Synthesis of Novel C/D Ring Modified Bile Acids.

Bile acid receptors have been identified as important targets for the development of new therapeutics to treat various metabolic and inflammatory diseases. The synthesis of new bile acid analogues can help elucidate structure-activity relationships and define compounds that activate these receptors selectively. Towards this, access to large quantities of a chenodeoxycholic acid derivative bearing a C-12 methyl and a C-13 to C-14 double bond provided an interesting scaffold to investigate the chemical manipulation of the C/D ring junction in bile acids. The reactivity of this alkene substrate with various zinc carbenoid species showed that those generated using the Furukawa methodology achieved selective α-cyclopropanation, whereas those generated using the Shi methodology reacted in an unexpected manner giving rise to a rearranged skeleton whereby the C ring has undergone contraction to form a novel spiro-furan ring system. Further derivatization of the cyclopropanated steroid included O-7 oxidation and epimerization to afford new bile acid derivatives for biological evaluation.

Synthesis of 12ß-Methyl-18-nor-bile Acids.

Decoupling the roles of the farnesoid X nuclear receptor and Takeda G-protein-coupled bile acid receptor 5 is essential for the development of novel bile acid therapeutics targeting metabolic and neurodegenerative diseases. Herein, we describe the synthesis of 12ß-methyl-18-nor-bile acids which may serve as probes in the search for new bile acid analogues with clinical applicability. A Nametkin-type rearrangement was applied to protected cholic acid derivatives, giving rise to tetra-substituted Δ13,14- and Δ13,17-unsaturated 12ß-methyl-18-nor-bile acid intermediates (24a and 25a). Subsequent catalytic hydrogenation and deprotection yielded 12ß-methyl-18-nor-chenodeoxycholic acid (27a) and its 17-epi-epimer (28a) as the two major reaction products. Optimization of the synthetic sequence enabled a chromatography-free route to prepare these bile acids at a multi-gram scale. In addition, the first cis-C-D ring-junctured bile acid and a new 14(13 → 12)-abeo-bile acid are described. Furthermore, deuteration experiments were performed to provide mechanistic insights into the formation of the formal anti-hydrogenation product 12ß-methyl-18-nor-chenodeoxycholic acid (27a).