Louisiana State University LSU Digital Commons LSU Doctoral Dissertations Graduate School 2016 Peptidomimetic Polymers: Advances in Monomer Design and Polymerization Methods Brandon Andrew Chan Louisiana State University and Agricultural and Mechanical College Follow this and additional works at: https://digitalcommons.lsu.edu/gradschool_dissertations Part of the Chemistry Commons Recommended Citation Chan, Brandon Andrew, "Peptidomimetic Polymers: Advances in Monomer Design and Polymerization Methods" (2016). LSU Doctoral Dissertations. 3676. https://digitalcommons.lsu.edu/gradschool_dissertations/3676 This Dissertation is brought to you for free and open access by the Graduate School at LSU Digital Commons. It has been accepted for inclusion in LSU Doctoral Dissertations by an authorized graduate school editor of LSU Digital Commons. For more information, please [email protected]. PEPTIDOMIMETIC POLYMERS: ADVANCES IN MONOMER DESIGN AND POLYMERIZATION METHODS A Dissertation Submitted to the Graduate Faculty of the Louisiana State University and Agricultural and Mechanical College in partial fulfillment of the requirements for the degree of Doctor of Philosophy in The Department of Chemistry by Brandon Andrew Chan B.S., University of Michigan – Ann Arbor, 2009 August 2016 Victrix causa diis placuit, sed victa Catoni -Lucan, Pharsalia ii ACKNOWLEDGEMENTS First and foremost I would like to thank my advisor Prof. Donghui Zhang for her guidance, mentorship, and the plethora of opportunities to be at the cusp of cutting edge research throughout my time in graduate school. I also want to thank her for her encouragement and enthusiasm for each of the works contained in this document. Without it, I may have easily lost interest early in my graduate school career. I also want to thank her for supporting my plans to attend law school to become a patent attorney. On a related note, I want to acknowledge Prof. John Pojman who put me in contact with the right people to answer my questions about pursuing patent law. I also want to thank Profs. Paul Russo and David Spivak for their support and encouragement for both completion of my degree and for support of my law school plans. I want to also thank those in the LSU Department of Chemistry who have lent much support to the collection of data and assistance with experiments I never thought I would have ended up running. Specifically I want to acknowledge Connie David and Dr. Jeonhoon Lee for their assistance in ESI MS and MALDI TOF MS respectively, Dr. Rafael Cueto for teaching me everything I ever wanted to learn about polymer characterization and help with instrumentation, Drs. Thomas Weldeghiorghis and Fengli Zhang for their assistance in running NMR experiments, Dr. Frank Fronczek for his assistance in X-ray crystallography, and Prof. Evgueni Nesterov for the generous use of the UV-vis spectrometer. I final want to thank all Zhang group members for their help, support, encouragement, and listening to my rants. I would also like to thank my wife, Katie, for her patience, love, and support as we both go through the graduate school process together. iii TABLE OF CONTENTS ACKNOWLEDGEMENTS..........................................................................................iii LIST OF TABLES.......................................................................................................vii LIST OF FIGURES......................................................................................................ix LIST OF SCHEMES..................................................................................................xvii LIST OF ABBREVATIONS AND ACRONYMS...................................................... xx ABSTRACT..............................................................................................................xxiii CHAPTER I. INTRODUCTION TO PEPTIDOMIMETIC POLYMERS....................1 1.1 Overview of peptidomimetic polymers..............................................................1 1.2 Polypeptides…………………………………………………………………... 2 1.2.1 Solid phase synthesis of polypeptides…………………………………... 3 1.2.2 Polypeptide synthesis via the ring-opening polymerization of N- carboxyanhydride monomers............................................................................. 4 1.2.3 Post-polymerization modification of polypeptides................................. 23 1.3 Polypeptoids…..……………………………………………………………...29 1.3.1 Solid phase synthesis of polypeptoids……………………………….....31 1.3.2 Ring-opening polymerization of N-alkyl substituted glycine based NCA monomers to synthesize polypeptoids..............................................................32 1.4 Ring-opening polymerization of N-thiocarboxyanhydrosulfides.....................43 CHAPTER II. MULTIVALENT BINDING INTERACTIONS OF MANNOSE FUNCTIONALIZED GLYCOPOLYPEPTIDES WITH CONCANAVALIN A...................................................................................................................................46 2.1 Objectives.........................................................................................................46 2.2 Multivalent binding, glycopolymers, and glycopolypeptides.......................... 46 2.2.1 Multivalent carbohydrate-lectin interactions.......................................... 47 2.2.2 Glycopolymers........................................................................................ 49 2.2.3 Glycopolypeptides...................................................................................56 2.3 Results and discussion......................................................................................65 2.3.1 Synthesis and characterization of glycopolypeptides..............................65 2.3.2 Circular dichroism of glycopolypeptides................................................ 69 2.3.3 Binding studies of PPLG and PPDLG mannose with ConA ................. 71 2.3.3.1 Binding kinetic study.................................................................. 72 2.3.3.2 Binding stoichiometry from quantitative precipitation assay..... 75 2.3.4 Varying binding epitope density............................................................. 78 2.4 Dynamic light scattering of glycopolypeptides................................................82 2.5 Conclusions...................................................................................................... 84 2.6 Experimental.................................................................................................... 87 2.6.1 Instrumentation and general considerations............................................ 87 2.6.2 Synthesis of γ-propargyl-L-glutamate N-carboxyanhydride...................88 2.6.3 General procedure for the polymerization of γ-propargyl-L-glutamate N- carboxyanhydride............................................................................................. 89 2.6.4 Glycosylation of poly(γ-propargyl-L-glutamate) via CuAAC................90 iv 2.6.5 Circular dichroism...................................................................................91 2.6.6 Turbidity assay........................................................................................ 91 2.6.7 Quantitative precipitation assay.............................................................. 91 2.7 Supplemental data for Chapter II..................................................................... 92 CHAPTER III. 1,1,3,3-TETRAMETHYLGUANIDINE PROMOTED RING- OPENING POLYMERIZATION OF N-BUTYL N-CARBOXYANHYDRIDE USING ALCOHOL INITIATORS.............................................................................. 94 3.1 Objectives.........................................................................................................94 3.2 Introduction to organocatalysis in polymerization...........................................94 3.3 Results and discussion......................................................................................97 3.3.1 Initial results............................................................................................ 97 3.3.2 Competition with TMG initiation......................................................... 100 3.3.3 Demonstration of a living polymerization............................................ 105 3.3.4 Kinetic study of the polymerization...................................................... 106 3.3.5 Expanding the breadth of alcohol initiators and their dependence on sterics and electronics.....................................................................................109 3.3.6 Elucidation of an initiating pathway..................................................... 110 3.3.7 Macroinitiation of Bu-NCA with poly(ethylene glycol) monomethyl ether................................................................................................................123 3.4 Conclusions.................................................................................................... 124 3.5 Experimental.................................................................................................. 126 3.5.1 Instrumentation and general considerations.......................................... 126 3.5.2 Synthesis of N-butyl N-carboxyanhydride............................................ 128 3.5.3 General polymerization procedure........................................................ 129 3.5.4 General kinetics procedure....................................................................131 3.6 Supplemental data for Chapter III.................................................................