THE DESIGN AND SYNTHESIS OF NOVEL PROTEASOME INHIBITORS:
STUDIES ON THE SYNTHESIS OF NAGELAMIDE M AND ANALOGS, THE
SYNTHESIS OF RAPAMYCIN BASED PROTEASOME INHIBITORS, AND THE
SYNTHESIS OF TCH BASED MOLECULAR PROBES FOR BINDING SITE
DETERMINATION
By
Matthew Basil Giletto

A DISSERTATION
Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of
Chemistry – Doctor of Philosophy
2017

ABSTRACT
THE DESIGN AND SYNTHESIS OF NOVEL PROTEASOME INHIBITORS:
STUDIES ON THE SYNTHESIS OF NAGELAMIDE M AND ANALOGS, THE
SYNTHESIS OF RAPAMYCIN BASED PROTEASOME INHIBITORS, AND THE
SYNTHESIS OF TCH BASED MOLECULAR PROBES FOR BINDING SITE
DETERMINATION
By
Matthew Basil Giletto
The two primary physiologic mechanisms for the recycling of amino acids from
no-longer needed or damaged proteins are autophagy and enzymatically via the
proteasome. Inhibition of the proteasome has emerged as the preeminent means for treating
cancers that constitutively overproduce proteins, particularly multiple myeloma.
Two drugs currently available for the treatment of multiple myeloma,
BortezomibTM and KyprolisTM, inhibit the proteasome by binding to the catalytically active
sites through a competitive mechanism. While initially effective, over time the resistance
that is typical of competitive binders emerges, and relapse rates are currently measured at
97 %, with the average survival time after being one year. Additionally the most common
side effect is neuropathy, which typically does not abate after discontinuation of
chemotherapy.
The current state of the art demonstrates the need not only for new proteasome
inhibitors, but inhibitors that act through a different mechanism. The Tepe group was the
first to develop such a molecule, imidazolines of the TCH-series, which bind to the
proteasome via a noncompetitive mechanism. The details of the interaction of these
molecules with the proteasome have been extensively studied, but the location of the
binding site remains elusive. In this work, several molecular probes were designed and

synthesized (two diazirine photoaffinity-TCH hybrids and a biotin-TCH hybrid) to
elucidate the location of the binding site. Currently biological testing is underway.
Additionally, a library of analogs based on the natural product rapamycin were
designed and synthesized. An analog was discovered that was equipotent to the natural
product itself, which could be synthesized on a gram scale in three steps from commercially
available materials. To discover the binding site of these molecules, a diazirine
photoaffinity probe was designed and synthesized. Enough biological data was generated
to refine the library and design and synthesize a second generation of the analogs; currently
biological testing of these analogs is underway.
Lastly, extensive studies on the total synthesis of the pyrrole-imidazole natural
product nagelamide M were designed and performed. These studies relied mainly on the
use of C-H activation to functionalize a methylene C-H bond adjacent to a heteroatom.
None of the key reactions were successful, and the synthesis stalled at an early stage.
Overall this thesis describes several advances in the areas of drug discovery and
proteasome inhibition, and perhaps most excitingly access to molecules that could
elucidate the binding site of the TCH molecules.

Copyright by
MATTHEW BASIL GILETTO
2017

Dedicated to my wife, Holeigh, and my daughter, Reagan.

v

ACKNOWLEDGMENTS

This has been an extraordinary adventure, and there are many people without whom it
would have been impossible, or at least much less enjoyable. I would like to thank first and
foremost my wife, Holeigh, for her belif in me and her unwavering support and devotion. And
for her patience as we discovered together how true it is that behind every successful man is a
woman rolling her eyes.
I would like to thank my families – old and new. Thanks to my parents, Joseph (Happy
Birthday!) and Geraldine, for their support and encouragement, and my siblings Jackie, Chris,
and Amanda. I would also like to thank my father- and mother-in-law, Dick and Karen Ries, for
taking me into their family as though I had always been a part of it. I’d also like to thank my
brother-in-law Josh, and his wife, Megan, and daughter, Jenna.
I could not have asked for better lab mates to go through graduate school with (“You only do
two days. That’s the day you go in and the day you come out.” – Wood Harris, The Wire). Travis
(my work wife) Bethel and Corey “Remo” Jones. We had many great discussions about chemistry
and many more about everything else in life, and I like to imagine the halls of the 5 th floor will
echo with our laughter for years to come. Thanks also to Evert Njomen (for tolerating us and for
her biological acumen) and other group members past (Mike Kuspit and Nicole Hewlett) and
present (Shuang Gao, Katarina Keel, and Shaffat Medhi).
Additionally I would like to thank the following people: Tanner McDaniel, Nick Boersma, Tim
Shannon, Kristen Gore, Yu-Ling Lien, Yukari Nishizawa-Brennan, Kelly Miller, Liz Santos,
Olivia Chesniak, Jason Karabatsos, Professor and Mrs. Karabatsos, and of course the inimitable
Rick Sanchez.

vi

I would like to thank Dr. Dan Holmes for his NMR assistance and Dr. Richard Staples for
solving the crystal structures I gave him. I would also like to thank Marvey “Marvelous” Olson,
for her help in dealing with the outside world and for always being a delight to interact with.
I would like to thank the staff of Schuler Books and Music and the Chapbook Café, because
that is where I wrote most of my dissertation, and because I have enjoyed so much time there.
I would like to thank my friends from California: Professor A. Richard Chamberlin, Professor
David van Vranken, Dr. Robert Fazio, Professor Justin R. Walensky, and Will Helibut.
Penultimately I would like to thank my committee, Dr. Wulff, Dr. Frost, and Dr. Odom, for
many enlightening and fruitful conversations. I would in particular like to thank Dr. Wulff for
introducing me to Macallan scotches and Nespresso machines.
Which brings me at last to Dr. Jetze Jans Tepe (I only recently learned what the second ‘J’
stood for). I would like to thank him for the opportunity to work in his laboratory and the creative
freedom he allowed me. And for tolerating my sense of humor.

vii

TABLE OF CONTENTS

LIST OF TABLES ........................................................................................................... ix
LIST OF FIGURES .......................................................................................................... x
KEY TO ABBREVIATIONS ..................................................................................... xxix
Chapter 1: Introduction ................................................................................................... 1
Chapter 2: Studies on the Total Synthesis of Nagelamide M and Analogs. ................ 7
Synthesis of the Oxaziridine: Studies on the Oxidation of Imines and Amination of
Ketones ........................................................................................................................... 9
The C-H Amination Reaction in Total Synthesis ..................................................... 11
Expanding the Substrate Scope of Rhodium Catalyzed C-H Amination .............. 15
The Intramolecular Rh2(esp)2 C-H Amination Pathway ........................................ 20
The Intermolecular Approach to Nagelamide M ..................................................... 24
C-H Azidation as a Method to Access These Substrates ......................................... 30
Chapter 3: The Synthesis of Analogs of Des-Guanidinyl Nagelamide M .................. 34
Chapter 4: Studies on the Aminohydroxylation of Indoles ......................................... 43
Chapter 5: Studies on the Diamination of Indoles ....................................................... 52
Studies On the Intermolecular Diamination of Indoles .......................................... 57
Chapter 6: Studies on the Functionalization of Indoles and Indanes ........................ 68
Chapter 7: The Synthesis of Rapamycin Analogs as Inhibitors of the Proteasome
and a Rapamycin-Based Diazirine Photoaffinity Probe.............................................. 74
Chapter 8: Synthesis of Two TCH-Diazirine Photoaffinity Labels and a TCH-Biotin
Conjugate ......................................................................................................................... 84
Chapter 9: Experimental ................................................................................................ 92
APPENDIX .................................................................................................................... 235
REFERENCES .............................................................................................................. 414

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LIST OF TABLES

Table 4.1: Screen of Conditions for Oxidatizing IV.2...................................................... 46
Table 9.1: Bond Lengths and Bond Angles for Compound III.10. ............................. 130
Table 9.2: Bond Angles and Bond Lengths for IV.2.......................................................145
Table 9.3: Bond Lengths and Bond Angles for Compound VI.5………………………173

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LIST OF FIGURES

Figure 1.1: Bortezomib and Kyprolis, Clinically Approved Proteasome Inhibitors. ......... 1
Figure 1.2: Dibromophakellin, Dibromophakellstatin, Nagelamide M and Indolophakellin..
............................................................................................................................................. 2
Figure 1.3: Crystal Structure of Indolophakellin and Overlay of the Core of Nagelamide M.
............................................................................................................................................. 3
Figure 1.4: C-H Activation in the Synthesis of PIA’s of the Orodin Family ..................... 4
Figure 1.5: The 1,2 Vicinal Diamination of Alkenes and Current Limits .......................... 5
Figure 1.6: The Proposed Use of C-H Amination To Access the Core of Nagelamide M . 6
Figure 2.1: Retrosynthesis of the Pyrrole-Imidazole Alkaloid Nagelamide M. ................. 8
Figure 2.2: The Synthetic Versatility of trans-4-Hydroxy-L-Proline ................................. 9
Figure 2.3: Attempted Oxaziridine Synthesis on Keto-Ester II.4 .................................... 10
Figure 2.4: Synthesis and Attempted Oxidation of Prolinyl Ketone II.7 ......................... 10
Figure 2.5: Attempted Oxaziridination of Prolinyl Ketones II.4 and II.5 ........................ 11
Figure 2.6: The C-H Oxidation Route to Taxol ................................................................ 13
Figure 2.7: The C-H Oxidation to Install a Key Hydroxyl Group in Palau’amine ........... 14
Figure 2.8: C-H Amination to Install a Cyclic Guanidine in Cylindridine A ................... 14
Figure 2.9: Du Bois Total Syntheses of (-)-Tetrodotoxin and (+)-Saxitoxin ................... 15
Figure 2.10: The Catalyst Rh2(esp)2 and Its Enhanced Activity ..................................... 16
Figure 2.11: An Early Example of C-H Amination in Total Synthesis ............................ 17
Figure 2.12: The First Example of an Iminoindinane As A Nitrene Precursor…………..18
Figure 2.13: Transition Metal (III) Porphyrin Complexes Catalyze C-H Amination ...... 19
Figure 2.14: Substrate Preference in Inter- Versus Intramolecular C-H Amination ........ 19
Figure 2.15: Intramolecular Radical Clock Probe for Radical Intermediates ................... 20

x

Figure 2.16: Early Examples of Intramolecular Rhodium Catalyzed C-H Amination ..... 21
Figure 2.17: Literature Precedent for an Intramolecular C-H α Amination ..................... 21
Figure 2.18: Synthesis of Urideo-Proline II.12 for C-H Amination................................. 22
Figure 2.19: Attempted C-H Amination of II.9 ................................................................ 22
Figure 2.20: Attempted C-H Amination of Benzyl Carbamate II.14 ............................... 23
Figure 2.21: Attempted C-H Amination of Sulfamate Substrate ...................................... 23
Figure 2.22: Attempted Intramolecular C-H Amination of Precursor II.17 ..................... 24
Figure 2.23: C-H Amination in the Total Synthesis of the Natural Product Manzacidin A 24
Figure 2.24: An Apparent Discrepancy in Results. .......................................................... 25
Figure 2.25: A Clock Experiment to Probe for the Presence of Radicals......................... 26
Figure 2.26: The Mechanism of the Intermolecular Rh2(esp)2 C-H Amination .............. 26
Figure 2.27: C-H Amination of Natural Products ............................................................. 27
Figure 2.28: Attempted Intermolecular C-H Amination of II.6 and II.7 ......................... 28
Figure 2.29: Attempted Intermolecular C-H Amination of II.6 and II.7 With DfsNH2 .. 29
Figure 2.30: Examples Illustrating the Selectivity of DfsNH2 ......................................... 30
Figure 2.31: Attempted C-H Animation of II.6 and II.7 with Sulfamate Ester II.19 ...... 30
Figure 2.32: C-H Azidation Using the Groves Procedure ................................................ 32
Figure 2.33: C-H Azidation Using the Hartwig Procedure............................................... 33
Figure 3.1: Retrosynthesis of Des-Guanidinyl Nagelamide M ......................................... 34
Figure 3.2; Successful Reaction of a Model System and the Desired Reaction ............... 35
Figure 3.3: Failed Tosylation of the Primary Alcohol in Compound III.3 ...................... 35
Figure 3.4: First Attempt at the Synthesis Prolinyl-Methanamine Core .......................... 36
Figure 3.5: Second Synthesis of Prolinyl-methanamine Core .......................................... 37
Figure 3.6: Proposed Completion of the Synthesis Using the Model Compound ............ 37
Figure 3.7: First Synthesis of the Protected cis-hydroxy Proline III.9 ............................. 38

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Figure 3.8: Proposed Completion of Synthesis of O-Protected III.1 ................................ 39
Figure 3.9: Proposed Completion of Des-Guanidinyl Nagelamide M ............................. 39
Figure 3.10: Nagelamide/Rapamycin Hybrid Analogs ..................................................... 41
Figure 3.11: Biological Activity of Nagelamide/Rapamycin Analog Hybrids................. 42
Figure 3.12: Proposed Synthesis of Sulfonate Analogs of Nagelamide/Rapamycin
Hybrids .............................................................................................................................. 42
Figure 4.1: Desired Indole Analogs .................................................................................. 43
Figure 4.2: The Desirable Qualities of Indoles in Oxidative Functionalization ............... 44
Figure 4.3: Proposed Regio-Reverse Aminohydroxylation of Indoles via a Novel Substrate
........................................................................................................................................... 45
Figure 4.4: Synthesis of the Indole Precursor ................................................................... 45
Figure 4.5: Unexpected Urazine Synthesiss. .................................................................... 47
Figure 4.6: Sulfonyloxaziridine-Mediated Oxidative Cyclization of a Precursor to
Agliferin ............................................................................................................................ 47
Figure 4.7: Attempted Oxidative Cyclization Indolyl-Urea IV.2 ..................................... 48
Figure 4.8: Synthesis of N-Benzyl Indole IV.8 ................................................................ 49
Figure 4.9: Copper(II) Catalyzed Oxyamidation of Indoles With a Sulfonyloxaziridine. 49
Figure 4.10: Cyclopentenyl Urea Model for Oxidative Cyclization................................. 50
Figure 4.11: Need for Electron Withdrawing Groups on Nitrene Precursors................... 50
Figure 5.1: The Oxidative 2,3-Diamination of Indoles..................................................... 52
Figure 5.2: The Diamination of Indoles ............................................................................ 53
Figure 5.3: Xu’s Methodology for the Aminohydroxylation of Alkenes/Indoles. ........... 54
Figure 5.4: Synthesis of a Diamination Precursor ............................................................ 54
Figure 5.5: Asymmetric Intramolecular Amiohydroxylation of Alkenes ......................... 55
Figure 5.6: Stereoconvergent Aminohydroxylation of Olefins. ....................................... 55
Figure 5.7: Proposed Mechanism for the Iron Nitrene Pathway. ..................................... 56

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Figure 5.8: 2,3-Dimethylimidazole-1-Sulfonyl Azide Triflate Functionalizing Indoles. . 57
Figure 5.9: Dauben's Intermolecular Oxyamidation of Indoles. ....................................... 58
Figure 5.10: Attempted Extention to Diamination on Indoles. ......................................... 58
Figure 5.11: The Shi Method for Diamination of Alkenes. .............................................. 59
Figure 5.12: Proposed Expansion of Shi Methodology to Include Diaziridines. ............. 59
Figure 5.13: Synthesis of the Diaziridine Substrate V.7. .................................................. 60
Figure 5.14: Substrate Alkenes for Diamination. ............................................................. 61
Figure 5.15: Attempts at Palladium-Catalyzed Diamination of V.9 and V.10 ................. 61
Figure 5.16: The Pd-Catalyzed Diamination of Dienes with Di-tert-butyldiaziridinone. 63
Figure 5.17: Expected 1H-NMR Shifts On Successful Oxidative Addition. ................... 64
Figure 5.18: Copper Catalyzed Diamination of Olefins. .................................................. 65
Figure 5.19: Deuterium Isomerization in the Copper Catalyzed Diamination of Dienes. 66
Figure 5.20: Copper Catalyzed Diamination With Diaziridines. ...................................... 67
Figure 6.1: Retrosynthesis of Dehydroxy-Analogs of Nagelamide M ............................. 68
Figure 6.2: Synthesis of Dehydroxy-Analog Cyclization Precursors. .............................. 69
Figure 6.3: Synthesis of a Guanidine Precursor from a Secondary Amine. ..................... 70
Figure 6.4: Attempted Intramolecular C-H Amination of Indoline Derivative IV.6. ....... 71
Figure 6.5: A Proposed Convergent Approach to Compound VI.7. ................................. 72
Figure 6.6: Synthesis of Indanyl C-H Amination Analogs. .............................................. 72
Figure 7.1: The Natural Products Rapamycin and FK-506. ............................................. 73
Figure 7.2: SAR-Optimized Analogs of Rapamycin. ....................................................... 74
Figure 7.3: The Synthesis of Rapamycin Analogs............................................................ 74
Figure 7.4: Synthesis of an Initial Analog of Rapamycin Based on Previous SAR Data. 75
Figure 7.5: First Generation Analogs and Activities. ....................................................... 76
Figure 7.6: L-Pipecolic Acid-Based Rapamycin Analogs Synthesized to Probe the SAR.78

xiii

Figure 7.7: Proline-Based Analogs. .................................................................................. 79
Figure 7.8: Group-Exhanged Analogs. ............................................................................. 80
Figure 7.9: Rapamycin Analog-Diazirine Photolabel and Control Compound. ............... 81
Figure 7.10: Photochemical Pathways From Diazirines to Carbenes and Carbocations...82
Figure 8.1: Initial Attempts at Synthesizing a TCH/Biotin Conjugate. ............................ 84
Figure 8.2: Synthesis of DMT-Protected Biotinol. ........................................................... 85
Figure 8.3: Attempted Coupling of DMT-Protected Biotinol to TCH-001. ..................... 85
Figure 8.4: Synthesis of a TCH/Biotin Conjugate. ........................................................... 86
Figure 8.5: Synthesis of a First Generation Photoaffinity Probe. ..................................... 87
Figure 8.6: Synthesis of 4-(3-(trifluoromethyl)-3H-diazirin-3-yl)benzaldehyde. ............ 88
Figure 8.7: Synthesis of a Second Generation TCH-Diazirine Photolabel. ...................... 89
Figure 9.1: Compound II.4.. ............................................................................................. 91
Figure 9.2: Compound II.5a.. ........................................................................................... 92
Figure 9.3: Compound II.5b.. ........................................................................................... 93
Figure 9.4: Compound II.5.. ............................................................................................. 94
Figure 9.5: Compound II.11.. ........................................................................................... 95
Figure 9.6: Compound II.12.. ........................................................................................... 96
Figure 9.7: Compound II.13.. ........................................................................................... 97
Figure 9.8: Compound II.14.. ........................................................................................... 97
Figure 9.9: Compound II.15a.. ......................................................................................... 98
Figure 9.10: Compound II.15b.. ....................................................................................... 99
Figure 9.11: Compound II.16.. ....................................................................................... 100
Figure 9.12: Compound II.7.. ......................................................................................... 101
Figure 9.13: Compound II.7a.. ....................................................................................... 102
Figure 9.14: Compound II.17.. ....................................................................................... 103

xiv

Figure 9.15: Compound II.6.. ......................................................................................... 104
Figure 9.16: Compound II.18.. ....................................................................................... 105
Figure 9.17: Compound II.19.. ....................................................................................... 106
Figure 9.18: Compound II.20a.. ..................................................................................... 107
Figure 9.19: Compound II.21a.. ..................................................................................... 108
Figure 9.20: Compound II.21.. ....................................................................................... 109
Figure 9.21: Compound II.22.. ....................................................................................... 109
Figure 9.22: Compound III.2a........................................................................................ 110
Figure 9.23: Compound III.2b.. ..................................................................................... 111
Figure 9.24: Compound III.2.......................................................................................... 112
Figure 9.25: Compound III.3.......................................................................................... 113
Figure 9.26: Compound III.4a........................................................................................ 113
Figure 9.27: Compound III.4.......................................................................................... 114
Figure 9.28: Compound III.5.......................................................................................... 115
Figure 9.29: Compound III.6a........................................................................................ 116
Figure 9.30: Compound III.6.......................................................................................... 117
Figure 9.31: Compound III.7a........................................................................................ 118
Figure 9.32: Compound III.8.......................................................................................... 118
Figure 9.33: Compound III.9.......................................................................................... 119
Figure 9.34: Compound III.10........................................................................................ 120
Figure 9.35: Compound III.11a...................................................................................... 121
Figure 9.36: Compound III.11........................................................................................ 122
Figure 9.37: Compound III.12a...................................................................................... 123
Figure 9.38: Compound III.12........................................................................................ 126
Figure 9.39: Compound III.13a...................................................................................... 127

xv

Figure 9.40: Compound III.13........................................................................................ 128
Figure 9.41: Compound III.14........................................................................................ 129
Figure 9.42: Compound III.15........................................................................................ 130
Figure 9.43: Compound III.16........................................................................................ 132
Figure 9.44: Compound III.17........................................................................................ 133
Figure 9.45: Compound III.18........................................................................................ 134
Figure 9.46: N-Boc-Homo-L-proline.. ............................................................................ 135
Figure 9.47: Compound II.4.. ......................................................................................... 136
Figure 9.48: Compound II.4.. ......................................................................................... 137
Figure 9.49: Compound II.4.. ......................................................................................... 137
Figure 9.50: Compound IV.1a.. ...................................................................................... 138
Figure 9.51: Compound IV.1.. ........................................................................................ 139
Figure 9.52: Compound IV.2.. ........................................................................................ 140
Figure 9.53: Compound IV.3a.. ...................................................................................... 142
Figure 9.54: Compound IV.3.. ........................................................................................ 143
Figure 9.55: Compound IV.4.. ........................................................................................ 144
Figure 9.56: Compound IV.5.. ........................................................................................ 145
Figure 9.57: Compound IV.6.. ........................................................................................ 146
Figure 9.58: Compound IV.7.. ........................................................................................ 147
Figure 9.59: Compound IV.7a.. ...................................................................................... 147
Figure 9.60: Compound IV.8.. ........................................................................................ 148
Figure 9.61: Compound IV.9.. ........................................................................................ 149
Figure 9.62: Compound V.1.. ......................................................................................... 150
Figure 9.63: Compound V.1a.. ....................................................................................... 151
Figure 9.64: Compound V.2.. ......................................................................................... 151

