Synthetic Approaches to the A-74528 and Enterocin Polyketides and Catalytic Asymmetric Radical–Polar Crossover Reactions

This dissertation communicates new methods in cyclopropane activation and hydrogen-atom-transfer-initiated alkene hydrofunctionalizations to access novel catalytic asymmetric reaction manifolds and challenging polyketide scaffolds. Chapter One delineates the discovery of the enterocin polyketide antibiotics and subsequent efforts to identify the biosynthetic origin of their intriguing architecture. A review of the synthetic efforts towards the enterocin polyketides demonstrates significant challenges associated with construction of their highly oxidized caged core. Chapter Two describes our efforts to synthesize deoxyenterocin utilizing a biomimetic aldol cascade strategy. Our attempts to build the core are thwarted, however, due to inherent instability observed in synthetic analogues of the putative biosynthetic octaketide precursor. In Chapter Three, a lack of synthetic technology to install bridgehead oxidation contained in the enterocin core is identified, and a propellane activation strategy to directly forge bis-bridgehead functionalization is devised. Successful implementation of an unexploited propellane activation mode enables difunctionalization of the bridged propellane bond. Chapter Four describes the isolation, structure elucidation, and bioactivity studies of A-74528, an aromatic polyketide bearing a densely functionalized perhydrophenanthrene core. Identification of the biosynthetic gene cluster reveals an unusual polycyclization operative in the biosynthesis. The single reported synthetic effort towards A-74528 demonstrates that the biomimetic cascade proposed likely remains unfeasible. Our development of a route utilizing a hydrogen-atom-transfer (HAT) mediated semi-pinacol ring expansion provides access to a key tetracyclic intermediate for further elaboration to a key cyclopropanol substrate for investigation of an oxidative cleavage-induced radical cyclization cascade. Chapter Five focuses on our laboratory’s development of the first catalytic asymmetric HAT-initiated alkene hydrofunctionalization. Identification of a cation-π interaction in the Co(salen) catalyst employed enables optimization to achieve a highly enantioselective hydroalkoxylation of alkenes