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Synthesis and Structural Studies of Novel Acyclic Unsymmetric Functionalized Imides and Mechanistic Studies on E

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Synthesis and Structural Studies of Novel Acyclic Unsymmetric Functionalized Imides and Mechanistic Studies on E SYNTHESIS AND STRUCTURAL STUDIES OF NOVEL ACYCLIC UNSYMMETRIC FUNCTIONALIZED IMIDES AND MECHANISTIC STUDIES ON E. COLI ASPARAGINE SYNTHETASE B By JOSE G. ROSA RODRIGUEZ A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 1996 To my wife and family. ACKNOWLEDGMENTS First I would like to thank my advisor, Dr. Nigel G. J. Richards, for his guidance, patience, support, and valuable input throughout this entire journey. Second, I would like to thank Dr. Sheldon M. Schuster for his advice, input, and useful discussions on enzyme kinetics, and for the excellent food I consumed on Friday afternoons. Third, I want to thank Dr. Susan K. Boehlein for her advice and instructive conversations and for conducting all enzyme assays in this study. I also would like to thank Dr. William Dolbier Jr., Dr. Eric Enholm, and Dr. Gus Palenik for their advice and valuable suggestions. I could not have done it without the help from these important people. They have my appreciation and best wishes for the future. Next, I would like to thank my colleagues Anthony (Tony) B. Dribben, Yannis (Janice) Karayannis, Nagraj (Nag) Bokinkere, Rajiv (Raju) Moghe, and Susan (Sue) Rasmussen for daily productive and nonproductive conversations in the topics of chemistry and life. Special thanks go to Tony Dribben for useful advice regarding computers and computational chemistry. I wish all of them the best in the future and hope to see them again. iii Special thanks go to my wife, Lymari Montalvo, for her company, love, and support throughout these years of graduate study and to her family, Jose A. Montalvo, Carmen Montalvo, and Omar Montalvo, for their support. My personal thanks go to my mother and father. Ana Lydia Rodriguez and Jose L. Rosa, my father's wife, Nancy Rosa, and my brothers and sister, Jose L. Rosa, Ricardo J. Rosa, and Ana B. Del Cueto, for helping me througout these years and throughout my life in one way or another. Last but not least, I want to thank Dr. John F. Helling and Dr. Michael J. Phillip for giving me the opportunity to develop myself as a professional at this institution. I will always be grateful. iv TABLE OF CONTENTS AKNOWLEDGEMENTS iii LIST OF FIGURES viii ABSTRACT xvlll CHAPTERS 1 STRUCTURE AND FUNCTION OF AMIDOTRANSFERASES AND E. COLI ASPARAGINE SYNTHETASE B 1 The Amidotransferases 1 Asparagine Synthetase 6 Structure and Function 6 Reaction Mechanism 10 E. Coli Asparagine Synthetase B 17 Structure and Function 17 Reaction Mechanism 18 Specific Aims 28 2 REVIEW OF ACYCLIC IMIDE SYNTHETIC METHODOLOGY 30 Introduction 30 Imides from Amides or Amines and Acid Anhydrides 32 Imides from Amides or Amines and Acid Chlorides 41 Imides from Nitriles and Carboxylic Acids 53 Imides from Amides 58 Imides from Amide Anions 59 Imides from Amides and Ketenes 62 Imides from Isocyanates and Acid Anhydrides 64 Miscellaneous Methods 65 Concluding Remarks 71 3 SYNTHESIS AND PROPERTIES OF HIGHLY FUNCTIONALIZED UNSYMMETRIC ACYCLIC IMIDES 73 Designing the Enzyme Imide Intermediate 73 Synthesis of Di-protected L-Glutamine Derivatives .... 