Mechanistic analysis of carbon–carbon bond formation by deoxypodophyllotoxin synthase

Significance The completion of the tetracyclic core of etoposide, classified by the World Health Organization as an essential medicine, by the Fe/2OG oxygenase deoxypodophyllotoxin synthase follows a hybrid radical-polar pathway not previously seen in other members of this enzyme class. The implication of a substrate-based benzylic carbocation in this mechanism will inform ongoing efforts to create analogs of this important drug with improved or emergent properties and represents a new route for resolution of the initial substrate radical that is common to members of the class. This study adds to our understanding on a growing number of biochemical transformations in which carbocation intermediates are likely to be crucial.