Total Synthesis of Complex Polycyclic Natural Products and the Development of Cyclization Methods

Abstract

Compounds isolated from natural sources serve as an inspiration for modern drug design and development due to their diverse and beneficial biological activities. The total synthesis of natural products has proven to be a testing ground for new strategies and methods in organic synthesis where progress made in the field of organic synthesis can be showcased. Additionally, the synthesis of natural products helps circumvent the material constraints of natural abundance allowing for further exploration of the properties of these materials. Many biologically active natural products feature multiple ring systems, which are often fused, resulting in intricate, highly functionalized core structures. Despite recent advances in developing efficient methods for carbon-carbon bond formation, the selective synthesis of these complex structures remains challenging since many of these methods are developed and optimized on simple molecular scaffolds. Thus, creating the opportunity for the development of new strategies and methods for their synthesis, as well as the refinement of existing strategies and methods for use in complex molecular settings. Chapter 1 details our lab’s 14-step total synthesis of (+)-cochlearol B, a meroterpenoid isolated from the fruiting bodies of the fungus Ganoderma cochlear. This natural product features a unique 4/5/6/6/6 polycyclic core structure bearing a heptasubstituted cyclobutane containing three contiguous stereocenters and has documented antifibrotic activity. This synthesis was enabled by a Kabbe condensation, alkenyl Catellani reaction, and visible-light-mediated [2+2]-photocycloaddition to rapidly construct the polycyclic core. Initial attempts to synthesize this natural product led to the discovery of intriguing side reactions which prompted further investigation and development. First was a deoxygenative cyclization of chromanones via a vinyl triflate intermediate to form cyclopentylchromene products which is detailed in Chapter 2. Mechanistic investigations suggest this transformation proceeds through elimination of the triflate to form a cyclic alkyne which then proceeds though an Alder-ene type reaction to form the cyclized products. Second was a radical cascade cyclization to form polycyclic cyclopropanes which is detailed in Chapter 3. This reaction utilizes visible-light enabled photocatalysis to effect a Dexter triplet energy transfer and initiate the radical cascade. Chapter 4 describes my efforts toward the divergent total synthesis of atropurpuran and the arcutin family of natural products, which were isolated from a variety of Aconitum plants. These natural products bare a unique cage-like framework featuring a bis-bicyclo[2.2.2]octane core. This enantioselective synthesis is enabled by a cascade cyclization strategy relying on the hidden symmetry featured in the core structures of the natural products. Initial attempts to form the peripheral cyclohexene ring relied on a Barbier cyclization followed by a condensation while the current strategy relies on a ring-closing carbonyl-olefin metathesis reaction. The work described herein details strategies to form complex polycyclic small molecules of medicinal interest and the development of methods to efficiently synthesize them.