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Synthesis and Biological Activity of N-Acyl Aziridines a Dissertation

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Synthesis and Biological Activity of N-Acyl Aziridines a Dissertation Synthesis and Biological Activity of N-Acyl Aziridines A dissertation presented to the faculty of the College of Arts and Sciences of Ohio University In partial fulfillment of the requirements for the degree Doctor of Philosophy Greggory M. Wells April 2016 © 2016 Greggory M. Wells. All Rights Reserved. 2 This dissertation titled Synthesis and Biological Activity of N-Acyl Aziridines by GREGGORY M. WELLS has been approved for the Department of Chemistry and Biochemistry and the College of Arts and Sciences by Stephen C. Bergmeier Professor of Chemistry and Biochemistry Robert Frank Dean, College of Arts and Sciences 3 ABSTRACT WELLS, GREGGORY M., Ph.D., April 2016, Chemistry Synthesis and Biological Activity of N-Acyl Aziridines Director of Dissertation: Stephen C. Bergmeier The development of new antimicrobial drugs is essential as the human population continues to build resistance to current treatments. Peptidomimetic compounds, those synthesized to mimic the behavior of naturally occurring biological proteins, have demonstrated promise in this area. Using bicyclic aziridine ring opening reactions, a library of N-acyl aziridinyl peptide isosteres has been synthesized and submitted to biological assays for cysteine protease inhibition, a common pathway to suppression of bacteria. Most of the compounds tested showed good activity against cathepsin B. This research required a novel synthetic approach to selectively generating oxazolidinones and aziridinyl ureas from fused bicyclic aziridines, which was accomplished with solvent selection, nucleophilic amine stoichiometry, and aziridine substitution. To extend the peptidic nature of these compounds, some success was achieved with acylation and amide coupling reactions. A practical approach to generating enantiomerically pure bicyclic aziridines was investigated, however the best enantioselective conditions provided only a 3 : 1 ratio. This stereoselective approach coupled with the ability to incorporate aziridines into peptide chains would ultimately lend a very powerful synthetic strategy for generating libraries of peptidomimetics with broad application potential. 4 DEDICATION I dedicate this dissertation to my mother, Shellie, whose unconditional love and support throughout my life has always given me the strength to carry on; and to my family and friends, who have waited with varying degrees of patience for its completion. 5 ACKNOWLEDGMENTS I want to thank, first and foremost, my academic and research advisor, Professor Bergmeier. Over the years, he has supported me personally and professionally, and without his guidance, support, and encouragement, I would be a very different person. For the years of scientific discussions, professional suggestions, and personal advice, and for her unconditional friendship, I give a very special thank you to Dr. Susann H. Krake. I also want to thank Professor Klaus Himmeldirk, whose academic style was the catalyst for my interest in organic chemistry. For the countless hours together in the lab and all of the academic and scientific support, I give thanks to Dr. Crina Orac, Dr. Iwona Maciagiewicz, Dr. John Bougher, Alicia Frantz, Dennis Roberts, Ian Armstrong, Rumita Laha, and Zilong Zheng. Thanks to Dr. Kevin Alliston and Dr. William C. Groutas at Wichita State University for selecting and performing the initial cathepsin B, thrombin, and HLE assays. I want to thank Professor Jennifer Hines and Chunxi Zeng for their contributions and support of the cathepsin B assay. Thanks to Dr. Nigel Priestley for the antibacterial testing. Thank you to Professor Jeffrey L. Petersen at West Virginia University for the crystallography analysis. I want to thank Dr. Ralf Hoffmann for sponsoring my research at Biotechnologisch-Biomedizinisches Zentrum, Universität Leipzig. Thank you to the undergraduate students who contributed to this research, Zachary Farr, Patrick Gilson, and Jackie Sheridan. Finally, thank you to my committee members, Professor Mark C. McMills, Professor Hao Chen, and Professor Douglas Goetz. 6 TABLE OF CONTENTS Page Abstract ..................................................................................................................................... 3 Dedication ................................................................................................................................. 4 Acknowledgments .................................................................................................................... 4 List of Tables .......................................................................................................................... 10 List of Figures......................................................................................................................... 12 List of Schemes ...................................................................................................................... 14 Chapter 1: Introduction .......................................................................................................... 18 Chapter 2: Optimization of Aziridinyl Urea Synthesis ........................................................ 26 2.1 Background and introduction ...................................................................................... 26 2.2 Synthesis of bicyclic aziridines................................................................................... 34 2.2.1 Selected allylic alcohols ....................................................................................... 35 2.2.2 Azidoformates ....................................................................................................... 38 2.2.2.1 Synthesis of trityl bicyclic aziridine............................................................. 38 2.2.2.2 Synthesis of propyl bicyclic aziridine .......................................................... 40 2.2.2.3 Synthesis of substituted bicyclic aziridines ................................................. 42 2.2.3 N-Tosyloxycarbamates......................................................................................... 44 2.2.3.1 Synthesis of N-tosyloxylcarbamates ............................................................ 44 7 2.2.3.2 Bicyclic aziridination reactions of N-tosyloxycarbamates ......................... 46 2.2.4 Carbamates ............................................................................................................ 49 2.3 Selectivity of bicyclic aziridine ring opening reactions ............................................ 52 2.3.1 Initial ring opening reactions ............................................................................... 53 2.3.2 Effects of solvent polarity and amine stoichiometry .......................................... 58 2.3.3 Additive study ....................................................................................................... 66 2.3.4 Aziridine substitution ........................................................................................... 68 2.4 Conclusions .................................................................................................................. 70 Chapter 3: Aziridinyl Ureas as Peptidomimetics ................................................................. 72 3.1 Introduction .................................................................................................................. 72 3.2 Aziridinyl urea compounds from amines ................................................................... 80 3.3 Aziridinyl urea compounds from amino acid and peptide derivatives ..................... 81 3.3.1 Preparation of amino acid and peptide derivatives............................................. 82 3.3.2 Trityl bicyclic aziridine reactions with amino acid derivatives ......................... 90 3.3.3 Substituted bicyclic aziridines with glycine benzylamide ................................. 91 3.3.4 Substituted bicyclic aziridines with amino acid and peptide derivatives .......... 93 3.4 Modifications of aziridinyl urea compounds ............................................................. 98 3.4.1 Alcohol to amine conversion attempts ................................................................ 99 3.4.2 Acylations ........................................................................................................... 104 8 3.4.2.1 Initial acylation attempts ............................................................................. 104 3.4.2.2 DCC coupling reactions .............................................................................. 106 3.4.2.3 CDI coupling reactions ............................................................................... 107 3.4.2.4 Isocyanate substitution reactions ................................................................ 110 3.4.2.5 Mitsunobu reaction...................................................................................... 111 3.4.3 Discussion of unsuccessful acylation attempts ................................................. 111 3.5 Biological activity of aziridinyl urea compounds .................................................... 114 3.5.1 Initial results for protease inhibition.................................................................. 114 3.5.2 Cathepsin B activity ........................................................................................... 117 3.5.3 Antibacterial results ............................................................................................ 121 3.6 Conclusions ...............................................................................................................
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