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Figure 9.65: Compound V.3.. ......................................................................................... 152
Figure 9.66: Compound V.4.. ......................................................................................... 153
Figure 9.67: Compound V.5a.. ....................................................................................... 154
Figure 9.68: Compound V.5.. ......................................................................................... 155
Figure 9.69: Compound V.6.. ......................................................................................... 156
Figure 9.70: Compound V.7.. ......................................................................................... 157
Figure 9.71: Compound V.9.. ......................................................................................... 157
Figure 9.72: Compound V.10a.. ..................................................................................... 158
Figure 9.73: Compound V.10.. ....................................................................................... 159
Figure 9.74: Compound VI.1.. ........................................................................................ 160
Figure 9.75: Compound VI.2.. ........................................................................................ 161
Figure 9.76: Compound VI.3a.. ...................................................................................... 162
Figure 9.77: Compound VI.3.. ........................................................................................ 163
Figure 9.78: Compound VI.4a.. ...................................................................................... 164
Figure 9.79: Compound VI.4b........................................................................................ 165
Figure 9.80: Compound VI.4c.. ...................................................................................... 166
Figure 9.81: Compound VI.4.. ........................................................................................ 167
Figure 9.82: Compound VI.5.. ........................................................................................ 168
Figure 9.83: Compound VI.6.. ........................................................................................ 168
Figure 9.84: Compound VI.7a.. ...................................................................................... 172
Figure 9.85: Compound VI.7.. ........................................................................................ 172
Figure 9.86: Compound VI.10a.. .................................................................................... 173
Figure 9.87: Compound VI.10.. ...................................................................................... 174
Figure 9.88: 2,2,2-trichloroethyl-(chloro(methylthio)methylene)sulfamate.. ................ 175
Figure 9.89: Compound VI.9.. ........................................................................................ 177

xvii

Figure 9.90: Compound VI.11.. ...................................................................................... 177
Figure 9.91: Compound VII.1a.. .................................................................................... 178
Figure 9.92: Compound VII.1.. ...................................................................................... 179
Figure 9.93: Compound VII.2a.. .................................................................................... 180
Figure 9.94: Compound VII.2.. ...................................................................................... 181
Figure 9.95: Compound VII.3a.. .................................................................................... 182
Figure 9.96: Compound VII.3.. ...................................................................................... 183
Figure 9.97: Compound VII.4a.. .................................................................................... 184
Figure 9.98: Compound VII.4.. ...................................................................................... 185
Figure 9.99: Compound VII.5 ........................................................................................ 186
Figure 9.100: Compound VII.6a.. .................................................................................. 187
Figure 9.101: Compound VII.6.. .................................................................................... 188
Figure 9.102: Compound VII.7a.. .................................................................................. 189
Figure 9.103: Compound VII.7.. .................................................................................... 190
Figure 9.104: Compound VII.8a.. .................................................................................. 190
Figure 9.105: Compound VII.8.. .................................................................................... 191
Figure 9.106: Compound VII.9.. .................................................................................... 192
Figure 9.107: Compound VII.10a.. ................................................................................ 193
Figure 9.108: Compound VII.10.. .................................................................................. 194
Figure 9.109: Compound VII.11a.. ................................................................................ 195
Figure 9.110: Compound VII.11.. .................................................................................. 196
Figure 9.111: Compound VII.12a.. ................................................................................ 197
Figure 9.112: Compound VII.12.. .................................................................................. 198
Figure 9.113: Compound VII.13.. .................................................................................. 199
Figure 9.114: Compound VII.14a.. ................................................................................ 200

xviii

Figure 9.115: Compound VII.14.. .................................................................................. 201
Figure 9.116: Compound VII.15.. .................................................................................. 202
Figure 9.117: Compound VII.16a. ................................................................................. 203
Figure 9.118: Compound VII.16. ................................................................................... 204
Figure 9.119: Compound VII.17.. .................................................................................. 204
Figure 9.120: Compound VII.18.. .................................................................................. 205
Figure 9.121: Compound VII.19.. .................................................................................. 206
Figure 9.122: Compound VII.20 .................................................................................... 207
Figure 9.123: Compound VII.21.. .................................................................................. 208
Figure 9.124: Compound VII.21.. .................................................................................. 209
Figure 9.125: Compound VII.22a.. ................................................................................ 210
Figure 9.126: Compound VII.22b.. ................................................................................ 211
Figure 9.127: Compound VII.22.. .................................................................................. 212
Figure 9.128: Compound VII.23.. .................................................................................. 213
Figure 9.129: Compound VII.24a.. ................................................................................ 214
Figure 9.130: Compound VII.24.. .................................................................................. 215
Figure 9.131: Compound VII.25.. .................................................................................. 216
Figure 9.132: Compound VIII.1a.. ................................................................................. 217
Figure 9.133: Compound VIII.1.. ................................................................................... 219
Figure 9.134: Compound VIII.2.. ................................................................................... 220
Figure 9.135: Compound VIII.3a.. ................................................................................. 221
Figure 9.136: Compound VIII.3.. ................................................................................... 222
Figure 9.137: Compound VIII.4.. ................................................................................... 223
Figure 9.138: Compound VIII.5.. ................................................................................... 226
Figure 9.139: Compound VIII.6. .................................................................................... 227

xix

Figure 9.140: Compound VIII.7a.. ................................................................................. 228
Figure 9.141: Compound VIII.7.. ................................................................................... 229
Figure 9.142: Compound VIII.8a.. ................................................................................. 230
Figure 9.143: Compound VIII.8.. ................................................................................... 231
Figure 9.144: Compound VIII.9.. ................................................................................... 232
Figure 10.1: 1H and 13C Spectra of Compound II.4.. ..................................................... 235
Figure 10.2: 1H and 13C Spectra of Compound II.5a.. ................................................... 236
Figure 10.3: 1H and 13C Spectra of Compound II.5b.. ................................................... 237
Figure 10.4: gCOSY Spectra of Compound II.5b... ....................................................... 238
Figure 10.5: gHMQC Spectra of Compound II.5b. ....................................................... 239
Figure 10.6: 1H and 13C Spectra of Compound II.5.. ..................................................... 240
Figure 10.7: 1H and 13C Spectra of Compound II.11.. ................................................... 241
Figure 10.8: 1H and 13C Spectra of Compound II.12.. ................................................... 242
Figure 10.9: 1H and 13C Spectra of Compound II.13.. ................................................... 243
Figure 10.10: 1H and 13C Spectra of Compound II.14.. ................................................. 244
Figure 10.11: 1H and 13C Spectra of Compound II.15a. ................................................ 245
Figure 10.12: 1H and 13C Spectra of Compound II.15b.. ............................................... 246
Figure 10.13: 1H and 13C Spectra of Compound II.16.. ................................................. 247
Figure 10.14: 1H and 13C Spectra of Compound II.7.. ................................................... 248
Figure 10.15: 1H and 13C Spectra of Compound II.7a.. ................................................. 249
Figure 10.16: 1H and 13C Spectra of Compound II.17a.. ............................................... 250
Figure 10.17: 1H and 13C Spectra of Compound II.6.. ................................................... 251
Figure 10.18: 1H and 13C Spectra of Compound II.18.. ................................................. 252
Figure 10.19: 1H and 13C Spectra of Compound II.19.. ................................................. 253
Figure 10.20: 1H and 13C Spectra of Compound II.20a.. ............................................... 254

xx

Figure 10.21: 1H and 13C Spectra of Compound II.21a.. ............................................... 255
Figure 10.22: 1H and 13C Spectra of Compound II.21.. ................................................. 256
Figure 10.23: 1H and 13C Spectra of Compound II.22.. ................................................. 257
Figure 10.24: 1H and 13C Spectra of Compound III.2a.. ................................................ 258
Figure 10.25: 1H and 13C Spectra of Compound III.2b.. ................................................ 259
Figure 10.26: 1H and 13C Spectra of Compound III.2.. .................................................. 260
Figure 10.27: 1H and 13C Spectra of Compound III.3.. .................................................. 261
Figure 10.28: gCOSY Spectra of Compound III.3......................................................... 262
Figure 10.29: gHMQC Spectra of Compound III.3 ....................................................... 263
Figure 10.30: 1H and 13C Spectra of Compound III.4a.. ................................................ 264
Figure 10.31: 1H and 13C Spectra of Compound III.4.. .................................................. 265
Figure 10.32: gCOSY Spectra of Compound III.4......................................................... 266
Figure 10.33: gHMQC Spectra of Compound III.4 ....................................................... 267
Figure 10.34: 1H and 13C Spectra of Compound III.5.. .................................................. 268
Figure 10.35: 1H and 13C Spectra of Compound III.6a. ................................................. 269
Figure 10.36: 1H and 13C Spectra of Compound III.6.. .................................................. 270
Figure 10.37: gCOSY Spectra of Compound III.6 ........................................................ 271
Figure 10.38: gHMQC Spectra of Compound III.6 ....................................................... 272
Figure 10.39: 1H and 13C Spectra of Compound III.7a. ................................................. 273
Figure 10.40: 1H and 13C Spectra of Compound III.7.. .................................................. 274
Figure 10.41: 1H and 13C Spectra of Compound III.8.. .................................................. 275
Figure 10.42: 1H and 13C Spectra of Compound III.9.. .................................................. 276
Figure 10.43: 1H and 13C Spectra of Compound III.10.. ................................................ 277
Figure 10.44: 1H and 13C Spectra of Compound III.11a.. .............................................. 278
Figure 10.45: 1H and 13C Spectra of Compound III.11.. ................................................ 279

xxi

Figure 10.46: gCOSY Spectra of Compound III.11....................................................... 280
Figure 10.47: gHMQC Spectra of Compound III.11 ..................................................... 281
Figure 10.48: 1H and 13C Spectra of Compound III.12a.. .............................................. 282
Figure 10.49: 1H and 13C Spectra of Compound III.12.. ................................................ 283
Figure 10.50: 1H and 13C Spectra of Compound III.13a.. .............................................. 284
Figure 10.51: 1H and 13C Spectra of Compound III.13.. ................................................ 285
Figure 10.52: 1H and 13C Spectra of Compound III.14.. ................................................ 286
Figure 10.53: 1H and 13C Spectra of Compound III.15.. ................................................ 287
Figure 10.54: 1H and 13C Spectra of Compound III.16.. ................................................ 288
Figure 10.55: 1H and 13C Spectra of Compound III.17.. ................................................ 289
Figure 10.56: 1H and 13C Spectra of Compound III.18.. ................................................ 290
Figure 10.57: 1H and 13C Spectra of N-Boc-Homo-L-proline.. ...................................... 291
Figure 10.58: 1H and 13C Spectra of Compound IV.1a.. ................................................ 292
Figure 10.59: 1H and 13C Spectra of Compound IV.1.. .................................................. 293
Figure 10.60: 1H and 13C Spectra of Compound IV.2.. .................................................. 294
Figure 10.61: gCOSY Spectra of Compound IV.2 ......................................................... 295
Figure 10.62: gHMQC Spectra of Compound IV.2 ....................................................... 296
Figure 10.63: 1H and 13C Spectra of Compound IV.3a.. ................................................ 297
Figure 10.64: 1H and 13C Spectra of Compound IV.3.. .................................................. 298
Figure 10.65: gHMQC Spectra of Compound IV.3.. ..................................................... 299
Figure 10.66: 1H and 13C Spectra of Compound IV.4.. .................................................. 300
Figure 10.67: 1H and 13C Spectra of Compound IV.5.. .................................................. 301
Figure 10.68: 1H and 13C Spectra of Compound IV.6. ................................................... 302
Figure 10.69: 1H and 13C Spectra of Compound IV.7.. .................................................. 303
Figure 10.70: 1H and 13C Spectra of Compound IV.7a.. ................................................ 304

xxii

Figure 10.71: 1H and 13C Spectra of Compound IV.8.. .................................................. 305
Figure 10.72: 1H and 13C Spectra of Compound IV.9.. .................................................. 306
Figure 10.73: gCOSY Spectra of Compound IV.9 ......................................................... 307
Figure 10.74: gHMQC Spectra of Compound IV.9.. ..................................................... 308
Figure 10.75: 1H and 13C Spectra of Compound V.1.. .................................................... 309
Figure 10.76: 1H and 13C Spectra of Compound V.1a.. .................................................. 310
Figure 10.77: 1H and 13C Spectra of Compound V.2.. .................................................... 311
Figure 10.78: 1H and 13C Spectra of Compound V.3.. .................................................... 312
Figure 10.79: gHMQC Spectra of Compound V.3 ......................................................... 313
Figure 10.80: 1H and 13C Spectra of Compound V.4.. .................................................... 314
Figure 10.81: 1H and 13C Spectra of Compound V.5a.. .................................................. 315
Figure 10.82: 1H and 13C Spectra of Compound V.5.. .................................................... 316
Figure 10.83: 1H and 13C Spectra of Compound V.6.. .................................................... 317
Figure 10.84: 1H and 13C Spectra of Compound V.7. ..................................................... 318
Figure 10.85: 1H and 13C Spectra of Compound V.9 ...................................................... 319
Figure 10.86: 1H and 13C Spectra of Compound V.10a.. ................................................ 320
Figure 10.87: 1H and 13C Spectra of Compound V.10.. .................................................. 321
Figure 10.88: 1H and 13C Spectra of Compound VI.1.. .................................................. 322
Figure 10.89: 1H and 13C Spectra of Compound VI.2.. .................................................. 323
Figure 10.90: gHMQC Spectra of Compound VI.2. ...................................................... 324
Figure 10.91: 1H and 13C Spectra of Compound VI.3a.. ................................................ 325
Figure 10.92: 1H and 13C Spectra of Compound VI.3.. .................................................. 326
Figure 10.93: gHMQC Spectra of Compound VI.3. ...................................................... 327
Figure 10.94: 1H and 13C Spectra of Compound VI.4a.. ................................................ 328
Figure 10.95: 1H and 13C Spectra of Compound VI.4b.. ................................................ 329

xxiii

Figure 10.96: 1H and 13C Spectra of Compound VI.4c.. ................................................ 330
Figure 10.97: 1H and 13C Spectra of Compound VI.4. ................................................... 331
Figure 10.98: 1H and 13C Spectra of Compound VI.5.. .................................................. 332
Figure 10.99: 1H and 13C Spectra of Compound VI.6.. .................................................. 333
Figure 10.100: 1H and 13C Spectra of Compound VI.7a. ............................................... 334
Figure 10.101: 1H and 13C Spectra of Compound VI.7.. ................................................ 335
Figure 10.102: 1H and 13C Spectra of Compound VI.10a. ............................................. 336
Figure 10.103: 1H and 13C Spectra of Compound VI.10.. .............................................. 337
Figure 10.104: 1H and 13C Spectra of Compound of 2,2,2-trichloroethyl(chloro(methylthio)methylene)sulfamate.. ..................................................................... 338
Figure 10.105: 1H and 13C Spectra of Compound VI.9.. ................................................ 339
Figure 10.106: 1H and 13C Spectra of Compound VI.11.. .............................................. 340
Figure 10.107: gHMQC Spectra of Compound VI.11.. ................................................. 341
Figure 10.108: 1H and 13C Spectra of Compound VII.1a............................................... 342
Figure 10.109: 1H and 13C Spectra of Compound VII.1................................................. 343
Figure 10.110: 1H and 13C Spectra of Compound VII.2a............................................... 344
Figure 10.111: 1H and 13C Spectra of Compound VII.2................................................. 345
Figure 10.112: gCOSY Spectra of Compound VII.2.. ................................................... 346
Figure 10.113: gHMQC Spectra of Compound VII.2.. .................................................. 347
Figure 10.114: 1H and 13C Spectra of Compound VII.3a............................................... 348
Figure 10.115: 1H and 13C Spectra of Compound VII.3................................................. 349
Figure 10.116: 1H and 13C Spectra of Compound VII.4a............................................... 350
Figure 10.117: 1H and 13C Spectra of Compound VII.4................................................. 351
Figure 10.118: 1H and 13C Spectra of Compound VII.5................................................. 352
Figure 10.119: gCOSY Spectra of Compound VII.5. .................................................... 353
Figure 10.120: gHMQC Spectra of Compound VII.5.. .................................................. 354
xxiv

Figure 10.121: 1H and 13C Spectra of Compound VII.6a............................................... 355
Figure 10.122: 1H and 13C Spectra of Compound VII.6................................................. 356
Figure 10.123: gHMQC Spectra of Compound VII.6.. .................................................. 357
Figure 10.124: 1H and 13C Spectra of Compound VII.7a............................................... 358
Figure 10.125: 1H and 13C Spectra of Compound VII.7................................................. 359
Figure 10.126: gCOSY Spectra of Compound VII.7 ..................................................... 360
Figure 10.127: 1H and 13C Spectra of Compound VII.8a............................................... 361
Figure 10.128: 1H and 13C Spectra of Compound VII.8................................................. 362
Figure 10.129: gCOSY Spectra of Compound VII.8. .................................................... 363
Figure 10.130: gHMQC Spectra of Compound VII.8 .................................................... 364
Figure 10.131: 1H and 13C Spectra of Compound VII.9................................................. 365
Figure 10.132: gCOSY Spectra of Compound VII.9.. ................................................... 366
Figure 10.133: gHMQC Spectra of Compound VII.9.. .................................................. 367
Figure 10.134: 1H and 13C Spectra of Compound VII.10a............................................. 368
Figure 10.135: 1H and 13C Spectra of Compound VII.10............................................... 369
Figure 10.136: 1H and 13C Spectra of Compound VII.11a............................................. 370
Figure 10.137: 1H and 13C Spectra of Compound VII.11............................................... 371
Figure 10.138: 1H and 13C Spectra of Compound VII.12a............................................. 372
Figure 10.139: 1H and 13C Spectra of Compound VII.12............................................... 373
Figure 10.140: 1H and 13C Spectra of Compound VII.13............................................... 374
Figure 10.141: 1H and 13C Spectra of Compound VII.14a............................................. 375
Figure 10.142: 1H and 13C Spectra of Compound VII.14............................................... 376
Figure 10.143: 1H and 13C Spectra of Compound VII.15............................................... 377
Figure 10.144: 1H and 13C Spectra of Compound VII.16a............................................. 378
Figure 10.145: 1H and 13C Spectra of Compound VII.16............................................... 379

xxv

Figure 10.146: 1H and 13C Spectra of Compound VII.17............................................... 380
Figure 10.147: 1H and 13C Spectra of Compound VII.18............................................... 384
Figure 10.148: gCOSY Spectra of Compound VII.18. .................................................. 382
Figure 10.149: gHMQC Spectra of Compound VII.18... ............................................... 383
Figure 10.150: 1H and 13C Spectra of Compound VII.19............................................... 384
Figure 10.151: 1H and 13C Spectra of Compound VII.20............................................... 385
Figure 10.152: 1H and 13C Spectra of Compound VII.21............................................... 386
Figure 10.153: 1H and 13C Spectra of Compound VII.22a............................................. 387
Figure 10.154: 1H and 13C Spectra of Compound VII.22b.. .......................................... 388
Figure 10.155: 1H and 13C Spectra of Compound VII.22............................................... 389
Figure 10.156: gCOSY Spectra of Compound VII.22.. ................................................. 390
Figure 10.157: gHMQC Spectra of Compound VII.22.. ................................................ 391
Figure 10.158: 1H and 13C Spectra of Compound VII.23............................................... 392
Figure 10.159: 1H and 13C Spectra of Compound VII.24a............................................. 393
Figure 10.160: 1H and 13C Spectra of Compound VII.24............................................... 394
Figure 10.161: 1H and 13C Spectra of Compound VII.25............................................... 395
Figure 10.162: 1H and 13C Spectra of Compound VIII.1a.. ........................................... 396
Figure 10.163: 1H and 13C Spectra of Compound VIII.1.. ............................................. 397
Figure 10.164: 1H and 13C Spectra of Compound VIII.2.. ............................................. 398
Figure 10.165: 1H and 13C Spectra of Compound VIII.3a.. ........................................... 399
Figure 10.166: 1H and 13C Spectra of Compound VIII.3.. ............................................. 400
Figure 10.167: 1H and 13C Spectra of Compound VIII.4.. ............................................. 401
Figure 10.168: 1H and 13C Spectra of Compound VIII.5.. ............................................. 402
Figure 10.169: gHMQC Spectra of Compound VIII.5. ................................................. 403
Figure 10.170: 1H and 13C Spectra of Compound VIII.6. .............................................. 404

xxvi

Figure 10.171: 1H and 13C Spectra of Compound VIII.7a.. ........................................... 405
Figure 10.172: 1H and 13C Spectra of Compound VIII.7.. ............................................. 406
Figure 10.173: 1H and 13C Spectra of Compound VIII.8a.. ........................................... 407
Figure 10.174: 1H and 13C Spectra of Compound VIII.8.. ............................................. 408
Figure 10.175: 1H and 13C Spectra of Compound VIII.9.. ............................................. 409
Figure 10.176: gHMQC Spectra of Compound VIII.9.. ................................................ 410
Figure 10.177: 19F Spectra of Compound VIII.9.. ......................................................... 411

xxvii

KEY TO ABBREVIATIONS

Asp

Aspartic acid

Boc

Tert-butoxycarbonyl

BHT

2,6-ditertbutyl hydroxytoluene

Bz

Benzyl

Cbz

Carbamoylbenzyloxy

DEAD

Diethylazodicarboxylate

DfsNH2

2,6-difluorophenyl sulfamate

IC50

Inhibition constant of 50 %

KIE

Kinetic isotope effect

Mbs

Methoxybenzenesulfonyl

NMR

Nuclear magnetic resonance

OAc

Acetate

Ph

Phenyl

PIA

Pyrrole-imidazole alkaloid

Rh2(esp)2

Bis[rhodium(α,α,α’,α’-tetramethyl-1,3
benzenedipropionic acid]

SAR

Structure activity relationship

TBAF

Tetra-N-butyl ammonium fluoride

TBDMS

Tert-butyl dimethyl silyl

TBDPS

Tert-butyl diphenyl silyl

Tces

Trichloroethoxysulfonyl

TEA

Triethylamine

TEMPO

(2,2,6,6-Tetramethyl-piperidin-1-yl)oxyl

TFA

Trifluoroacetic acid

Ts

Tosyl

xxviii

Chapter 1: Introduction
Multiple myeloma (MM) is a cancer of differentiated B-cells that is treated with
competitive inhibitors of the proteasome.1 Inhibiting the proteolytic activity of the proteasome in
turn inhibits the action of signal transduction molecules necessary for tumorigenesis (NF-κB,
TNF-α, IL-6 and others), effectively interrupting the cancer cycle and treating the disease.2 All
currently approved proteasome inhibitors, BortezomibTM and KyprolisTM, and those in
Figure 1.1: Bortezomib and Kyprolis, Clinically Approved Proteasome Inhibitors

development act through a competitive mechanism.3 They directly bind the three primary active
sites in the proteasome, occluding any interaction between enzyme and substrate (a protein
targeted for degradation).4 While initially effective at treating MM, nearly all patients (~97 %)
treated with approved proteasome inhibitors for MM relapse and develop resistance to treatment,
after which the mean time of survival is less than 1 year.5 This highlights the need not merely for
new inhibitors of the proteasome to treat MM, but inhibitors that work through new mechanisms.
Prior art developed in the Tepe research group led to the discovery of an imidazoline scaffold,
TCH-013,6 that has been shown to inhibit the activity of the proteasome through a
noncompetitive pathway, providing the first example of a small molecule to act through such a
mechanism. Additionally, the Tepe group synthesized several natural products containing similar
structural motifs, among them dibromophakellin and dibromophakellstatin,7 for evaluation as

1

proteasome inhibitors. This was a successful endeavor on multiple fronts. It led to the
Figure 1.2: Dibromophakellin, Dibromophakellstatin, Nagelamide M and Indolophakellin

development of a new method for adding protected guanidines to double bonds in addition to
providing the target molecules in sufficient quantity for biological evaluation. As expected,
dibromophakellin and dibromophakellstatin were active against the proteasome (IC50 = 11.9 µM
and 25.3 µM, respectively8), in comparable levels of activity to the imidazolines of the TCH
series (IC50 = ~200 nM to ~2 µM5,6). A crystal structure of an indole analog of dibromophakellin
was obtained in which it was bound to a different domain than BortezomibTM. The indolophakellin pictured in Figure 3 is the first example of a noncovalently binding inhibitor of the
proteasome that binds to the S3 site exclusively. This discovery constitutes a new mechanism of
proteasome inhibition, and opens the door to the development of an entirely new class of
structures for drug design.8

2

Figure 1.3: Crystal Structure of Indolophakellin and Overlay of the Core of Nagelamide M

Overlaying the core of one such structure, the Pyrrole-Imidazole Alkaloid (“PIA”)
nagelamide M,9 on to this crystal structure in silico reveals the potential to recapture all the
established binding interactions and potentially add one with Asp 126. These features, in
addition to the potential for methodology development and a first total synthesis, have attracted
our interest and prompted our attempt at a total synthesis of this molecule.

3

Figure 1.4: C-H Activation in the Synthesis of PIA’s of the Orodin Family

Considering the high degree of heteroatom substitution in the target natural product and
the success of the C-H activation chemistry in the synthesis of related molecules and natural
products of the orodin family12 (Figure 4), this method seemed an ideal place to start. At the
onset of these studies (to the present), no examples of C-H amination with a methylene carbon
adjacent to a heteroatom (nitrogen or oxygen) to form a [5.5] membered ring had been reported.
While this is a very precise example to seek, it is a prevalent motif in this family of natural
products and achieving this transformation could provide alternative routes to other complex
members the family of orodin derived PIA’s.13

4

From the perspective of methodology development, this problem is another manifestation
of the elusive 1,2 vicinal diamination, which still poses significant challenges (Figure 5).14-21 The
current state of the art typically involves the oxidation of an alkene in the presence of a suitable
Figure 1.5: The 1,2 Vicinal Diamination of Alkenes and Current Limits

nitrogen source. Such an approach to nagelamide M would be less than ideal for several reasons.
In addition to the lack of literature precedent, 2,3-dihydro-1H-pyrroles are known to aromatize to
pyrroles under oxidative conditions.22,23 The intramolecular diamination of alkenes is more
developed than the intermolecular approach,21 but again such an approach to nagelamide M
would have several undesirable aspects. The issue of oxidative lability of 2,3-dihydro-1Hpyrroles could be exacerbated by adding a nitrogen at the 3-position, making synthesis and
handling of such a precursor likely to be. If these obstacles were overcome the oxidation event,
in the absence of asymmetric induction, would yield racemic products. While such a
transformation may ultimately be possible, it is less desirable than substrate-induced asymmetry,
which could be built in from the chiral pool.
These combined challenges reinforced the attractiveness of using a C-H bond as the
oxidative substrate, as highlighted in Figure 6. In this case, the small size of the [5.5] ring system

5

being formed would require the cis fused product form exclusively,46 and the stereochemistry
could be established in the cyclization substrate. This particular problem has been an active area
of research; in fact C-H activation is the only avenue currently available to access these
structures. Solving this problem is significant because success would constitute an expansion of a
prominent methodology, adding to the overall goal of synthesis by selective C-H oxidation, and
Figure 1.6: The Proposed Use of C-H Amination To Access the Core of Nagelamide M

because it would provide rapid access to the core of nagelamide M and analogs that are expected
to bind to a novel site in the proteasome.

6

Chapter 2: Studies on the Total Synthesis of Nagelamide M and Analogs
A retrosynthetic analysis of nagelamide M is presented in Figure 2.1, with the main
challenges in this synthesis involving two oxidations, each highlighted in compounds II.1 and
2.2. More generally the problem could be formulated as the oxidative guanidinylation of a 3hydroxyproline, but a one-step method for such a transformation on saturated compounds is not
known.
The first key disconnection of the first step is the C-H amination of a methylene C-H
bond α to a nitrogen atom. The only guiding example of such a transformation described in the
literature involves an N-tosylated piperidine undergoing an intramolecular α-amination to form a
[5.5] bicycle.24 This example (Figure 2.1 and 2.17) is significant because it shows such a
transformation is possible, and with the work presented herein will provide an account of the
challenges encountered in attempting to expand this methodology.

