Synthesis of 12β-Methyl-18--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 12β-methyl-18--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 Δ- and Δ-unsaturated 12β-methyl-18--bile acid intermediates ( and ). Subsequent catalytic hydrogenation and deprotection yielded 12β-methyl-18--chenodeoxycholic acid () and its 17--epimer () 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 -C-D ring-junctured bile acid and a new 14(13 → 12)--bile acid are described. Furthermore, deuteration experiments were performed to provide mechanistic insights into the formation of the formal anti-hydrogenation product 12β-methyl-18--chenodeoxycholic acid ().