Copper Catalyzed Enatioselective Inverse Electron Demand Diels-Alder Reaction of Transient Nitrosoalkenes

We are currently making natural products that are active against cancer, the number one leading causes of mortality worldwide. Our long-term goal is to understand how these natural products work against cancer, how we can reduce side effects, and how we can improve their activity so that some of these natural products or their derivatives could be used as therapeutics. Using an Inverse-Electron demand Diels-Alder (IEDDA) reaction, we performed experiments to synthesize precursors of the natural products that could themselves be active against cancer.

            The essence of these natural products to be anti-cancer supports the testing of the hypothesis. We chose the IEDDA reaction to make precursors for hexahydropyrrolo(2,3-b)indole(HPI) natural products. To test the hypothesis we have developed a protocol that utilizes the data obtained with liquid chromatography mass-spectroscopy (LCMS) methods. This involves conducting these reactions at low temperatures followed by an assay with LCMS. We use these results to then analyze and improve the selectivity of the reaction. Through LCMS we improve our enantiomer excess of our HPI precursors.

            Our results prove our hypothesis of using IEDDA reaction as a methodology to make HPI precursors. In fact, we were successful in making enantiomerically pure products (98:2 ratio of the wanted to unwanted product).

            Our next step in our research would be to send our products to our collaborators. In order to understand fully how these anti cancer molecules work and how we can improve them to one day be used as therapeutics for patients in the future.