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Aminooxy Reagents for Synthesis and Analysis : Expanding the Role of Oximation

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Aminooxy Reagents for Synthesis and Analysis : Expanding the Role of Oximation University of Louisville ThinkIR: The University of Louisville's Institutional Repository Electronic Theses and Dissertations 5-2013 Aminooxy reagents for synthesis and analysis : expanding the role of oximation. Sebastien Laulhe University of Louisville Follow this and additional works at: https://ir.library.louisville.edu/etd Recommended Citation Laulhe, Sebastien, "Aminooxy reagents for synthesis and analysis : expanding the role of oximation." (2013). Electronic Theses and Dissertations. Paper 796. https://doi.org/10.18297/etd/796 This Doctoral Dissertation is brought to you for free and open access by ThinkIR: The University of Louisville's Institutional Repository. It has been accepted for inclusion in Electronic Theses and Dissertations by an authorized administrator of ThinkIR: The University of Louisville's Institutional Repository. This title appears here courtesy of the author, who has retained all other copyrights. For more information, please contact [email protected]. AMINOOXY REAGENTS FOR SYNTHESIS AND ANALYSIS: EXPANDING THE ROLE OF OXIMATION by Sébastien Laulhé B.S., Ecole Nationale Supérieure de Chimie de Montpellier, 2007 M.S., Ecole Nationale Supérieure de Chimie de Montpellier, 2009 M.S., University of Louisville, 2012 A Dissertation Submitted to the Faculty of the College of Arts & Sciences of the University of Louisville In Partial Fulfillment of the Requirements For the Degree of Doctor of Philosophy Department of Chemistry University of Louisville Louisville, Kentucky May 2013! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! AMINOOXY REAGENTS FOR SYNTHESIS AND ANALYSIS: EXPANDING THE ROLE OF OXIMATION by Sébastien Laulhé B.S., Ecole Nationale Supérieure de Chimie de Montpellier, 2007 M.S., Ecole Nationale Supérieure de Chimie de Montpellier, 2009 M.S., University of Louisville, 2012 A Dissertation Approved on April 17, 2013 by the Following Dissertation Committee: Thesis Director: Dr. Michael H. Nantz Dr. Christopher T. Burns Dr. James L. Wittliff Dr. Xiang Zhang ! ii! ! DEDICATION To all the wonderful people I met in the Department of Chemistry. To my parents, my brother, my family, and my friends. “¡Lúchalo!” ! iii! ! ACKNOWLEDGEMENTS I have been very fortunate to have Professor Michael H. Nantz as my thesis advisor. His support and his brilliant mind have made these years of hard work among the best I have had. It is fair to say that with him “work time becomes fun time”. He is a natural leader with a nurturing and fair, yet strict, management style. This great balance results in respect and admiration from his students and is what has driven me to give the best I have to the service of chemistry. For the past 5 years, Prof. Nantz has enthusiastically supported my ideas and encouraged independent learning. More importantly, he has pushed me to achieve excellence and develop my full potential. His influence in my scientific education is the one of a father, and over the years of support and advice, “The Baus” has become one of my best friends. I want to thank my committee members Dr. Christopher T. Burns, Dr. James L. Wittliff, and Dr. Xiang Zhang, for their valuable help and suggestions during my years in the Department of Chemistry. Much of the work presented in this thesis resulted from collaborations with great minds such as Dr. Tantillo, Dr. Kang, Dr. Achilefu, and their respective graduate students. In particular, I want to thank my friend and collaborator Dr. Bogdan Bogdanov for his insight in mass spectrometry and soccer. ! iv! ! Among the reasons my experience as a Ph.D. student has been so positive is also due to the incredible people I worked with each day. I learned a lot from Xuan Huang, my elder coworker, and Souvik Biswas, my great friend and hopefully future collaborator. Music (“Dead Mouse! Where?! Where?!”) and lunch (“Are we eating?”) have been a common point with Stephanie Mattingly and Ralph Knipp, my contemporaries, with whom I have had both hilarious and serious conversations. Sadakat Gori Ali and Sara Biladeau, the youngest, have also contributed to the fun in the lab and the work I have accomplished, and I am grateful for their help. I have been very fortunate to work with and train undergraduate students Joe Moore, Leah Johannes, Tyler Geers, and Michael Parsons. I have had great fun with all of them and I hope I was able to show them how fun and rewarding chemistry can be. I will miss all of the Nantz Team since it has provided a great environment in which to work and every member has been essential to maintaining the equilibrium of a fun and productive lab. Together, we are definitely the Nantz Alpha Team. I also thank Mohamed, Sarah, Govi, and Katie for their friendship and their help with the Chemistry Graduate Student Association. We have had great times and we did a great job together. Former CGSA colleagues and friends, Ricky and Susan, provided valuable advice for survival in graduate school. I would like to thank the Institute for Molecular