New cascade cyclization approach towards the amorfrutin class
Amorfrutins are compounds found naturally in the plants Amorpha fruticosa and Glycyrrhiza foetida that have wide ranging potential benefits for human health, such as in the treatment of both type 2 diabetes and certain cancers. In mice, amorfrutins A and B have been shown to bind to and activate PPARγ (a nuclear receptor contributing to lipid and glucose metabolism). This interaction results in increased insulin resistance in the mice without unwanted side effects that come with other PPARγ-targeting drugs such as increase in fat storage or hepatotoxicity. Meanwhile, amorfrutin C could possibly be used in cancer treatment by inducing apoptosis in colon cancer cells through targeting the cells’ mitochondria.
Existing chemical syntheses of these compounds are lengthy, require the use of protection and deprotection steps, and often include lowly selective functionalization steps. As a result, we developed a new, convergent synthesis through an optimized cascade cyclization that can produce a wide range of derivatives in fewer linear steps and with easily obtainable starting materials. The cascade cyclization also provides new methodology in aromatic scaffold synthetic design that is beneficial for developing biologically important compounds in a more facile way. We tested this approach by performing cyclization reactions under varying conditions and verifying that the compounds produced are as desired, and we investigated overall reaction selectivity using nuclear magnetic resonance (NMR). Additionally, this cascade cyclization approach can be extended to produce cannabinoid derivatives and other natural compounds that may exhibit health benefits.
Working at the Boyce Thompson Institute this summer was a great experience. I had the chance to apply what I had learned about chemistry in school to work on synthesis in the lab, and also learned much more by working with a graduate student mentor and conducting real chemical reactions. I got to use many different techniques and lab equipment this year, such as nuclear magnetic resonance (NMR) and Schlenk lines, which broadened my experience of science. Additionally, talking to graduate students and faculty at BTI has helped me think about applying to college next year and careers in science.