The Rapid Synthesis of Colibactin Warhead Model Compounds Using New Metal-Free Photocatalytic Cyclopropanation Reactions Facilitates the Investigation of Biological Mechanisms.

Abstract

Herein, we report the synthesis of a series of colibactin warhead model compounds using two newly developed metal-free photocatalytic cyclopropanation reactions. These mild cyclopropanations expand the known applications of eosin within synthesis. A halogen atom transfer reaction mode has been harnessed so that dihalides can be used as the cyclopropanating agents. The colibactin warhead models were then used to provide new insight into two key mechanisms in colibactin chemistry. An explanation is provided for why the colibactin warhead sometimes undergoes a ring expansion-addition reaction to give fused cyclobutyl products while at other times nucleophiles add directly to the cyclopropyl unit (as when DNA adds to colibactin). Finally, we provide some evidence that Cu(II) chelated to colibactin may catalyze an important oxidation of the colibactin-DNA adduct. The Cu(I) generated as a result could then also play a role in inducing double strand breaks in DNA.