Concise Synthesis of Cyctetryptomycin A and B Enabled by Zr‐Catalyzed Dimerization

A concise synthetic strategy utilizing a Zr catalyst for the construction of cyctetryptomycin A and B is reported. Cyctetryptomycin A and B are recently isolated, complex tetrameric natural products for which total synthesis has not been previously reported. This study presents a practical approach for the construction of two consecutive quaternary carbon centers with a Zr catalyst. Furthermore, the first total synthesis of cyctetryptomycin A and B was achieved by this Zr‐catalyzed radical coupling. The radical dimerization reaction mediated by the Zr catalyst required 1,2‐bis(diphenylphosphino)ethane (dppe) as an indispensable additive. Through both experimental and theoretical investigations into the mechanism of this Zr‐catalyzed reaction, the specific role of dppe was elucidated. In addition, the synthetic approach was extended to enable the practical synthesis of other dimeric natural products, including tetratryptomycin A, dibrevianamide F, and ditryptophenaline. Finally, the synthetic mechanism of cyctetryptomycin A and B, through the oxidative macrocyclization of tetratryptomycin A by CttpC, was newly elucidated by both experimental and docking simulations. A concise synthesis of cyctetryptomycin A and B employing a zirconium‐catalyzed dimerization and CttpC‐catalyzed oxidative macrocyclization is presented, including in‐depth mechanistic analysis of the zirconium‐catalyzed C−C bond formation and its various applications. Additionally, the previously unknown detailed reaction mechanism of the CttpC‐catalyzed oxidative macrocyclization of tetratryptomycin A has been elucidated.