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Synthetic Applications of Lithium(trimethylsilyl)diazomethane and Design of Flourophores for Microscopy

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thesis
posted on 01.07.2016 by Matthew J. O'Connor
The following thesis involves several projects in two major areas. In the first, synthetic applications of lithium(trimethylsilyl)diazomethane (LTMSD) were investigated. These projects range from formal [3+2] cycloadditions with electron deficient olefins to sequential reactions involving multiple bond formations and fragmentations in a single flask. In the second research area, fluorophores were designed and synthesized for in vivo microscopy applications. Focus in this project was on analogs of two major classes: benzophenoxazines and 2-dicyanomethylen-3-cyano-4,5,5-trimethyl-2,5-dihydrofurans (TCF). Chapter I focuses on the development and application of a formal [3+2] cycloaddition between LTMSD and α,β unsaturated esters (enoates). The scope of this reaction was explored, and the protonolytic ring-opening of the newly generated Δ2-pyraozlines leads to a new method for synthesizing the α-tert-alkyamino carboxylic ester functionality. This methodology was applied in a synthesis of the amathaspiramide family of natural products. Chapter II extends this methodology to two new classes of substrates, α-methylene- and α-benzylidene-β-hydroxy esters and α,β-unsaturated pseudoephedrine-derived amides. The hydroxy group proved to be a key controlling element in the diastereoselectivity of the reaction. Chapter III further explores the chemistry of LTMSD in tandem reaction processes involving Grob-type C–C fragmentations, alkylidene carbene-mediated Li–N insertions, and dipolar cycloadditions by controlling the reaction parameters. This chemistry was used to synthesize a variety of new heterocycles including pyrazoles, cyclic hemiaminals and diazepine derivatives. Chapter IV involves the second area of research in which fluorophores were designed and synthesized for in vitro microscopy studies. The benzophenoxazine class of fluorophores were found to be superior to the tricyanofurans in the fluorescence assays in terms of their fluorescence intensity and behavior in the cell. A Nile Red-based fluorophore was successfully utilized in simultaneous in situ quantification of two cellular lipid pools.formations and fragmentations in a single flask. In the second research area, fluorophores were designed and synthesized for in vivo microscopy applications. Focus in this project was on analogs of two major classes: benzophenoxazines and 2-dicyanomethylen-3-cyano-4,5,5-trimethyl-2,5-dihydrofurans (TCF). Chapter I focuses on the development and application of a formal [3+2] cycloaddition between LTMSD and α,β-unsaturated esters (enoates). The scope of this reaction was explored, and the protonolytic ring-opening of the newly generated Δ2-pyraozlines leads to a new method for synthesizing the α-tertalkyamino carboxylic ester functionality. This methodology was applied in a synthesis of the amathaspiramide family of natural products. Chapter II extends this methodology to two new classes of substrates, α-methylene- and α-benzylidene-β-hydroxy esters and α,β-unsaturated pseudoephedrinederived amides. The hydroxy group proved to be a key controlling element in the diastereoselectivity of the reaction. Chapter III further explores the chemistry of LTMSD in tandem reaction processes involving Grob-type C–C fragmentations, alkylidene carbene-mediated Li–N insertions, and dipolar cycloadditions by controlling the reaction parameters. This chemistry was used to synthesize a variety of new heterocycles including pyrazoles, cyclic hemiaminals and diazepine derivatives. Chapter IV involves the second area of research in which fluorophores were designed and synthesized for in vitro microscopy studies. The benzophenoxazine class of fluorophores were found to be superior to the tricyanofurans in the fluorescence assays in terms of their fluorescence intensity and behavior in the cell. A Nile Red-based fluorophore was successfully utilized in simultaneous in situ quantification of two cellular lipid pools.

History

Advisor

Lee, Daesung

Department

Chemistry

Degree Grantor

University of Illinois at Chicago

Degree Level

Doctoral

Committee Member

Wardrop, Duncan Gevorgyan, Vladimir Mohr, Justin Bruzik, Karol

Submitted date

2016-05

Language

en

Issue date

01/07/2016

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