7

Figure 2.1: Retrosynthesis of the Pyrrole-Imidazole Alkaloid Nagelamide M

The oxaziridine moiety shown in compound II.2 could be formed by the oxidation of an
imine or the amination of a ketone, both of which are established transformations in the
literature.25,26
The bromopyrrole amide could be synthesized by condensing the amine II.2 and 4,5dibromo-1H-pyrrole-2-carboxylic acid.27 Methodology has been developed by the Du Bois group
for transforming an amine into an appropriately functionalized guanidine capable of undergoing
C-H amination reactions.28 As the stereochemistry established at this point will define the
stereochemistry of the guanidine moiety, the ultimate choice of which path is used would depend
on optimization studies that remain to be conducted. Conjugate addition of a vinyl sulfone at the

8

Figure 2.2: The Synthetic Versatility of trans-4-Hydroxy-L-Proline

proline nitrogen would install the appropriate precursor alkyl chloride for the ethanesulfonate
side chain. Aminoproline II.3 (Figure 2.1) would be synthesized from the commercially
available and inexpensive trans-4-hydroxy-L-proline. To explore all these possibilities, the
substrates shown in the Figure 2.2 were each synthesized on a multi-gram scale to test their
potential utility in the total synthesis of nagelamide M.
Synthesis of the Oxaziridine: Studies on the Oxidation of Imines and Amination of Ketones
While it is possible to synthesize N,O-acetals (such as the one desired for nagelamide M)
by C-H amination of an ether, other methods are available and were investigated. The oxidation
of imines by peracids29 (and other oxidants30) is well known and explored for its potential utility.

9

Figure 2.3: Attempted Oxaziridine Synthesis on Keto-Ester II.4

The keto-ester II.4 was synthesized according to a known literature procedure, and first
combined with benzylamine in DCM and sodium sulfate. Analysis of the crude reaction mixture
revealed no imine formation, only decomposition of starting material (Figure 2.3). It was thought
that having the carboxylate carbon in the correct oxidation state before synthesis of the
Figure 2.4: Synthesis and Attempted Oxidation of Prolinyl Ketone II.7

oxaziridine would be beneficial, as conditions capable of reducing the carboxylate would likely
also reduce the oxaziridine (which may or may not be desirable). To this end, II.5 was
synthesized and subjected to the same conditions as II.4. Unfortunately, typical dehydrating
conditions did not result in formation of the imine. The substrates themselves require mild
conditions for imine formation, leaving little room for optimization. Acid catalysis could cause
competitive enolate chemistry in both cases, and II.5 could undergo N-deprotection.

10

Consequently, this approach was abandoned to investigate the amination of ketones.
The electrophilic amination of ketones is also a known though lesser used method to
prepare oxaziridines and is postulated to operate through an addition-elimination mechanism.26
This transformation is attractive because it would leave the oxaziridine nitrogen open for
functionalization with the guanidine precursor (compound II.2, Figure 2.1). The reaction was
attempted with both of the ketones above with hydroxylamine-O-sulfonic acid, unfortunately
with no success.
Figure 2.5: Attempted Oxaziridination of Prolinyl Ketones II.4 and II.5

Again, the sensitivity of the substrates and the poor solubility of hydroxylamine-O-sulfonic acid
limited the possibilities for optimization.
While these failures were a disappointment, they did effectively eliminate all other
substrates for the oxidative synthesis of these targets apart from the C-H bond, the current state
of the art of which is discussed below.
The C-H Amination Reaction in Total Synthesis
The selective oxidation of carbon-hydrogen bonds is one of the preeminent challenges of
modern synthetic chemistry.30,31 If realized in its ideal state, such a technology would add to the
synthetic chemists repertoire of retrosynthetic motifs any desired C-H bond, constituting an
advance with the potential to revolutionize organic chemistry.
The most obvious embodiment of this revolution would be the simplification and/or
shortening of the syntheses of heteroatom containing molecules of academic or commercial

11

interest. To create a picture of the current state of the art and how this work endeavors to add to
it, some highlights from this growing body of work are discussed below.
While not an PIA, proof of this concept, the selective and sequential oxidation of C-H
bonds to synthesize a complex natural product, is provided by the Baran group in their progress
towards the natural product Taxol.33,36 Originally discovered in 1971, and the target of multiple
total syntheses,34,35 this molecule of interest to the academic community as well as industry
(currently sold as Paclitaxel for the treatment of breast cancer). Currently it is only available
through semisynthesis, in which an advanced intermediate is synthesized in genetically
engineered organisms and isolated for further chemical manipulation.36 The Baran group is
currently engaged in efforts to make the large scale chemical synthesis of Taxol a reality by
employing a sequence of C-H activations to oxidize the starting material (+)-taxadiene to the
intermediate (-)-taxuyunnanine D (shown in Figure 2.6).33 The purpose of this endeavor is not to
replace the semisynthesis as the source of Taxol for the pharmaceutical industry, but to discover
a synthetic route that will produce enough material for medicinal chemistry to develop and
optimize the SAR of Taxol.
The natural products en route to the natural product are classified by number of
oxidations relative to (+)-taxadiene, with Taxol itself being a level 11 taxane (9 C-H oxidations
and 2 double bond installations). Over 100 level 11 taxanes have been discovered with unknown
pharmacological potential.36 Successfully completing this synthesis would in principle grant
access to those compounds. Impressively, by pairing the relative order of C-H bond reactivity
with an oxidizing agent of the appropriate strength, they achieve completely regio- and
stereoselective transformations of the target.

12

Figure 2.6: The C-H Oxidation Route to Taxol

In an example closer to nagelamide M, several of the PIA’s in Figure 4 feature the
selective activation of a C-H bond on an advanced intermediate37 which install heteroatoms that
would be difficult or impossible to otherwise install. The utility of this transformation is
highlighted in Figure 2.7 in the landmark total synthesis of palau’amine.38

13

Figure 2.7: The C-H Oxidation to Install a Key Hydroxyl Group in Palau’amine

The Baran group employed the C-H oxidation highlighted in blue at a late stage on a highly
functionalized intermediate; this approach was devised after previous routes involving earlier
introduction of the indicated hydroxyl group stalled intractably.38
The key C-N bond formation in the total synthesis of cylindridine A39 was accomplished
via C-H amination of a tertiary C-H bond (Figure 2.8). This result is of particular interest as the
total synthesis of this molecule was attempted in our laboratory as well.40 The crucial C-N bond
formation achieved with this methodology was resistant to a large variety of more conventional
amination conditions.
Figure 2.8: C-H Amination to Install a Cyclic Guanidine in Cylindridine A

The Du Bois group developed C-H amination technology shown in Figure 2.9 that
enabled the first enantioselective total synthesis of the natural product saxitoxin,41,42 (which was
recently reviewed)43 approximately fifty years after it was first isolated in 195744 (and
14

structurally characterized in 197545,47). Prior to this it had only been synthesized twice (both
times as the racemate) by the Kishi group48-50 and the Jacobi group.51,52
Tetrodotoxin, the famous Japanese fugu poison, had only been successfully synthesized
twice before this route was discovered: originally racemic by Kishi53 in 1972 and more recently
an enantioselective route was disclosed by the the Isobe54 group. In a comparison of the
Figure 2.9: Du Bois Total Syntheses of (-)-Tetrodotoxin and (+)-Saxitoxin

enantioselective versions the C-H amination route employed by Du Bois is much shorter (66
steps in Isobe versus 28 in Du Bois), highlighting the power of this technique to improve organic
synthesis.
As these examples show, the utility of C-H activation in the synthetic manipulation of the
guanidine and urea motifs, either directly46 or with other precursors (carbamates46 or
sulfamates41) made this area of research an attractive means through which to synthesize many of
the molecules of interest to the Tepe Research Group.
Expanding the Substrate Scope of Rhodium Catalyzed C-H Amination
At the outset of these studies, several examples of metal catalyzed C-H activations
15

(aminations and oxidations) had recently been reported. This subject has been recently
reviewed.56 For instance, urea’s and guanidine’s have been shown to undergo intramolecular Ncyclization46 when in proximity to an oxidatively activated C-H bond.19 Silver,57 rhodium,58
palladium,59 and have all been shown to catalyze C-H amination60 or oxidation61 reactions. The
most developed system for the necessary C-H aminations required to install the guanidine in
nagelamide M (or a urea analog) was the rhodium dimer developed in the Du Bois group.
Figure 2.10: The Catalyst Rh2(esp)2 and Its Enhanced Activity62

This catalyst, Bis[rhodium(α, α, α’, α’-tetramethyl-1,3-benzenedipropionic acid], or
“Rh2(esp)2”, is pictured in Figure 1.10. While the simpler rhodium acetate dimer, Rh2(OAc)4,
hadbeen shown to be effective at catalyzing C-H amination and carbene insertion,62 drastic
improvements in catalyst activity were achieved upon this ligand substitution. Many strapped
dicarboxylate catalysts were synthesized in an SAR study, and none were comparable to
Rh2(esp)2 in performance or substrate scope.62 X-ray crystallographic analysis of these structures
provides some insight as to the reason for this boost in performance. The four carboxylates
would prefer to coordinate to the rhodium dimer at a ninety degree angle,63 and this angle is best
realized in the Rh2(esp)2 system. The other catalyst systems exhibit less than ideal bond angles in
this respect, presumably inducing a degree of torsional strain that accelerates catalyst
16

degradation. While Rh2(OAc)4 exhibits almost ideal bond angles,68,69 ligand substitution is
observed under the standard reaction conditions, which presumably leads to catalyst
decomposition through a different pathway.
Another advantage of a bidentate ligand system in a metal catalyzed process is the
potential for stereoinduction, and there has been success on this front.70 This feature made this
route to nagelamide M even more appealing for the possibility that (if necessary) stereoinduction
could be reagent, and not merely substrate, controlled.71
The mechanism of the rhodium catalyzed C-H amination has been an area of intense
study. The uncatalyzed C-H amination reaction had been observed in the early 1960’s, in the
Figure 2.11: An Early Example of C-H Amination in Total Synthesis

total syntheses of the alkaloids garryine72 and atisine73 (pictured in Figure 2.11). In both cases, an
azide was photolysed to the nitrene which underwent insertion with a C-H bond to form a ring.
Neither reaction proceeded in high yield, nor were these examples particularly amenable to
generalization (both exhibited a conformationally rigid system which positions the nitrene
precursor in a position to form a six-membered ring), but they provide examples that the
amination of a C-H bond is within the capability of a suitably disposed nitrene.
The next step in the evolution of this reaction came from a search for alternate sources
(i.e. not originating from an alkyl or acyl azide) of nitrene precursors. Abramovitch74 and
coworkers discovered that sulfonyliminoiodinanes, of the general formula RSO2N=IPh, can

17

Figure 2.12: The First Example of an Iminoindinane As A Nitrene Precursor

function as nitrene equivalents (Figure 1.12). Although in very low yield and under forcing
conditions (1 % from 130 oC benzene), the C-H amination product N- methanesufonyl aniline
was synthesized.
The penultimate advance came when Breslow75 and coworkers showed that preformed
sulfonyliminoiodinanes could perform C-H amination reactions in the presence of a transition
metal catalyst as shown in Figure 2.13. The focus of the study was the transition metals iron (III)
and manganese (III) in porphyrin rings, but dirhodium tetraacetate was used included as an
additional example, and prophetically gave the highest yields.
The most recent innovation was contributed by the Du Bois group76,77 (and the Che
group78 in the context of rhodium porphyrins), when it was reported that the nitrene precursor
could be generated in situ from multiple sources (carbamates,76 sulfamates,79 and
sulfonamides80) and in the presence of a dirhodium or diruthenium transition metal catalyst
effectively perform C-H aminations. This expanded the scope of the methodology beyond the
previous limitation requiring the preformation of the iminoindinane precursor because many of
the currently viable substrates do not form isolable iminoindinanes.

18

Figure 2.13: Transition Metal (III) Porphyrin Complexes Catalyze C-H Amination

Both the intermolecular and intramolecular rhodium catalyzed C-H aminations were
employed in studies attempting the total synthesis of nagelamide M. Experimental and
computational data support a concerted, asynchronous C-H insertion mechanism for the
intramolecular pathway.62 The intermolecular process is thought to proceed by a related but
distinct mechanism, and many of the intermediates have been directly observed by mass
spectrometry.77 The primary difference between the two reactions is substrate preference. The
Figure 2.14: Substrate Preference in Inter- Versus Intramolecular C-H Amination

intramolecular reaction prefers tertiary over benzylic positions when given the option, while the
reverse is true for the intermolecular process (Figure 2.14).80 The Du Bois group proposed an
explanation for this phenomenon by using linear free energy relationships and IR stretching
parameters to develop a model for calculating the difference between the energy of activation of
the benzylic and tertiary C-H amination reactions.29 The mathematical model developed was
used to accurately predict the most tertiary C-H-selective analog to date.

19

As these approaches require the preparation of different compounds, the data gleaned
from these studies will be organized as approaching from the intermolecular and intramolecular
pathways separately.
The Intramolecular Rh2(esp)2 C-H Amination Pathway
The mechanism of this reaction has been extensively studied, and the current opinion
rests on a concerted asynchronous mechanism. One important clue comes from the
stereospecificity of the reaction. To date, there have been no examples of an erosion of
stereochemistry when enantiomerically or diastereomerically pure substrates are used.76,81,82
While this itself does not exclude a radical mechanism, this result argues against it. The
stereoretentive properties of this reaction suggest such a radical, if it exists, has a rate of internal
return high enough to maintain the absolute configuration at the reacting center (~200 fs).76
Additional support for this mechanism comes from the observed KIE of 2.6 and a Hammett ρ
value of -0.55.81,82 Finally, the intramolecular radical clock shown in Figure 2.15 was
Figure 2.15: Intramolecular Radical Clock Probe for Radical Intermediates

synthesized, and under reaction conditions no radical fragmentation products were observed. The
rate constant for fragmentation of this particular clock is believed to be on the order of 7 x 1010
s-1.82 These results combined argue strongly for a concerted, asynchronous mechanism.
The earliest precursors for oxidative C-H amination investigated by the Du Bois group
were α-ethereal C-H bonds with primary carbamates72 and sulfamate esters (Figure 2.16).73 The
combination of either of these precursors with PhI(OAc)2 and a commercial rhodium catalyst,

20

Rh2(OAc)4 or Rh2(oct)4, results in C-H amination to form the oxazolidin-2-one or [1,2,3]oxathiazinane-2,2-dioxide, respectively.
Figure 2.16: Early Examples of Intramolecular Rhodium Catalyzed C-H Amination

As was previously cited, one example exists for the intramolecular synthesis of a C-H
amination α to an amine,24 shown in Figure 2.17. Two challenges present themselves in the case
of a total synthesis of nagelamide M; first the oxidative lability of to α-amino methylene
hydrogens is sparsely precedented, and second is the limiting effect of bond angles on this
reaction. The various nitrene precursors that could serve in this capacity are often indiscriminate
of the electronics of the target but sensitive to the steric restrictions of the ring being formed.
Figure 2.17: Literature Precedent for an Intramolecular C-H α Amination

Sulfamates have been shown to form 5 and 6 membered rings,62 and the regioselectivity of this
ring closure will inform the development of this reaction manifold in this synthesis. As the C-H
amination reaction had been extended to include appropriately functionalized guanidines and
ureas46 and the natural product (or analogs of interest) contains those motifs, the urideo-proline
shown was synthesized. The cyclization precursor trichloroethoxysulfonyl urea, “Tces Urea”,
was synthesized according to a literature procedure.46

21

Figure 2.18: Synthesis of Urideo-Proline II.12 for C-H Amination

When subjected to C-H amination conditions to generate the [5.5] bicycle, no product
was observed (Figure 2.19). On considering the reasons for its failure, it was thought the Boc
group might be large enough to sterically occlude the nitrene-rhodium complex from
Figure 2.19: Attempted C-H Amination of II.9

reaching the desired C-H bond. As this type of bond (Figures 2.1, 2.17) had been shown
amenable to the desired oxidation, the failure was presumed to be due to steric constraints rather
than electronics. To test this theory the Cbz-protected variant of II.12 was synthesized, as it was
though exchange of a tert-butyl group for a benzyl group would provide enough space for the
oxidizing species to react at the desired bond. A carbamate was used in place of the Tces Urea
because carbamates have also been viable substrates for C-H amination73 and it was thought
formation of the second ring might be facilitated by having it on the opposite face of the ester
(again in an attempt to make the steric environment more favorable). This reaction failed under
C-H amination conditions as well.

22

Figure 2.20: Attempted C-H Amination of Benzyl Carbamate II.14

At that point, a more intensive search of the literature82 revealed that similar substrates
had failed, perhaps due to the increased sp2-character of the proline carbamate. In an effort to
circumvent this, the carbamate protecting group was substituted for a tosylate, which is in accord
with the literature example.24 Still considering the problem to be one of sterics and not
electronics, the carbamate ester was exchanged for sulfamate ester II.16 shown in Figure 2.21.
Bond angle has been shown to influence the ring formation in these reactions,62 and it was
Figure 2.21: Attempted C-H Amination of Sulfamate Substrate

thought the larger O-S-N bond angle (compared to the O-C-N bond angle of the carbamate)
might be more successful. This approach failed as well.
The following precursor II.17 was synthesized. Silyl ester II.7 was already in hand as a
precursor for intermolecular C-H amination; this intermediate was readily reduced to its alcohol
and sulfamoylated by known procedures.75 At the time this study was conducted, the only
intramolecular C-H amination forming a seven-membered ring was the one reported in Figure
2.17.24 The only other relevant example provided in the total synthesis of manzacidin A, which
used C-H amination as a key step to install an N,O-acetal like the one desired for nagelamide M.

23

Figure 2.22: Attempted Intramolecular C-H Amination of Precursor II.17

Of note is the success of the reaction in spite of the sterically bulky TBDPS-protected tertiary
alcohol,28 inferring the smaller TBDMS-protected tertiary alcohol would not be a steric
impediment to the reaction. The formation of a seven-membered ring in is entropically less
favorable than the six-membered ring, but the local electronic and steric environments in the two
intermediates are almost identical, and as such the chance for success in this manifold could not
be ignored. Intermediate II.17 also provides for comparison of the electronics of activating a
secondary α-amino C-H bond compared to a tertiary α-alkoxy C-H bond, as another possible
product compared to that shown in Figure 2.23 is a seven-membered ring such as that shown in
Figure 2.17.
Figure 2.23: C-H Amination in the Total Synthesis of the Natural Product Manzacidin A

The Intermolecular Approach to Nagelamide M
The mechanism of this reaction has been studied as intensely as its intramolecular cousin,
with the current opinion resting on a stepwise asynchronous oxidation event. The currently
accepted catalytic cycle is depicted in Figure 2.26. Primary KIE’s are high: 5.2 – 6.9 (depending
on the amine source), suggesting C-H bond breaking is extensive in the transition state.
Reactions with similarly high primary KIE’s include ruthenium and copper-catalyzed nitrene

24

insertion reactions,76 which are generally believed to proceed through a stepwise mechanism.
The data derived from cyclopropyl radical clock substrates varies. Fiori and Du Bois76
disclose that no ring opening is observed, and in a different publication, Roizen, Zalatan, and Du
Bois85 disclose small amount of isomerization for a nearly identical system (Figure 2.24). Apart
from the nitrogen source (which would not be expected to influence the stereochemical outcome
of the reaction) the main difference in conditions is solvent; the di-tert-butyl iodoacetate is
substituted for the diacetate merely to enhance the solubility of the oxidant. While solvent can be
optimized to improve yield, it has not been known to alter the mechanism of the reaction.84 The
Figure 2.24: An Apparent Discrepancy in Results

cyclopropyl sulfamate shown in Figure 2.25 was used to probe the intermolecular reaction, and
the lack of intramolecular cyclization product is informative. A radical pathway could be used to
explain the formation of cinnamaldehyde, but no direct evidence was observed for the possible
radical intermediates. This is the only system reported to date that displays such fragmentation
characteristics, perhaps due to the thermodynamically preferential formation of the extensively
conjugated cinnamaldeyde system.

25

Figure 2.25: A Clock Experiment to Probe for the Presence of Radicals

While overwhelming evidence existed for the proposed mechanism, definitive evidence
was not obtained until 2012. Several of the proposed intermediates were observed for the first
time in a series of elegant mass spectrometry experiments.77 The species proposed to be
responsible for the oxidation event was directly detected, and the proposed catalytic cycle is
shown in Figure 2.26.
Figure 2.26: The Mechanism of the Intermolecular Rh2(esp)2 C-H Amination

26

Figure 2.27 provides examples of the successful intermolecular C-H amination of natural
products.87 These examples established precedent that the same reaction might work on the
desired substrate, and as these were the only related examples available at the time, the success
of this approach would constitute an expansion of the methodology.
Notably, the reaction was shown to be successful on α-amino methylene C-H bonds (in
cinnazirine), however the oxidation proceeded to the amidine product. It also selected the αamino reaction site over the benzylic position, which is contrary to the established preference.
The first breakthrough in intermolecular C-H amination in this manifold used 2,2,2Figure 2.27: C-H Amination of Natural Products

trichoroethxysulfonamide, “TcesNH2”, as the nitrogen source.80 Prior to this discovery, TcesNH2
was used successfully in the rhodium catalyzed aziridination of alkenes.88 As shown, it strongly

27

prefers benzylic hydrogens, though it will react with tertiary carbons. This was the first nitrogen
source used in attempts to synthesize the N,O-acetal of nagelamide M from precursors II.6 and
II.7 (Figure 2.28). The ethereal oxygen attached to this carbon would presumably be beneficial
from an electronic perspective, as has been shown in the intramolecular case.89 This approach
was particularly attractive because the lactone substrate II.6 was obtained on a multigram scale
stereoselectively from an intramolecular Mitsonobu reaction of N-Cbz-trans-4-hydroxy-Lproline.90,91 The established stereochemistry concomitantly set the stereochemical outcome of the
C-H amination product as that reported for the natural product, and if successful this would have
defined all the stereochemistry necessary for an enantioselective total synthesis of nagelamide
M. The silyl protected proline II.7 was prepared on a multigram scale has the opposite relative
stereochemistry than that desired for the natural product, but the correct stereoisomeric alcohol
could be obtained through several methods. Lactone II.6 has been cleaved using methanol and
sodium azide in quantitative yield,90 additionally the Mitsonobu inversion of the alcohol of a
functionalized trans-hydroxy-L-proline is known.91 Either of these procedures could be used to
Figure 2.28: Attempted Intermolecular C-H Amination of II.6 and II.7

obtain the desired stereochemistry, but this step was postponed awaiting a successful C-H
amination event. These substrates were inert when subjected to established conditions.

28

The Du Bois group has made progress is modulating the preferential intermolecular C-H
amination of benzylic C-H bonds in the presence of tertiary C-H bonds, allowing for
optimization based on the nitrogen source. One such reagent, shown in Figure 2.29, is 2,6difluorophenyl sulfamate, “DfsNH2”.85 The development of this reagent was guided by the
observation that in intermolecular C-H amination reactions involving tertiary C-H bonds as the
only target, much of the TcesNH2 was consumed despite little product being formed.85 The
implication was that the methylene C-H bonds were being oxidized preferentially in comparison
to the target tertiary C-H bond. To counteract this effect, aryl and phenolic sulfonamides were
designed. The one that performed the best was the aforementioned 2,6-difluorophenol derivative,
which was synthesized according to a literature procedure84 for use in these studies.
It should be noted that none of the examples provided in the publication show amination
at a tertiary ether as desired in II.6 and II.7; as the closest examples show selection for aliphatic
Figure 2.29: Attempted Intermolecular C-H Amination of II.6 and II.7 With DfsNH2

tertiary C-H bonds in the presence of α-keto tertiary C-H bonds and α-ester tertiary C-H bonds.85
For each example shown in Figure 2.30 the regioisomer shown is the only one formed.

