UC Irvine

This dissertation details the development of a synthetic route for the access of highly oxidized polycyclic scaffolds relevant to the total synthesis of bruceantin and bruceolide-type quassinoids, which bear a characteristic carbomethoxy-substituted tetrahydrofuran bridging C8 and C13. Chapter 1 introduces the quassinoid class of natural products, with particular emphasis on the biological activity of its pentacyclic congeners. Persistent challenges associated with establishing the dense oxidation patterns and stereochemical arrays of pentacyclic quassinoids are discussed through previous synthetic campaigns toward congeners possessing the bridging tetrahydrofuran motif. A modern strategy toward the total synthesis of quassin, enabled by an MHAT-mediated annulation and previously developed by the Pronin laboratory, is also presented.Chapter 2 describes the development and execution of a MHAT-mediated annulation approach toward bruceantin, beginning with efforts to assemble the tricarbocyclic core with oxidation incorporated at all requisite carbons. The evolution of this strategy toward construction of the desired pentacyclic architecture is presented, including studies directed at installation of the C8–C13 tetrahydrofuran and fused δ-lactone. The unanticipated reactivity exhibited by highly oxidized polycyclic intermediates is disclosed, revealing challenges associated with introducing the requisite oxidation at an early stage of quassinoid synthesis. These studies culminated in an elaborated tetracyclic scaffold, serving as an advanced platform for the total synthesis of bruceantin.