Natural products are the source of many valuable folk medicines and pharmaceutical agents. However, due to their structural complexity, short and efficient syntheses of natural products are still a challenge to perform in the laboratory setting. In the pursuit to construct biologically significant alkaloids, there are numerous synthetic problems that cannot be easily solved using traditional imine or iminium chemistry. In this dissertation, we detail our efforts to develop Mannich-type and Pictet–Spengler-type reactions by engaging nitrones to achieve superior results to their iminium congeners. Chapter 1 will provide a brief introduction into nitrone chemistry. To begin, the methods commonly used for the synthesis of nitrones will be described. Then, while there are many types of transformations that nitrones can undergo, this section will focus on asymmetric reactions of nitrones as electrophiles. Our intent is not to comprehensively cover nitrone chemistry, but to highlight some useful examples to demonstrate the current state-of-the-art chemistry available and general challenges still exist in this area. Chapter 2 will present our investigations into Mannich-type reactions of cyclic nitrones. Though 2-substituted and 2,6-disubstituted piperidine moieties are found in an array of natural products and synthetic drugs, there are only a finite number of approaches for their synthesis. Within, is described two distinct Mannich-type reactions capable of generating β-N-hydroxy-aminoketones in both a racemic and asymmetric format. The first procedure uses β-ketoacids under catalyst-free conditions, while the second employs methyl ketones in the presence of chiral thioureas. Both processes have broad scope, with the latter providing products with high enantioselectivity. The combination of these methods enabled the 8-step total syntheses of (–)-lobeline and (–)-sedinone. Chapter 3 will detail our work on Pictet–Spengler reactions of ketonitrones. Despite substantial investigation into the synthesis of β-carbolines, due to their diverse medicinal properties and complex structures, effective methods to access aza-quaternary centers through direct Pictet–Spengler reactions remain limited. Herein, we report on the discovery of a facile procedure that utilizes a variety of ketonitrones activated by acyl chlorides to induce such Pictet–Spengler reactions. Notably, the reaction process is mild, fast, and high-yielding for a collection of >40 substrates. In addition, an asymmetric variant of the process with good levels of enantioselectivity was established by deploying an acyl bromide and thiourea promoter. Lastly, the products can also be transformed in a number of distinct ways by taking advantage of the resultant N–O bond. Chapter 4 will reveal our current efforts in the exploration of iso-Pictet–Spengler reactions utilizing ketonitrones. During the last decade, iso-Pictet–Spengler reactions have been of interest to provide access to underexplored indole core structures, which may have potential as drug candidates. In spite of this, the sparse examples that create aza-quaternary centers require stoichiometric chiral reagents and/or substrate control for the cyclization to occur with high enantioselectivity. Here, is proposed the development of catalytic, enantioselective iso-Pictet–Spengler reactions that produce three distinct scaffolds with aza-quaternary centers. To achieve this, we envision employing the power of organocatalysis and the unique reactivity of nitrones.



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