Riccardin C, a member of a family of macrocyclic bisbibenzyl natural products, has been reported to exhibit interesting biological activity against a liver X receptor. Liver X receptor is a transcription factor that regulates synthesis of proteins involved in regulation of cholesterol homeostasis and activation of liver X receptor results in increase of the levels of HDL-cholesterol and decrease of the levels of LDL-cholesterol. As a result, small molecules activating liver X receptor may produce leads for the development of new pharmaceutical agents for regulation of cholesterol homeostasis. However, a strained structure of Riccardin C makes it a poor starting point for the development of libraries of liver X receptor ligands. Therefore, our goals is to develop a simplified analog of Riccardin C, which retains Riccardin C biological activity but is easier to synthesize. To further streamline the development of libraries of Riccardin C analogs we developed a modular synthesis, where a precursor of each phenol ring is synthesized independently and which are then assembled into a final structure. The key steps of the synthesis are Suzuki and Heck couplings as well as Yamaguchi macrocyclization. Our work on optimization of these steps as well as on the choice of protecting groups to ensure selective macrocyclization will be presented.

Modular approach to the synthesis of riccardin C analogs

251st National Meeting (2016)

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