Synthesis of 12β-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 12 beta-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 Delta(13,14)- and Delta(13,17)-unsaturated 12 beta-methyl-18-nor-bile acid intermediates (24a and 25a). Subsequent catalytic hydrogenation and deprotection yielded 12 beta-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 12 beta-methyl-18-nor-chenodeoxycholic acid (27a).

Automated summary

Decoupling the roles of the farnesoid X nuclear receptor and the Takeda G-protein-coupled bile acid receptor 5 is crucial for developing novel bile acid therapeutics targeting metabolic and neurodegenerative diseases. The synthesis of 12 beta-methyl-18-nor-bile acids as probes for new bile acid analogues with clinical applicability was described, along with the mechanism insights provided by deuteration experiments. Optimization of the synthetic sequence enabled a chromatography-free route to prepare these bile acids at a multi-gram scale, highlighting the potential for future therapeutic developments.