Diversity and Drug Design (IMD3) for their financial support via the Arno Spatola Endowment Graduate Research Fellowship and for their help for my career development. I am thankful and proud to have been part of the Department of Chemistry. I am grateful for its warm welcome and the supportive faculty members and staff. ! v! ! Rebecca Bottom has been my most vocal and intense supporter for the past five years. Without her help and her love I probably would not have accomplished all this. The support from her family has also made me feel at home. Finally, I need to thank my parents, Philippe Laulhé and Maria Victoria Gascón for their constant support and the great education they gave me; the best brother in the world, Alexandre Laulhé, who has always been there for me and for whom I will do anything; my step-father and great friend Anthony Reversat; and my step-mother Maria Eugenia. Their love and support have been essential to me. I am very grateful for my grandparents Abuelo, Abuela, Mapita, and George, all of whom filled my life with love, joy, and wisdom. Last, but not least, my uncles, aunts, and cousins have always been just as supportive, as well as the Bayol, the Duhau, and the Elie families. ! vi! ! ABSTRACT AMINOOXY REAGENTS FOR SYNTHESIS AND ANALYSIS: EXPANDING THE ROLE OF OXIMATION April 17, 2013 Sébastien Laulhé The reaction between an aminooxy moiety (RONH2) and a carbonyl group of either an aldehyde or a ketone — known as an oximation reaction — is a versatile click chemistry coupling that generates a robust oxime ether linkage. The oximation reaction is chemoselective and can be performed under mild conditions in a large variety of solvents, including water. The attractive properties of the aminooxy group and derived oximation reactions, reviewed in Chapter 1, inspired us to use this chemistry as a key feature of our research. Specifically, we prepare functionalized aminooxy compounds so that the oximation chemistry can then serve as a prelude to new synthetic or analytical methods. For example, Chapter 2 presents an improved preparation of O- (diphenylphosphinyl)hydroxylamine (DPPH), an aminooxy-containing reagent, using the classic Schotten-Baumann conditions. We show how DPPH can then be used as a chemoselective nitrogen transfer reagent for a one-pot aldehyde-to-nitrile functional group transformation. Sixteen aldehydes were smoothly transformed to their ! vii! ! corresponding nitriles by heating at 85 °C with DPPH in toluene. The reaction can be accomplished in the presence of alcohol, ketone, ester, or amine functionality. In another application, we use functionalized aminooxy reagents to achieve quantitative multiplexed gas chromatography-mass spectrometry (GC-MS) analysis. Specifically, we chemoselectively derivatize carbonyl (aldehyde and ketone) metabolites using the aminooxy-containing reagents. Chapter 3 presents a focused fundamental study of the propensity of oxime ethers to undergo MS-induced fragmentations, such as the McLafferty rearrangement. In particular, we studied structural factors that promoted α,β- fragmentation in oximes of both ketones and aldehydes, as well as the derived silyl ethers of these adducts. We determined that 1) the propensity of the McLafferty rearrangement was greatly enhanced by oxygen at the b-position of silyl oxime ethers, 2) the McLafferty rearrangement is more prominent for E-isomers of oxime and silyl oxime ethers than for the corresponding Z-isomers, and 3) Z-isomers of silyl oxime ethers with CH2 at the b- position generate nitrilium ions to a greater extent than their corresponding E-isomers. Chapter 4 describes the 3-step synthesis of a new class of stable isotope-labeled derivatizing reagents –– aminooxyethyl propionate reagents (AEP) –– that enable multiplexed GC-MS analysis of small molecule carbonyl compounds. The AEP reagents contain 1) an aminooxy moiety, and 2) a propionate ester moiety that generates a reporter isotope-labeled mass spectral tag (MST) in the form of an ethyl carbenium ion via an ester a-cleavage. The AEP MSTs appear in an m/z zone of minimal interference (ZMI) in the range m/z 32-34. This is a key feature in that unobstructed observation of reporter MSTs in this zone significantly improves simultaneous quantitation of carbonyl analytes from multiple samples without recourse to MS peak deconvolution strategies. Also, and ! viii! ! in contrast to known isotope coding reagents for GC-MS, AEP reagents are not affected by the chromatographic isotope effect. The versatility of the technology for carbonyl metabolite profiling and absolute quantification is demonstrated by an analysis of turmeric extract, serving as a representative complex biological sample. A series of analogous methyl ketones were profiled from characteristic MS fragmentations of the AEP-derived oxime ether adducts, and two members, 2-nonanone and 2-undecanone, were quantified using AEP-labeled external standards. Finally, Chapter 5 concludes with additional demonstrations of click chemistry. We used oximation to ligate linker molecules to fluorophores and gold nanoparticles (AuNPs) to generate a fluorescent nano-entity for breast cancer location and diagnosis.
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