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Chemical synthesis of structurally complex and diverse natural products has been explored by synthetic chemists throughout centuries. The scientific essence within inspires and guides relevant fields in society and science, for example, pharmaceutical industry, material science, and agricultural industry. In this vein, people cultivate the toolbox of synthetic chemistry, hoping to invent stronger, cheaper, and more versatile reagents and catalysts to enable shorter pathways toward those “formidable” molecules. The advancement of synthetic methodology and natural product synthesis therefore become two powerful engines, boosting the evolution of organic chemistry and related fields. By this principle, this dissertation describes four components on how strategies are designed and developed toward 1) Halophosphonium pre-reagents for alkene hydro- and deuterio-halogenation; 2) synthesis of diverse bromo-chamigrene natural products; 3) biomimetic and nonbiomimetic synthetic studies of fungal metabolite homodimericin A; and 4) a unified solution toward the Myrioneuron alkaloids. In the first chapter, the discovery of a group of halophosphonium reagents will be discussed starting from their structural precedents, halogenation reagent series XDSX (X = Cl, Br, I). The optimization process and the substrate scope exploration will then be covered. The latter portion of the chapter will be focusing on our attempts to elucidate the structures of these reagents, and the efforts on investigating the active reaction intermediate and related mechanisms. A case of application in isotope incorporation onto alkene substrates is included as well. Then chapter 2 will detail the evolution of two generations of synthetic strategies toward the bromo-chamigrene natural product aplydactone. The first-generation strategy enabled a highly stereoselective bromo-cyclization key reaction while its product proved unable to proceed to the desired natural product. The second-generation strategy features a Lewis acid promoted Diels-Alder reaction in assembling the core spirocycle structure of bromo-chamigrenes. This ultimately led to the synthesis of three members in the family and a formal synthesis of aplydactone. As an intermittent part, chapter 3 serves to introduce the story of a hexacyclic fungal metabolite homodimericin A. Failure in discovering a suitable biomimetic condition of dimerization guided us to a non-biomimetic route. Although we reached a key intermediate that can potentially be transformed into a putative biosynthetic intermediate, the project was terminated there since the synthesis of the molecule was reported by other research groups. Finally, in chapter 4, the evolution of a unified strategy toward the Myrioneuron alkaloids will be delineated. The diversity in structures and biological activities of various family members is introduced in the first place, followed by the proposed biosynthetic analysis of the family tree. The currently known synthetic efforts toward these alkaloids will be covered, especially a significant report of a special member, myrioneurinol, from Weinreb. We then explore our 20-step synthesis of this molecule, featuring an aza-Michael cyclization reaction as a key step. The application of this type of cyclization will be plotted in the synthesis of two other family members myrioxazine A and schoberine B as well.


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