Florida International University FIU Digital Commons FIU Electronic Theses and Dissertations University Graduate School 7-17-2006 Syntheses of aza analogs of kainoids Mingping Di Florida International University DOI: 10.25148/etd.FI14062265 Follow this and additional works at: https://digitalcommons.fiu.edu/etd Part of the Chemistry Commons Recommended Citation Di, Mingping, "Syntheses of aza analogs of kainoids" (2006). FIU Electronic Theses and Dissertations. 2795. https://digitalcommons.fiu.edu/etd/2795 This work is brought to you for free and open access by the University Graduate School at FIU Digital Commons. It has been accepted for inclusion in FIU Electronic Theses and Dissertations by an authorized administrator of FIU Digital Commons. For more information, please contact [email protected]. FLORIDA INTERNATIONAL UNIVERSITY Miami, Florida SYNTHESES OF AZA ANALOGS OF KAINOIDS A dissertation submitted in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in CHEMISTRY by Mingping Di 2006 To: Interim Dean Mark Szuchman College of Arts and Sciences This dissertation, written by Mingping Di, and entitled Syntheses of Aza Analogs of Kainoids, having been approved in respect to style and intellectual content, is referred to you for judgment. We have read this dissertation and recommend that it be approved. John T. Landrum Fenfei Leng Philip Stoddard Stanislaw Wnuk Kathleen S. Rein, Major Professor Date of Defense: July 17, 2006 The dissertation of Mingping Di is approved. Interim Dean Mark Szuchman College of Arts and Sciences Interim Dean Stephan L. Mintz University Graduate School Florida International University, 2006 ii ( Copyright 2006 by Mingping Di All rights reserved. iii DEDICATION I dedicate this dissertation to my parents and my brothers, who have supported me in all my crazy endeavors; and most importantly, my wife, who, since I married her, has always supported me with unconditional love. iv ACKNOWLEDGMENTS I would like to thank Dr. Kathleen Rein, my major professor, for her support, guidance and endless advice throughout my Ph.D. experience at FIU and my pursuit of the future career. Thanks to the members of my committee, Dr. John T. Landrum, Dr. Philip Stoddard, Dr. Fenfei Leng and Dr. Stanislaw Wnuk for their helpful comments and kind support during my stay at FIU and my pursuit of a postdoctoral position. I need to thank Dr. Kevin E. O'Shea for his friendly official / personal support during my pursuit of the doctoral degree at FIU and a postdoctoral position. I need to thank Ms. Zaida Morales-Martinez for helping me to attend the American Chemical Society national meeting in Anaheim, CA in 2004. I would like to thank all of the people in my laboratory: Richard, Robert, Dragan, Jamie, Li, Tianying, Lori and Minglei for their friendship and support. Thanks to the departmental secretaries Rosa and Judy for their support. The support from all of the staff in the Chemistry Department: Yali, Myron, Lilia and Lisa is acknowledged. Thanks to the FIU Graduate School for financial support with the FIU Presidential Enhanced Assistantship and Dissertation Year Fellowship. Thanks to FIU Graduate Student Association for a travel award. The financial support from National Institutes of Health and National Institute of Environmental Health Sciences to carry out this work is gratefully acknowledged. I would like to thank my family and my wife's family for their support. Finally, I would like to acknowledge the support and love from my wife every day, which has been my most important source of encouragement during the program. v ABSTRACT OF THE DISSERTATION SYNTHESES OF AZA ANALOGS OF KAINOIDS by Mingping Di Florida International University, 2006 Miami, Florida Professor Kathleen S. Rein, Major Professor The kainoids are a class of non-proteinogenic pyrrolidine dicarboxylates that exhibit both excitatory and excitotoxic activities. These activities are a result of the ability of the kainoids to act as glutamate receptor agonists by activating ionotropic glutamate receptors. The parent of this group of compounds is x-kainic acid. Kainic acid is isolated from the seaweed Diginea simplex and has been used in Asian countries as a treatment for intestinal worms in children. In addition it is used extensively by neuropharmacologists for the study of glutamate receptors. Several years ago, the world's sole supplier of kainic acid discontinued this product. Since that time, other sources have appeared, however, the price of kainic acid remains significantly higher than it once was. We have thus been working on synthesizing aza analogs of kainoids which would be less costly but potentially potent alternatives to kainic acid via the dipolar cycloadditions of diazoalkanes with trans diethyl glutaconate. These 1, 