29

Figure 2.30: Examples Illustrating the Selectivity of DfsNH2

The most recent improvement to this reaction employs 2,2,3,3,3-pentafluoropropanol-1sulfamate as the nitrogen source (Figure 2.31). The efficacy of this reagent, which provides the
highest tertiary-to-benzylic selectivity ratio yet observed (9.5:1), was predicted by a
mathematical model of linear free energy relationships derived from the ground state IR
stretching parameters of a library of sulfamate esters.32
Figure 2.31: Attempted C-H Animation of II.6 and II.7 with Sulfamate Ester II.19

None of these reagent combinations formed any desired product, and the methodology
has not been developed further. This impasse prompted a change of tactic from C-H amination to
C-H azidation.
C-H Azidation as a Method to Access These Substrates
During the course of these studies, several significant advances in the field of C-H
azidation were disclosed. Azides were initially not considered as a route to access these
molecules due to the reasons these publications address: typically harsh reaction conditions and

30

limited substrate scope of azidation reactions. However, the successful installation of an azide
instead of a protected amine on the described substrates would be just as desirable as the initially
sought after amines, as one the fundamental transformation is the same, and a reduction would
be required to reveal the desired amine in either case.
Hypervalent or electrophilic iodine species, for example IN3, have been established as
viable sources for aliphatic C-H azidation for some time,92 but the use of this reagent is limited
primarily to simple aliphatic molecules due to harsh conditions and the relative instability of the
products. It does, however, provide the necessary proof-of-principle from which this manifold
can be improved.
Transition metals have been successfully employed in this area. Palladium has been used
to catalyze allylic azidations using NaN3 as an azide source,93 and an iron catalyst with the
appropriate ligand has been reported to catalyze enantioselective C-H azidation of β-ketoesters
with an azidiodinane.94 The drawback to these methods is their dependence on local functionality
to activate the C-H bond. This was the limit of the state of the art until the Hartwig95 and
Groves96 groups each disclosed (respectively) iron and manganese catalyzed C-H azidation of
unactivated, highly functionalized substrates.
The Groves system uses aqueous NaN3 as the azide source, iodosobenzene as the
stoichiometric oxidant, and either a manganese porphyrin or manganese salen complex as the
catalyst. The manganese salen catalyst, initially described by Jacobsen,97 was prepared according
to the known procedure for use in these studies. This is, of course, out of step with the typical
progression of methodology development, in which a racemic process is developed and
subsequently rendered asymmetric. The reverse order was chosen here simply due to the
comparative ease and inexpense of preparing the salen catalyst in comparison to purchasing or

31

synthesizing the porphyrin. Additionally there were no examples in which the porphyrin catalyst
worked and the salen catalyst did not.
Figure 2.32: C-H Azidation Using the Groves Procedure

The intermediates II.6 and II.7 did not show any reactivity under the proscribed
conditions (Figure 2.32). The reaction mechanism is thought to proceed through C-H abstraction
by an Mn-centered radical, followed by recombination with an azide radical. The evidence for
this comes from the dependence on regioselectivity on catalyst architecture (see published
examples96) and KIE experiments. The azidation was conducted on a 1:1 mixture of toluene and
d8-toluene yielding a primary KIE of 9.3 (with the Manganese-salen catalyst),96 which is
substantially higher than the reported KIE of ~5 for hydrogen abstraction by azide radicals.95,98
The reason for the lack of reactivity of the starting materials to these conditions is not apparent,
as each has structural features that would favor radical abstraction; each would constitute a
tertiary carbon centered radical that would benefit from stabilization by a local oxygen-centered
lone pair. The lactone II.6 might experience a barrier to radical C-H abstraction from the
conformationally rigid structure inhibiting the required planarization of the intermediate, but
conformationally stable radicals have been reported.99
The Hartwig group published a method using an iron catalyst with a box ligand and
iodoazide II.21 as an azide source as shown in Figure 2.33. The azide is easily prepared in two
32

steps from commercially available 2-iodobenzoic acid,92 and the ligand is prepared in one step100
by a known procedure.
Figure 2.33: C-H Azidation Using the Hartwig Procedure

II.6 and II.7 again proved inert to reaction conditions. The proposed mechanism is radical
mediated, and the authors conducted several control experiments to detect radical intermediates.
Additives that are known to quench radicals (TEMPO, BHT) completely inhibited the reaction,
and replacing the catalyst with benzoyl peroxide and heat led to a decrease in yields and
selectivity. The failure of the reaction is likely due to the same reasons as the Mn-salen system,
but they remain obscure.
At present the substrates chosen for the total synthesis of nagelamide M have proven to
be synthetic dead-ends and the synthesis is stalled as described.

33

Chapter 3: Synthesis of Des-Guanidinyl Nagelamide M
Given the synthetic inaccessibility of nagelamide M, but not wanting to abandon the
project, the possibility of synthesizing a des-guanidinyl analog was proposed. Molecules of this
series are of additional interest for potential biological activity. A retrosynthetic anaysis is shown
in Figure 3.1 below. The key reaction in the forward direction is the conjugate addition between
functionalized proline III.1 and vinyl sulfone III.2, a reagent that was developed to synthesize
protected taurine derivatives. This vinyl sulfone has been prepared on a multigram scale and
Figure 3.1: Retrosynthesis of Des-Guanidinyl Nagelamide M

in a model system did react with (S)-pyrrolidin-2-ylmethanol to produce the desired product,
establishing precedent for the desired reaction.
In the original report disclosing the preparation and reactivity 102of the vinyl sulfone,
primary and secondary amines were shown to be viable substrates and free hydroxyl groups were

34

tolerated. Somewhat surprising was the lack of an example containing a proline derivative,
which was the reason for testing the model system. Completing the synthesis with the model
system would grant access to des-guanidinyl-des-hydroxyl nagelamide M. This compound would
be desirable in establishing an SAR for these molecules, but also for establishing conditions to
repeating the route with III.1, an intermediate that is more difficult to prepare.
Figure 3.2: Successful Reaction of a Model System and the Desired Reaction

The attempted conversion of the prolinol to the O-tosylate (for subsequent nitrogenation)
yielded only decomposition. The reason for this remain unclear as the conditions were mild,
however the failure of this reaction established the need to convert the primary hydroxyl group to
the protected amine before the conjugate addition step.
Figure 3.3: Failed Tosylation of the Primary Alcohol in Compound III.3

35

This result prompted the first attempt at the synthesis of a protected pyrrolidin-2ylmethanamine. Commercially available benzyl (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate
was tosylated and reacted with potassium phthalimide (Figure 3.4) to yield the bis-N-protected
proline synthon. Reductive cleavage of the Cbz group failed under various hydrogenolytic
conditions, necessitating a redesign in the route. The reason for the failure of this reaction is not
immediately apparent; speculatively the conjugate acid generated in these conditions, TEA-HCl,
could be acidic enough to catalyze the reverse reaction of the conjugate addition, but no direct
evidence was obtained for this (the only observed products were decomposed unidentifiaby). The
protecting group was changed from Cbz to Boc, as the rest of the molecule is expected to be
stable to acidic conditions.
Figure 3.4: First Attempt at the Synthesis Prolinyl-Methanamine Core

Starting from commercially available (S)-pyrrolidin-2-ylmethanol the desired compound
was obtained by Boc-protection and O-tosylation. The tosyl group was displaced with sodium
azide, which was reduced to the amine with hydrogen and palladium. The Boc-group on the
orthogonally protected proline core could be selectively deprotected with heat or acid, but this
molecule was not completed due to the discovered negative impact of the methanamine on the
SAR (such analogs are biologically inactive as shown in Figure 3.11).

36

Figure 3.5: Second Synthesis of Prolinyl-methanamine Core

The proposed completion of the route is shown in Figure 3.6 below. After selective Bocgroup removal the proline free base could be reacted with the vinyl sulfone to generate the
protected taurine synthon. Hydrogenolysis of the Cbz-protecting group would likely reveal the
primary amine. Coupling the amine to the carboxylic acid would likely require optimization,
ideally beginning with neutral conditions. TBAF could be used to remove the silyl group
revealing the sulfonic acid which could be purified by ion exchange chromatography.
While the biological effect of the ethanesulfonic acid moiety in this system has not been
Figure 3.6: Proposed Completion of the Synthesis Using the Model Compound

determined, experimental evidence suggests the bromopyrrole has a negative effect on biological
activity. If the ethanesulfonic acid promotes biological activity, a different group could be
attached as a side chain (Figure 3.11).
The preparation of the cis-hydroxy proline is detailed in the scheme below. Initially, the

37

nitrogen was Cbz protected and the carboxylic acid esterified before the Mistunobu inversion of
the C-4 stereocenter.92 The Cbz-group was chosen because of its stability to acid, with the
thought of subsequent selective hydrolysis of the nitro-benzoate ester. Such an approach would
allow for orthogonal differentiation of the hydroxyl groups in III.9, rather than relying on
differentiation from degree of substitution. Surprisingly, III.9 was resistant to hydrolysis
Figure 3.7: First Synthesis of the Protected cis-hydroxy Proline III.9

(starting material was recovered, in addition to a small amount of decomposed material) of the
benzoate ester and reduction of the bis-ester with lithium borohydride (decomposition). The
failure of these reactions may be rooted in the Cbz-protecting group, so this sequence was
modified to incorporate the N-Boc protected variant91 of trans-4-hydroxy-L-proline.

38

Figure 3.8: Proposed Completion of Synthesis of O-Protected III.1

The synthesis of the des-guanidinyl nagelamide M core was discontinued at the point of the
azide (compound III.12) due to the discovered negative biological impact of having a nitrogen at
that position. Some of the structures accessed on the way to this structure may find use as
components of other molecules, guided by the newly obtained SAR data; these possibilities are
explored in Figure 3.12. A proposed completion of the route to the original des-nagelamide M is
shown in Figure 3.9.
Figure 3.9: Proposed Completion of Des-Guanidinyl Nagelamide M

Whether or not molecules of the des-guanidinyl nagelamide M series will possess

39

biological activity against the proteasome can only be determined by experiment, but other
inquiries into the SAR of these compounds can be made. Comparing molecules of the desguanidinyl nagelamide M series to known inhibitors of the proteasome based on the natural
product rapamycin (discussed in Chapter 6), some similarities are observed that can be
capitalized on. The key features of the des-guanidinyl nagelamide M analogs are the
ethanesulfonate moiety and the dibromopyrrole moiety. It would be illuminating to isolate these
features synthetically and test the biological activity of analogs containing only one variation, or
analogs containing one variation from compounds of known activity. Such a study would reveal
the importance of each structural change and most completely define the SAR.

40

Figure 3.10: Nagelamide/Rapamycin Hybrid Analogs

The proposed analogs were synthesized and tested for biological activity (results shown
in Figure 3.11). The amide analogs III.14 and III.16 were inactive in proteasome inhibition
assays, as was the dibromopyrrole III.17, shown in Figure 3.11. Consequently, the coupling
reaction of benzyl (S)-2-(aminomethyl) pyrrolidine-1-carboxylate and 4,5-dibromo-1H-pyrrole2-carboxylic acid was not attempted, as the additive effect of two non-productive modifications
was not expected to be productive. The ester analogs were active, and the most active, III.15,
was chosen for further development.

41

Figure 3.11: Biological Activity of Nagelamide/Rapamycin Analog Hybrids

The influence of the ethanesulfonate on the SAR could be explored in the same way,
using the most active molecule from Figure 3.11. Potential routes to second-generation
nagelamide/rapamycin sulfonate analogs are outlined in Figure 3.12 below.
Figure 3.12: Proposed Synthesis of Sulfonate Analogs of Nagelamide/Rapamycin Hybrids

Removal of the Cbz-group was successful (and the product amine was fully
characterized, III.18) but the conjugate addition step was not, yielding only starting materials.
Standard variations to improve yield in conjugate addition reactions (adding excess nucleophile,
using heat) did nothing to influence the yield.

42

Chapter 4: Studies on the Aminohydroxylaton of Indoles
A parallel line of research was initiated to study the oxidative functionalization of
indoles, as the desired [5.5] ring appended to a benzene ring would also be of interest as a
proteasome inhibitor, and the literature surrounding this transformation is more plentiful than the
C-H amination of methylene C-H bonds previously attempted. Many of the shortcomings
encountered using a 2,3-dihydropyrrole as a substrate would not apply to an indole, rendering the
intramolecular approach shown in Chapter 1, Figure 5 potentially viable on a 3-amino indole
substrate.
Figure 4.1: Desired Indole Analogs

In terms of inhibitor design, a bromine in the 6-position on this indole would place it in a similar
location to that of the bromine in indolo-phakellin,8 and consequently would be expected to
contribute to the binding interaction. If the route was successful, it could be readily altered to
include a 6-bromo derivative.
The fundamental transformation desired in this system is the aminohydroxylation of an

43

indole, with a urea nitrogen acting as the amine source. Using urea as an amine source is not
thought to be an obstacle, since they have been used successfully in the intermolecular
diamination of alkenes.12 While the literature is replete with examples of the aminohydroxylation
of alkenes103 there are relatively few such examples on indoles.104-110
Figure 4.2: The Desirable Qualities of Indoles in Oxidative Functionalization

All of these examples give 2-hydroxy-3-amino indoles, which is the opposite of the
required substitution pattern. The success of this transformation would constitute the
development of a new methodology that offers the opposite regiochemical outcome compared to
the previous examples. The indole IV.2 (R, R2 = H, R1 = Bn, Figure 4.2 and 4.4) was synthesized
as a substrate for oxidation followed by intramolecular cyclization (Figure 4.3).

44

Figure 4.3: Proposed Regio-Reversed Aminohydroxylation of Indoles via a Novel Substrate

From the commercially available methyl indole-3-carboxylate the product IV.2 was
synthesized and the structure was confirmed by X-ray crystallography. Extensive studies on the
oxidative functionalization of this substrate were conducted, the results of which are shown in
Table 4.1. The conditions screened mostly resulted in decomposition, but some unexpected
reactivity was observed in certain instances.
Figure 4.4: Synthesis of the Indole Precursor

45

Table 4.1: Screen of Conditions for Oxidatizing IV.2

reactant

solvent

oxidant

result

0.6 mmol IV.2

CD3OD

NBS

decomposition

0.6 mmol IV.2

CD3OD

mCPBA

decomposition

0.6 mmol IV.2

CD3OD

Tert-butyl
hydroperoxide

precipitate

0.6 mmol IV.2

CD3OD

NCS

inert

0.6 mmol IV.2

CD3OD

Cat. H2SO4

inert

0.6 mmol IV.2

CD3OD

Palau’chlor (IV.3a)

decomposition

0.6 mmol IV.2

CD3OD

d3 TFA

decomposition

0.6 mmol IV.2

CD3OD

SAE

decomposition

0.6 mmol IV.2

CD3OD

DMDO

inert

0.6 mmol IV.2

CD3OD

oxaziridine

decomposition

0.6 mmol IV.2

CD3OD

Bromine in CD3OD

inert

0.6 mmol IV.2

CD3OD

Bromine in HOAc

inert

0.6 mmol IV.2

CD3OD

TcesNH2, Rh2(esp)2,
PhI(OAc)2

inert

0.6 mmol IV.2

CD3OD

OsO4, NMO

inert

Of note was the product observed with the reaction of IV.2 with TBHP in methanol. A
precipitate was formed that was putatively identified as urazine IV.3.79 This assignment was
made based on the highly symmetric 1H NMR spectrum and HRMS data effectively gave a mass
of [M-2], which correlates with [M-H] for IV.3 fragmented as N-benzyl-N-indolyl urea.

46

Figure 4.5: An Unexpected Urazine Synthesis

Attempts to repeat the experiment were unsuccessful, precluding complete characterization.
In a search of the literature for instructive examples as to how to proceed, the total
synthesis of agliferin from the Harran group111 indicated a similar transformation had been
performed using a Davis oxaziridine on a 2-aminoimidazole ring, with the amide nitrogen acting
Figure 4.6: Sulfonyloxaziridine-Mediated Oxidative Cyclization of a Precursor to Agliferin

as a nucleophile. The indole IV.2 did indeed react with the nitro-oxaziridine, however no
products were isolable from the reaction mixture. Indications of product formation were obtained
in the form of 1H NMR (disappearance of C-H signals from C2 and C3 on the indole ring).
Taken this example in addition to the success the Dauben group109 reported in the
oxidative functionalization of indoles with electron withdrawing protecting groups on the indole
nitrogen (Figure 4.8), it was thought installing such a group might tune the reactivity of the C2C3 alkene to allow for the desired oxidation to occur. The Boc group was chosen for its electron
withdrawing character in addition to its likely ability to increase the solubility of the substrate.

47

As the conditions for early N-Boc protection of the indole nitrogen were too harsh for its survival
to the end urea, the Boc protection was attempted on the indole IV.2. A small amount of product
was obtained, and assigned the structure IV.4. The assignment was tentative, as the location of
N-Boc protection is most likely the indole nitrogen, this was not independently verifiable. When
the N-Boc indole IV.4 was reacted with the nitro-oxaziridine in d4-CD3OD, a solid precipitated
out of the reaction mixture. This was isolated and redissolved in d6-DMSO. It was pure enough
Figure 4.7: Attempted Oxidative Cyclization Indolyl-Urea IV.2

to be subjected to useful analysis, and a tentative structure IV.5 was assigned (Figure 4.7). The
Boc- protected urea was not stable to purification and the synthesis was not reproducible;
consequently the reaction could not be repeated.
Similar difficulties were encountered when preparing N-benzoyl or N-tosyl derivatives
(which underwent deprotection during hydrazine installation). While not an electron
withdrawing group, an N-benzyl derivative IV.8 shown in Figure 4.8 was successfully prepared
on a gram scale in the hope that, once reacted with the nitro-oxaziridine, the reaction would
again be successful and the presence of N-benzyl group would render the products isolable.

48

Figure 4.8: Synthesis of N-Benzyl Indole IV.8

During these studies another reference was discovered involving the copper (II) catalyzed
oxyamidation of indoles with sulfonyloxaziridines.108 There are marked differences between the
examples and the system in question (no examples included a nitrogen at the 3-position on the
indole, and the benzyl group is not electron withdrawing like the acetate), but copper catalysis
might offer a solution to this problem. Under the same conditions the indolyl-urea IV.2 yielded
degradation products.
Figure 4.9: Copper(II) Catalyzed Oxyamidation of Indoles With a Sulfonyloxaziridine

The failure of the indole-urea reaction manifold to yield any information (or product)
whatsoever was highly unsatisfying considering the extensive literature precedent for related
systems.104-110 To investigate the effect of the ring nitrogen atom α to the alkene, the alkenyl urea
IV.9 shown in Figure 4.10 was designed and synthesized. The alkenyl urea was subjected to the
same battery of oxidative conditions as the indole urea IV.2 above, all of which yielded only
decomposition. In contrast to the indole urea, the alkenyl urea was not stable to storage or

49

purification through column chromatography.
Figure 4.10: Cyclopentenyl Urea Model for Oxidative Cyclization

This system was, however, more directly comparable to other systems and all successful
examples had an electron withdrawing group at the nitrogen involved in the cyclization (Figure
4.10). When considered alongside the Du Bois work, the need for electronic deactivation of
urea’s and guanidine’s emerges as the deciding factor in successfully manipulating these groups
(Figure 4.11).53
Figure 4.11: Need for Electron Withdrawing Groups on Nitrene Precursors

50

At this point the focus of the project was turned to the diamination of indoles.

51

Chapter 5: Studies on the Diamination of Indoles
It was thought that simplifying the target from Indolo-nagelamide M to a dehydroxy
analog might make for a more accessable target. The diamination of an indole would be required
to synthesize this new target, des-hydroxyl-Indolo-nagelamide M.
The related intermolecular diamination of indoles is rare (either inter- or intramolecular).
Two close examples are given112,113 of the 2,3-diazidation of N-tosyl indole, however neither
reported transformation to the 2,3-diamine. The diimidation of indole has been reported,114 but
otherwise these structures are synthesized by intramolecular oxidative cyclization.
Figure 5.1: The Oxidative 2,3-Diamination of Indoles

In addition to the precedent for aminohydroxylations, suitably functionalized indoles are
known to undergo cyclizations to form cyclotryptamines (Figure 5.1).115,116 As discussed
previously the direct diamination of indoles is rare, which is perhaps not surprising considering

52

the persistent lack of a solution for the general problem of the diamination of alkenes. The
closest procedures for alkenes involve using masked diamines (like tert-butyl
sulfaomylcarbamate). 124
The rarity of diamination of indoles is contrasted with the comparatively large number of
methods for the amino-hydroxylation of alkenes103 and indoles.110 Several of these involve the
activation of an N,O-bond, followed by subsequent reaction with an alkene. The simple
substitution of the N,O-substrate for an N,N-substrate in an otherwise identical system as a point
of departure for the extension of the successful aminoydroxylation procedures to the yetundiscovered general diamination procedures seems to suggest itself. In addition to contributing
a solution to the diamination of indoles, these compounds could be transformed into analogs of
biological interest.
Figure 5.2: The Diamination of Indoles

The Xu group published methodology for the intramolecular aminohydroxylation of
alkenes103 and indoles110 whose mechanistic rationale invokes an iron nitreneoid as a reactive
intermediate. The tested substrate is shown in Figure 5.4. Having achieved synthetically useful

53

yields and ee’s, this system was chosen for modification in an attempt to achieve the diamination
of indoles. The synthetic route to the aminohydroxylation substrates was easily modified to
Figure 5.3: Xu’s Methodology for the Aminohydroxylation of Alkenes/Indoles

synthesize the desired substrate, available on a gram-scale in four steps from commercially
available indole-3-carboxaldehyde.110
When subjected to the same reaction conditions as the aminohydroxylation reaction
(acetonitrile, 23oC, Fe(OAc)2 and phenanthroline) no reaction was observed. This was a puzzling
result, as the proposed mechanism (discussed below) defines the rate-determining step as
reductive cleavage of the N,O-bond, which based on bond dissociation energies should be
approximately as labile as the N,N-bond.117
Figure 5.4: Synthesis of a Diamination Precursor

Mechanistic insight into this process are derived from the enantioselective reaction using

54

alkenes as a substrates, and is useful in pondering the failure of this reaction. While the above
Figure 5.5: Xu’s Asymmetric Intramolecular Amiohydroxylation of Alkenes

reaction is an enantioselective recitation of the same process with indoles, a new feature was
elucidated in the study of this system. Using a mixture of the cis and trans olefins shown in
Figure 5.5 (and the same chiral ligand 2), two products were observed: one a stereoconvergent
aminohydroxylation of the alkene and the other an aziridine (Figure 5.6). The sense of
enantioinduction of the two products is the same, and they were not observed to interconvert
under the reaction conditions. These results suggest two mechanistic possibilities, after reductive
cleavage of the N-O bond a radical transfer process might operate (either through a KharaschFigure 5.6: Stereoconvergent Aminohydroxylation of Olefins

type process or an iron nitrene), to form the oxazolidine ring and give the phenyl group time to
isomerize. The distribution of final products are envisioned to originate from the favorability
between radical recombination with the -OR group (presumably still appended to the iron
ligand), or reductive elimination of the iron complex with recombination of the nascent nitrogen
radical with the benzyl radical from the initial N-O cleavage. This is noteworthy to the discussion
55

Figure 5.7: Proposed Mechanism for the Iron Nitrene Pathway

because the rhodium nitrenes studies previously do not exhibit these characteristics (i.e. Rh
nitrenes react to give stereospecific products, iron nitrenes react to give stereoconvergent
products). If the proposed mechanism is correct and the initial step is N,O-bond cleavage, the
failure of this reaction is puzzling as the N,N-bond is considerably weaker than the N,O-bond (55
kcal/mol versus 38 kcal/mol respectively).117
It was thought changing the nature of the target from the starting indole might be a more
effective approach, specifically exploring the oxidation of indoles to iminoindolines (which
could be subsequently transformed into the desired intermediates en route to des-hydroxyIndolo-nagelamide M). A method for achieving this transformation was recently disclosed using
a sulfonyl azide (Figure 5.8). The reaction is believed to proceed through a cycloaddition of the
azide with the alkene, followed by nitrogen extrusion to an aziridine which undergoes ring
opening via a 1,2-hydride shift. Nearly all the examples were 3-alkyl substituted, however when
indole and N-methylindole were reacted with an excess of the sulfonyl azide, the bis-imide was
obtained (as the amidine-imide). The implication is the 3-alkyl group inhibits the reaction, and

56

Figure 5.8: 2,3-Dimethylimidazole-1-Sulfonyl Azide Triflate Functionalizing Indoles

the sulfonyl azide might be reactive enough to overcome the inert nature of the indole urea.
If obtained, such a product could be manipulated to a desirable structure in several ways.
Pyridine has been used to remove SO2 from sulfonamides to reveal diamines,14 which in this case
would give the coveted 3-aminoindole motif. Alternatively the amidine could be reduced to the
geminal diamine122 and further functionalized (perhaps into a urea with an appropriately
substituted isocyanate).123 Under the published reaction conditions, the starting indolyl urea was
inert.
Studies On the Intermolecular Diamination of Indoles
Initial studies in this area were inspired by work from the Dauben group in the aminohydroxyation of N-protected indoles,109 using a modified version of the Du Bois rhodium nitrene
chemistry. The reaction was typically high yielding and tolerated functionality at the 3-position
of the indole (not shown; unfortunately no examples including a heteroatom directly adjacent
were disclosed). In the example with R = benzenesulfonyl and acetic acid as the nucleophile

57

Figure 5.9: Dauben’s Intermolecular Oxyamidation of Indoles

(which was successfully repeated by the author on the same scale and at the same yield to
confirm the methodology), syn addition is the only product observed. This result was verified
with X-ray crystallography, but no explanation for the stereochemistry was proposed.
As the starting materials were readily available, preliminary tests were conducted to
extend this methodology to the diamination of indoles, simply by using an amine nucleophile
instead of an oxygen based nucleophile. The first attempt, simply using benzyl amine in excess,
did not lead to any product formation. Notably, the reaction mixture turned purple on the
addition of benzyl amine.
In an attempt to modify the electronics of the nitrogen source and enable the reaction, NBoc benzyl amine was synthesized and used as the excess nucleophile. While no purple color
was observed, no reaction was observed either.
Figure 5.10: Attempted Extention to Diamination on Indoles

