Total Synthesis of Gukulenin B via Sequential TropoloneFunctionalizations

:the synthesis of functionalized aromatic compounds is a central theme ofresearch for modern organic chemistry. Despite the increasingfinesse in thefunctionalization offive- and six-membered aromatic rings, their seven-membered-ringsibling, tropolone (2-hydroxy-2,4,6-cycloheptatrien-1-one), remains a challenging targetfor synthetic derivatization. This challenge primarily emanates from the unique structuraland chemical properties of tropolonoid compounds, which often lead to unexpected andundesired reaction outcomes under conditions developed for the functionalizations ofother aromatic moieties. Herein, we describe the total synthesis of one of the mostcomplex natural tropolonoids, gukulenin B. Our synthetic route features a series of site-selective aromatic C-H bond functionalizations and C-C bond formations, whosereaction conditions are judiciously tuned to allow uncompromised performance on thetropolone nucleus. Theflexibility and modularity of our synthesis are expected to facilitate further synthetic and biological studies ofthe gukulenin family of cytotoxins. In addition, the methods and tactics developed herein for the functionalization of the tropolonemoiety could inspire and enable chemists of multiple disciplines to take advantage of this privileged yet underexplored structuralmotif.