The polyphenolic extracts of milk thistle, known as silymarin, have been used for centuries in the treatment of liver disorders. Silymarin has been demonstrated to modulate androgen receptor function, and its constituents have been evaluated individually for anti-cancer properties. Isosilybins A and B, two of seven flavanolignan constituents of silymarin, have shown promising <i>in vitro</i> and <i>in vivo</i> activity against prostate cancer, but only account for a small fraction of silymarin by mass. Furthermore, the molecular target(s) of these compounds are unknown. No selective or asymmetric synthesis of these compounds has been previously reported, precluding further investigation of their molecular pharmacology. The asymmetric formation of the 2-aryl benzopyranone core, characteristic of flavanones, has prevented the preparation of enantiopure silybin natural products and is a challenging problem in the greater context of flavanone synthesis. A modular synthetic route was designed to support further pharmacological exploration and address this synthetic challenge. The total synthesis of (-)-isosilybin A was completed to demonstrate the utility of this route and serve as a platform to explore new approaches to the asymmetric formation of highly substituted 2-aryl benzopyranones. A catalytic, biomimetic cyclization of a highly functionalized chalcone was developed to solve this challenging problem. This catalytic system, comprised of a bi-functional cinchona alkaloid urea, uniquely enables the direct cyclization of polyphenolic chalcones to flavanones in an asymmetric fashion. A robust and flexible approach to the requisite chalcone provides an entry to the preparation of the entire isomeric family of silybin natural products.

Total synthesis of (-)-isosilybin A

251st National Meeting (2016)

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