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SYNTHESIS OF SUBSTITUTED PYRROLIDINES USING NITRONE ANION CYCLOADDITIONS By NAGRAJ K. BOKINKERE 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 1997 This work is dedicated to anna, amma and anu, ACKNOWLEDGMENTS First and foremost I would like to acknowledge my research advisor, Nigel Richards, for his support, enthusiasm and guidance through out my research career. I would also like to thank him for providing the opportunity to work in diverse fields, creating a stimulating atmosphere for research and contributing to my growth as a scientist. I would also like to thank the members of my committee Dr. Baker, Dr. Battiste, Dr. Brey, and Dr. Dolbier, for their guidance, support and the generous gifts of their time and advice whenever I needed it. I am truly grateful. I am thankful to the faculty at the department of Chemistry for the superior teaching, advice, and the goodwill I had the good fortune to benefit from. I appreciate the help of all the support personnel at the department of Chemistry. I would also like to acknowledge Dr. Ion Ghiviriga and Dr. Craig Porter for their help with the NMR work. I am grateful to John Munsen for his friendship and his help on the antibody project. I would like to thank my colleagues, past and present, for all their help in the lab, their friendship and the camaraderie, that made working so easy. Thanks are due to iii Srini, Jenny, Craig, Jose, Sue, Ian, Steve N. Tony, Astra, , Yannis, Rajiv, Ramanan, Amy, Mihai and Steve G, Eve, Mike, Kim, Carlos, Jen, and Soina. I truly appreciate and will greatly miss all the wonderful friends I have known in Gainesville. I would especially like to thank Lucian and Lani for their friendship, kindness, company and all the excellent food and several pots of coffee that I have enjoyed. I would like to thank Tony and Carl for introducing me to gator football, and all the southern slang that I hope to show off up north. You are truly good friends and I hope to see you soon. I would also like to thank Yannis for his friendship and the benefit of his expert opinion on every conceivable subject. I would like thank Yannis and Tony for the thorough and painstaking profreading of the manuscript. I am also grateful to Sanjay and Suhas for their friendship and company. I would like to acknowledge my longtime friends Chary and Satish for their support and friendship. Words cannot begin to express the gratitude I feel towards my mom, amma, dad, anna, and sister anu, so I will not even try. Finally, it is my pleasure to thank Dr. Deyrup for accepting me at this department; without his decision to accept me, none of this would be possible. I will always be grateful. iv TABLE OF CONTENTS ACKNOWLEDGEMENTS Hi ABSTRACT viii INTRODUCTION 1 Pyrrolidine Rings fromAzomethine Ylides 6 Synthesis of Azomethine Ylides 6 Desilylation of W-(Trimethylsilyl)methyl Iminum Ions 6 Ring Opening of Aziridines: Thermal and Photochemical 9 Treatment of Amine W-oxides with a Strong Base 13 Pyrrolidine Rings fromAzaallyl Anions 14 Synthesis of the Azaallyl Anion 15 Deprotonation of Imines 16 Anionic Cycloreversion of W-Lithioimidazolidines 17 Clevage of Carbon-silicon and Carbon-tin Bonds 18 NitArcoindeist:yRoefacPtriootnosnsanNdexCthatroacttheeriNsittircosne Group 2212 Behrend Rearrangement 23 Proposed Chemistry 24 Some Anticipated Problems 26 Synthesis of Nitrones 28 Condensation of N-Monosubstituted Hydroxylamines with Carbonyl Compounds 29 Oxidation of W,W-Disubstituted Hydroxylamines 30 Other Methods to Synthesize Nitrones 31 Specific Aims 32 SUCCESSFUL CYCLOADDITIONS WITH THE NITRONE ANION: A USEFUL NEW REACTION WITH AN OLD FUNCTIONAL GROUP 35 Introduction 35 Synthesis of the Nitrone 36 Nitrone Anion as a Nucleophile 37 Nitrone Anion as a Dipole 39 Effect of Varying the Counter Ion of the Base 41 Li+ as the Counter Ion 41 K+ as the Counter Ion 42 Cu+ as the Counter Ion 42 Cycloadditions with Sulfone Substituted Dipolarophiles 43 Stereochemical Assignments of Cycloadducts 45 V Systematic Study of Reaction Conditions in Cycloaddition Reactions 48 Concerted versus Stepwise Processes 50 Attempts to Isolate an Intermediate 53 Analysis of the Pathways to Observed Cycloadducts 54 Conclusion 57 SYNTHESIS OF PROLINE ANALOGS USING NITRONE ANIONS 58 Introduction 58 Substituted Prolines as Constrained Amino Acid Analogs 59 Strategies Towards the Synthesis of Proline Analogs 60 Synthesis of tert-Butyl Glyoxalate 61 Synthesis of tert-Butoxy