Arisugacin, a potent and selective inhibitor of acetylcholinesterase (AchE), has significant implications in the therapeutic treatment of Alzheimer's disease based on the cholinergic hypothesis. Given the biological relevance and the synthetic interest surrounding arisugacin, this research proposal illustrates 1) approaches to the total synthesis of arisugacin, 2) detailed plans for developing a formal [3+3] cycloaddition method, and 3) development of a proposed binding site model for arisugacin. These research ideas are presented in three distinct sections. In the first section, a total synthesis of arisugacin is proposed on the basis on a formal [3+3] cycloaddition reaction involving alpha,beta-unsaturated imuniums that we have developed recently. The synthetic sequence features the utility of the [3+3] cycloaddition strategy in constructing the pentacyclic core of arisugacin. An alternative approach to the same key pentacycle using condensation reactions of alpha,beta-unsaturated acids is also described. This total synthesis is convergent and should be practical for synthesis of structural analogs as well as studies involving a proposed binding-site model. In the second section, efforts are devoted to develop the formal [3+3] cycloaddition reaction involving alpha,beta-unsaturated iminiums and diketo equivalents. This formal cycloaddition reaction represents a unique approach to synthesis of heterocycles. Three specific areas of its synthetic application are proposed: 1) To examine various diketo equivalents and alpha,beta-unsaturated iminiums to widen the scope of this reaction, 2) to develop intramolecular formal [3+3] cycloaddition reactions, and 3) to explore stereoselective formal [3+3] cycloadditions for natural product synthesis. In the final section, a binding-site model for arisugacin is proposed based on structural comparison. Various tricyclic CDE- ring analogs are being evaluated to determine the structural significance of the DE-ring. Synthesis of tetracyclic and pentacyclic analogs are proposed to further examine the binding- site model. These studies should be significant because they can provide a variety of useful synthetic methodologies for natural product synthesis and important insight into the binding property of arisugacin to AChE, thereby leading to potential discovery of novel and effective therapeutics structurally modeled after arisugacin for Alzheimer's disease.
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