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Synthesis and Evaluation of Novel Tropane Compounds As Potential Therapeutics for Drug Abuse University of New Orleans ScholarWorks@UNO University of New Orleans Theses and Dissertations Dissertations and Theses 8-8-2007 Synthesis And Evaluation Of Novel Tropane Compounds As Potential Therapeutics For Drug Abuse Harneet Kaur University of New Orleans Follow this and additional works at: https://scholarworks.uno.edu/td Recommended Citation Kaur, Harneet, "Synthesis And Evaluation Of Novel Tropane Compounds As Potential Therapeutics For Drug Abuse" (2007). University of New Orleans Theses and Dissertations. 586. https://scholarworks.uno.edu/td/586 This Dissertation is protected by copyright and/or related rights. It has been brought to you by ScholarWorks@UNO with permission from the rights-holder(s). You are free to use this Dissertation in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s) directly, unless additional rights are indicated by a Creative Commons license in the record and/ or on the work itself. This Dissertation has been accepted for inclusion in University of New Orleans Theses and Dissertations by an authorized administrator of ScholarWorks@UNO. For more information, please contact [email protected]. Synthesis And Evaluation Of Novel Tropane Compounds As Potential Therapeutics For Drug Abuse A Dissertation Submitted to the Graduate Faculty of the University of New Orleans in partial fulfillment of the requirements for the degree of Doctor of Philosophy in The Department of Chemistry by Harneet Kaur M.S. (Hons) Panjab University 2001 M.S. University of New Orleans 2004 August 2007 To my family, for their love and support Father: Dr. Paramjit Singh Mother: Sukhvinder Kaur Husband: Rohit Singh ii ACKNOWLEDGMENTS I would like to express sincere gratitude to my research advisor, Professor Mark L. Trudell for his guidance, support and encouragement throughout the period of my study and research. I would also like to thank my committee members, Professor Guijun Wang, Professor Branko Jursic, Professor John B. Wiley and Professor Matthew A. Tarr. In addition, I would like to acknowledge Dr. Edwin D. Stevens for solving X-ray crystal structures for us. I would also like to thank Dr. Sari Izenwasser of the University of Miami for the biological tests included in this dissertation. Additionally, I wish to express my gratitude to Dr. Amy Newman of National Institute on Drug Abuse (NIDA), for hosting me while the University of New Orleans was recovering from the hurricanes. Dr. Peter Grundt and Dr. Noel Paul of NIDA are also acknowledged for their help. I wish to express many thanks and appreciation to my husband, Rohit, for fruitful discussions and overall support. The National Institute on Drug Abuse and the University of New Orleans are gratefully acknowledged for financial support of this work. iii TABLE OF CONTENTS LIST OF SCHEMES.......................................................................................................... vi LIST OF FIGURES ......................................................................................................... viii LIST OF TABLES............................................................................................................. ix ABSTRACT.........................................................................................................................x INTRODUCTION ...............................................................................................................1 1.1 Structure of Cocaine and Its Abuse Potential ...........................................................1 1.2 Cocaine and the Dopamine Transporter ...................................................................4 1.3 The Dopamine Hypothesis........................................................................................6 1.4 Heterogeneity of Dopamine Transporter Binding ....................................................8 1.5 Challenges to the Dopamine Hypothesis ..................................................................9 1.6 Medication Development for Cocaine Abuse.........................................................10 1.7 Binding Affinity and Inhibition Constant...............................................................13 1.8 Structure Activity Relationship Studies of 3-Phenyltropanes ................................14 1.9 Structure Activity Relationship Studies of Meperidine Analogues........................22 1.10 Design Strategy for Novel Tropane Analogues......................................................27 RESULTS AND DISCUSSION........................................................................................34 2.1 Attempted Synthesis of 3-Aryl-3-carbomethoxytropane and its Analogues ..........34 iv 2.2 Attempted Synthesis of 3-Aryl-3-propyltropane and its Analogues.......................38 2.3 Synthesis of 3-Aryl-3-methoxytropanetropane and its Analogues.........................40 2.4 Synthesis of 3-Aryl-3-arylmethoxytropanetropane Derivatives.............................46 2.5 Novel 3-Aryl-2-nortropene Derivatives as “Triple” Reuptake Inhibitors ..............55 2.6 Future Directions ....................................................................................................62 CONCLUSION..................................................................................................................67 EXPERIMENTAL SECTION...........................................................................................69 REFERENCES ................................................................................................................101 APPENDIX......................................................................................................................116 VITA................................................................................................................................134 v LIST OF SCHEMES Scheme 1 Retrosynthetic analysis for the preparation of target molecules with alkyl and allyl esters...............................................................................................31 Scheme 2 Retrosynthetic analysis for the preparation of target molecules with benzyl esters and benzyl ethers ................................................................................32 Scheme 3 Retrosynthetic analysis for the preparation of N-H analogues.......................33 ........................................................................................................................ Scheme 4 Reduction of the unreacted starting material..................................................35 Scheme 5 Use of freshly prepared phenyllithium reagent for transforming 3-tropinone36 Scheme 6 Attempted functional group interconversion of the hydroxyl group to the nitrile.............................................................................................................37 Scheme 7 Formation of the unsaturated compound via β-elimination...........................38 Scheme 8 Retrosynthetic analysis for the formation of 3-aryl-3-propyl-tropane analogues.......................................................................................................39 Scheme 9 Attempted functional group interconversion of the hydroxyl group into the oxalate...........................................................................................................40 Scheme 10 Retrosynthetic route for the synthesis of 3-phenyl-3-methoxytropane and its analogues..................................................................................................41 Scheme 11 Quarternerization of the tertiary amine .........................................................41 Scheme 12 Synthetic route for the synthesis of 3-aryl-3-methoxytropane derivatives....42 vi Scheme 13 Retrosynthetic route for the synthesis of 3-aryl-3-arylmethoxytropane and its derivatives ................................................................................................46 Scheme 14 Retrosynthetic route for the synthesis of 3-aryl-2-nortropene derivatives.....................................................................................................60 Scheme 15 Attempted synthesis of 3-aryl-2-nortropene derivatives ...............................61 Scheme 16 Synthesis of 3-aryl-2-nortropene derivatives ................................................62 Scheme 17 Retrosynthetic route for the synthesis of analogues of 67.............................65 Scheme 18 Synthetic route for the synthesis of analogues of 67.....................................66 vii LIST OF FIGURES Figure 1 Dopamine hypothesis .....................................................................................7 Figure 2 Schematic representation of putative interaction of cocaine with its receptor sites. ...............................................................................................11 Figure 3 Target compounds as hybrid structures of 3β-phenyltropanes and meperidine....................................................................................................30 Figure 4 Structures of some chelating ligands used to enhance reactivity of the alkyllithium reagents.....................................................................................36 Figure 5 Transformation at the O-H bond of the tropane ............................................40 Figure 6 X-ray structure of 3β-phenyl-3-hydroxytropane 55a....................................43 Figure 7 Benzyl ether analogues, 59a-e and 60a-e......................................................47
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