Controlling the Radical 5-exo-trig Cyclization Reaction in the Synthesis of Duocarmycin Analogs

Student Author(s)

Sarah Wieskamp

Faculty Mentor(s)

Dr. Pravin Patil; Dr. Moses Lee

Document Type


Event Date



CC-1065 and the duocarmycins are natural products that contain the cyclopyrroloindolone (or CPI) subunit. These compounds and their analogs bind in the minor groove of AT-rich sequences of DNA and they covalent bond with adenine-N3. This leads to potent cytotoxicity against the growth of cancer cells in vitro and in vivo. One efficient approach for synthesizing the CPI moiety is through the 5-exo-trig radical cyclization of a free radical and an adjacent 3-chloro-2-allylic moiety. Recently we reported that the cyclization proceeded via a benzofurano radical. The reaction yielded an unpredictable mixture of 6- benzyloxy-N-t-butoxycarbonyl-3-(chloromethyl)furano[e]indoline and 7-benzyloxy-N-t-butoxycarbonyl-3-chloro-1,2,3,4- tetrahydrofurano[f]quinoline. The purpose of this study is to gain a deeper understanding of the mechanism of the cyclization reaction, therefore allowing researchers to devise a practical way to control the reaction. Also, in this study thiophene and benzo derivatives will be studied to investigate the structure-reactivity relationship of the radical cyclization process. Computational modeling using DFT calculations of the radical reaction will provide further insight into the molecular electrostatic and dipole moment of the intermediates. This will enable us to have a better understanding of how electronic factors can affect reactivity. Results from these studies will be presented.

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