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Synthetic Studies on the Marineosins and Other Related Complex Prodiginines


Chapter One provides an overview of complex prodiginine alkaloids: streptorubin, roseophilin, and the marineosins. This includes a brief discussion of the prototypical structural features of the prodiginine class of natural products, their isolation, and biochemical properties including the putative biological mechanism of action. Previous research efforts from our laboratory are discussed to highlight our desired strategy for approaching these structural motifs and our goal (this thesis) of developing a unified entry to the C9 ansa linked prodiginines. A brief discussion of the completed efforts and total syntheses of prodiginine alkaloids is provided. The chapter concludes with a detailed discussion of the reported efforts by other research groups en route to targeted total synthesis of the marineosins.

We have developed a unique method of constructing the pyrrolophane core via a late stage phosphoryl-transfer mediated macroaldolization, which was utilized in the production of roseophilin. Chapter Two chronicles our efforts to adapt this approach to the marineosins, which were precluded by the inability to install an adequate transfer group. Due to these issues, a macrocyclic Heck process was explored as a potential alternative method of ring construction. However, these studies were halted when it was determined that β-substitution on the coupling partner drastically affected the feasibility of the Heck process.

Chapter Three discusses in detail our efforts to capitalize on the electron rich nature of the prodiginine core to engage a reactive functionality on the aliphatic chain and induce macrocyclization. Initial efforts were aimed at photoinduced electron transfer mediated macroannulations. However, low material throughput as a result of a capricious reduction procedure and an inability to obtain pure seco precursors impeded detailed investigations in this area. Further examinations in this manner of approach, attempted to construct the pyrrolophane in a bioinspired radical-engagement. Studies in this area were suspended due to an apparent lack of reactivity of the lipochromophore. Model system studies in this area resulted in the discovery of a novel photoinduced transformation and the development of a new method of constructing C9-substituted prodiginines.

Chapter Four details our efforts to utilize the reactivity discovered in model system studies, which culminated in the synthesis of marineosin A. The photoinduced rearrangement of pyridinophane N-oxides proved particularly powerful in the production of the requisite acyl pyrrolophane. After elaboration to a postulated biosynthetic precursor of the marineosins, a cycloisomerization could be effected by treatment with MnO2. These two key methods allowed for a highly convergent and concise synthesis.

The readily apparent utility of the photoinduced rearrangement methodology caused us to revisit roseophilin. Chapter Five presents how the aforementioned rearrangement allows for facile access to the roseophilin pyrrolophane, which can be readily acylated with isobutyryl chloride. Studies in this area are ongoing to convert this acylated material into an intermediate that intercepts our previous roseophilin synthesis.

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