@article{Enantioselective:3057,
      recid = {3057},
      author = {Lynch-Colameta, Tessa Jean},
      title = {Development of Enantioselective Reactions Utilizing  Nitrones as Effective Iminium Surrogates},
      publisher = {University of Chicago},
      school = {Ph.D.},
      address = {2021-06},
      pages = {412},
      abstract = {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.},
      url = {http://knowledge.uchicago.edu/record/3057},
      doi = {https://doi.org/10.6082/uchicago.3057},
}