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 of 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 was to gain a deeper understanding of the mechanism of the cyclization reaction, therefore allowing us to devise a practical way to control the reaction. Computational modeling using DFT calculations of the radical reaction provided insight into the molecular electrostatic and dipole moment of the intermediates. Accordingly, the reaction was optimized through carefully choosing the compatible solvent. Ultimately we discovered that a polar solvent favored the production of the indoline product. Conversely, a polar solvent favored the quinolone product. Details of the reactions will be presented.

Taming the radical 5-<i>exo-trig</i> cyclization reaction in the synthesis of duocarmycin analogs

245th National Meeting (2013)

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Taming the radical 5-exo-trig cyclization reaction in the synthesis of duocarmycin analogs