The Shi group at Colorado State University has developed a transition metal catalyzed
methodology for the synthesis of diamines from alkenes using strained diaziridinones as a
nitrogen source. The method favors dienes, which function to suppress β–hydride elimination, or
if terminal aliphatic alkenes are used an internal alkene is generated through β–hydride
elimination. This method provides access to the desired 1,2-diamine and to date has only been

58

explored on the context of di-tert-butyldiaziridinones, di-tert-butylthiadiaziridine 1,1-dioxide,
1,2-di-tert-butyl-3-cyaniminodiaziridine derivative (as described in the Shi group’s recent
review).124 If diaziridines were shown to possess similar reactivity in this manifold
Figure 5.11: The Shi Method for Diamination of Alkenes

such a discovery would constitute a significant advance in the methodology, as they inherently
possess stereochemistry and the potential for transfer of this information to substrates would
constitute a stereoselective diamination of alkenes. Their use in this methodology is
conspicuously absent, in spite of their being strained heterocycles, presumably capable
Figure 5.12: Proposed Expansion of Shi Methodology to Include Diaziridines

of the same reactivity as diaziridinones. This could be because the initial reports of alkene
diamination by diaziridinones (and related compounds) with palladium121 and copper122 were
both published in 2010, and the first enantio- and diastereo-selective synthesis of diaziridines
was not reported until 2013.128
To test the viability of diaziridines as nitrogen sources under the Shi reaction conditions,

59

the following precursor was prepared, along with the alkene substrates. The bromo aldimine was
prepared by acid catalyzed condensation of toluenesulfonamide and p-brombenzaldehyde, and
N-benzyl-O-benzoyl hydroxylamine was prepared from a literature procedure.128 This particular
Figure 5.13: Synthesis of the Diaziridine Substrate V.7

diaziridine was chosen for operational simplicity (in its pure form it is a solid) and because
bromine is an excellent marker for detection in mass spectroscopy. It should also be noted that
this catalyst was successfully used as a diastereoselective phase transfer catalyst in the synthesis
of diaziridines, the O-benzhydryl derivative was used for the enantioselective variant of this
reaction. The benzhydryl derivative was prepared once but was not used in these studies.
Difficulty was encountered in reproducing the compound synthetically, and at this point in the
investigation the enantioselective variant could be postponed pending the success of the racemic
variant. The catalyst used was the one shown in Figure 5.13, which gave diastereomerically pure
diaziridines128 (as measured by 1H NMR).
The substrate dienes were prepared from literature procedures (Figure 5.14):
phenylbutadiene was prepared in one step from cinnamaldehyde,130 and the 3-vinylindole in two
steps from indole-3-carboxaldeyde.131 The first substrate was prepared for direct comparison
with Shi’s work, being one of the test substrates used in their work. The vinylindole was
prepared because of direct interest to this work; since the Shi group demonstrated the electronic

60

nature of the diene was not influential on the outcome of the reaction, indolyl diene V.10 was
expected to be a viable substrate for the methodology. In many examples electron rich substrates
reacted with virtually the same efficacy as their electron poor analogs. Only one example was
published using an aminodiene,125 and while the effect of the diene substrate is a secondary
Figure 5.14: Substrate Alkenes for Diamination

mechanistic concern (the rate determining step being cleavage of the N-N bond), no examples
included such an extensively conjugated system. Additionally, this would have been the desired
substrate for the development of this method. Unfortunately, under the reaction conditions shown
(duplicating the optimized conditions), no reaction occurred with either the vinylindole or the
phenylbutadiene. To analyze these results, a discussion of the reaction mechanism is necessary.
Figure 5.15: Attempts at Palladium-Catalyzed Diamination of V.9 and V.10

Shown below is the proposed catalytic cycle for the palladium catalyzed diamination of
dienes with diaziridinone and Pd(PPh3)4. Several features deserved comment. First is the NMR
evidence for the oxidative addition of the palladium to the diazirirdinone. The four membered

61

palladium (II) intermediate displays a downfield shift of ~0.5 ppm in the tert-butyl proton
resonances.125 After all the closed ring signal disappeared, a diene was added and the expected
new diamine signals were observed. The remainder of the process follows the standard oxidative
addition-reductive elimination catalytic cycle for palladium addition to alkenes.
Additionally, the palladium catalyzed variant prefers dienes to control the facile βhydride elimination pathway. Terminal aliphatic alkenes have been used successfully with this
method,125 and either result in alkene transposition with the nascent diamine occupying the
internal position124 (with di-tert-butyldiaziridinone), effectively diaminating an alkane and
regenerating the original alkene, or the terminal position with the generation of a new internal
alkene124 (with di-tert-butylthiadiaziridine 1,1-dioxide).
The demonstration that the rate-limiting step is oxidative addition of palladium to the NN bond126 implies that if the local environment around the new 4-membered palladacycle was
chiral, the product diamine might be rendered chiral as well. After a series of ligand screens, the
Shi group discovered one ligand that performed admirably in the desired fashion, and this
reaction manifold can be rendered asymmetric with high yield and high ee’s.124 Alternatively, the
product imidazolidinone can be deprotected and enantiomerically separated by crystallization.124

62

Figure 5.16: The Pd-Catalyzed Diamination of Dienes with Di-tert-butyldiaziridinone

The only drawback to this method are the forcing conditions used in the deprotection;
typically the tert-butyl groups are removed by refluxing in concentrated HCl, and removal of the
carbonyl in the remaining urea often requires additional forcing conditions to reveal the desired
diamine. This limits the substrate scope of the reaction and would require early use in the
synthesis of complex molecules. Transfer of stereochemical information would be expected if an
enantiomerically (or diastereomerically) pure diaziridine was reactive in this manifold, based on
the demonstrated asymmetric induction observed from chiral palladium ligands.
Analysis of the crude reaction mixture by 1H NMR showed no change in the reaction
mixture during the proscribed course. Since the rate limiting step is oxidative addition to the
N,N-bond, a change in 1H NMR similar to that seen in di-tert-butyldiaziridinone would be
expected if a four-membered diaziridine-palladacycle was formed. Luckily, the benzyl protons of

63

V.7 occupy an otherwise empty region of the spectrum and are very distinct: a quartet centered
around 3.29 ppm with coupling constants of J = 24.0 and 13.0 Hz. Presumably, if oxidative
addition has occurred, this peak would have experienced a downfield shift to approximately 3.8
ppm. The crude reaction mixture reveals this not to have been the case, as the signals remained
unchanged throught the course of the reaction.
Figure 5.17: Expected 1H-NMR Shifts On Successful Oxidative Addition

At this point it was decided to repeat the reaction using the copper catalyzed variant. This
reaction is thought to proceed through a radical process (discussed below) and it was
hypothesized that the N,N-bond, while inert to oxidative addition by palladium, might be it was
susceptible to radical reduction with copper.
The Shi group additionally discovered a copper (I) catalyzed variant of the same reaction
with several distinct features, the most prominent of which is reagent-based control of
regioselectivity.126 Depending on the particular copper salt used, either internal or terminal
diamination could be effected, though a terminal double bond is required in the diene substrate in
all cases. Mechanistically the reaction is thought to proceed through two different pathways, and
the regioselectivity is thought to originate from the relative position of the equilibrium between
two copper species (shown in the Figure 5.18). The first step is likely reduction of the N-N bond
to form a nitrogen centered radical that is likely in equilibrium with the four-membered copper
64

(III) species shown in the figure.
The addition to terminal double bonds is thought to proceed through a radical process.
Figure 5.18: Copper Catalyzed Diamination of Olefins

The direct observation of the copper (II) radical species by EPR provides support for this. The
nitrogen centered radical could add to the terminal end of the double bond, producing the
resonance stabilized radical shown in the figure, which may exist in equilibrium with the sixmembered copper (III) containing ring shown adjacent. The last step would involve reductive
elimination of the copper (III) species or radical combination in the copper (II) species to form
the diamination product. Additional evidence for the radial mechanism in the diamination of
terminal double bond comes in the observed isomerization of the deuterated substrate shown
above.125

65

Figure 5.19: Deuterium Isomerization in the Copper Catalyzed Diamination of Dienes

The first clue that the internal diamination mechanism proceeded through a different
mechanism comes from the fact that the internal diamination product observed shows no
deuterium isomerization.125 To further probe the mechanistic possibilities, careful study of the
reaction using 1,4-diphenylbutadiene as a substrate was performed. Little to no product was
formed under these circumstances, suggesting radical addition to an internal double bond is
unfavorable, even in the presence of such an extensively conjugated system.124 This information,
coupled with the fact that manipulating the reaction conditions can strongly favor terminal versus
internal addition, suggested that copper acts similarly to palladium in the palladum catalyzed
version of this reaction.
The reactions shown below in Figure 5.20 were preformed according to the proscribed
procedures. Again, analysis of the crude reaction mixtures with 1H NMR revealed no reaction
occurred, merely the persistence of starting materials. The evidence that diazridines are not
viable substrates for this reaction manifold could be related to the structural differences between
these two classes of molecules. The carbonyl in di-tert-butyl diaziridinone has an IR stretching
frequency132 of 1880 cm-1, which is above the typical range for carbonyl compounds, indicating a
high degree of mechanical strain. This likely weakens the N,N-bond in way that is absent in the
diaziridine. Additionally, the tert-butyl groups are known to add kinetic stability to small,
reactive heterocycles134 and were presumably chosen (at least in part) for this reason. It is

66

Figure 5.20: Copper Catalyzed Diamination With Diaziridines

possible they assist in activation of the N,N-bond to relieve steric congestion. If this in correct,
they could also sterically prevent reductive elimination to reform the N,N-bond. These features
obviously play a crucial role in N,N-bond activation, and these results confirm their presence is
required for reactivity.

67

Chapter 6: Studies on the Functionalization of Indolines and Indanes
Another route to des-hydroxyl-Indolo-nagelamide M was envisioned using the amination
of a C-H bond as a substrate, as opposed to the oxidation of an alkene. The new route to these
compounds is shown in Figure 6.1.
Figure 6.1: Retrosynthesis of Dehydroxy-Analogs of Nagelamide M

The proline derivative, if successfully synthesized, would yield the closest analog to
nagelamide M. To synthesize this analog would require the C-H activation at a secondary
carbon, which is not amply precedented. The likelihood of synthesizing this molecule is thus
rendered somewhat speculative. In contrast the indole derivative, if successfully synthesized, is
anticipated to proceed more smoothly, as the final step requires the well-precedented C-H
amination of a benzylic C-H bond. Surprisingly, neither 2-aminoproline and 2-aminoindoline nor

68

their carbamates were known compounds at the time these studies were initiated. The closest
literature precedent for this transformation involves the transformation shown below on Zpyroglutamic acid.135 Using the method for the synthesis of acyl azides developed by Sheehan,136
the carboxylic acid was transformed into a benzyl carbamate via a Curtius rearrangement. In
parallel, the known guanidine precursor was prepared in four steps from commercially available
p-methoxybenzenesulfonyl chloride.41
Hydrogenolysis of the Cbz group was achieved in both cases (Figure 6.2), but the free
amines were not amenable to purification. Attempts at coupling the crude amine with the
guanidine precursor were not successful, and this route was abandoned.
Figure 6.2: Synthesis of Dehydroxy-Analog Cyclization Precursors

Data collected from several sources (Figure 4.10) implies the need for electronic
deactivation of guanidines and ureas to render them viable for synthetic manipulation.
Methodology pioneered by the Du Bois group in the manipulation of these moieties has focused
on substituents that have electron-withdrawing character for the steps that require synthesis (i.e.,
the C-H amination step) and are removable through mild reductive cleavage. To this end, the
“Tces”, 2,2,2-trichloroethoxysulfamate, and the “Mbs”, p-methoxybenzenesulfonyl, groups have
emerged as the most useful. In addition to tuning the reactivity of the guanidine or urea, they
exhibit the added benefit of simplying purification. In many cases the Tces or Mbs protected

69

cyclization product can be purified by standard silica gel chromatography, which is often not the
case with guanidines or ureas protected with more conventional groups (Boc or Cbz).136 The
Mbs moiety has been used primarily in the context of intramolecular C-H aminations (total
synthesis of saxitoxin41), while Tces has been used in both inter- and intramolecular C-H
aminations.46
The guanidine precursor was designed for installation into primary and secondary
amines, but there are no examples of CH animation on benzylic carbons on indolines with the
Mbs moiety. To test the viability of this reaction and potentially design a biologically active
analog, the guanidine precursor was installed in the indoline core and the synthesis was
continued to the fully protected guanidine. The synthesis of this analog provides an opportunity
to test the transformation of the methylthio-moiety to the guanidine with mercury (II) chloride
and hexamethyldisilylazide.
Figure 6.3: Synthesis of a Guanidine Precursor from a Secondary Amine

During the course of this synthesis, the question was posed as to whether the steric
constraints of this molecule would prohibit the ring closure: mainly, could the guanidine nitrogen
in IV.4 could reach the benzylic carbon and form the structure shown in Figure 5.3. Additionally
there are no examples of the guanidine or urea amination precursors forming six-membered
rings. To answer this question, a crystal structure of VI.4 was obtained, disclosing the exact bond
angles and bond lengths. Substituting the –NH2 bond length from the crystal structure of the free
base of guanidine137 allows for a reasonable approximation of the new structure and for an

70

approximation of the distance to benzylic carbon C3 (Figure 6.3). The law of cosines was used to
determine the some of the necessary bond lengths and angles that would be required to form the
product IV.4. The results of this analysis (detailed in the Supporting Information) revealed the
benzylic carbon to be too far away for the (hypothetical) guanidine nitrogen to form a bond with
it, and synthesis of this molecule was discontinued.
The intramolecular C-H amination of indoline-2-carboxylate derivative VI.6 allows for a
comparison of the oxidative susceptibility of a tertiary α-amino C-H bond and a secondary
benzylic C-H bond. Sulfamates have been shown to form five and six membered rings. The
possibility of ring size (forming a [5.5] ring) may have been the factor leading to the failure of
these routes, as the published examples only involve [5.6] rings. In either case the product would
be useful, as the direct guanidinylation of sulfamates followed by cleavage of the sulfamate and
Figure 6.4: Attempted Intramolecular C-H Amination of Indoline Derivative IV.6

extrusion of SO2 was reported in several intermediates in the total synthesis of saxitoxin.41 Such
an intermediate could be oxidatively cyclized and the hydroxymethyl group could be left as is,
shortened by a methylene unit through an oxidation followed by a Bayer-Villager rearrangement,

71

or oxidized to a carboxylic acid (which could be decarboxylated through a Barton
decarboxylation).
Figure 6.5: A Proposed Convergent Approach to Compound VI.7

Substrate VI.6 was inert to reaction conditions as well.
One final simplification was conceived and carried out in a final attempt to make these
molecules, shown in Figure 5.6. These analogs were designed from commercially available 2indanol and 2-aminoindan, following the. The substitution of the indole nitrogen for a methylene
(as compared to the analogs described in Figure 6.2) was expected to make the product easier to
synthesize, as as several similar examples have been published.46 The Tces-guanidine precursor
Figure 6.6: Synthesis of Indanyl C-H Amination Analogs

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VI.10 was reactive under these conditions but it produced an intractable mixture of (presumably)
multiple products, none of which were isolable. The Tces urea compound VI.8 was inert to
reaction conditions.

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Chapter 7: Rapamycin Analogs as Inhibitors of the Proteasome and a
Rapamycin-Based Diazirine Photoaffinity Probe
Not wanting to limit the discovery of new protesome inhibitors to the pyrrole-imidazole
alkaloid family alone, other natural products were considered for work in this area. To that end,
the natural product rapamycin was selected as a candidate, owing to its discovery to allosterically
inhibit the proteasome with an IC50 = 1.9 m.136 The synthesis of a series of analogs designed
based on rapamycin and its congener FK-506 was published137 in an SAR study attempting to
probe their effect on peptidyl-proline isomerase inhibitors (before the Schrieber group disclosed
the mechanism on action involved the inhibition of mTor).138 This work would serve as a guide
for our work with these compounds.
Figure 7.1: The Natural Products Rapamycin and FK-506

In collaboration with the Gaczynska group, 136 which studies proteasome inhibition, a
series of analogs based on the SAR optimized motifs was planned to further their studies. The
original SAR, published by the Holt group137 disclosed four key features for optimum potency in
their molecules, which are shown in Figure 7.2. Additionally, the Gacyznska group had

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Figure 7.2: SAR-Optimized Analogs of Rapamycin

synthesized a lead compound based on these structures with potency close to the natural product.
Using this combined data as a starting point, the synthesis of these molecules was
planned around L-pipecolic acid and L-proline, which can be functionalized at the carboxylic
acid and the amine with known chemistry to synthesize the desired molecules. The general
scheme for the synthesis of these compounds is shown in Figure 7.3.
Figure 7.3: The Synthesis of Rapamycin Analogs

The initial target was modeled closely on the SAR proposed by Holt and the synthesis is
shown in the figure below. Racemic pipecolic acid was Cbz-protected at the ring nitrogen and
the acid was esterified with 3-phenyl propanol. The Cbz group was removed by hydrogenolysis
and after column chromatography was acylated with the acid chloride shown.

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Figure 7.4: Synthesis of an Initial Analog of Rapamycin Based on Previous SAR Data

Having developed a viable route, a first-generation series of analogs were planned,
varying ring size and the nature of the aryl moiety. In addition to the target molecule shown
above, the protected intermediates were tested for biological activity. Two of these molecules
were unexpectedly more potent than the strongest known thus far, and this discovery prompted a
change in the direction of the project. All of the molecules tested in the initial series are shown in
the figure below (all biological testing and reported activities were performed by the Gaczynska
group).

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Figure 7.5: First Generation Analogs and Activities

The activity of each of the enantiomers of pipecolic acid compared to the racemate is
worth discussing. Typically there is either an order (or more) of magnitude difference in activity
between enantiomers or their individual activities add up to that of the racemate.139 As these
characteristics were not observed in this system, molecular modeling was used in an attempt to
explain this result (modeling conducted by C. Jones, Tepe Group). The modeling results indicate

77

the enantiomers bind to two different subunits of the -ring, which in the absence of other
empirical data is a reasonable explanation for the observed results.
The analogs based on L-pipecolic acid are shown in Figure 7.6, with the most potent
being VII.4, with R1 as carbamoylbenzyloxy and R2 as the 3,4,5-trimethoxyphenyl alcohol.
Surprisingly, the most potent analog synthesized did not include either a 6-membered ring or a
functionalized aryl moiety; rather it was analog VII.8, an L-proline derivative with R1 as
carbamoyloxybenzyl and R2 as 3-phenyl-1-propanol.

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Figure 7.6: L-Pipecolic Acid-Based Rapamycin Analogs Synthesized to Probe the SAR

A comparison of the most potent analog from each series leads to several illuminating
conclusions. The aryl functionality of R2 in the pipecolic acid series is substantially larger with
its three methoxy groups as opposed to the simple benzene ring in the proline series. The IC50’s

79

of VII.4 and VII.5 demonstrate the size of the trimethoxy-aryl group is not a hindrance to
binding, however binding is almost completely inhibited upon contracting the ring size from 6 to
5. The conformational dynamics of 5-membered rings is known to be substantially different135
from that of 6-membered rings, and analogs synthesized to exploit this feature are shown in
Figure 7.7.
Figure 7.7: Proline-Based Analogs

These observations along with molecular modeling drew us to the following compounds,
in which the R1 and R2 groups had been exchanged on the heterocyclic core. Another compound
of interest in the Tepe group is a proteasome activator based on the 2-phenothiazine core. This
compound was modeled in silico and the binding conformation looks similar to VII.4 with R
groups interchanged, as shown in Figure 7.8. These molecules were synthesized to explore the
possibility of creating molecular switches, with tunable proteasome activating or inhibiting
characteristics, based on the location of the side chains.

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Figure 7.8: Group-Exchanged Analogs

These analogs were inert when tested for proteasome activation and inhibition (E.
Njomen, Tepe group).
While in silico studies of small molecules bound to proteins can be very instructive, they
are much more so if used in collaboration with biological data; if the binding site of these
inhibitors was known the modeling data could be much more effective in designing analogs. To
that end, an analog incorporating a diazirine photolabel was synthesized (Figure 7.9) by coupling
amine VII.23 and 3-(3-methyl-3H-diazirin-3-yl)propanoic acid (synthesized from levulanic
acid).140 This compound was synthesized in the hope that upon binding and irradiation, the
diazirine would extrude dinitrogen to reveal a carbene, which would insert into a local covalent
bond. The covalently bound inhibitor-protein complex would then be enzymatically digested and

81

analyzed by mass spectrometry, the results of which would reveal the binding site. This method
Figure 7.9: Rapamycin Analog-Diazirine Photolabel and Control Compound

of elucidating the binding site of small molecules to proteins has been in existence for some
time141 and has a long history of success.
It should be noted that in both the precursor 3-(3-methyl-3H-diazirin-3-yl)propanoic acid
and VII.24, the diazirine carbon140 (chemical shift  = 72 in CDCl3) was absent in 13C NMR.
Support for the proposed structures is given in the 1H NMR, high-resolution mass spectrometry,
and IR analysis. Additionally, the compounds are stable to storage and in solution (arguing
against the presence of a carbene), however the proposed structures remain unconfirmed.
Additional 13C NMR experiments (HMBC) were unable to find the missing carbon.
Although diazirines were first synthesized in 1960,142 their use as photoprobes was not
discovered until the 1970’s by the Knowles group.143 Scheme 7.10 below shows the pathways for
diazirine photolysis. Studies of these systems by ultrafast spectroscopy indicates the
photochemistry of diazirines is complex, and many exotic intermediates have been characterized
chemically and spectroscopically.141

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Scheme 7.10: Photochemical Pathways From Diazirines to Carbenes and Carbocations

The principal modification to diazirine photolables has been the incorporation of an αtrifluoromethyl group, which was discovered ten years later.144 This modification has been
shown to preferentially influence the formation of a carbene over other less reactive
intermediates.141As a general trend, aromatic diazirines generate more carbenes in comparison to
aliphatic diazirines.141 Generally the α-trifluoromethyl group will favor the formation of the
carbene and render any diazo-intermediate so stable as to be unreactive to normal photolysis
conditions (the chemistry of aryl α-trifluoromethyl diazirines is explored in Chapter 8).
The diazirine photolabel was tested for biological activity (Gaczynska group) and found
to be of sufficiently active to conduct the photolabeling experiment. We are currently awaiting
the results of this data from our collaborators (Bohmann Group, Southwest Research Institute).

