Towards the efficient and scalable synthesis of fluorinated lead components

Abstract

Bile acids (BAs) are steroidal organic compounds found within the bile fluid of all vertebrates. They are biosynthesised within the liver and have the primary physiological function of solubilising and digesting dietary fats. Research within the last two decades have shown BAs can operate as signalling molecules to affect a number of vital physiological functions; the BA-activated receptors of note are the Farnesoid X receptor (FXR) and Takeda G-protein coupled receptor 5 (TGR5). Activation of these receptors have therefore become attractive targets for the treatment of various metabolic disorders including non-alcoholic steatohepatitis (NASH), while emerging evidence has revealed certain BAs to exhibit neuroprotective properties. A geminal difluorinated BA has been identified as a lead compound for treating Parkinson’s disease and its optimised synthesis is discussed herein. Various fluorination routes are explored, with the optimum route identified combining an organocatalytic and silyl enol ether fluorination approach. The synthesis of novel fluorinated BA analogues as agonists of the FXR is also discussed, which have shown promising preliminary biological results for the treatment of NASH.

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Identifiers

ORCID for Lawrence Tam: orcid.org/0000-0001-9659-8526

ORCID for Bruno Linclau: orcid.org/0000-0001-8762-0170

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