A diversity-oriented synthesis approach was used to prepare analogues of the flavonoid class of natural products that have increased stereochemical complexity and unnatural appendages or substitution patterns. Reduced flavone analogues were accessed through [4+2] and [3+2] cycloaddition reactions with various γ-pyrones, and the resulting products were further functionalized to generate diverse libraries. Additionally, a route to access amino-flavanols that utilizes microwave-assisted organic synthesis to rapidly generate analogues was developed. The route begins with a microwave-assisted aldol condensation to generate chalcone intermediates, followed by a Corey-Bakshi-Shibata reduction and subsequent Sharpless asymmetric epoxidation to access the different stereoisomeric epoxy alcohols. The final step is a microwave-assisted, regioselective, acid-catalyzed epoxide opening with various amines followed by an intramolecular S<sub>N</sub>Ar reaction to generate the amino-flavanols in an optimized one-pot procedure. Analogues of these flavonoid scaffolds were synthesized and are currently being screened in a diverse set of biological assays to assess performance diversity in order to better understand what type of molecules should be included in screening collections to discover novel chemical probes for complex biological processes and historically challenging disease targets.

Stereoselective synthesis of flavonoid analogues and evaluation of biological performance diversity

254th National Meeting (2017)

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