76 Synthesis of Di-protected L-Aspartic Acid Derivatives 79 Synthesis of Protected Imide Intermediate 80 Deprotections of Imide Intermediate 85 Other Novel Imide Derivatives of L-Glutamine 86 Deprotections of Novel Ny-Acylated L-Glutamine V Derivatives 94 Stability Studies of Novel Ny-Acylated L-Glutamine Derivatives 97 The Structure of Ny-Acylated L-Glutamine Derivatives 121 4 MECHANISTIC STUDIES OF E. COLI ASPARAGINE SYNTHETASE B 137 Introduction 137 Enzyme Assay Design 139 Reaction of Imide 12 with Wild Type E. Coli Asparagine Synthetase B 144 Studies of Imide 12 with CIA and CIS Mutants of E. Coli Asparagine Synthetase B 146 5 INHIBITION STUDIES OF E. COLI ASPARAGINE SYNTHETASE B 155 Re-engineering the Function of E. Coli Asparagine Synthetase B from Amidohydrolase to Nitrile Hydratase 155 Introduction 155 Rational Design and Synthesis of a Nitrile L- Glutamine Analog 160 Stability Studies of Nitrile L-Glutamine Analog... 161 Studies of Nitrile L-Glutamine Analog with E. Coli Asparagine Synthetase B 172 Design and Synthesis of Other Potential Inhibitors of E. Coli Asparagine Synthetase B 176 Introduction 176 Rational Design and Synthesis of L-Glutarimide . 177 Rational Design and Synthesis Towards an a,p- Unsaturated L-Glutamine Analog 180 Inhibition Studies of Potential Inhibitors with Wild-Type E. Coli Asparagine Synthetase B 183 6 CONCLUSIONS 184 Synthesis and Properties of Acyclic Unsymmetric Functional ized Imides 184 Mechanistic and Inhibition Studies on E. coli Asparagine Synthetase B 185 7 EXPERIMENTAL 188 Materials, Instruments, and Methods 188 Nuclear Magnetic Resonance Experiments 189 Enzymatic Assays 190 Theoretical Calculations 193 Synthetic Procedures and Chemical Data of Compounds 194 vi APPENDIX 266 LIST OF REFERENCES 267 BICX3RAPHICAL SKETCH 281 vii LIST OF FIGURES Ficrure page 1-1. Transfer of the amido nitrogen from L-glutamine 1 for the biosynthesis of other molecules via pathways A-P 2 1-2. Reaction catalyzed by the synthetase domain of Amidotransferases 4 1-3. Reaction catalyzed by the glutamine amidotransferase domain (GAT) of Amidotransferases 4 1-4. Primary sequence alignment of Class II glutamine- dependent amidotransferases . Residue numbers correspond to D-fructose-6-phosphate amidotransferase. Taken from Boehlein, Richards and Schuster (39) 8 1-5. Reactions catalyzed by Asparagine Synthetase; (ill) ammonia-dependent activity; (iv) glutamine- dependent activity; (v) glutaminase activity 9 1-6. Formation of ^^O-p-aspartyl-AMP intermediate 6 and generation of L-asparagine 4 and i^q-amp in E, coli AS 11 1-7. Proposed mechanism of Asparagine Synthetase based on studies upon glutamine PRPP amidotransferase (8) 13 1-8. Kinetic mechanism showing order of substrate binding, nitrogen transfer, and product release in AS; A. glutamine-dependent activity in mouse pancreas AS; B. glutamine-dependent activity in beef pancreas AS; C. ammonia-dependent activity of beef pancreas AS 15 1-9. Proposed mechanism for glutamine-dependent nitrogen transfer in E. coli AS-B involving acyclic unsymmetric imide 12 as a reaction intermediate 19 