Synthesis of Novel C/D Ring Modified Bile Acids

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Drug Discovery

Background:

• Bile acid receptors are key targets for treating metabolic and inflammatory diseases.
• Developing novel bile acid analogues is crucial for understanding structure-activity relationships and selective receptor activation.

Purpose of the Study:

• To investigate the chemical manipulation of the C/D ring junction in bile acids using a specific derivative.
• To synthesize new bile acid analogues for biological evaluation.

Main Methods:

• Utilized a chenodeoxycholic acid derivative with a C-12 methyl and C-13 to C-14 double bond as a scaffold.
• Examined the reactivity of the alkene substrate with zinc carbenoid species generated via Furukawa and Shi methodologies.
• Performed O-7 oxidation and epimerization on cyclopropanated steroids.

Main Results:

• Furukawa methodology resulted in selective α-cyclopropanation of the bile acid scaffold.
• Shi methodology led to an unexpected rearrangement, forming a novel spiro-furan ring system via C ring contraction.
• Generated new bile acid derivatives through further derivatization for biological testing.

Conclusions:

• Selective cyclopropanation and skeletal rearrangement of bile acid derivatives can be achieved using different carbenoid methodologies.
• These novel bile acid analogues offer potential for developing new therapeutics targeting bile acid receptors.