Cholic acid chemistry

The Schiesser group also recently described the preparation of some stannanes (24-27) derived from cholestanol (Scheme 4), cholic acid (Scheme 5) and lithocholic acid (equation 14), and their application to enantioselective radical chemistry . ... 

Several examples have appeared in the literature in which this linker has been employed in combinatorial chemistry strategies. Thus, it has been used in a Pd-mediated three-component coupling strategy for the solid-phase synthesis of tropane derivatives [46], in the solid-phase synthesis of aspartic acid protease inhibitors [47], in the attachment of cholic acid as a template for a combinatorial approach [48] and, more recently, in the solid-phase synthesis of pyrrolidines via 2-aza allyl anion cycloadditions with alkenes [49]. 

It is difficult to discuss Wieland s work without including the research of his contemporary and fellow German Adolph Windaus (1876-1959). It was clear that hile acids such as cholic acid not only were found jointly with cholesterol (C27H46O) but that, in addition to the similarities in formula, they shared some color reactions in common. It was also known that some oxidations of cholesterol produce acetone, while acetone is not formed in oxidations of cholic acid. Loss of a three-carbon acetone unit leaves a C24 unit, the same carbon number as in cholic acid. Windaus received the 1928 Nobel Prize in chemistry for clarifying the relationships between cholesterol and other steroids. His initial structure for cholesterol, consistent with the early incorrect representation of cholic acid, was also incorrect. The correct structure (below) was published in 1932. 

Davis. A.P. Bonar-Law. R.P. Sanders, J.K.M. Receptors Based on Cholic Acid. In Comprehensive Supramolecular Chemistry, Murakami, Y., Ed. Suprainolecular Reactivity and Transport Bioorganic Systems, Pergamon Oxford, 1996 Vol. 4, 257-286. 

The history of cholic acid is intimately woven through the entire history of the isolation and chemistry of the bile acids. This most common acid was isolated in 1838 and 1843 but was first studied carefully by Strecker in 1848 (7). The name cholic acid given by Demarcay had already been used by Gmelin (14), probably for glycocholic acid, so that other names were substituted for the free bile acid. The name cholalic acid, which persisted for several decades, was given by Strecker (19). It referred to the treatment of bile with alkali in order to obtain the nitrogen-free bile acid. Strecker (19) obtained the correct C24H4QO5 empirical formula for cholic acid. 

Chemically, the bile acids are hydroxylated derivatives of cholanic acid, a tetracyclic steroid acid of 24 carbon atoms. The acids occur in nature largely as the water-soluble sodium salts of peptide conjugates of glycine and taurine. The free acids are liberated by saponification or specific enzyme hydrolysis. The chemistry of the bile acids has been reviewed in Chapter 1 of this volume (1). In view of their highly polar nature, special attention is called to the recent discovery of the cholic acid conjugates of ornithine (2, 3) and the 3a-sulfate esters of glycolithocholic and taurolithocholic acids (4). 

The physical chemistry of micellar structure and formation has been reviewed extensively elsewhere[40,45-47], and is only briefly summarized. The concentration at which micellar aggregation of bile salts molecules occurs (critical micellar concentration, CMC) is affected by bile salt structure, pH, temperature and a variety of other factors. Conjugated bile salts have a higher CMC than the unconjugates, and the CMC for trihydroxycholanates (cholic acid) is higher than for the dihydroxy derivatives. Among the latter, deoxy-cholate forms micelles at a lower CMC than does chenodeoxycholate. 

Some of the issues raised above did not apply in the early days of supramolecular chemistry, when the focus was on crown ethers and cryptands which do not have self-complementary functionality. In contrast, our own work has required the disposition of neutral H-bond donor groups, which almost always contain H-bond acceptors. The separation of these groups by rigid spacers has therefore been a strict requirement. The traditional device for this purpose has been the aromatic ring, to which we have turned in some of our most recent work (Section 5). However, we have developed a special interest in an alternative, the steroid nucleus as present in cholic acid (1). This... 

Our own involvement in carbohydrate recognition grew out of our interest in cholic acid as a building block for supramolecular chemistry. Having designed and synthesized the first cholaphane f> we were looking for an application. Prompted by the work of Aoyama on calixarene 17, the first synthetic carbohydrate receptor, we realised that the cavity of 16 was nicely complementary to a monosaccharide. H NMR... 

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