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Chapter 8: Synthesis of Two TCH-Diazirine Photoaffinity Labels and a TCHBiotin Conjugate
A great deal of work has been done to elucidate the nature of the binding interaction
between compounds of the TCH series and the proteasome, and most of the details of that
interaction are now known.5,6 The final piece of the puzzle yet to be solved is the location of the
binding site (or sites) of the TCH molecules to the proteasome. Attempts at using X-ray
crystallography, as in the case of Indolophakellin (Figure 3), have not been successful, leaving
the matter to molecular probes. Two of the most commonly used probes are active moleculebiotin hybrids and diazirine photoaffinity probes, and both were employed in attempts to modify
the TCH pharmacophore to create hybrid probes for binding studies.
Biotin has been used successfully in this area when chemically incorporated into a
biologically active molecule.146 The difficulty with this method is ascertaining to what extent, if
any, the biotin conjugate alters the activity profile of the molecule in question. Since this cannot
be determined beforehand, several known TCH molecules were synthesized for ligation to biotin
at various locations in the hopes of synthesizing a probe that would have comparable activity to
its parent TCH compound.
The structural diversity in the library of known TCH compounds is extensive and offers
many opportunities for the incorporation of a biotin label. Another known TCH compound,
TCH-157 (compound VIII.1, Figure 8.1), possessing an aniline was prepared for coupling with
biotin. Attempts to functionalize TCH-157 with biotin are shown in Figure 8.1 (TCH-157 was
prepared6 on a gram scale). EDCI coupling with the unaltered biotin to TCH-157 in DMF was
attempted, but unsuccessful. Attention was then turned to the commercially available 4,4’dimethoxytrityl (“DMT”) protected biotin and the hydroxylsuccinimide biotin. The large DMT

84

group addresses the poor solubility of biotin, and the hydroxylsuccinimide serves both to
increase solubility in organic solvents as well as activate the carbonyl group for coupling. The
aniline functionality in TCH-157 has been successfully coupled to carboxylic acid derivatives
Figure 8.1: Initial Attempts at Synthesizing a TCH/Biotin Conjugate

in the synthesis of other molecules (Figure 7.5), which makes the failure of these two reactions

85

puzzling, however no coupled product was observed.
As discussed, biotin and its reduced congener biotinol are exhibit poor solubility in
organic most solvents,147 making them difficult to work with in a synthetic context. Several
solutions have been reported to circumvent this problem, but the most popular is the one shown
below in Figure 8.2, which employs the use of the 4,4’-dimethoxytrityl (‘DMT’) protecting
Figure 8.2: Synthesis of DMT-Protected Biotinol

group to enhance solubility. The DMT group adds regioselectively to the position shown,
regardless of the amount added. All of the intermediates are purified by column chromatography
and the final protected biotinol can be prepared on a multigram scale as a white solid. This
reaction failed to provide any coupled product as well (Figure 8.3).
Figure 8.3: Attempted Coupling of DMT-Protected Biotinol to TCH-001

Biotin and several modified forms are commercially available, one of which being a
PEG-ylated azide. The azide moiety of this molecule could react with an alkyne to form a
triazole via “Click” chemistry, effectively creating a TCH-biotin probe. This method has been
successfully used before,147 and an alkynyl ester of TCH-001 was synthesized as shown in

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Figure 8.4 for this reaction. This reaction was successful, and the probe is currently under
investigation for biological activity.
Figure 8.4: Synthesis of a TCH/Biotin Conjugate

Another important tool for elucidating the binding site of TCH compounds is
photoaffinity probes. These probes are typically employed in determining binding site locations
in small molecule-protein interactions by synthesizing a hybrid molecule consisting of a known
biologically active component and a diazirine, which functions as a protected carbene. The
hybrid molecule is exposed to the target of interest (typically a protein or enzyme) under
conditions that allow for binding (at least for binding of the original active compound; the main
drawback in the use of photoaffinity probes is the possible influence of the probe on biological
activity of the parent compound). The free carbene is generated by irradiating diazirines with a
specific wavelength of light to generate a carbene and cause dinitrogen expulsion as a leaving
group. The hope is the controlled generation of such a reactive intermediate in close proximity to
the binding site of the parent compound to form a covalent bond. In this case, the protein/TCH
conjugate would be enzymatically digested and the binding site would be identified using mass

87

spectrometry.
Many photoaffinity probes have been prepared and incorporated into complex molecules,
providing many alternatives should a given route fail. An initial foray into this area involved the
preparation of known diazirine 3-(3-methyl-3H-diazirin-3-yl)propanoic acid and EDCI coupling
to TCH-157.
Figure 8.5: Synthesis of a First Generation Photoaffinity Probe

It should be noted that in both the precursor 3-(3-methyl-3H-diazirin-3-yl)propanoic acid
and VIII.6, the diazirine carbon140 (chemical shift  = 72 in CDCl3) was absent in 13C NMR.
Support for the proposed structures is given in the 1H NMR, high-resolution mass spectrometry,
and IR analysis. Additionally, the compounds are stable to storage and in solution (arguing
against the presence of a carbene), however the proposed structures remain unconfirmed.
Additional 13C NMR experiments (HMBC) were unable to find the missing carbon.
This molecule was successfully synthesized and preliminary testing (by E. Njomen, Tepe
group) indicated the molecule is biologically active. A sample was sent to our collaborators for
the photolabelling and mass spectrometry experiments.
The chemistry of diazirines and their use as biological probes has been discussed in

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Chapter 7. Considering the possibility that an -trifluoromethyl probe might succeed where an
alkyl probe failed, the aryl α-trifluoromethyl diazirine shown in Figure 8.6 was synthesized on a
1 g scale (the precursor diaziridine has been synthesized on a 20 g scale). Somewhat
surprisingly, the product was discovered to be volatile, something that is not mentioned in
Figure 8.6: Synthesis of 4-(3-(trifluoromethyl)-3H-diazirin-3-yl)benzaldehyde

literature descriptions of this compound.145 As an alternative strategy to isolating the aldehyde,
the crude deprotection reaction was extracted into DCM, dried over sodium sulfate, and carried
on to the reductive amination step.

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Figure 8.7: Synthesis of a Second-Generation TCH-Diazirine Photolabel

Somewhat surprisingly (after purification by silica gel chromatography and purification
on an Autocolumn) the product isolated was the imine, which was obtained on a ~ 200 mg scale.
The relative stability of this compound (as compared to typical imines, most of which are subject
to hydrolysis on silica gel) may make it suitable for photolabeling studies, though the best course
of action would be to reduce the imine (to prevent hydrolysis on the timescale of the labelling
experiment).
This result is expected to be particularly significant because of the great success of the
aryl -trifluoromethyl diazirine group in photolabeling experiments, and because of its structural

90

similarity to TCH-165, the benchmark of the TCH-series of molecules. Labeling experiments
and other biological experiments are currently under way.

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Chapter 9: Experimental
Figure 9.1: Compound II.4

(S)-1-benzyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (II.4). To a 250 mL roundbottom
flask containing a stir bar was added (2S,4R)-1-benzyl 2-methyl 4-hydroxypyrrolidine-1,2dicarboxylate (8.2 g, 29.3 mmol). To the open flask was added reagent grade acetone (300 mL),
and stirring commenced. To this mixture was added the Jones reagent3 (8.79 g CrO3, 88 mmol)
dropwise over a period of 5 minutes. After addition was complete an exotherm was observed and
bubbles formed. After approximately 10 minutes a green precipitate was observed (presumably
CrIII salts) and a purple color persisted in solution. The reaction was allowed to proceed at room
temperature for an additional 30 minutes, at which time 2-propanol was added (5 mL). On
addition of the alcohol the green color previously noted turned blue. The reaction mixture was
filtered to remove solids and concentrated to a 2-layered mixture. To this material was added
diethyl ether (50 mL) and this was filtered through Florisil. The Florisil was washed twice with
diethyl ether and the filtrate was concentrated in vacuo to yield a clear oil. The product was
purified by column chromatography (35:65 ethyl acetate: hexanes) to yield the product as a clear
oil (3.7 g, 46 %). Spectroscopic data matches that reported for this compound.146 1H NMR (500
MHz) (CDCl3) (amide rotamers) δ: 7.37 – 7.32 (5H, m), 5.23 (1H, app d), 5.16 – 5.13 (1H, m),
4.89 – 4.82 (1H, m), 4.02 – 3.91 (2H, m), 3.77 – 3.63, (3H, m), 2.99 – 2.90 (1H, m), 2.62 – 2.58
(1H, app dd). 13C NMR (125 MHz) (CDCl3) (amide rotamers) δ: 207.7, 207.1, 171.8, 171.8,
154.9, 154.1, 135.9, 128.6, 128.5, 128.4, 128.3, 128.0, 67.7, 67.6, 56.0, 55.9, 52.8, 52.6, 52.4,
41.1, 40.5, 25.6.

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Figure 9.2: Compound II.5a

(2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (II.5a). To a 250 mL
roundbottom flask was added a stir bar, (4.0 g, 22.0 mmol) and DCM (50 mL). Stirring
commenced and the reaction vessel was sealed and flushed with N2 for 10 minutes. To this
solution was added TEA (9.2 mL, 6.67 g, 66.0 mol) dropwise via syringe. The reaction was
cooled to 0o C by placing the vessel in an ice water bath. The seal was removed and di-tert-butyl
dicarbonate (25 mmol, 5.4 g) was added in one portion, after which the reaction vessel was
resealed and flushed with N2. The solution was allowed to warm to room temperature and stir
overnight. The reaction mixture was transferred to a separatory funnel, HCl (50 mL of 6.6 M)
was added, and the organic layer extracted. The layers were separated and the organic layer was
washed with saturated sodium carbonate (2 x 100 mL) and water (100 mL). The organic layer
was dried over sodium sulfate and concentrated in vacuo to yield the product as a clear oil (4.7 g,
91 %). Spectroscopic data matches that reported for this compound.147 1H NMR (500 MHz)
(CDCl3) (amide rotamers) δ: 4.49 to 4.37 (2H, m), 3.72 (3H, s), 3.65 - 3.48 (3H, m), 2.77 – 2.66
(1H, br m), 2.62 - 2.43 (1H, m), 2.07 - 1.98 (1H, m), 1.43 (9H, 2 s). 13C NMR (125 MHz)
(CDCl3) (amide rotamers) δ: 173.7, 173.4, 154.5, 154.0, 80.4, 80.3, 70.0, 69.3, 57.9, 57.4, 54.7,
54.6, 52.2, 52.0, 39.0, 38.4, 28.3, 28.2.

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Figure 9.3: Compound II.5b

(2S,4R)-tert-butyl 4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate. (II.5b) To a 250
mL roundbottom flask was added a stir bar, (2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine1,2-dicarboxylate (11.5 g, 45.0 mmol) and THF (40 mL). Stirring commenced and the reaction
vessel was cooled to 0o C in an ice water bath. Lithium borohydride (45 mL of a 2.0 M solution
in THF, 90.0 mmol) was added dropwise and the reaction was allowed to warm to room
temperature and stir overnight, during which time the reaction mixture solidified. It was
quenched with saturated ammonium chloride (added dropwise until no more gas evolved). Water
was added (50 mL) followed by ethyl acetate (100 mL). The biphasic mixture was transferred to
a separatory funnel and partitioned. The aqueous layer was washed with ethyl acetate (50 mL).
The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to yield
a clear oil. The crude was purified by silica gel chromatography (1:1 ethyl acetate: DCM). The
product was obtained as a clear oil (4.0 g, 41 %). Spectroscopic data matches that reported for
this compound.148 1H NMR (500 MHz) (CDCl3) (amide rotamers) δ: 5.19 – 5.18 (1H, m), 4.34
(1H, s), 4.12 (1H, m), 3.66 (1H, m), 3.57 – 3.49 (2H, m), 3.43 – 3.40 (1H, s), 2.62 (1H, br s),
2.05 – 2.01 (1H, m), 1.68 – 1.58 (1H, m) 1.46 (9H, s). 13C NMR (125 MHz) (CDCl3) (amide
rotamers) δ: 157.0, 80.6, 69.2, 67.0, 58.8, 55.7, 37.4, 28.4.
Figure 9.4: Compound II.5

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(S)-tert-Butyl 4-Oxo-2-(((triisopropylsilyl)oxy)methyl)-pyrrolidine-1-carboxylate (II.5). To a
250 mL roundbottom flask was added a stir bar, (2S,4R)-tert-butyl 4-hydroxy-2-(hydroxymethyl)
pyrrolidine-1-carboxylate (4.0 g, 18.4 mmol), DMAP (0.150 g, 1.8 mmol) and DCM (100 mL).
The reaction vessel was sealed, stirring commenced, and the sealed vessel was flushed with
nitrogen. TEA (3.0 mL, 2.2 g, 22 mmol) was added dropwise via syringe, followed by TIPS-Cl
(4.5 mL, 3.6 g, 19 mmol). The reaction mixture was allowed to stir overnight. The following
day, water (100 mL) was added to quench the reaction. The biphasic mixture was transferred to a
separatory funnel and partitioned. The organic layer was dried over sodium sulfate and the crude
material was concentrated in vacuo. The crude protected alcohol was purified by silica gel
chromatography (1:1 ethyl acetate: hexanes) to yield 4.5 g (65 %) of the mono-TIPS alcohol,
which was carried on to the next step.
To a 250 mL roundbottom flask was added a stir bar, the mono-TIPS alcohol from above
(8.8 mmol, 3.3 g), and 50 mL dichloromethane. Activated 4 Å molecular sieves (13.0 g) were
added, followed by tetra-N-propylammonium perruthenate (0.44 mmol, 0.154 g), followed by 4methylmorpholine N-oxide (1.54 g, 13.2 mmol). The vessel was sealed and the reaction mixture
was stirred overnight and then filtered through silica plug with ethyl acetate, and the filtrate was
concentrated by in vacuo. The residue was purified by silica gel column chromatography (2:3
ethyl acetate: hexanes) to yield 2.2 g (95%) of the product as a colorless liquid. Spectroscopic
data matches that reported for this compound.149 1H NMR (500 MHz) (CDCl3) (amide rotamers)
δ: 4.46 − 3.61 (5H, m), 2.83−2.63 (1H, m), 2.60−2.46 (1H, m), 1.48 (9H, s), 1.16−0.95 (21H, m);
C NMR (125 MHz) (CDCl3) (amide rotamers) δ: 210.8, 210.3, 153.7, 80.2, 80.2, 65.9, 65.4,

13

60.3, 55.8, 55.3, 54.1, 53.5, 40.7, 40.1, 28.4, 28.3, 21.0, 17.8, 17.6, 14.1, 12.2, 12.0, 11.8, 11.7,

95

11.5.
Figure 9.5: Compound II.11

2,2,2-trichloroethyl carbamoylsulfamate (II.11). To a 100 mL roundbottom flask was added a
stir bar, chlorosulfonyl isocyanate (3.3 mL, 5.30 g, 37.5 mmol), and chlorobenzene (17 mL).
Sitrring commenced and a solution of 2,2,2-trichloroethanol (3.6 mL, 5.60 g, 37.5 mmol) in
chlorobenzene (25 mL) was added dropwise via syringe. The reaction was heated at reflux for 12
h. Following this period, the reaction was cooled to room temperature and the condenser was
replaced by a short path distillation head equipped with a 100 mL receiving flask. The
chlorobenzene was removed by distillation to give a light brown viscous residue. This material
was dissolved in DCM (40 mL) and the solution was cooled to 0 °C in an ice-water bath.
Hexamethyldisilazane (7.9 mL, 6.04 g, 37.5 mmol) was then added dropwise via syringe. The
reaction mixture was stirred at room temperature for 4 hours. The solution was concentrated in
vacuo to give an off-white solid, which was subsequently dissolved in methanol (40 mL) and
acetic acid (300 μL). The resulting slurry was stirred vigorously for 5 hours after which time all
volatile materials were removed in vacuo and the oily product was dried azetropically with
toluene (50 mL). The remaining solid was recrystallized from ethyl acetate: hexanes (300 mL of
a 3:1 mixture) to give the desired product as an amorphous white powder (2.21 g, 22%).
Spectroscopic data matches that reported for this compound.150 1H NMR (d6-DMSO) (500 MHz)
δ: 7.09 (br s, 2H), 5.42 (br s, 2H), 4.49 (2H, s). 13C NMR (d6-DMSO) (125 MHz) δ: 161.1, 96.5,
77.9. M.P. = 165 o C.

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Figure 9.6: Compound II.12

(2S,4S)-1-tert-butyl 2-methyl 4-(1-((2,2,2-trichloroethoxy)sulfonyl)ureido)pyrrolidine-1,2dicarboxylate (II.12). To a 250 mL roundbottom flask containing a stir bar was added (2S,4R)1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (1.8 g, 7.3 mmol), 2,2,2trichloroethyl carbamoylsulfamate (2.52 g, 9.4 mmol), and triphenylphosphine (2.46 g, 9.4
mmol). The reaction vessel was sealed with a septum and freshly distilled THF (15 mL) was
added via syringe. Stirring commenced and all solids dissolved. Diisopropylazodicarboxylate
(DIAD) was added dropwise (1.86 mL, 1.89 g, 9.4 mmol). A yellow color was observed during
DIAD addition, but this color disappeared shortly after addition was complete. The reaction was
allowed to stir at room temperature overnight. The next day the reaction mixture was
concentrated in vacuo to an oil. The crude product was purified by flash column chromatography
(gradient 1:9 to 3:7 ethyl acetate: hexanes, Rf = 0.15). The desired fractions were combined and
concentrated to give the product as a white solid (2.8 g, 78 %). 1H NMR (500 MHz) (CDCl3)
(amide rotamers) δ: 7.03 (1H, br s), 6.11 - 5.95 (1H, br d), 5.41 (1H, br s), 4.66 (2H, s), 4.52 4.38 (1H, dd, J = 11 Hz), 3.75 (3H, s), 2.55 – 2.45 (1H, m), 2.39 (1H, app d, J = 14 Hz), 1.80
(1H, s), 1.45 (9H, app d). 13C NMR (125 MHz) (CDCl3) (amide rotamers) δ: 172.4, 172.3, 159.4,
153.9, 153.6, 93.5, 80.9, 80.8, 78.4, 77.6, 76.4, 57.4, 57.2, 52.5, 52.4, 52.2, 51.6, 36.1, 35.1, 28.3,
28.2. HRMS calc’d for [M+Na] = 520.0091, observed [M+Na] = 520.0094. IR (NaCl, DCM):
1744, 1693, 1639, 1444, 1407, 1344, 1177, 1017, 853. M.P. = 120 – 121o C.

97

Figure 9.7: Compound II.13

1-benzyl 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (II.13). To a 100 mL
roundbottom flask containing a stir bar was added trans-4-hydroxy-L-proline methyl ester HCl
salt (5.4 g, 30.0 mmol), followed by water/dioxane mixture (60 mL of a 1:1 solution). Stirring
commenced, and sodium bicarbonate was added (5.6 g, 40.0 mmol). To the stirring mixture was
added Cbz-Cl dropwise (5.0 mL, 5.9 g, 35.0 mmol). The reaction mixture was allowed to stir
overnight. The following day the reaction mixture was concentrated to approximately half the
original volume in vacuo. The crude reaction mixture was transferred to a separatory funnel and
extracted with DCM (4 x 50 mL). The organic layers were combined and washed with dilute
HCl (20 mL of a 1.0 M solution). The organic layer was dried over sodium sulfate and
concentrated to dryness in vacuo to yield the product as a clear oil (8.2 g, 99 %). Spectroscopic
data matches that reported for this compound.151 1H NMR (500 MHz) (CDCl3) (amide rotamers)
δ: 7.36 – 7.27 (5H, m), 5.21 – 5.00 (2H, m), 4.52 – 4.48 (2H, m), 3.76 – 3.63 (3H, m), 2.35 –
2.26 (1H, m), 2.12 – 2.06 (1H, m). 13C NMR (125 MHz) (CDCl3) (amide rotamers) δ: 173.2,
172.0, 155.0, 154.5, 136.3, 136.2, 128.4, 128.4, 128.0, 128.0, 127.9, 127.8, 70.1, 69.4, 67.2, 57.8,
57.6, 55.2, 54.6, 52.4, 52.1, 39.1, 38.4.
Figure 9.8: Compound II.14

(2S,4R)-1-benzyl 2-methyl 4-(carbamoyloxy)pyrrolidine-1,2-dicarboxylate (II.14). To a 100

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mL roundbottom flask containing a stir bar was added (2S,4R)-1-benzyl 2-methyl 4hydroxypyrrolidine-1,2-dicarboxylate (2.0 g, 7.1 mmol). The vessel was sealed with a septa and
flushed with nitrogen. DCM (30 mL) was added and stirring commenced. To this mixture,
trichloroacetyl ioscyanate was added dropwise (1.0 mL, 1.59 g, 8.5 mmol). The reaction progress
was monitored by TLC (1:1 ethyl acetate: hexanes), which indicated starting material was
consumed (after 10 minutes). The crude reaction mixture was concentrated in vacuo to a foam.
The reaction mixure was dissolved in methanol (30 mL) and 25 mg potassium carbonate was
added (as a catalyst to generate methoxide). The reaction progress is monitored by TLC (1:1
ethyl acetate: hexanes), and on completion (10 minutes) the reaction was stopped by
concentrating in vacuo to give the crude product as an oil. The pure product is obtained by
column chromatography (1:1 ethyl acetate: hexanes, Rf = 0.60) as a clear oil (2.1 g, 92 %). 1H
NMR (500 MHz) (CDCl3) (amide rotamers) δ: 7.36 – 7.28 (5H, m), 5.23 – 5.01 (3H, m), 4.70
(2H, br s), 4.48 – 4.40 (1H, m), 3.81 – 3.69 (3H, m), 3.54 (1H, s), 2.48 – 2.40 (1H, m), 2.23 –
2.15 (1H, m). 13C NMR (125 MHz) (CDCl3) (amide rotamers) δ: 172.6, 172.5, 155.6, 154.7,
154.1, 128.4, 128.4, 128.1, 128.1, 127.9, 127.9, 73.3, 72.6, 67.3, 57.8, 57.6, 52.6, 52.5, 52.3,
52.2, 36.7, 35.7. HRMS calc’d for [M+H] = 323.1243, observed [M+H] = 323.1248. IR (NaCl,
DCM): 1732, 1716, 1701, 1596, 1420, 1354, 1212, 1074, 1032.
Figure 9.9: Compound II.15a

(2S,4R)-methyl 4-hydroxy-1-tosylpyrrolidine-2-carboxylate (II.15a). To a 250 mL
roundbottom flask containing a stir bar was added trans-4-hydroxy-L-proline (5.0 g, 38.1 mmol)
and sodium carbonate (8.29 g, 79.8 mmol), followed by 100 mL water. To this mixture was
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added tosyl chloride (8.55 g, 45.6 mmol). The mixture was allowed to stir at room temperature
for 48 hours, during which time nearly all the tosyl chloride dissolved. After this time, the
reaction mixture was acidified with 2N HCl until bubbles stopped evolving. During acidification,
a solid precipitated. This was filtered and washed with water (50 mL) and hexanes (50 mL). The
solid was dried in vacuo to constant weight to yield the product as a white solid (6.68 g, 55 %).
Spectroscopic data matches that reported for this compound.152 1H NMR (500 MHz) (d6-DMSO)
δ: 12.74 (1H, br s), 7.67 (2H, app quartet, J = 6.5, 2.0 Hz), 7.39 (2H, d, J = 8.0 Hz), 4.84 (1H, d,
J = 3.5 Hz), 4.19 (1H, br d, J = 3.5 Hz), 4.01 (1H, t, J = 8.0 Hz), 3.44 (1H, quartet, J = 10.0, 4.0
Hz), 3.07 (1H, app quartet, J = 11.5, 2.0 Hz), 2.38 (3H, s), 1.94 – 1.91 (2H, m). 13C NMR (125
MHz) (d6-DMSO) δ: 173.7, 143.6, 134.8, 130.0, 127.9, 68.8, 60.0, 56.7, 21.4. M.P. = 151 oC.
Figure 9.10: Compound II.15b

(2S,4R)-methyl 4-hydroxy-1-tosylpyrrolidine-2-carboxylate (II.15b). To a 250 mL
roundbottom flask containing a stir bar was added (6.61 g, 23 mmol) and methanol (100 mL).
Stirring commenced and the vessel was cooled to 0 oC in an ice-water bath. To this mixture was
slowly added thionyl chloride (1.5 mL, 2.44 g, 21 mmol) dropwise over 10 minutes. The icewater bath was removed and the reaction vessel was placed in a heating mantle. A reflux
condenser was attached to the roundbottom flask and the reaction mixture was heated to reflux
overnight. The next day, the reaction was cooled to room temperature and transferred to a
separatory funnel. To this was added ethyl acetate (100 mL) and water (50 mL). The water layer
was separated and discarded. The mixture was then washed with saturated sodium bicarbonate

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(50 mL) and water again (50 mL). The organic layer was dried on sodium sulfate and
concentrated to dryness in vacuo to yield the product as a white solid (7.42 g, 99 %).
Spectroscopic data matches that previously reported for this compound.153 1H NMR (500 MHz)
(CDCl3) δ TMS: 7.76 (2H, d, J = 9.5 Hz), 7.31 (2H, d, J = 8.5), 4.44 (1H, quintet, J = 6.5, 4.0,
2.5 Hz), 4.38 (1H, t, J = 7.5 Hz), 3.73 (3H, s), 3.59 (1H, dd, J = 11.0, 4.0 Hz), 3.37 (1H, dt, J =
11.0, 2.0 Hz), 2.41 (3H, s), 2.26 – 2.17 (1H, m), 2.11 – 2.06 (1H, m), 1.18 (1H, br s). 13C NMR
(125 MHz) (CDCl3) δ TMS: 172.5, 143.8, 134.6, 129.6, 127.7, 70.1, 59.3, 56.3, 52.5, 39.4, 22.5.
Melting point = 94 – 96o C.
Figure 9.11: Compound II.16

(2S,4R)-methyl 4-(sulfamoyloxy)-1-tosylpyrrolidine-2-carboxylate (II.16). A 50 mL
roundbottom flask containing a stir bar was sealed and flushed with nitrogen. To this vessel was
added chlorosulfonyl isocyanate (1.15 mL, 1.88 g, 21,75 mmol) and stirring commenced. The
vessel was cooled in an ice-water bath and 95 % formic acid was added dropwise (0.67 mL,
0.825 g, 21.75 mmol). Vigorous bubbling and solidification of the mixture was observed. To this
was added acetonitrile (5 mL), upon which the solid dissolved. The reaction was allowed to
proceed for 8 hours, during which time it warmed to room temperature.
In a separate roundbottom flask (50 mL) containing a stir bar was added (2S,4R)-methyl
4-hydroxy-1-tosylpyrrolidine-2-carboxylate (2.94 g, 9.8 mmol). The vessel was sealed with a
septa and flushed with nitrogen. To this was added dimethylacetamide (20 mL) by syringe. The
mixture was stirred until the solid dissolved, upon which time this solution was withdrawn into a
syringe and added dropwise to the chlorosulfonyl isocyanate/formic acid mixture from the first
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reaction vessel, and was allowed to proceed overnight.
To the reaction mixture was added ethyl acetate (100 mL). This was transferred to a
separatory funnel and the crude mixture was washed four times with water (100 mL) and four
times with saturated sodium chloride (100 mL). This was dried over sodium sulfate and
concentrated in vacuo. The crude was recrystallized by dissolving in ethyl acetate and adding
hexanes to yield the pure product as a brown solid (1.97 g, 51 %). 1H NMR (500 MHz) (d6DMSO) δ: 7.68 (2H, d, J = 7.5 Hz), 7.56 (2H, br s), 7.32 (2H, d, J = 8.0 Hz), 4.95 (1H, br t, J =
2.0 Hz), 4.18 (1H, t, J = 7.5 Hz), 3.72 (1H, dd, J = 12.0, 4.0 Hz), 3.65 (3H, s), 3.50 (1H, br d, J =
12.0 Hz), 2.49 (1H, br t, J = 1.5 Hz), 2.38 – 2.34 (4H, m), 2.29 – 2.23 (1H, m). 13C NMR (125
MHz) (d6-DMSO) δ: 171.8, 144.3, 134.4, 130.3, 127.7, 77.6, 59.3, 54.1, 52.8, 36.8, 21.5. HRMS
[M+H] calc’d = 379.0634, observed [M+H] = 379.0634. IR (NaCl, DCM): 1752, 1598, 1437,
1372, 1310, 1180, 1160, 1055, 955, 898, 819. M.P. = 138 – 139o C.
Figure 9.12: Compound II.7

methyl (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-tosylpyrrolidine-2-carboxylate (II.7). To
an oven dried 100 mL roundbottom flask containing a stir bar was added (2S,4R)-methyl 4hydroxy-1-tosylpyrrolidine-2-carboxylate (3.0 g, 10.0 mmol), followed by acetonitrile (30 mL).
To this mixture was added (in the order described) imidazole (1.02 g, 15.0 mmol), TBS-Cl (1.65
g, 11.0 mmol), and DMAP (0.043 g, 0.35 mmol). The vessel was sealed with a septa and flushed
with nitrogen. Within 15 minutes crystals precipitated (presumably imidazole HCl salt). The
reaction was allowed to proceed overnight.

