-cholestane-3a,7a,12a,24a,25-pentol indicated that cholic acid arised from the cleavage of a 24,25- glycol. 

Fig. 10 (b). The sequence leading to the oxidation and cleavage of the side chain of 5P-cholestane-3a,7a,12a-triol pathway for side-chain cleavage in cholic acid biosynthesis. 

Other clinical signs consist of progressive neurologic dysfunction, cataracts, and premature atherosclerosis (SI). The disease is inherited as an autosomal recessive trait, but is usually only detected in adults when cholesterol and cholestanol have accumulated over many years (S2). Biochemical features of the disease include striking elevations in tissue levels of cholesterol and cholestanol and the presence of unusual bile acids, termed bile alcohols, in bile. These bile alcohols are mainly 5 -cholestane-3a,7a,12a,24S, 25-pentol, Sp-diolestane-3a,7a,12a,23 ,25-pentol and 5P-du)lestane-3a,7a,12a,25-tetrol (S2). As chenodeoxycholic acid is deficient in the bile of patients with CTX, it was postulated that early bile salt precursors are diverted into the cholic acid pathway and 12a-hydroxy bile alcohols with an intact side chain accumulate because of impaired cleavage of the cholesterol side chain and decreased bile acid production (S2). HMG-CoA reductase and cholesterol 7a-hydroxylase activity are elevated in subjects with CTX (N4, N5), so that sufficient 7a-hydroxycholesterol should be available for bile acid synthesis. 

Conjugation of the carboxylic group in cholic acid involves participation of a cholic acid CoA ligase and a cholyl-CoA glycine (taurine) acyltransferase [153-158]. Since the primary product of the thiolytic cleavage of the CoA ester of 3a,7a,12a-tri-hydroxy-24-oxo-5/8-cholestanoic acid is the CoA ester of cholic acid, it is probable that only the transferase may be involved in the primary formation of cholic acid in the liver. A description of the properties of the CoA synthetase and the transferase is given in Chapter 11. 

Dias, J. R., and R. Ramachandra Studies Directed toward Synthesis of Quassinoids. 2. D-Ring cleavage of Cholic Acid Derivatives. J. Org. Chem. 42, 1613 (1977). 

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