Benzocycloheptadienes as a platform for the total synthesis of seven-membered ring-containing natural products: Synthetic studies on the icetexane diterpenoids and the cortistatins

A general strategy for the synthesis of seven-membered ring-containing natural products has been developed, wherein alkynyl indenes undergo a metal-catalyzed enyne cycloisomerization reaction. The resulting benzocycloheptadienes serve as versatile intermediates in a number of total syntheses.;An overview of the icetexane diterpenoid family of natural products is presented. The structure, isolation and biological activity of the icetexanes is followed by a discussion of their biosynthetic relationships. Subsequent to this, a summary of the synthetic efforts toward these compounds that have been reported in the literature to date is presented.;A general synthetic strategy toward the icetexane natural products was devised, which focused on utilizing an enyne cycloisomerization reaction to construct the tricyclic benzocycloheptadiene core of this family. Following preliminary model studies, the total synthesis of (+/-)-salviasperanol was achieved.;Building upon these initial studies, the total syntheses of (+/-)-5,6-dihydro-6alpha-hydroxysalviasperanol, (+/-)-brussonol and (+/-)-abrotanone were completed. The completion of this work resolved a number of inconsistencies in the literature regarding the stereochemical assignment of several icetexane natural products and synthetic derivatives.;Efforts were initiated to complete the synthesis of (+/-)-komaroviquinone and (+/-)-coulterone, two additional members of the icetexane family. The tricyclic core of these natural products was successfully assembled and several strategies to complete the total synthesis of these compounds were explored.;The enyne cycloisomerization reaction developed for the construction of the icetexane framework was extended to the synthesis of the tetracyclic core of the cortistatin family of rearranged steroidal alkaloids. An oxidative dearomatization was employed to complete the synthesis of the cortistatin pentacycle.;A second-generation synthesis of the pentacyclic core of the cortistatins enabled further synthetic studies which led to the formal total synthesis of (+/-)-cortistatin A. Efforts to functionalize the A ring of the cortistatin core were initiated, and the pentacyclic core of cortistatins K and L was assembled.