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The following day the reaction was quenched by adding methanol (2 mL), which
dissolved the precipitate. The crude reaction was transferred to a separatory funnel and
partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was washed
with brine (2 x 30 mL). The organic layer was dried over sodium sulfate and concentrated in
vacuo to yield the crude product as a clear oil. The crude product was purified by silica gel
chromatography (1:4 ethyl acetate: hexanes, Rf = 0.48) to yield the pure product as a white solid
(3.6 g, 87 %). 1H NMR (500 MHz) (CDCl3) δ: 7.74 (2H, d, J = 7.0 Hz), 7.30 (2H, d, J = 8.5 Hz),
4.37 - 4.25 (1H, m), 4.23 (1H, t, J = 7.5 Hz), 3.79 (3H, s), 3.64 (1H, dd, J = 20.0 Hz, 4.0 Hz),
3.19 – 3.17 (1H, m), 2.45 (3H, s), 2.08 – 2.04 (2H, m), 0.70 (9H, s), - 0.81 (6H, app t, J = 3.0
Hz). 13C NMR (125 MHz) (CDCl3) δ: 172.6, 143.6, 134.2, 129.6, 127.7, 70.3, 59.7, 56.7, 52.5,
40.1, 25.5, 21.5, 17.7, - 4.9, - 5.1. HRMS = [M+H] calc’d = 414.1770, observed = 414.1769. IR
(NaCl, DCM): 2952, 2856, 1740, 1471, 1350, 1020, 838. M.P. = 74 o C.
Figure 9.13: Compound II.7a

((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-tosylpyrrolidin-2-yl)methanol (II.7a). To a 100
mL roundbottom flask containing a stir bar and methyl (2S,4R)-4-((tert-butyldimethylsilyl)oxy)1-tosylpyrrolidine-2-carboxylate (2.2 g, 5.8 mmol) was added THF (50 mL). The reaction vessel
was sealed and flushed with nitrogen while stirring commenced. To this mixture was added
dropwise lithium borohydride (3.5 mL of a 2.0 M solution in THF, 7.0 mmol). The reaction
mixture was allowed to stir overnight. The following day, the reaction mixture was quenched
with saturated ammonium chloride (1.5 mL) and the crude reaction mixture was concentrated to
dryness as a white solid. This material was dissolved in ethyl acetate (50 mL) and washed with

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water (50 mL). The aqueous phase was extracted with an additional portion of ethyl acetate (50
mL) and the organic phases were combined, dried over sodium sulfate, and concentrated to
dryness in vacuo to yield a white solid. The crude product was purified by silica gel
chromatography (1:4 ethyl acetate: hexanes, Rf = 0.15) to yield the product as a white solid (2.0
g, 89 % yield). 1H NMR (500 MHz) (CDCl3) δ: 7.74 (2H, d, J = 8.5 Hz), 7.30 (2H, d, J = 7.0
Hz), 4.25 (1H, br s), 3.89 (1H, t, J = 7.0 Hz), 3.67 – 3.62 (3H, m), 3.22 (1H, br d, J = 11.0 Hz),
3.06 (1H, br s), 2.42 (3H, m), 1.92 – 1.87 (1H, br m), 1.76 – 1.72 (1H br m), 0.70 (9H, s), - 0.082
(3H, s), - 0.102 (3H, s). 13C NMR (125 MHz) (CDCl3) δ: 143.7, 133.5, 129.7, 127.8, 69.4, 65.2,
60.9, 58.6, 38.7, 25.5, 21.5, 17.8, - 4.9, - 5.0. HRMS calc’d for [M+H] = 386.1821, observed =
386.1829. IR: (NaCl, DCM): 3434, 2858, 1644, 1471, 1372, 1183.
Figure 9.14: Compound II.17

((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-tosylpyrrolidin-2-yl)methyl sulfamate (II.17). An
oven dried 100 mL roundbottom flask containing a stir bar was sealed with a septa and flushed
with nitrogen. To this vessel was added chlorosulfonyl isocyanate (1.0 mL, 1.70 g, 12.0 mmol)
via syringe. Stirring commenced and the reaction vessel was cooled to 0 oC in an ice water bath.
To the reaction mixture was added 95 % formic acid (0.450 mL, 12.0 mmol) dropwise via
syringe. Vigorous evolution of gas was observed, and the reaction mixture turned into a white
solid before addition of the formic acid was complete. To the white solid was added acetonitrile
(10 mL) via syringe, after which the precipitate dissolved. The reaction mixture was allowed to
warm to room temperature over 8 hours. In a separate reaction vessel, ((2S,4R)-4-((tertbutyldimethylsilyl)oxy)-1-tosylpyrrolidin-2-yl)methanol (2.0 g, 5.20 mmol) was dissolved in

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dimethylacetamide (20 mL) and transferred to the reaction vessel containing the chlorosulfonyl
isocyanate/formic acid/acetonitrile mixture via cannula. The combined reaction mixture was
allowed to stir at room temperature overnight. The following day, the reaction mixture was
quenched by the addition of ethyl acetate (200 mL). The crude reaction mixture was transferred
to a separatory funnel and washed with water (3 x 300 mL) and brine (3 x 300 mL). The crude
reaction mixture was purified by silica gel chromatograpy (1:3 ethyl acetate: hexanes, Rf = 0.15)
to yield the product as a clear oil (0.900 g, 37 % yield). 1H NMR (500 MHz) (CDCl3) δ: 7.72
(2H, d, J = 7.5 Hz), 7.31 (2H, d, J = 7.5 Hz), 5.19 (2H, br s), 4.55 (1H, dd, J = 10.0, 5.5 Hz),
4.41 (1H, dd, J = 10.0, 2.5 Hz), 4.29 (1H, quintet, J = 5.5, 4.5 Hz), 3.90 – 3.79 (1H, m), 3.62
(1H, dd, J = 11.0, 4.0 Hz), 3.18 – 3.15 (1H, m), 2,42 (3H, s), 2.11 – 2.06 (1H, m), 1.85 – 1.80
(1H, m), 0.07 (9H, s), - 0.09 (3H, s), - 0.10 (3H, s). 13C NMR (125 MHz) (CDCl3) δ: 144.0,
133.2, 129.8, 127.8, 71.6, 69.4, 57.7, 57.0, 38.4, 25.6, 21.5, 17.9, - 4.9, - 5.1. HRMS calc’d for
[M+Na] = 487.1369, observed = 487.1387. IR (NaCl, DCM): 3482, 2952, 2856, 1458, 1340,
1157, 1094, 951, 835. M.P. = 72 o C.
Figure 9.15: Compound II.6

(1S,4S)-benzyl 3-oxo-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (II.6). To a 250 mL
roundbottom flask was added a stir bar and (2S,4R)-1-((benzyloxy)carbonyl)-4hydroxypyrrolidine-2-carboxylic acid, 10.07 g, 38.0 mmol), followed by triphenylphosphine
(11.0 g, 42.0 mmol). The reaction vessel was sealed and flushed with nitrogen. Freshly distilled
THF (130 mL) was added by syringe. Stirring commenced and the reaction vessel was cooled to
0 oC in an ice-water bath. Diisopropylazodicarboxylate (DIAD) was added dropwise (8.26 mL,

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8.48 g, 42.0 mmol). During DIAD addition a white solid formed. Ten minutes after DIAD
addition the reaction vessel was removed from the ice-water bath, and allowed to stir at room
temperature overnight (shortly after removing the ice-water bath the solid formed on DIAD
addition dissolved). The following day the reaction mixture was concentrated in vacuo. The
crude reaction mixture was redissolved in a minimum amount of ethyl acetate and purified by
silica gel chromatography (gradient 1:9 to 1:1 ethyl acetate: hexanes) to afford the purified
compound as a solid (4.2 g, 48 % yield). Spectroscopic data matches that previously reported for
this compound.154 1H NMR (500 MHz) (CDCl3) δ: 7.38 – 7.31 (5H, m), 5.19 – 5.10 (3H, br s),
4.75 – 4.61 (1H, br s), 3.60 (1H, d, J = 10 Hz), 3.54 (1H, br s), 2.23 (1H, td, J = 11, 2.5, 1), 2.03
(1H, br s). 13C NMR (125 MHz) (CDCl3) δ: 170.7, 154.4, 135.8, 128.5, 128.3, 128.1, 78.2, 67.9,
67.7, 57.6, 50.0, 39.2. M.P. = 94 – 95o C.
Figure 9.16: Compound II.18

2,6-difluorophenyl sulfamate (II.18). A 100 mL roundbottom flask containing a stir was sealed
with a septa and flushed with nitrogen for 5 minutes. To the reaction vessel was added
chlorosulfonyl isocyanate (3.75 mL, 6.06 g, 43 mmol), followed by acetonitrile (6 mL). The
reaction vessel was cooled to 0 °C in an ice water bath. To the cooled reaction mixture was
added 95 % formic acid dropwise (1.65 mL, 2.02 g, 43.7 mmol). During the addition vigorous
bubbling was observed and the reaction mixture solidified to a white solid. After the addition of
formic acid was complete, acetonitrile was added for a second time (12 mL). The white solid
dissolved to produce a clear solution, which was removed from the ice bath and allowed to stir at
room temperature for 2 hours. This reaction mixture was again cooled to 0 °C before addition of

106

the alcohol. A separate 50 mL reaction vessel was charged with 2,6-difluorophenol (2.53 g, 19.5
mmol), sealed with a septa and flushed with nitrogen for 5 minutes. To this was added dimethyl
acetamide (10 mL). The alcohol/dimethylacetamide solution was transferred to the
chlorosulfonyl isocyanate/acid solution via cannula, and the mixture was allowed to stir at room
temperature overnight.
The following day, water was added to the reaction mixture (80 mL). This was
transferred to a separatory funnel and washed twice with ether (80 mL). The organic layers were
combined and washed four times with water (150 mL per wash). The organic layer was dried
over sodium sulfate and concentrated to dryness in vacuo. The crude product was recrystallized
by dissolving in hot acetone and adding chloroform, to yield the title compound as a pink solid
(2.91 g, 72 %). Spectroscopic data matches that reported for this compound.155 1H NMR (500
MHz) (d6-acetone) δ: 7.52 (2H, br s), 7.43 – 7.37 (1H, m), 7.21 – 7.15 (1H, m). 13C NMR (125
MHz) (d6-acetone) δ: 156.2, 127.9, 126.9, 112.6. M.P. = 103 o C.
Figure 9.17: Compound II.19

2,2,3,3,3-pentafluoropropanol sulfamate (II.19). A 100 mL roundbottom flask containing a
stir was sealed with a rubber septa and flushed with nitrogen for 5 minutes. To the reaction
vessel was added chlorosulfonyl isocyanate (6.0 mL, 9.9 g, 70.0 mmol). The reaction vessel was
cooled to 0 °C in an ice water bath. To the cooled reaction mixture was added 95 % formic acid
dropwise (2.62 mL, 3.12 g, 69.0 mmol). During the addition vigorous bubbling was observed
and the reaction mixture solidified to a white solid. After the addition of formic acid was
complete, anhydrous acetonitrile was added (18 mL). The white solid dissolved to produce a

107

clear solution, which was removed from the ice bath and allowed to stir at room temperature for
6 hours. This reaction mixture was again cooled to 0 °C before addition of the alcohol. A
separate 50 mL reaction vessel was charged with 2,2,3,3,3-pentafluoropropanol (5.0 g, 33.0
mmol), sealed with a septa and flushed with nitrogen for 5 minutes. To this was added anhydrous
dimethylacetamide (18 mL). The alcohol/dimethylacetamide solution was transferred to the
chlorosulfonyl isocyanate/acid solution via cannula, and the mixture was allowed to stir at room
temperature overnight.
The next day water (20 mL) was added to the reaction mixture and the reaction mixture
was transferred to a separatory funnel. This was washed twice with ethyl acetate (50 mL). The
organic layers were combined and washed with water (4 x 50 mL). The organic layer was dried
on sodium sulfate and concentrated in vacuo. The crude product was purified by silica gel
chromatography (3:7 ethyl acetate hexanes) to yield the purified product as a clear oil (4.83 g, 64
%). Spectroscopic data matches that reported for this compound.156 1H NMR (500 MHz) (d6acetone) δ: 7.20 (2H, br s), 4.71 (2H, dt, J = 12.5 Hz, 1.0 Hz). 13C NMR (125 MHz) (d6-acetone)
δ: 120.2 (qt, JCF = 283.6, 34.2 Hz), 113.7 (tq, JCF = 253.4, 38.0 Hz), 65.2 (t, JCF = 27.9 Hz).
Figure 9.18: Compound II.20a

6,6'-((1E,1'E)-(((1R,2R)-cyclohexane-1,2 diyl)bis(azanylylidene)) bis(methanylylidene))
bis(2,4-di-tert-butylphenol) (II.20a). To a 100 mL flask with a stir bar was added anhydrous
ethanol (25 mL), followed by (1R, 2R)-1,2-diamino-cyclohexane (1.0 g, 8.7 mmol). To this
mixture was added 3,5-di-tert-butyl-2-hydroxybenzaldehyde (4.1 g, 17.5 mmol). The vessel was

108

attached to a reflux condenser which was sealed with a septa and flushed with nitrogen. The
sealed reaction vessel was heated to reflux for 1.5 hours. Solid persisted throughout the reflux
period. After the prescribed time, the reaction mixture was cooled to room temperature and the
product was filtered through a fritted funnel and washed with cold ethanol (3 x 50 mL). The
precipitate was dried in vacuo to yield the product as a yellow solid (4.07 g, 85 %).
Spectroscopic data matches that known for this compound.157 1H NMR (500 MHz) (CDCl3):
13.7 (1H, br s), 8.31 (1H, s), 7.31 (1H, d, J = 2.5 Hz), 6.99 (1H, d, J = 3.5 Hz), 3.30 (1H, m),
1.96 – 1.87 (2H, m), 1.74 (1H, m), 1.54 – 1.42 (10H, m), 1.24 (9H, s). 13C NMR (125 MHz)
(CDCl3): 165.8, 157.9, 139.8, 136.3, 126.7, 126.0, 117.8, 72.4, 34.9, 34.0, 33.2, 31.4, 29.4, 24.3.
HRMS calc’d for [M+H] = 547.4264, observed = 547.4276. M. P. = 224 o C.
Figure 9.19: Compound II.20

6,6'-((1E,1'E)-(((1R,2R)-cyclohexane-1,2 diyl)bis(azanylylidene)) bis(methanylylidene))
bis(2,4-di-tert-butylphenol) manganese chloride (II.20). To a 100 mL roundbottom flask
containing a stir bar was added 6,6'-((1E,1'E)-(((1R,2R)-cyclohexane-1,2 diyl)bis(azanylylidene))
bis(methanylylidene)) bis(2,4-di-tert-butylphenol) (0.546 g, 1.0 mmol), followed by
manganese(II) tetrahydrate (1.22 g, 5.0 mmol), followed by ethanol (25 mL). Stirring
commenced, a reflux condenser was attached to the reaction vessel, and the reaction mixture was
heated to reflux for 8 hours. After 7 hours had elapsed, LiCl (0.212 g, 5.0 mmol) was added in
one portion, and refluxing continued for the final hour. After this, the reaction mixture was

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allowed to cool to room temperature and 25 mL water was added. The reaction vessel was sealed
and placed in a – 20 oC freezer overnight. The following day, the reaction mixture was filtered
on a fritted funnel and the dark brown solid that was collected was washed with water (50 mL).
Remaining solvent was removed in vacuo and to yield the pure product as a brown solid (0.858
g, 130 %; the product is known to crystallize with one or more molecules of ethanol, which
account for the excess yield158). HRMS calc’d for [M-Cl] = 599.3409, observed = 599.3414. M.
P. = no melting observed below 250 o C (consistent with the literature report).
Figure 9.20: Iodosylbenzene

Iodosylbenzene. This compound was prepared according to a literature procedure.13 To a 1000
mL roundbottom flask containing a stir bar was added diacetoxyiodobenzene (16.0 g, 50.0
mmol). To this vessel was added aqueous NaOH (1.88 M, 532 mL), and this mixture was stirred
at room temperature for 3 hours. After this period, the reaction mixture was filtered (fritted
funnel) and washed three times with water (250 mL per wash). The solid product was air dried
and transferred to a 250 mL roundbottom flask in which it was dried in vacuo overnight to yield
the product as a free flowing yellow powder (9.36 g, 90 %). M.P. = 220 o C.
Figure 9.21: Compound II.21a

1-hydroxy-1λ3-benzo[d][1,2]iodaoxol-3(1H)-one (II.21a). In a 250 mL roundbottom flask was
added a stir bar, 2-iodo-benzoic acid (8.95 g, 36 mmol), and aqueous acetic acid (100 mL of a 30

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% acetic acid/water solution). To this mixture was added sodium metaperiodate (7.72 g, 36
mmol). The reaction mixture was placed in a heating mantle on a magnetic stir plate and stirring
commenced. The reaction vessel was wrapped in aluminum foil (to protect it from ambient
light), the vessel and apparatus were placed behind a blast shield. The reaction mixture was
heated to reflux for four hours then cooled to room temperature. Once cool water was added (50
mL). The reaction mixture was stirred for an additional 40 minutes. At this point, the reaction
mixture was filtered, and the solid was washed twice with water (50 mL) and three times with
acetone (50 mL). The solid was dried in vacuo to yield the product as a white, crystalline powder
(8.8 g, 92 %). Spectroscopic data match that reported for this compound.159 1H NMR (500 MHz)
(d6-DMSO) δ: 8.03 – 7.93 (3H, m), 7.83 (1H, d, J = 8.0 Hz), 7.69 (1H, t, J = 7.5 Hz). 13C NMR
(125 MHz) (d6-DMSO) δ: 168.1, 134.9, 131.9, 131.9, 131.5, 130.8, 126.7, 120.8. M.P. = 251 o C.
Figure 9.22: Compound II.21

1-azido-1λ3-benzo[d][1,2]iodaoxol-3(1H)-one (II.21). To an oven dried 100 mL roundbottom
flask was added a stir bar and 1-hydroxy-1λ3-benzo[d][1,2]iodaoxol-3(1H)-one (2.12 g, 8 mmol).
The flask was sealed with a septa and flushed with nitrogen for 5 minutes. To the sealed vessel
was added acetonitrile (20 mL). Stirring commenced, and the solid dispersed to form a
suspension. To the stirring suspension was added TMSN3 dropwise via syringe (2.12 mL, 2.12 g,
16 mmol). The reaction was allowed to proceed overnight. Within one hour of adding the
TMSN3 the solid had dissolved, and over time a solid began to precipitate.
The following day, the reaction was quenched by the addition of ether (50 mL) and the
suspension was filtered (fritted funnel) and washed with ether. The yellow solid was dried in

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vacuo to yield the product (1.00 g, 44 %). Spectroscopic data matches that reported for this
compound.159 1H NMR (500 MHz) (20:1 CDCl3:TFA) δ: 8.36 – 8.34 (1H, m), 8.32 – 7.98 (2H,
m), 7.85 (1H, t, J = 7.5 Hz). 13C NMR (125 MHz) (CDCl3) δ: 170.6, 169.8, 138.0, 137.0, 134.1,
133.8, 132.3, 132.2, 128.9, 128.7, 127.0, 126.4, 118.6, 117.7, 115.6, 113.3, 111.0. IR (NaCl,
DCM): 3002, 2597, 2453, 2131, 2061, 1990, 1653, 1437, 1314. M.P. = 135 o C (detonation).
Figure 9.23: Compound II.22

2,6-bis((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)pyridine (II.22). To an oven dried 100 mL
roundbottom flask was added a stir bar, pyridine-2,6-dicarbonitrile (0.387 g, 3 mmol), and
Zn(OTf)2 (0.054 g, 0.015 mmol). The reaction vessel was sealed with a septa and purged with
argon for 5 minutes. To this mixture was added anhydrous toluene (20 mL). This mixture was
stirred for 5 minutes, at which time (S)-(+)-2-amino-3-methyl-1-butanol (0.618 g, 6 mmol) was
added via syringe dissolved in anhydrous toluene (10 mL). The reaction mixture was heated to
reflux for 48 hours. After this period, the reaction mixture was cooled to room temperature and
transferred to a separatory funnel. The crude reaction mixture was partitioned between ethyl
acetate (20 mL) and saturated sodium bicarbonate (30 mL). The organic later was washed with
brine (30 mL), dried over sodium sulfate and concentrated in vacuo to yield the product as a
white solid (0.730 g, 80 %). Spectroscopic data matches that reported for this compound.160,161
1

H NMR (500 MHz) (CDCl3) δ: 8.22 (2H, d, J = 8.0 Hz), 7.86 (1H, t, J = 7.5 Hz), 4.54 (2H,

quart., J = 8.0 Hz, 2.0 Hz), 4.23 (2H, t, J = 8.0 Hz), 4.17 – 4.14 (2H, m), 1.87 (2H, septet, J = 7.0

112

Hz), 1.05 (6H, d, J = 6.0 Hz), 0.94 (6H, d, J = 6.0 Hz). 13C NMR (125 MHz) (CDCl3) δ: 162.2,
146.9, 137.1, 125.7, 72.9, 70.9, 32.8, 19.0, 18.3. M.P. = 148 oC.
Figure 9.24: Compound III.2a

2,2-dimethylbutane-1,4-diol (III.2a). An oven dried 1000 mL roundbottom containing a stir bar
was charge with 500 mL THF and cooled to 0 oC in an ice bath. Stirring commenced and lithium
aluminum hydride (7.4 g, 200.0 mmol) was added slowly. The reaction vessel was sealed with a
septa and flushed with nitrogen. In a separate oven dried reaction vessel (250 mL) 2,2-dimethyl
succinic acid (10.0 g, 68.0 mmol) was dissolved in THF (100 mL). An endotherm was observed
on dissolution. The succinic acid/THF solution was cannulated into the LAH/THF solution,
during which hydrogen gas evolved. After the gas evolution stopped, the reaction vessel was
removed from the ice water bath and placed in a heating mantle. A reflux condenser was affixed
to the roundbottom flask and the septa was transferred to the top of the condenser (to keep the
reaction apparatus under positive pressure of nitrogen). The reaction mixture was heated to
reflux and allowed to reflux overnight. The following day the reaction mixture was cooled to 0 o
C in an ice bath and quenched with methanol (20 mL), water (20 mL), and 15 % w/v potassium
hydroxide (20 mL). The reaction mixture was concentrated in vacuo to ~ 20 % original volume
and the inorganic salts were separated by filtration on a fritted funnel. The inorganic salts were
washed twice with boiling ethyl acetate (2 x 100 mL). The organic layers were combined and
dried over magnesium sulfate and filtered. The organic layers were dried again over sodium
sulfate (twice) and concentrated in vacuo to yield the product as a clear oil (6.5 g, 81 %).
Spectroscopic data matches that reported for this compound.162 1H NMR (500 MHz) (CDCl3) δ:

113

3.71 (2H, t, J = 5.5 Hz), 3.34 (2H, s), 1.55 (2H, t, J = 5.5 Hz), 0.922 (6H, s). 13C NMR (125
MHz) (CDCl3) δ: 71.5, 59.1, 42.7, 34.9, 24.9.
Figure 9.25: Compound III.2b