Carbonyl Substituted Nitrones 63 Reactions of Nitrone 314 65 Cyclization of Nitrone 314 66 Structural Assignment of 315 67 Synthesis of N-Benzyl-a-tert-butoxycarbonyl Nitrone 72 Cyclization of Nitrone 318 73 Determinating the Stereochemistry of 319 and 320 74 Conclusion 76 STUDIES TOWARD THE SYNTHESIS OF COCAINE METABOLITE ANALOGS USING NITRONE ANIONS 78 Introduction 78 Results and Discussion 80 Synthesis of the Cyclic Nitrone by Intramolecular Cyclization a Hydroxylamine and an Aldehyde 80 Towards the Synthesis of Suitably Substituted Cyclic Nitrones 81 Synthesis of a Cyclic Nitrone from Malic Acid 85 Generation of an Anticocaine Antibody 88 Design and Strategy Towards an Anticocaine Antibody 89 Synthesis of the Norcocaine Hapten 92 Linking the Hapten to a Carrier Protein 94 Synthesis of the Norcocaine MAP 95 Synthesis of the Norcocaine-Carrier Conjugate 97 Immunization and Results 98 INTRAMOLECULAR CYCLOADDITIONS OF NITRONE ANIONS 100 Introduction 100 Intramolecular Cycloadditions of Nitrones 101 Intramolecular Cycloadditions of Nitrones in Natural Products Syntheses 105 Intramolecular Cycloadditions of Azaallyl Anions 106 Results and Discussion 109 vi Intramolecular Cycloadditions of Unactivated Dipolarophiles 114 Intramolecular Cycloadditions of Moderately Activated Dipolarophile Compounds 116 Cycloadditions of Highly Activated Dipolarophiles ...121 Conclusions 123 FUTURE WORK 124 EXPERIMENTAL 128 Materials, Instruments and Methods 128 Synthetic Procedures and Chemical Data of Compounds 130 APPENDECIES 178 A CRYSTAL STRUCTURE DATA FOR 212 178 B NOESY SPECTRUM OF 207 183 C NOESY SPECTRUM OF 208 184 D NOESY SPECTRUM OF 213 185 E NOESY SPECTRUM OF 214 186 F HETCOR SPECTRUM OF 315 187 G HMBC SPECTRUM OF 315 188 H NOESY SPECTRUM OF 319 189 I HMQC SPECTRUM OF 554 190 J HMBC SPECTRUM OF 554 191 LIST OF REFERENCES 192 BIOGRAPHICAL SKETCH 202 vii Abstract of Dissertation Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy SYNTHESIS OF SUBSTITUTED PYRROLIDINES USING NITRONE ANION CYCLOADDITIONS By Nagraj K. Bokinkere August, 1997 Chairman: Dr. Nigel G. J. Richards Major Department: Chemistry Nitrones have long been used in organic synthesis. There are several examples of nitrones undergoing dipolar cycloaddition reactions, and examples exist where nitrones act as electrophiles. However, not much is known about nitrone anions. The few examples reported have indicated that these anions are susceptible to dimerization Upon . deprotonation of a nitrone, there exist two dipoles in the system capable of reacting with a dipolarophile in a cycloaddition reaction, one being the usual nitrone dipole to form an isoxazolidine ring. The other, more intriguing, possibility is the new dipole reacts to form a pyrrolidine ring. There have been no published reports of a nitrone anion undergoing a cycloaddition reactions so far. viii N-benzyl-a-phenyl nitrone was shown to undergo cycloadditions with £-methyl cinnamate and E-2- phenylsulfonyl styrene to form the corresponding ( ) pyrrolidine rings. N-methyl and W-benzyl-a-tert-butoxycarbonyl nitrones have also been shown to undergo cycloaddition reactions with E-methyl cinnamate. Thus, functionalized nitrone anions have been shown to undergo cycloadditions with the incorporation of useful and reactive substituents on the ensuing pyrrolidine rings. Finally, nitrones have been shown to undergo intramolecular cycloaddition reactions to form complex tricyclic molecules. A series of intramolecular substrates were synthesized from a salicylaldehyde nucleus, with different stabilization of the nitrone anion and varying degrees of activation of the dipolarophile. Only a moderate stabilization of the dipolarophile was required for successful cycloaddition. ix CHAPTER 1 INTRODUCTION Synthesis of the pyrrolidine ring using the [3+2] methodology has received great attention in the past. This is due to the regular appearance of the pyrrolidine ring in various natural products and many biologically active compounds (Figure 1-1). Kainic acid, 1, was isolated from the Japanese alga diginea simplex. Kainic acid has been shown to selectively block neuronal processes and is a valuable 1: Kainic Acid 2: Borrecapine 3: Quinocarcin Figure 1-1: Pyrrolidine in natural products. tool in the study of neurofunctioning (1). It also possesses potent anthelmintic and insecticidal activities. Pyrrolidine rings are most prevalent in alkaloids. Borrecapine, 2, and guinocarcin, 3, Figure 1-1, are alkaloids which possess