Date of Thesis

Summer 2026

Description

Bile acids are produced as the end product cholesterol metabolism in the liver. Before making their way into the gastrointestinal tract, primary bile acids—cholic acid and chenodeoxycholic acid—are first conjugated with glycine or taurine at the C24 carboxylic acid as a means of assisting with transport throughout the gut. These amino acid conjugated bile acids have been known to be synthesized in the liver for approximately 100 years, but it is only recently in the last five years that novel microbially conjugated bile acids (MCBAs) have been discovered in the gut of SPF mice including phenylalanine, tyrosine, and leucine conjugates of both cholic acid and deoxycholic acid and deoxycholic acid conjugates with alanine and proline. These MCBAs are thought to have the potential of treating gastrointestinal diseases by acting as either agonists or antagonists for the activation or suppression of nuclear receptors that are present in the gut such as the farnesoid X receptor (FXR). Not only this, but these MCBAs have been shown to act as chiral selectors for the separation of enantiomers using micellar-electrokinetic-chromatography, but only when the C12 hydroxyl group is present. To this day, there is not an efficient synthetic method for the synthesis of the amino acid conjugated bile acids even though they are thought to have such important applications. An efficient and scalable synthesis for amino acid conjugated bile acids is described here in this thesis along with the investigation of the aggregation properties of these conjugates in aqueous solution through critical-micelle-concentration determination. This efficient synthesis and aggregation investigation would allow for the rapid production of conjugated bile acids along with a better understanding to apply these compounds as bile acid chiral selectors. Additionally, it is the goal of this thesis to develop a chemoselective Mitsunobu reaction for the functionalization of the C24 carboxylic acid through a one and two carbon homologation. This functionalization again has the potential to affect chiral separations and help promote the rational design of better bile acid chiral selectors. The Mitsunobu has been shown to be chemoselectively substitute primary alcohols over secondary alcohols and using this concept, different pronucleophiles capable of one and two carbon homologations are compared in terms of chemoselectivity, while also developing a reaction that can efficiently synthesize C25 and C26 bile acids without the use of protecting groups. The two pronucleophiles investigated in this thesis include acetone cyanohydrin for a one carbon homologation and triethyl methantricarboxylate (TEMT) for the two-carbon homologation. Conditions have been optimized for both pronucleophiles as a starting point for understanding pronucleophile reactivity that will allow for a better design for the investigation of more pronucleophiles.

Keywords

Mitsunobu, Bile Acid, Conjugates, microbially conjugated bile acids, homologation, bis-homologation, efficient, scalable

Access Type

Masters Thesis (Bucknell Access Only)

Degree Type

Master of Science

Major

Chemistry

First Advisor

Michael Krout

Second Advisor

David Rovnyak

Third Advisor

Hasan Arslan

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