Applications of the formal oxa-[3+3] cycloaddition to natural product synthesis

The formal [3+3] cycloaddition is a condensation reaction that occurs between an unsaturated aldehyde and a 1,3-diketone or equivalent. The reaction results in a new 2H-pyran or 2H-pyridine fused to the diketone. For a number of years, we have studied this reaction, and have been especially interested in the development of the reaction and its application to the synthesis of biologically active natural products.; The first portion of this thesis concerns our total synthesis of arisugacin A. Arisugacin A is a natural product that shows promise as a potential Alzheimer's Disease therapy. We have applied the [3+3] cycloaddition to the synthesis of the arisugacin skeleton, and advanced this intermediate to the natural product. We have also modified the synthesis to render it enantioselective. Along the way methods to functionalize the [3+3] product were developed.; The second, and major portion of the research concerns our progress towards the total synthesis of phomactin A. Phomactin A is a marine natural product with a highly unusual structure that has elicited significant attention from the synthetic community due to its challenging framework. We felt that phomactin A would present an excellent opportunity for us to adapt our formal oxa-[3+3] cycloaddition to an intramolecular setting.; The synthesis of the cyclization precursor was not straightforward, and a number of approaches are discussed. We developed a synthesis of the precursor that was robust, and capable of producing large quantities of material. We investigated the cyclization and found that the reaction was indeed a success. We were able to develop some new chemistry, and advance this intermediate a great number of steps towards the natural product. Along the way, we have discovered many interesting conformational nuances inherent to the phomactin system that should prove interesting to organic chemists.