Computational Investigations Into Organic And Bioorganic Reaction Pathways

Author

Sebastien Hebert, Wayne State University

Access Type

WSU Access

Date of Award

January 2020

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Chemistry

First Advisor

H. B. Schlegel

Abstract

This thesis covers computational studies investigating reaction mechanisms and chemical behavior of allene oxide cyclization, oxidative damage to DNA leading to the formation of guanine-thymine crosslinks, 2Ih, Iz, Ghox, parabanic and oxaluric acids, aminyl radical initiated tandem cyclizations, and substituent effects on the stereochemistry of glycoside formation. Allene oxide cyclization to cyclopentenone was considered using a variety of high level methods, density functional theory, multireference methods, and both restricted and unrestricted wavefunctions. Homolytic cleavage to an oxyallyl intermediate was found to be the most stable pathway, with formation of a cyclopropanone intermediate leading to cyclopentenone formation. Nucleophilic addition of thymine and carbonate to guanine was investigated to better understand the competition between these processes across a range of pHs. Redox potentials and pKas were calculated for relevant radical intermediates. Relatively slow thymine addition to guanine was found to compete with relatively rapid carbonate radical combination to guanine, due to the low concentration of carbonate radical. Oxidation of guanine in the presence of reducing agents was considered experimentally to better understand the behavior of oxidative damage to DNA under biologically relevant conditions. The dominant product, 5-carboxyamido-5-formamido-2-iminohydantoin (2Ih), was then investigated computationally to better understand its competitive nature with the commonly produced 8-oxo-guanine (8oxoG) and spiroiminodihydantoin (Sp) oxidative damage products. Removal of reducing agents in these studies found 2Ih formation in competition with imidazolone (Iz), which has also been shown to be produced under numerous other experimental conditions. Iz formation is also anomalous in that dependence on pH and the presence / absence of superoxide is dependent on whether guanine or 8oxoG is the reactant. Various different experimental studies find widely varying behavior in Iz formation, including production of oxidized Gh (Ghox) and parabanic and oxaluric acids, without a clear mechanistic pathway that explains the chemistry involved. Computational investigation into Iz formation considered superoxide addition to guanine radical, 8oxoG radical, and the C8-hydroxy guanine radical were all considered as separate reactants. The reactivity of each was found to be unique and provided an explanation of the experimental findings, reconciling various different conditions into a single, compound chemical pathway. Aminyl radical initiated tandem cyclization was investigated to better understand a novel, tin-free pathway. 5-exo,5-exo and 6-exo,5-exo cyclization pathways were investigated using electron-withdrawing and electron-neutral substituents to modify the electronic nature of the olefin involved in this pathway. Monocyclization was found to be favored for electron-neutral groups and bicyclic ring formation favored for electron-withdrawing groups, which is consistent with expectations based on radical stability. 6-exo,5-exo cyclization was found to be competitive with nitrogen reduction via solvent hydrogen atom transfer. Anomeric carbon substitution and / selectivity has been thoroughly studied in the field of sugar chemistry. C2 substituents are known to influence this selectivity, with substituents such as acetate groups offering exclusive  selectivity. Substituents such as the O-paramethoxybenzyl group found no selectivity. Recently, it was found that in a disaccharide system replacing C2’ substitution of azide with benzylidene reversed the expected selectivity. To better understand this, each set of substituents, azide and benzylidene at C2’ and acetate and O-paramethoxybenzyl at C2, were investigated. Eight relevant conformations of the disaccharide were investigated and both neutral (reactant) and cation (intermediate of SN1 mechanism) charge states were considered. While the cause of the selectivity is still under investigation, only one of the eight conformations considered was determined to have a favorable nucleophilic addition intermediate, suggesting it may be relevant to the selectivity.

Recommended Citation

Hebert, Sebastien, "Computational Investigations Into Organic And Bioorganic Reaction Pathways" (2020). Wayne State University Dissertations. 2450.
https://digitalcommons.wayne.edu/oa_dissertations/2450