Structure of Hyocholic Acid

The structure of hyocholic acid was proposed by Haslewood (24) and by Ziegler (7) to be 3a,6a,7 -trihydroxy-5 -cholanic acid (I, Fig. 1). Since it was known that pig bile contains hyodeoxycholic acid (3a,6a-dihydroxy) and chenodeoxycholic acid (3a,7a-dihydroxy) the bile was assumed to contain possibly also an acid with both 6a- and 7a-hydroxyl groups. Chemical evidence for the vicinal glycol structure in hyocholic acid was found after chromic oxidation. The product, 3-keto-6,7-secocholanic acid-6,7-dioic 

TABLE I. Physical Properties of 3a,6,7,-Trihydroxy-5 7-cholanic Acids and 

Acid Melting point. [a]2 D Infrared maxima. References 

Hyocholic acid forms an acetonide (IV). Although it could not be crystallized [Ziegler (7) Haslewood (24)], its formation was substantiated by chromatographic mobility and data of quantitative acetylation. Formation of the acetonide gave evidence for the m-glycol structure in hyocholic acid. The a-orientation of this 6,7-glycol was deduced from data of molecular rotations. Based on values from Barton and Klyne (34), the calculated molecular rotation of 3a,6a,7a-trihydroxy-5/3-cholanic acid would be —13 and that of the 3a,6a,7 -isomer, +249. The observed molecular rotation of hyocholic acid was +19. It was therefore concluded that hyocholic acid is the 3a,6a,7a rather than the 3a,6/3,7/3-isomer [Ziegler (7)]. 

Confirmative evidence of the proposed structure was obtained from partial synthesis of hyocholic acid [Hsia et al. (30)]. An important intermediate in the synthesis was 3a,6a-dihydroxy-7-keto-5 -cholanic acid (VII, Fig. 2), first prepared by Takeda et al. (35). The 3 - and 6a-hydroxyl groups in VII were established by the formation of hyodeoxycholic acid (IX) after hydrogenolysis of the ethylenedithioketal derivative (VIII) with Raney nickel. Hyocholic acid was obtained from VII either by reduction with sodium borohydride or by hydrogenation in the presence of platinum both methods were known to produce the axially oriented 7a-hydroxy from 7-keto bile acids [Mosbach et al. (36) Iwasaki (37)]. More direct evidence for the la-hydroxyl group in hyocholic acid was found in a later study [Hsia et al. (8)], when hyocholic acid was derived from bromohydrin acetate XII (Fig. 3), 

---

Fig. 1. Structure of hyocholic acid. [Adapted from Haslewood (24) and Ziegler (7).]...

---