Expanding the Chemistry of Polyoxygenated Heterocycles

Heterocyclic compounds have undisputed significance in disciplines that stretch across chemistry and biology. The ever-growing utility of heterocyclic chemistry spans the development of therapeutic agents, catalysis and ligand design, to the preparation of chemical probes utilized in biological investigations. The chemistry described in this thesis focuses on reaction development for the generation of extensively functionalized polyoxygenated heterocycles and the incorporation of these synthetic tools in the arena of natural product synthesis. Chapter One introduces the dogma of discovering new pharmaceutical leads by acknowledging long-appreciated traditional medicinal knowledge in the context of ethnomycology. The biosynthetic analyses of several key bioactive fungal metabolites are subsequently discussed, underpinning the string of synthetic campaigns presented in this thesis. Chapter Two describes the evolution of a new synthetic method that strategically exploits the intrinsic reactivity of o-benzoquinones within the confines of dibenzofuran synthesis. The nascent idea was brought to maturity with the development of an unconventional approach whereby the target dibenzo[b,d]furan scaffold was directly constructed through the union of simple phenols/naphthols and o-benzoquinones through a Michael-oxidation-oxa-Michael sequence. The scope of this transformation was evaluated with a broad range of phenolic substrates and a tactical insertion of this methodology into a total synthesis endeavor led to a concise synthesis of two dibenzofuran natural products. Chapter Three details a nine-step synthesis of boletopsin 11, a polyoxygenated p-terphenyl dibenzofuran fungal metabolite. Our synthetic approach employs a one-pot oxidation-oxa-Michael sequence ensued by a palladium-catalyzed directed ortho-C(sp2)-H arylation reaction to forge efficiently the entirety of the carbon skeleton. Efforts directed at optimizing the latter reaction revealed a tandem ortho-C(sp2)-H arylation event-an unprecedented mode of reactivity which superseded the scope of the original methodology report. Chapter Four outlines the first total synthesis of suillusin. The molecular framework was constructed in one step using a multicatalytic Michael-benzoin condensation cascade followed by a Rubottom-Swern oxidation strategy to yield the requisite oxidation state of the skeletal framework. The successful completion of the synthesis enabled the investigation of the enantiopurity of the natural isolate and its unexplored biosynthetic origin