3-dipolar cycloadditions yielded 2- pyrazolines or pyrazoles. The 2-pyrazolines may be precursors to aza analogs of kainoids. The regioselectivity of these 1, 3-dipolar cycloadditions and isomerization of the 1- pyrazolines to 2-pyrazolines was evaluated. Reductions of the 2-pyrazolines yielded aza analogs of kainoids. vi TMS diazomethane, due to the commercial availability, has been frequently used as a synthetic reagent in 1, 3-dipolar cycloadditions, particularly in the preparation of novel amino acid analogs. A survey of the recent literature indicates that the regioselectivity of the double bond isomerization of TMS substituted 1-pyrazolines is variable and at first glance, unpredictable. In an effort to develop a mechanistic rational for the isomerization which could account for the products obtained, a systematic survey of dipolar cycloadditions between TMS diazomethane and O, P-unsaturated dipolarophiles was undertaken. It was suggested that the steric demand of the dipolarophiles had a profound effect on both the relative stereochemistry of dipolar cycloaddition reactions of TMSCHN 2 and the preferred direction of isomerization of the resulting 1 -pyrazoline. vii TABLE OF CONTENTS CHAPTER PAGE 1. Introduction ..................................................................................................................... 1 1.1 Ionotropic Glutamate Receptors (iGluRs) ................................................................ 1 1.2 Kainoids .................................................................................................................... 6 1.3 Crystal stuctures of iGluRs ligand binding cores: Molecular mechanisms underlying ligand-binding affinity and specificity and iGluR gating properties......... 10 1.3.1 AMPA receptor ................................................................................................ 12 1.3.2 Kainate receptor ................................................................................................ 15 1.3.3 Gating mechanism .. 18 1.4 1Synthesis S.4 y th si ofo kainoidsk i ig .............................................................................................. 212 1.4.1 Pyrrolidine ring synthesis from an acyclic precursor ....................................... 21 1.4.2 Modification of an existing pyrrolidine ring..................................................... 25 1.5 Objective of research .............................................................................................. 27 1.6 Modeling study of aza analog of kainoids 58 in kainate receptor GluR6............... 29 1.7 R esearch design ............................................................................................ 38 2. Results and Discussion ........................................... 42 2.1 1,3-Dipolar cycloadditions between diazoalkanes and trans-diethyl glutaconate.. 42 2.2 Reductions of 2-pyrazolines ................. ................... .. 50 2.2.1 Reductions of unprotected 2-pyrazolines 64b, 65a and 65b ............................. 50 2.2.2 Reductions of protected 2-pyrazolines............................................... .... 51 2.2.3 Possible routes to access the target compounds 58 and 59............................... 67 2.3 1,3-dipolar cycloadditions of trimethylsilyldiazomethane revisited.................. 68 3. Experimental Section................................................................................................... 76 3.1 General procedure ................................................................................................. 76 3.2 Materials and methods for molecular modeling study............................................ 76 3.3 Synthesis ................................................................................................................. 77 4 . C onclusion ............................................................. ................................................... 105 R eferences.. ................................................................................................................... 109 VITA ............................................................................................................................... 121 viii LIST OF TABLES TABLE PAGE 1. Conformations of aza-KA 58a in the iGluR6 receptor ................................................. 33 2. Hydrogen bonding interactions between ligands and iGluR6 receptor ........................ 34 3. Conformations of aza-KA 58b in the iGluR6 receptor ................................................ 37 4. Estimated relative docking energies for 58a and 58b ................................................ 38 5. Dipolar Cycloaddition of Diazoalkanes and trans Diethyl glutaconate ....................... 42 6. Reduction