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Synthesis of Phosphonate Derivatives and Phosphonate Peptide Analogues Louisiana State University LSU Digital Commons LSU Historical Dissertations and Theses Graduate School 1996 Synthesis of Phosphonate Derivatives and Phosphonate Peptide Analogues. Maria De fatima Fernandez Louisiana State University and Agricultural & Mechanical College Follow this and additional works at: https://digitalcommons.lsu.edu/gradschool_disstheses Recommended Citation Fernandez, Maria De fatima, "Synthesis of Phosphonate Derivatives and Phosphonate Peptide Analogues." (1996). LSU Historical Dissertations and Theses. 6338. https://digitalcommons.lsu.edu/gradschool_disstheses/6338 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 o f 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 afreet 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 corner and continuing from left to right in equal sections with small overlaps. Each original is also photographed in one exposure and is included in reduced form at the back of the book. 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. UMI A Bell & Howell Information Company 300 North Zeeb Road, Ann Arbor MI 48106-1346 USA 313/761-4700 800/521-0600 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 DERIVATIVES AND PHOSPHONATE PEPTIDE ANALOGUES 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 Maria de Fatima Fernandez B.S., Pontificia Universidad Catolica del Peru, Lima, Peru, 1989 December 1996 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. UMI Number: 9720352 UMI Microform 9720352 Copyright 1997, by UMI Company. All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code. UMI 300 North Zeeb Road Ann Arbor, MI 48103 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. A mis (Padres A uyusto y Luisa A m i esposo (Fernando ii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Senor, Hazme un instrumento de tu paz, donde day a odio, siemdreyo amor, donde fiayz ofetisa, perdon; donde daya duda,fe; donde. daya discordia, union; donde daya error, verdad; donde daya desesperacion, esperanza; donde daya oscuridad, (uz; donde daya tristeza, afeyria. 9(az Senor, que no Susquz sex consoCado sino consoiar; ser comprendido, sino comprender; sex amado, sino amar; Torque eseneCdax que recidimos, es pexdonando que somos perdonados, y es muriendo, que voCvemos a nacer. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ACKNOWLEDGEMENTS I would like to thank God for the opportunity to study for my Ph.D. degree at Louisiana State University. Besides the academic knowledge, it was a great opportunity to meet people from all over the world and know their cultures through them. I would like to express my deepest appreciation and gratitude to my major professor, Dr. Robert P. Hammer, for his invaluable support and thoughtful guidance which made the completion of this dissertation possible. Special thanks are extended to Drs. William Daly, Mark McLaughlin, George Stanley and Joseph Liuzzo for being my committee members. I sincerely appreciate their enthusiasm, encouragement, and advice to me. I would also like to acknowledge Dr. David Vargas, Mr. Marcus Nauman and Dale Trilivan for their patient assistance in operating the NMR instruments. I am also grateful to Mr. Jeff Corkem, Mr. Roily Singh, Dr. Tracy McCarley and Dr. Wenzhe Lu for running mass spectral samples. I would like to give many thanks to Dr. Frank Fronczek for providing X-ray structures presented in this dissertation. Special thanks are given to Dr. Mark McLaughlin, Dr. George Stanley and Dr. Andrew Maverick for allowing me to work in their laboratories at the beginning of this project. I cherish deeply the friendship of Zoila Culquichicon, Denis Salgado, Cok Vlaar, Joey Kappel, all my colleagues and friends who all made me feel part of a family during my stay in Baton Rouge. The most substantial contribution to my entire educational career are, of course, from my parents and sisters. They have sacrificed greatly in allowing and supporting me to pursue my education and career goals. I sincerely dedicate this dissertation to Luisa, Augusto, Maria del Rosario, Luisa, Liliana and Maria Consuelo. Finally, I would like to thank my husband, Fernando Sotelo, for his understanding, support, love, and encouragement which have always been and continue to be the source of my strength and inspiration in my life. iv Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. TABLE OF CONTENTS ACKNOWLEDGEMENTS................................................................................................... iv LIST OF TABLES...................................................................................................................ix LIST OF FIGURES...................................................................................................................x LIST OF SCHEMES............................................................................................................... xi LIST OF ABBREVIATIONS............................................................................................... xii ABSTRACT..............................................................................................................................xv CHAPTER 1. INTRODUCTION........................................................................................................ 1 1.1 Phosphonates and Phosphonopeptides ............................................................ 1 1.2 Phosphonate and Phosphonopeptide Solution and Solid-Phase Synthesis ............................................................................................................. 4 1.3 Goal of the Present Research .............................................................................7 CHAPTER 2. A SYNTHESIS OF PHOSPHONATE AND THIOPHOSPHONATE ESTERS AND AMIDES FROM HYDRO GEN-PHOSPHINATES BY A NOVEL ONE-POT ACTIVATION-COUPLING-OXIDATION PROCEDURE..............................................................................................................10 2.1 Results and Discussion .....................................................................................10 2.1.1 Stereoselective Coupling Studies .........................................14 2.1.2 Synthesis of /f-Phosphinates and a-Amino-alkyl-tf- Phosphinates .......................................................................... 17 2.1.3 Synthesis of Protected a-Amino-Alkyl-tf-Phosphinate Esters.......................................................................................19 2.1.4 Synthesis of Model Phosphate and Phosphonamidate Dipeptides in Solution ......................................................... 20 2.2 Experimental Material ..................................................................................... 25 2.2.1 Technical Information ........................................................... 25 2.2.2 General Procedure ..................................................................25 2.2.3 Synthesis and Characterization of H-Phosphinates ...........26 2.2.4 Synthesis and Characterization of Phosphonates and Thiophosphonate Esters and Amides ................................ 28 2.2.4.1 X-ray Structure Analysis .......................................................32 2.2.5 Synthesis and Characterization of a-Amino-Alkyl-//- Phosphinates .......................................................................... 39 2.2.6 Synthesis and Characterization of Protected a- Amino- Alkyl-i/-Phosphinate ............................................................44 2.2.7 Synthesis and Characterization of Protected oc-Amino- Alkyl-i/-Phosphinate Esters ............................................... 46 2.2.8 Synthesis and Characterization of Model Phosphate and Phosphonamidate Dipeptides
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