Table Of ContentSYNTHESIS 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
