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Synthesis of Phosphonate and Thiophosphonate Peptide Analogs As Inhibitors of Carboxypeptidase A

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Synthesis of Phosphonate and Thiophosphonate Peptide Analogs As Inhibitors of Carboxypeptidase A Louisiana State University LSU Digital Commons LSU Historical Dissertations and Theses Graduate School 2000 Synthesis of Phosphonate and Thiophosphonate Peptide Analogs as Inhibitors of Carboxypeptidase A. Hong Fan Louisiana State University and Agricultural & Mechanical College Follow this and additional works at: https://digitalcommons.lsu.edu/gradschool_disstheses Recommended Citation Fan, Hong, "Synthesis of Phosphonate and Thiophosphonate Peptide Analogs as Inhibitors of Carboxypeptidase A." (2000). LSU Historical Dissertations and Theses. 7151. https://digitalcommons.lsu.edu/gradschool_disstheses/7151 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 Historical Dissertations and Theses by an authorized administrator of LSU Digital Commons. For more information, please contact [email protected]. INFORMATION TO USERS This manuscript has been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer. The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginning at the upper left-hand comer and continuing from left to right in equal sections with small overlaps. Photographs included in the original manuscript have been reproduced xerographically in this copy. Higher quality 6* x 9” black and white photographic prints are available for any photographs or illustrations appearing in this copy for an additional charge. Contact UMI directly to order. Bell & Howell Information and Learning 300 North Zeeb Road, Ann Arbor, Ml 48106-1346 USA u t v l 800-521-0600T Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. NOTE TO USERS This reproduction is the best copy available UMI Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. SYNTHESIS OF PHOSPHONATE AND THIOPHOSPHONATE PEPTIDE ANALOGS AS INHIBITORS OF CARBOXYPEPTIDASE A 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 Hong Fan B.S., Beijing Institute of Chemical Technology, Beijing, China, 1990 May, 2000 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. UMI Number. 9963946 UMI* UMI Microform9963946 Copyright 2000 by Bell & Howell Information and Learning Company. All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code. Bell & Howell Information and Learning Company 300 North Zeeb Road P.O. Box 1346 Ann Arbor. Ml 48106-1346 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ACKNOWLEDGEMENTS I would like to extend my deepest appreciation to my major professor, Dr. Robert P. Hammer, for his guidance, friendship, constant support throughout this work, his belief that students independently approach and solve problems, and conversely, his assistance when needed. I would to express my sincere gratitude to Dr. Robert M. Strongin for his encouragement and friendship. Special thanks are extended to Drs. Mark L. McLaughlin, Andrew Maverick, and Walter Keithly for being my committee members. They have always been helpful and concerned. I would like to acknowledge the following people: Dr. Tracy McCarley, Dr. Wenzhe Lu, and Ms. Laura Baker for their patient assistance in mass spectral analysis; Dr. Dale Treleaven, Dr. Zhe Zhou for their assistance in NMR spectroscopy. I cherish deeply the friendship of all my lab mates, colleagues, and friends who made me feel part of a family during my stay in Baton Rouge. I would like to express my appreciation to my wife, Judy Zhang, for her unconditional love and unwavering support, which have always been and continue to be the source of my strength and inspiration in my life. Also to my parents, Zheng Fan and Xiaoha Luo, for their understanding and spiritual assistance given, which have made this work possible. ii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. TABLE OF CONTENTS ACKNOWLEDGEMENTS...................................................................................................... ii LIST OF TABLES.......................................................................................................................v LIST OF FIGURES....................................................................................................................vi LIST OF SCHEMES................................................................................................................. ix LIST OF ABBREVIATIONS AND ACRONYMS........................................................... xii ABSTRACT................................................................................................................................ xv CHAPTER 1. INTRODUCTION.............................................................................................1 1.1 Enzymes and Their Inhibitors ..............................................................................L 1.2 Carboxypeptidase A and Its Inhibitors ..............................................................3 1.3 Synthesis of Phosphonate and Thiophosphonate Peptide Analogs ............... 8 1.4 Goal of the Project ..............................................................................................15 CHAPTER 2. SYNTHESIS OF AMINOPHOSPHONOUS ACIDS AND THEIR DERIVATIVES......................................................................18 2.1 Synthesis of l-Amino-2-methylpropanephosphonous Acid ........................18 2.2 Synthesis of 1-Amino-ethylphosphonous Acid ............................................. 20 2.3 Protection of Aminophosphonous Acid .......................................................... 20 2.3.1 Protection of N-terminal of Aminophosphonous Acid ...................21 2.3.2 Protection of Phosphoninous Terminal .............................................24 2.4 Experimental Material.......................................................................................26 CHAPTER 3. SYNTHESIS OF PHOSPHONOPEPTIDE ANALOGS BY USING ONE-POT PROCEDURE................................36 3.1 Solid-Phase Synthesis ........................................................................................36 3.2 SPPS with Amino Phosphonites...................................................................... 38 3.3 Solution Phase Synthesis of Phosphonopeptide Analogs ..................46 3.3.1 S ynthesi s Phosphonite Dipeptide Analogs ...................................... 46 3.3.2 Solution Phase One-pot Synthesis Approach ..................................48 3.4 Summary ..............................................................................................................6 6 3.5 Experiment M aterial..........................................................................................67 CHAPTER 4. SYNTHESES OF PHOSPHONATE AND THIOPHOSPHONATE PEPTIDE ANALOGS BY ESTERIFICATION-OXIDATION STRATEGY .......................... 78 4.1 Synthesis of Phosphonotripeptide Analogs ................................................... 79 4.2 Ester Deprotection .............................................................................................81 4.2.1 Deprotection of Methyl Esters ............................................................81 4.2.2 Deallylation of Allyl Esters ................................................................83 iii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 4.3 Enzyme Assays .................................................................................................. 90 4.4 Experimental Material...................................................................................... 92 REFERENCES.........................................................................................................................105 VITA......................................................................................................................................... 110 iv Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LIST OF TABLES Table 1.1 Inhibition of CPA by tripeptide phosphonates ................................................. 7 Table 3.1 Cleavage methods ............................................................................................. 44 V Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
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