(–)-Podophyllotoxin is one of the most potent microtubule depolymerizing agents and has served as an important lead compound in antineoplastic drug discovery. Here, we report a short chemoenzymatic total synthesis of (–)-podophyllotoxin and related aryltetralin lignans. Vital to this approach is the use of an enzymatic oxidative C–C coupling reaction to construct the tetracyclic core of the natural product in a diastereoselective fashion. This strategy allows gram scale access to (–)-deoxypodophyllotoxin and is readily adaptable to the preparation of related aryltetralin lignans.
Biocatalytic C–C coupling: Podophyllotoxin, a potent microtubule depolymerizing agent, was synthesized in a concise manner through a strategic use of three oxidative processes. Highlights of the route include a gram-scale biocatalytic C–C coupling to construct the tetracyclic core of the natural product and a chemoselective late-stage installation of the secondary alcohol at C7.