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Open Access Publications from the University of California

Scholarly Works (6 results)

  • Thesis
  • Peer Reviewed
UC Davis Electronic Theses and Dissertations (2021)

The purpose of this dissertation is to showcase the use of computational chemistry to understand and corroborate chemical observations from experiments.This report will begin with highlighting the importance of considering the conformational space of an organic molecule. Instead of a static picture, molecules have degrees of freedom in space and they can equilibrate between different conformations. This flexibility can affect a molecule’s reactivity and spectral properties. Chapter 2 and 3 focus the study of structures. Here, we used computational data to correlate to experimental observations, and subsequently guide decisions on synthesis. Then, we move from the study of structures to mechanisms, highlighting the ability of using quantum chemistry to compare reaction energetics. For example, using transition state theory (TST), we can predict if a chemical transformation is kinetically feasible and which product is favored under the experimental conditions. The final chapter describe a purely computational project which considers the two major assumptions involved in the previous chapters: 1) a chemical reaction obeys conventional TST; 2) the inclusion of implicit solvent environment is sufficient to simulate realistic solvent effect. This chapter will consider the limitations of these two assumptions using a bifurcating pericyclic model reaction, in which the inclusion of explicit solvent molecule affects product selectivity.

    Cover page: A Study of Structures, Mechanisms, and Theories through Computational Chemistry
    • Article
    • Peer Reviewed
    UC Davis Previously Published Works (2020)
    Herein we interrogate a type of heterolytic fragmentation reaction called a 'divergent fragmentation' using density functional theory (DFT), natural bond orbital (NBO) analysis, ab initio molecular dynamics (AIMD), and external electric field (EEF) calculations. We demonstrate that substituents, electrostatic environment and non-statistical dynamic effects all influence product selectivity in reactions that involve divergent fragmentation pathways. Direct dynamics simulations reveal an unexpected post-transition state bifurcation (PTSB), and EEF calculations suggest that some transition states for divergent pathways can, in principle, be selectively stabilized if an electric field of the correct magnitude is oriented appropriately.
      Cover page: Tipping the balance: theoretical interrogation of divergent extended heterolytic fragmentations
      • Article
      • Peer Reviewed
      UC Davis Previously Published Works (2019)
      Serlyticin-A is a secondary metabolite first isolated from a culture of Serratia ureilytica grown using squid pen as the sole carbon/nitrogen source. A previous study by Kuo et al. demonstrated that it has antioxidative and antiproliferative properties. However, the proposed chemical structure of serlyticin-A is likely incorrect based on the thermodynamic instability of its three contiguous heteroatom-heteroatom bonds. Here, we use quantum chemical calculations to predict 1H and 13C chemical shifts for serlyticin-A and demonstrate a discrepancy between the calculated and experimental chemical shifts. We then propose several reasonable alternative structures for serlyticin-A. Considering the known antioxidant and antiproliferative activity of hydroxamic acids as well as their stability and prevalence in natural products of bacterial origin, we believe that serlyticin-A is most likely 3-indolylacetohydroxamic acid (4). We provide our rationale for this assignment as well as experimental data for pure 3-indolylacetohydroxamic acid obtained via de novo synthesis. This study highlights the power of computational NMR shift prediction to revise chemical structures for natural products like serlyticin-A.
        Cover page: Reconsidering the Structure of Serlyticin‑A
        • Article
        • Peer Reviewed
        UC San Francisco Previously Published Works (2021)
        We previously identified a spiro [piperidine-4,1-pyrido [3,4-b]indole] class of co-potentiators that function in synergy with existing CFTR potentiators such as VX-770 or GLGP1837 to restore channel activity of a defined subset of minimal function cystic fibrosis transmembrane conductance regulator (CFTR) mutants. Here, structure-activity studies were conducted to improve their potency over the previously identified compound, 20 (originally termed CP-A01). Targeted synthesis of 37 spiro [piperidine-4,1-pyrido [3,4-b]indoles] was generally accomplished using versatile two or three step reaction protocols with each step having high efficiency. Structure-activity relationship studies established that analog 2i, with 6'-methoxyindole and 2,4,5-trifluorobenzyl substituents, had the greatest potency for activation of N1303K-CFTR, with EC50 ∼600 nM representing an ∼17-fold improvement over the original compound identified in a small molecule screen.
          Cover page: 1-BENZYLSPIRO[PIPERIDINE-4,1'-PYRIDO[3,4-b]indole] 'co-potentiators' for minimal function CFTR mutants.
          • Article
          • Peer Reviewed
          UC Davis Previously Published Works (2019)
          The Cadogan cyclization is a robust but harsh method for the synthesis of 2 H-indazoles, a valuable class of nitrogen heterocycles. Although nitrene generation by exhaustive deoxygenation is widely accepted as the operating mechanism in the reductive cyclization of nitroaromatics, non-nitrene pathways have only been theorized previously. Here, 2 H-indazole N-oxides were synthesized through an interrupted Cadogan/Davis-Beirut reaction and are presented as direct evidence of competent oxygenated intermediates; mechanistic implications for both reactions are discussed. Isolation and characterization of these N-oxides enabled a formal Cadogan cyclization at room temperature for 2 H-indazole synthesis.
            Cover page: Accessing Multiple Classes of 2H‑Indazoles: Mechanistic Implications for the Cadogan and Davis–Beirut Reactions
            • Article
            • Peer Reviewed
            UC Davis Previously Published Works (2019)
            The Davis-Beirut reaction provides access to 2H-indazoles from aromatic nitro compounds. However, N-aryl targets have been traditionally challenging to access due to competitive alternate reaction pathways. Previously, the key nitroso imine intermediate was generated under alkaline conditions, but as reported here, the photochemistry of o-nitrobenzyl alcohols empowered Brønsted acid catalyzed conditions for accessing N-aryl targets. Anilines and alkyl amines give different outcomes under optimized conditions; the proposed mechanism was studied using quantum chemical calculations.
              Cover page: Davis–Beirut Reaction: A Photochemical Brønsted Acid Catalyzed Route to N‑Aryl 2H‑Indazoles
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