Date of Thesis
Bile acids are metabolites biosynthesized from cholesterol in the liver and further modified through bacterial enzymatic pathways. Although classically understood to function in the metabolism of fat and expulsion of cholesterol, bile acids also serve as cell signaling molecules in glucose metabolism and inflammation. Allo bile acid derivatives differ from the more common primary and secondary bile acids in the C(5) stereocenter of their steroid nucleus. This difference largely impacts their topology and biological activity. Allolithocholic acid (alloLCA), a derivative of lithocholic acid (LCA), has been specifically found to increase levels of Foxp3, a transcription factor that serves a role in the differentiation of regulatory T cells (Tregs). AlloLCA therefore has the potential to impact the physiological state of certain autoimmune and inflammatory disorders. This metabolite is limited in its accessibility as it is not commercially available. As is often the case with interesting natural products, synthetic organic chemistry is required to obtain alloLCA in quantities sufficient for immunological study.
We aimed to develop a stereoselective synthesis toward alloLCA through a series of oxidations and reductions in the A ring of the steroid nucleus. After protection of the C(24) carboxylic acid, oxidation to an a, b-unsaturated ketone was performed using PCC and HIO3. The key step of our synthetic approach was the stereoselective reduction of this enone, successfully accomplished through copper hydride conditions. This crucial transformation enabled the completion of the synthesis of alloLCA in six steps with a 27% yield and 7.4:1 dr.
bile acid, lithocholic acid, stereoselective
Honors Thesis (Bucknell Access Only)
Bachelor of Science
Kelly, Samantha P., "Development of a Stereoselective Synthesis of Allolithocholic Acid" (2017). Honors Theses. 663.