1-10. Kinetic mechanism of E. coli AS-B 22 viii 1-11. Proposed mechanism for nitrogen transfer in E. coli AS-B involving tetrahedral intermediate 8. ...24 1- 12. Proposed mechanism for nitrogen transfer in E. coli AS-B involving imide intermediate 12 25 2- 1. Diversity of imidic compounds: 16 = acyclic, 17 = functionalized acyclic, 18 = highly functionalized acyclic, 19 and 20 = cyclic 31 2-2. Mechanistic pathways for the reaction between amides 4 3 and acid anhydrides 4 4 to give imides 49, nitriles 4 8, and acids 4 7 38 2-3. Formation of bisphenylacetimide 5 7 via phenylacetyl carbonium ion intermediate 5 3 39 2-4. Formation of acetonitrile 6 4 and benzoic acid 6 5 from heating acetamide 6 1 and benzoyl chloride 62 41 2-5. Fomooation of acetylbenz amide via intermediate 7 5 and acetonitrile and benzoic acid via intermediate 7 6 43 2-6. Mechanistic pathways for the formation of (a) nitrile 8 0 and acid 81, (b) imide 8 3, and (c) triacylamine 8 5 45 2-7. Synthesis of functionalized symmetric imides 9 7 and 9 8 and rearrangement of 9 8 to amide 9 9 48 2-8. Base promoted rearrangement of unsymmetric imides 103b, c to amides 104-107 49 2-9. Synthesis of functionalized imides 131-13 3 from nitrile 12 9 and acid 130 54 2-10. Synthesis of functionalized unsymmetric imides 136 and 137 55 2-11. Mechanism for nitrile and carboxylic acid group exchange via imide intermediate 144 56 2-12. Synthesis of cyclic imides 157 and 159 from diprotected L-asparagines 155 and 156 and L- glutamine 15 8 60 2- 13. Formation of imides 17 3 from isocyanates 17 0 and acid anhydrides 171 via intermediate 17 2 64 3- 1. Retrosynthetic analysis for the formation of imide 12 starting from N-protected-L-glutamine 211 and N-protected-L-aspartic acid 212 75 ix 3-2. Synthesis of N,C-diprotected-L-glutamine 213a-c from N-protected-L-glutamine 211a and 211b or C- protected-L-glutamine 217. Reagents and conditions: i; a) CS2CO3, MeOH/H20, pH 8, 0 oc- R.T., quant., b) BnBr, DMF/MeOH, R.T., 95%. ii; BnOH, TsOH(cat.), benzene reflux, 59%. iii; t-BuOH, DCC, DMAP(cat.), THF, 0 OC-R.T. , 83%. iv; iii, 85%. v; (t-Bu02C)20, triethyl amine, THF, 0 OC-R.T., 98% 77 3-3. Synthesis of p-activated N-Carbobenzyloxy-a- benzyl-L-aspartic acid 215a,b from N- Carbobenzyloxy-L-aspartic acid 212. Reagents and conditions: i; AC2O, R.T., 95%. ii; BnOH, 80 OC, 61%. iii; PCI5, Et20, 0 OC-R.T., 89%. iv; DCC, CH2CI2, 0 OC, 90% 79 3-4. Acid catalyzed reaction between amide 213a and acid anhydride 215b to give new products 2 20- 222 81 3-5. N-acylation of amides 213 by acid chloride 215a in the presence of pyridine to give unsymmetric imides 216, N,N-diacylamines 22 3, and nitriles 224 82 3-6. Deprotection of imide 216b to give free acid- imide 22 5 and amino acid-imide 12. Reagents and conditions: i; TFA, CH2CI2, 0 oc, 94%. ii; 10% Pd/C, 1,4-cyclohexadiene, EtOH/THF, reflux, 90% 86 3-7. Synthesis of electrophiles 2 2 8, 22 9, and 231. Reagents and conditions: i; BnOH, 100 ^C, 948%. ii; PCI5, Et20, 0 oC-R.T. iii; DCC, CH2CI2, 0 °C-R.T., 93%. iv; PCI5, Et20, R.T 87 3-8. Acid catalyzed N-acylation of amides 213 by acid anhydrides 2 32 to give unsymmetric imides 233 and by-products 2 2 0, 2 3 4, and 235 89 3-9.
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