UC Davis

Described herein are three distinct synthetic routes toward the first asymmetric total synthesis of alopecurone C and other flavonostilbenoid natural products via C–H insertion with donor/donor carbenes. The first chapter details the isolation, biological activities, and synthetic challenges of flavonostilbenoid natural products, including the alopecurone, gnetoflavanol, and rhamnoneuronal families. The second chapter focuses on the first-generation synthetic route to alopecurone C, which features the largest-scale asymmetric C–H insertion reaction of a donor/donor carbene reported to date. This reaction was achieved with only 0.1 mol% catalyst, yielding excellent selectivity on a 10-gram scale. However, despite extensive efforts, late-stage sp² C–H functionalization could not be achieved, precluding the completion of the synthesis. The third chapter presents the second-generation synthetic route to alopecurone C, which utilizes the first efficient synthesis of highly hindered and electron-rich diaryl hydrazone and rhodium carbene. The corresponding C–H insertion reaction revealed a selectivity-determining step distinct from that in the first-generation route. Unfortunately, the route was rendered abortive due to unsuccessful benzylic oxidation and unexpected racemization of (2S)-naringenin. The fourth chapter introduces the ultimate third-generation synthetic route to alopecurone C and gnetoflavanol B. This strategy, to the best of my understanding, represents the first kinetic resolution via a C–H insertion reaction to simultaneously address all three stereogenic centers. Furthermore, these three synthetic routes collectively provide the opportunity to modify nearly all functional groups of alopecurone C, establishing a strong foundation for future structure-activity relationship (SAR) studies.