Date of Thesis

Summer 2023

Description

Bile acids are naturally made from cholesterol and then derivatized through biotransformation by gut bacteria in most vertebrates including humans. Iso bile acids designates the C3-β hydroxy subfamily of bile acid derivatives, with emerging biological discoveries but low commercial accessibility. Previous synthesis of iso bile acid targeted only a few substrates and some are limited by poor stereoselectivity of the methods. This thesis herein reports a concise three-step synthesis of iso bile acids generalizable to four common bile acid substrates with consistent yields above 85%. A base-catalyzed Mitsunobu reaction using TFA as the pronucleophile was employed to achieve the key C3 inversion, affording a synthetically useful intermediate that could be converted into the corresponding iso bile ester or undergo selective acylation at the sterically hindered C7 and C12 hydroxyl positions with above 90% yield. Rigorously dry condition was proven optimal for the Mitsunobu reaction, with azeotrope using benzene sufficient to remove extraneous water trapped in the reactant under high humidity in the atmosphere.

The later chapter uncovers the extent and targeting step in the mechanism of water sensitivity in the Mitsunobu reaction. We observed that 0.25 equiv of water diminished the yield by 33%, and 1 equiv of water is sufficient to terminate the reaction with no conversion. Depending on the order the addition of pronucleophile, the first two stable intermediates betaine and H-betaine or phosphorane all exhibit high water sensitivity and rapid decomposition to O=PPh3 with presence of water, whilst the last oxyphosphonium intermediate only expresses a medium reactivity with water in the beginning of the reaction.

Keywords

Mitsunobu reaction, iso bile acid

Access Type

Masters Thesis (Bucknell Access Only)

Degree Type

Master of Science

Major

Chemistry

First Advisor

Michael Krout

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