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Title page for ETD etd-12212017-141542

Type of Document Dissertation
Author Struble, Thomas James
URN etd-12212017-141542
Title Enantioselective synthesis of carbon-oxygen and carbon-nitrogen bonds using bisamidine Brønsted acid/base catalysis, investigations of intermediates, applications, and mechanistic insights of catalyst symmetry effects unveiled by DFT
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Jeffrey N. Johnston Committee Chair
Lawrence J. Marnett Committee Member
Ned A. Porter Committee Member
Steven D. Townsend Committee Member
  • DFT
  • Catalyst Symmetry
  • Stereodivergent
  • NK1 antagonist
  • Organocatalysis
  • Eanantioselective
  • Carbon Dioxide
  • Chiral Urea
Date of Defense 2017-12-07
Availability restricted
As a class of reagents, organocatalysts have served the enabling role for many high-value reactions. Innovations in organocatalysis, along with these new reactions, have improved our access to new developmental therapeutics while creating new opportunities to reach previously inaccessible chemical space. Organocatalysts, including enzymes, often rely on hydrogen bonding interactions to coordinate heteroatoms for stabilization of transition states to achieve high levels of enantioselectivity and diastereoselectivity. A few types of hydrogen bonding catalysis have been demonstrated and a subset of these use a polar ionic hydrogen bond for coordination and stabilization. BisAmidine (BAM)-based catalysts commonly employ C2-symmetry as a guiding principle, and they leverage polar ionic hydrogen bonds in catalysis.

A new set of iodocyclization reactions were developed using a stilbene diamine-derived BAM catalyst that allows for the first one pot, three component reactions employing polar ionic hydrogen bond catalysts. The reactions use an achiral homoallylic alcohol or amine to capture carbon dioxide, an inexpensive and readily abundant feedstock, to form a carbon-oxygen bond in high yields and enantioselection. Mechanistic details of the CO2 capture reaction are elucidated using a combination of in situ IR, titrations to determine pKa, and DOSY NMR studies. Catalyst complexes are proposed based on the combination of data from the previous mechanistic experiments. The mechanistic details are used to inform the development of new reactions and can use pKa matching as a guiding principle for derivatization and development of new catalysts.

The BAM catalysts can achieve high enantioselection in many carbon-carbon and carbon-oxygen bond forming steps, but has yet to find success in selective formation of a carbon-nitrogen bond-derived stereocenter. A new urea cyclization reaction was developed using a BAM catalyst that can control an ambident nucleophile, achieving high selectivity for nitrogen cyclization, while maintaining high enantioselection and yield. In addition, regioselectivity depends on the geometry of the alkene allowing for control of products and access to both imidazolidinones (5-endo or 5-exo products) and tetrahydropyrimidin-2(1H)-ones (6-endo products). The chiral urea products are valued building block for 1,2-diamines, hydantoins, and pharmaceutically-relevant compounds. A convergent and scalable route to an NK1 antagonist is explored and carried out using this new methodology.

Finally, mechanistic insight of the stereodivergent BAM-catalyzed nitroester addition to aldimines is advanced using density functional theory (DFT) calculations. An unexpected binding mode for the aldimine to a non-symmetric catalyst plays a key role in stereoselection, and an otherwise high energy conformation for this catalyst’s backbone is supported by high-level calculation. The binding mode of the aldimine is altered from a bidentate to a monodentate coordination while preserving the facial selectivity of the aldimine, allowing access to both diastereomers of the products by alteration of the binding pocket of the catalyst.

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