Chemistry and Chemical Biology ETDs

Publication Date

Summer 8-1-2023

Abstract

Part I covers Chapters 1, 2, and 3

cycloaddition reactions, that is utilized in biorthogonal chemistry. This metal free version The strain promoted azide-alkyne cycloaddition (SPAAC) reaction is one of the popular 1,3-dipolar of click reaction offers advantage over copper catalyzed click reaction. Since it eliminates the use of copper that is toxic to cells, it is considered favorable for biocompatible reaction. Due to the increased reactivity with dipoles without the use of metal catalyst, cycloalkynes, in particular cyclooctynes, have been employed as the biorthogonal reagent in biorthogonal chemical reaction for the study of a biological processes in vivo. The appropriate structure of the alkyne is important to achieve optimum reactivity, while it is challenging to design the strained cycloalkynes. This part of the dissertation focuses on the synthesis and reactivity of strained cycloalkynes.

The chapter 2 describes about the new method of synthesis for dibenzocyclooctynes containing heteroatom in the endocycle. The ring expansion strategy mediated by in situ generated carbene is utilized to convert seven-membered cyclic ketone into cyclooctyne. This strategy was found to be successful in the synthesis of dibenzocyclooctyne containing endocyclic oxygen, ODIBO in two-pot and three steps.

The two main strategies that are followed to improve the reactivity of cycloalkynes are increasing the strain and tuning of electronics. Numerous cyclooctynes have been studied regarding the optimization of the cycloaddition reaction through the influence of strain in the ring and electronic effect from the placement of the heteroatom in the alkyne. These strategies have contributed to the increment in the rate of SPAAC reaction. However, some cyclooctynes in literatures have been reported to be physically unstable due to very high strain present in the ring. In search of the balance between reactivity and stability, it is necessary to explore the cycloalkynes of larger ring sizes that could be physically stable. Such cycloalkynes are likely to be reacting slower than cyclooctynes but their reactivity could be increased by tuning the electronics of the cyclic alkynes. The chapter 2 describes the synthesis of a novel class of cycloalkynes, heteroatom embedded biaryl cyclononynes containing sulfate, sulfamate, and sulfamide linkers. The reactivity of these cyclononynes with different dipolar molecules was studied by reaction kinetic experiments. The study suggests that biaryl cyclononyne containing sulfate is more reactive compared to the cyclononynes composed of sulfamate and sulfamide.

Part II covers Chapter 4.

The dicarbofunctionalization reaction of alkene enables an addition of two groups by formation of two new C-C bonds across C-C double bond in a single step. Transition metal catalyzed dicarbofunctionalization reaction of alkene is one of the efficient strategies that allows the rapid synthesis of building blocks, and extension of the complexity of molecular structure in process of construction of compounds, such as, natural products, pharmaceuticals, bioactive compounds, and materials. However, C-C bond forming reaction of alkene involving transition metal catalysis suffers from the β-hydride elimination that gives rise to unwanted Heck product. Different approaches have been taken to address this issue. Utilization of geometrically constrained alkenes, coordinating groups, and π-allyl/π-benzyl metal species are the main strategies that have demonstrated success in suppression of the β-hydride elimination step for accomplishment of alkene dicarbofunctionalization reactions. Here, Ni-catalyzed α-carbonylalkylarylation of vinylarenes is described. Along with solving the synthetic challenge by suppressing the β-hydride elimination, the developed reaction method provides access to products containing γ,γ-diarylcarbonyl motif, which is present in various compounds of medicinal importance, such as Zoloft, an antidepressant drug. The primary, secondary, and tertiary α-halocarbonyls, and arylzinc reagents containing electronic diversity successfully contributed to product formation for generation of the secondary, tertiary, and quaternary carbon centers. The method is also applicable for α-carbonylalkylarylation of styrene linked with indomethacin, a nonsteroidal anti-inflammatory (NSAID) drug.

Part III covers chapter 5.

The carbofluorination reaction of an alkyne allows an addition of the carbon-based entities and the fluorine atom on an alkyne by formation of new C-C and C-F bonds on C-C triple bond in a single step. The reaction under catalytic condition participates as one of the efficient approaches for generation of monofluoroalkenes, which are present in various fluorinated organic compounds of biological and medicinal importance. Here, discovery of an intramolecular acylfluorination reaction of the alkynes with Lewis acid and transition metal catalysts is described. The reaction utilized the strategy of C-F bond activation and its functionalization from alkyne tethered acyl fluorides. The substrates enable maximum utilization of an atom economy by providing all three essential components (alkyne, acyl, and fluorine) for a reaction with catalyst. C-F bond is the strongest bond in organic molecules and less reactive, which makes it very difficult to be cleaved. However, C-F functionalization is of high interest as it possesses a potential for the development of reactions in order to install various functional groups, that would be necessary in synthesis of organic molecules. Additionally, it provides possibility of recycling of the fluorine atom through development of atom economical reactions. Both Lewis acids and transition metal catalysts enabled the acylfluorination of the internal alkynes on aromatic and aliphatic substrates with complete regioselectivity. The mixture of stereoisomeric alkenes was obtained. The reaction delivered the products with cyclic structures containing α-β-unsaturated ketone and monofluoroalkene. The product containing oxygen heterocycle resembles the core structure of flavonoids.

Language

English

Keywords

Bioorthogonal, Click chemistry, strained cycloalkyne, Strain promoted azide alkyne cycloaddiition, Carbofluorination, C-F bond activation, Dicarbofunctionalization

Document Type

Dissertation

Level of Degree

Doctoral

Department Name

Department of Chemistry and Chemical Biology

First Committee Member (Chair)

Prof. Martin Kirk

Second Committee Member

Prof. Matthew Aronoff

Third Committee Member

Prof. Jeffrey Rack

Fourth Committee Member

Prof. Mark Walker

Fifth Committee Member

Prof. Christopher Johnston

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