4-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylbutan-1-ol (III.2b). To a 250 mL roundbottom
containing 2,2-dimethylbutane-1,4-diol (6.50 g, 55.0 mmol) was added DMF (100 mL) and
imidazole (8.5 g, 125.0 mmol) and TBDPS-Cl (13.0 mL, 13.7 g, 50.0 mmol) The reaction vessel
was sealed with a septa and flushed with nitrogen, and allowed to stir at room temperature for 60
hours. The reaction mixture was quenched with saturated sodium bicarbonate (100 mL) and
extracted with ether (4 x 50 mL). The crude product was purified by silica gel chromatography
(1:9 acetone: hexanes) to yield the title compound (14.6 g, 75%) as a colourless oil.
Spectroscopic data matches that reported for this compound.162 1H NMR (500 MHz) (CDCl3) δ:
7.59–7.63 (4H, m), 7.46 – 7.38 (6H, m), 3.71 (2H, t, J = 5.5 Hz), 3.37 (2H, d, J = 6.5 Hz), 3.25
(1H, t, J = 6.5 Hz), 1.56 – 1.53 (2H, m), 1.05 (9H, s), 0.897 (6H, s). 13C NMR (125 MHz)
(CDCl3) δ: 135.5, 134.7, 132.9, 129.8, 127.7, 71.5, 61.0, 41.9, 35.0, 26.7, 26.5, 25.0, 19.0.
Figure 9.26: Compound III.2

4-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylbutyl ethenesulfonate (III.2). To a 250 mL
roundbottom flask was containing 4-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylbutan-1-ol (3.4
g, 9.5 mmol) was added a stir bar and DCM (100 mL). The reaction vessel was sealed with a
septa and flushed with nitrogen. Stirring commenced and the reaction vessel was cooled to 0 oC
in an ice-water bath. To the stirring mixture was added dropwise 2-chloroethane-1-sulfonyl

114

chloride (2.18 mL, 3.4 g, 20.9 mmol). Once addition of the sulfonyl chloride was complete, TEA
(7.25 mL, 5.25 g, 52.0 mmol) was added dropwise. After the TEA addition was complete, the
reaction had turned rust-colored and a solid had precipitated. The reaction mixture was allowed
to stir overnight while warming to room temperature. The following day the reaction mixture
was quenched with the addition of 10 % w/v sodium carbonate (100 mL). The biphasic mixture
was transferred to a separatory funnel and partitioned. The organic layer was dried over sodium
sulfate and concentrated in vacuo. The crude product was dissolved in a minimum amount of
DCM and purified by silica gel chromatography (10 % acetone in hexanes) to yield the pure
product as a brown oil (2.5 g, 59 %). Spectroscopic data matches that reported for this
compound.162 1H NMR (500 MHz) (CDCl3) δ: 7.66 – 7.64 (4H, m), 7.45 – 7.38 (6H, m), 6.44 –
6.31 (2H, m), 6.04 (1H, d, J = 9.5 Hz), 3.85 (2H, s), 3.70 (2H, t, J = 6.5, 6.5 Hz), 1.58 (2H, t, J =
7.0, 7.0 Hz), 1.03 (9H, s), 0.961 (6H, s). 13C NMR (125 MHz) (CDCl3) δ: 135.5, 133.5, 132.2,
130.0, 129.6, 127.7, 78.8, 60.3, 40.9, 33.8, 26.8, 24.2, 19.0.
Figure 9.27: Compound III.3

4-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylbutyl (S)-2-(2-(hydroxymethyl)pyrrolidin-1yl)ethane-1-sulfonate (III.3). To a 100 mL roundottom flask containing a stir bar and 4-((tertbutyldiphenylsilyl)oxy)-2,2-dimethylbutyl ethenesulfonate (2.5 g, 5.6 mmol) was added DCM
(20 mL). Stirring commenced and to the reaction mixture was added (S)-pyrrolidin-2-ylmethanol
(5.0 g, 4.95 mmol). The reaction mixture was allowed to stir overnight and the following day
concentrated in vacuo. The crude material was purified by silica gel chromatography (dissolved

115

in DCM and applied to the column, eluted in 3:7 acetone: hexanes) to yield the product as a clear
oil (2.6 g, 95 %). 1H NMR (500 MHz) (CDCl3) δ: 7.68 – 7.66 (4H, m), 7.45 – 7.38 (6H, m), 3.96
(2H, app quartet, J = 9.5, 2.5 Hz), 3.73 (2H, t, J = 6.5, 6.5 Hz), 3.63 (1H, dd, J = 11.0, 3.0 Hz),
3.39 (1H, br d, J = 11.0 Hz), 3.32 – 3.21 (3H, m), 3.18 – 3.14 (1H, m), 2.80 – 2.76 (1H, m), 2.66
– 2.63 (1H, m), 2.55 (1H, br s), 2.31 – 2.26 (1H, m), 1.90 – 1.73 (4H, m), 1.60 (2H, t, J = 6.5, 6.5
Hz), 1.05 (9H, s), 0.972 (6H, s). 13C NMR (125 MHz) (CDCl3) δ: 135.5, 133.5, 129.6, 127.7,
77.6, 64.7, 62.1, 60.3, 54.2, 49.4, 48.3, 40.9, 33.8, 27.3, 26.8, 24.2, 23.7, 19.0. HRMS calc’d for
[M+H] = 548.2866, observed = 548.2879. IR (NaCl, DCM): 3420, 3073, 2958, 1644, 1352,
1165, 1108, 956, 822, 739.
Figure 9.28: Compound III.4a

benzyl (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (III.4a). To a 500 mL roundbottom
flask containing a stir bar was added (S)-pyrrolidin-2-ylmethanol (2.90 mL, 3.0 g, 29.7 mmol)
followed by DCM (100 mL). Stirring commenced and the reaction vessel was cooled to 0 oC in
an ice-water bath. To the stirring mixture was added TEA (5.6 mL, 4.04 g, 40.0 mmol) followed
by Cbz-Cl (3.7 mL, 4.42 g, 26.0 mmol). The reaction vessel was sealed with a septa and allowed
to warm to room temperature while stirring overnight. The following day, the reaction mixture
was transferred to a separatory funnel and extracted with dilute HCl (50 mL of a 10 % v/v
solution). The organic layer was dried over sodium sulfate and concentrated in vacuo to yield the
crude product as a pink oil. The crude material was purified by silica gel chromatography (1:1
ethyl acetate: hexanes) to yield the pure product as a clear, colorless oil (6.0 g, 86 %).
Spectroscopic data matches that reported for this compound.163 1H NMR (500 MHz) (CDCl3)
(amide rotamers) δ: 7.37 – 7.30 (5H, m), 5.15 (2H, dd, J = 13.5, 1.0 Hz), 4.38 (1H, br s), 4.04 –

116

3.95 (1H, m), 3.68 – 3.61 (2H, m), 3.58 – 3.53 (1H, m), 3.41 – 3.36 (1H, m), 2.07 – 2.00 (1H,
m), 1.91 – 1.75 (2H, m), 1.62 – 1.55 (1H, m). 13C NMR (125 MHz) (CDCl3) (amide rotamers) δ:
157.2, 136.4, 128.5, 128.1, 127.9, 67.2, 60.8, 47.3, 28.6, 24.0.
Figure 9.29: Compound III.4

benzyl (S)-2-((tosyloxy)methyl)pyrrolidine-1-carboxylate (III.4).To a 250 mL roundbottom
flask containing a stir bar and benzyl (S)-2-((tosyloxy)methyl)- pyrrolidine-1-carboxylate (6.0 g,
25.5 mmol) was added DCM (50 mL) followed by TEA (4.8 mL, 3.53 g, 35.0 mmol) and tosyl
chloride (4.85 g) in one portion. The reaction mixture was allowed to stir overnight. The
following day the the reaction mixture was transferred to a separatory funnel and extracted with
dilute HCl (35 mL of a 10 % v/v solution). The organic layer was dried over sodium sulfate and
concentrated in vacuo to yield the crude product as an orange oil. The crude material was
purified by silica gel chromatography (1:1 ethyl acetate: hexanes) to yield the pure product as a
clear oil (6.3 g, 65 %). Spectroscopic data matches that reported for this compound.164 1H NMR
(500 MHz) (CDCl3) (amide rotamers) δ: 7.73 (2H, ddd, J = 11.5, 27.0, 8.5 Hz), 7.38 – 7.26 (7H,
m), 5.09 – 4.96 (2H, m), 4.19 – 3.90 (3H, m), 3.42 – 3.32 (2H, m), 2.42 (3H, d, J = 7.5 Hz), 2.00
– 1.79 (5H, m). 13C NMR (125 MHz) (CDCl3) (amide rotamers) δ: 154.7, 154.2, 144.8, 144.7,
136.6, 136.3, 135.5, 132.8, 130.0, 129.8, 129.8, 128.5, 128.1, 128.0, 128.0, 127.8, 127.8, 127.7,
127.5, 69.8, 69.6, 67.0, 66.7, 57.6, 56.1, 55.4, 49.3, 47.0, 46.7, 28.5, 27.6, 26.8, 24.2, 23.8, 23.7,
22.8, 21.6.

117

Figure 9.30: Compound III.5

benzyl (S)-2-((1,3-dioxoisoindolin-2-yl)methyl)pyrrolidine-1-carboxylate (III.5). To a 100
mL oven-dried roundbottom flask containing a stir bar and benzyl (S)-2-((tosyloxy)methyl)pyrrolidine-1-carboxylate (6.3 g, 16.2 mmol) was added potassium phthalimide (5.0 g, 27.0
mmol). The reaction vessel was sealed with a septa, flushed with argon, and DMF (40 mL) was
added via syringe. The reaction vessel was heated to 70 oC in an oil bath and stirred overnight.
The following day the reaction was diluted with ethyl acetate (100 mL), transferred to a
separatory funnel and washed with aqueous sodium bicarbonate (150 mL) and brine (3 x 70 mL).
The organic layer was dried over sodium sulfate and concentrated in vacuo to yield the crude
product as an oil. The crude material was purified by silica gel chromatography (1:2 ethyl
acetate: hexanes, Rf = 0.28) to yield the pure product as an oil (3.4 g, 58 %). 1H NMR (500
MHz) (CDCl3) (amide rotamers) δ: 7.82 – 7.80 (1H, m), 7.76 – 7.75 (1H, m), 7.69 – 7.66 (2H,
m), 7.33 – 7.26 (5H, m), 5.12 – 4.77 (2H, m), 4.40 – 4.31 (1H, m), 3.91 – 3.81 (1H, m), 3.69
(1H, ddd, J = 33.5, 13.5, 6.0 Hz), 3.50 – 3.39 (2H, m), 2.03 – 1.89 (3H, m), 1.83 – 1.79 (1H, m).
C NMR (125 MHz) (CDCl3) (amide rotamers) δ: 168.5, 168.3, 155.2, 154.8, 136.9, 136.4,

13

133.9, 133.7, 132.1, 131.8, 129.8, 128.3, 127.8, 127.8, 127.7, 127.6, 123.2, 123.2, 66.9, 66.5,
55.9, 55.6, 46.5, 46.1, 40.5, 29.1, 28.3, 23.6, 22.6. HRMS calc’d for [M+H] = 365.1501,
observed = 365.1508. IR (NaCl, DCM): 3065, 2955, 1771, 1716, 1699, 1653, 1558, 1506, 1418,
1361, 1109.

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Figure 9.31: Compound III.6a

tert-butyl (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (III.6a). To a 100 mL
roundbottom flask containing a stir bar was added (S)-2-(hydroxymethyl)pyrrolidine (1.0 mL,
1.0 g, 9.9 mmol) and DCM (30 mL). Stirring commenced and to the reaction mixture was added
Boc anhydride (1.96 g, 9.0 mmol) as a solid in one portion. The reaction vessel was sealed with a
septa and flushed with nitrogen, and allowed to proceed overnight. The following day the
reaction mixture was concentrated in vacuo to yield the crude product as a yellow oil. The crude
material was purified by silica gel chromatography (1:3 ethyl acetate: hexanes) to yield the pure
product as a clear oil (1.68 g, 93 %). Spectroscopic data matches that reported for this
compound.165 1H NMR (500 MHz) (CDCl3) (amide rotamers) δ: 4.78 -4.76 (1H, m), 3.97 – 3.95
(1H, m), 3.65 – 3.55 (3H, m), 3.46 – 3.41 (1H, m), 3.32 – 3.27 (1H, m), 2.03 – 1.96 (1H, m),
1.84 – 1.71 (3H, m), 1.54 – 1.46 (13H, m). 13C NMR (125 MHz) (CDCl3) (amide rotamers) δ:
157.2, 80.2, 67.8, 60.2, 47.5, 28.9, 28.4, 24.0.
Figure 9.32: Compound III.6

tert-butyl (S)-2-((tosyloxy)methyl)pyrrolidine-1-carboxylate (III.6). To a 500 mL
roundbottom flask containing a stir bar was added tert-butyl (S)-2-(hydroxymethyl)pyrrolidine1-carboxylate (12.4 g, 62.0 mmol) followed by DCM (200 mL). The reaction vessel was sealed
with a septa, flushed with nitrogen, and cooled to 0 oC in an ice-water bath. To the stirring
mixture was added TEA (11.2 mL, 8.08 g, 80.0 mmol) followed by tosyl chloride (12.3 g, 65.0
mmol, dissolved in 50.0 mL DCM). The reaction was allowed to stir overnight while warming to

119

room temperature. The following day the reaction mixture was transferred to a separatory funnel
and washed with 10 % HCl (50 mL) and brine (150 mL). The crude product was concentrated in
vacuo to yield a brown oil which was purified by silica gel chromatography (1:4 ethyl acetate:
hexanes, Rf = 0.46) to yield the pure product as a clear oil (4.1 g, 19 %). Spectroscopic data
matches that reported for this compound.165 1H NMR (500 MHz) (CDCl3) (amide rotamers) δ:
7.76 (2H, d, J = 7.5 Hz), 7.34 (2H, br s), 4.12 – 3.86 (3H, m), 3.34 – 3.26 (2H, m), 2.44 (3H, s),
1.96 – 1.78 (5H, m), 1.38 (9H, d, J = 25.0 Hz). 13C NMR (125 MHz) (CDCl3) (amide rotamers)
δ: 154.4, 154.0, 144.9, 144.7, 132.8, 130.0, 129.8, 129.0, 128.1, 127.8, 126.0, 79.9, 79.5, 69.9,
67.7, 55.5, 46.9, 46.4, 30.7, 28.3, 27.6, 23.8, 23.7, 22.8, 21.6, 21.4. HRMS calc’d for [M+Na] =
378.1351, observed = 378.1375. IR (NaCl, DCM): 2975, 1694, 1395, 1364, 1175, 969, 665, 552.
Figure 9.33: Compound III.7a

tert-butyl (S)-2-(aminomethyl)pyrrolidine-1-carboxylate (III.7a). To a 250 mL roundbottom
flask was containing a stir bar was added tert-butyl (S)-2-(tosyloxymethyl)pyrrolidine-1carboxylate (37.0 g, 104 mmol) followed by DMF (60 mL). Stirring commenced, and to the
reaction mixture was added sodium azide (8.12 g, 125.0 mmol). The reaction vessel was sealed
with a septa, flushed with nitrogen, and heated to 70 oC overnight. The following day, the
reaction mixture was cooled to room temperature and transferred to a separatory funnel. The
reaction mixture was partitioned between ethyl acetate (200 mL) and 10 % HCl (100 mL). The
organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to a
yellow oil. The crude material was purified by passing it through a silica plug (eluting in 1:4
ethyl acetate: hexanes) to yield the product, tert-butyl (S)-2-(azidomethyl)pyrrolidine-1-

120

carboxylate, as a clear oil (9.5 g, 40 %). The product was dissolved in methanol (150 mL) to
which 10 % palladium on carbon was added (1.5 g). A stir bar was added to the reaction vessel
and stirring commenced. A hydrogen balloon was affixed to the reaction vessel and hydrogen
gas was applied to the stirring mixture overnight. The following day the hydrogen balloon was
removed and the reaction mixture was concentrated in vacuo. The black oil was dissolved in
ethyl acetate and filtered through celite. The filtrate was concentrated in vacuo to yield an oil.
The crude material was extracted into aqueous HCl and partitioned. The aqueous layer was made
basic and back-extracted into ethyl acetate (3 x 100 mL). The organic layers were dried over
sodium sulfate and concentrated in vacuo to yield the pure product as a clear oil (5.0 g, 21 %)
Spectroscopic data matches that reported for this compound.166 1H NMR (500 MHz) (CDCl3)
(amide rotamers) δ: 3.78 – 3.70 (1H, m), 3.44 – 3.30 (2H, m), 2.83 – 2.76 (1H, m), 2.65 (1H, dd,
J = 13.0, 6.5 Hz), 1.93 – 1.85 (1H, m), 1.84 – 1.80 (3H, m), 1.45 (9H, br s), 1.15 (2H, br s). 13C
NMR (125 MHz) (CDCl3) (amide rotamers) δ: 155.1, 79.3, 79.1, 59.7, 46.9, 46.6, 45.4, 29.0,
28.5, 28.4, 23.8, 23.1.
Figure 9.34: Compound III.7

tert-butyl (S)-2-((((benzyloxy)carbonyl)amino)methyl)pyrrolidine-1-carboxylate (III.7). To
a 250 mL roundbottom flask containing a stir bar was added tert-butyl (S)-2(aminomethyl)pyrrolidine-1-carboxylate (4.1 g, 20.0 mmol) followed by DCM (100 ml). The
reaction vessel was stirred, sealed with a septa, and flushed with nitrogen. To the stirring mixture
was added TEA (4.17 mL, 3.03 g, 30.0 mmol), followed by Cbz-Cl (3.50 mL, 4.25 g, 25.0
mmol). A precipitate formed on Cbz-Cl addition and the reaction mixture was allowed to stir

121

overnight. The following day, the mixture was transferred to a separatory funnel and washed
with 10 % HCl (1 x 50 mL), followed by saturated aqueous sodium bicarbonate (1 x 100 mL).
The organic layer was partitioned, dried over sodium sulfate, and concentrated in vacuo to yield
a clear oil. The crude material was purified by silica ge chromatography (1:3 ethyl
acetate:hexanes, Rf = 0.35) to yield the product as a clear oil (4.00 g, 60 %). 1H NMR (500 MHz)
(CDCl3) (amide rotamers) δ: 7.35 – 7.31 (5H, m), 6.02 (1H, br s), 5.13 – 5.09 (2H, m), 3.94 –
3.88 (1H, m), 3.44 – 3.24 (4H, m), 2.00 – 1.80 (4H, m), 1.45 (9H, br s). 13C NMR (125 MHz)
(CDCl3) (amide rotamers) δ: 128.4, 127.9, 79.7, 66.7, 66.4, 56.8, 47.0, 46.0, 29.2, 28.5, 28.4,
23.8. HRMS calc’d for [M+H] = 355.1971, observed = 355.1968.
Figure 9.35: Compound III.8

1-benzyl 2-ethyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (III.8). To a 250 mL
roundbottom flask containing a stir bar was added trans-4-hydroxy-L-proline (2.62 g, 20.0
mmol) followed by sodium carbonate (3.15 g, 30.0 mmol) and water (50 mL). Stirring
commenced and the solids dissolved. To the stirring mixture was added toluene (50 mL)
followed by Cbz-Cl (2.71 mL, 3.23 g, 19.0 mmol) via syringe. The reaction mixture was stirred
vigorously overnight. The following day, the reaction mixture was transferred to a separatory
funnel and partitioned. The aqueous layer was made acidic (pH ~ 2 by pH paper) and extracted
with ethyl acetate (2 x 100 mL). The organic layer was dried over sodium sulfate and
concentrated in vacuo to yield the product, (2S,4R)-1-((benzyloxy)carbonyl)-4hydroxypyrrolidine-2-carboxylic acid as a clear oil (5.06 g, 96 %). This material was carried on
to the next step with no further purification. The oil previously obtained was dissolved in ethanol
122

(200 mL) and cooled to 0 oC in an ice-water bath. Stirring commenced and to the reaction
mixture was added thionyl chloride (2.5 mL, 4.1 g, 35.0 mmol). The reaction vessel was
transferred to a heating mantle and heated to reflux overnight. The following day, the reaction
mixture was cooled to room temperature and concentrated in vacuo to yield a clear oil. The crude
oil was dissolved in ethyl acetate (150 mL), transferred to a separatory funnel and washed with
sodium bicarbonate (100 mL) and brine (100 mL). The organic layer was dried over sodium
sulfate and concentrated in vacuo to yield the product as a clear oil (5.56 g, 98 %). Spectroscopic
data matches that reported for this compound.167 1H NMR (500 MHz) (CDCl3) (amide rotamers)
δ: 7.35 – 7.30 (5H, m), 5.18 – 5.02 (2H, m), 4.51 – 4.45 (2H, m), 4.23 – 4.18 (1H, m), 4.03 –
3.98 (1H, m), 3.72 – 3.54 (2H, m), 2.35 – 2.26 (1H, m), 2.12 – 2.06 (1H, m), 1.99 – 1.26 (1H,
m), 1.28 – 1.09 (3H, m). 13C NMR (125 MHz) (CDCl3) (amide rotamers) δ: 172.7, 172.5, 154.9,
154.5, 136.4, 136.2, 128.4, 128.3, 128.0, 127.9, 127.9, 127.8, 70.2, 69.4, 67.2, 67.2, 61.3, 61.1,
57.9, 57.7, 55.2, 54.6, 39.2, 38.4, 14.1, 13.9.
Figure 9.36: Compound III.9

1-benzyl 2-ethyl (2S,4S)-4-((4-nitrobenzoyl)oxy)pyrrolidine-1,2-dicarboxylate (III.9). To a
500 L roundbottom flask containing 1-benzyl 2-ethyl (2S,4R)-4-hydroxypyrrolidine-1,2dicarboxylate (17.8 g, 60.0 mmol) and a stir bar was added THF (250 mL). Stirring commenced
and to the reaction mixture was added triphenylphosphine (22.2 g, 85.0 mmol) and paranitrobenzoic acid (13.7 g, 85.0 mmol). The reaction vessel was sealed and flushed with nitrogen.
The reaction vessel was cooled to 0 oC in an ice bath and diethyl azodicarboxylate (13.3 mL,
123

14.7 g, 85.0 mmol) was added dropwise. The reaction mixture was allowed to stir overnight. The
following day the crude reaction mixture was concentrated in vacuo to a yellow solid. The crude
product was dissolved in ethyl acetate (100 mL) and extracted with saturated sodium bicarbonate
(100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate and concentrated
in vacuo to yield an orange solid. The crude product was dissolved in dichloromethane (100 mL)
and filtered through a plug of silica gel. The product was concentrated again in vacuo and the
purified product was obtained by recrystallization from ethyl acetate as a white solid (14.35 g, 54
%). 1H NMR (500 MHz) (CDCl3) (amide rotamers) δ: 8.30 (2H, d, J = 8.5 Hz), 8.15 (2H, d, J =
8.5 Hz), 7.39 – 7.31 (5H, m), 5.60 (1H, br s), 5.24 – 5.13 (2H, m), 2.65 (1H, dd, J = 9.5, 2.0 Hz),
4.20 – 4.14 (1H, m), 4.07 (1H, q, J = 7.5, 7.5 Hz), 3.91 – 3.83 (2H, m), 2.64 – 2.48 (2H, m), 1.21
– 1.06 (3H, m). 13C NMR (125 MHz) (CDCl3) (amide rotamers) δ: 171.4, 171.2, 163.9, 163.8,
154.5, 150.7, 136.2, 134.9, 134.9, 130.9, 130.8, 128.5, 128.4, 128.1, 128.1, 128.0, 127.9, 123.5,
74.3, 73.3, 67.4, 67.3, 61.4, 61.4, 58.0, 57.6, 52.8, 52.4, 36.6, 35.6, 14.1, 14.1. HRMS calc’d for
[M+H] = 443.1454, observed = 443.1454. IR (NaCl, DCM): 1722, 1715, 1705, 1525, 1416,
1348, 1272, 1196, 1103, 1061, 1013. M.P. = 136 oC.
Figure 9.37: Compound III.10

1-(tert-butyl) 2-methyl (2S,4S)-4-((4-nitrobenzoyl)oxy)pyrrolidine-1,2-dicarboxylate
(III.10). To an oven-dried 500 mL roundbottom flask containing a stir bar was added 1-(tertbutyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (18.2 g, 74.0 mmol) followed

124

by freshly distilled THF (250 mL). To the reaction vessel was added triphenylphosphine (25.1 g,
96.0 mmol) and para-nitrobenzoic acid (15.8 g, 95.0 mmol). The reaction vessel was sealed with
a septa and flushed with nitrogen. Stirring commenced and the reaction vessel was cooled to 0 oC
in an ice-water bath. To the stirring mixture was added dropwise diethylazodicarboxylate (15.1
mL, 16.8 g, 97.0 mmol). The reaction mixture was allowed to stir overnight while warming to
room temperature. The following day, the reaction mixture was concentrated in vacuo to approx.
20 % original volume and diluted with ethyl acetate (200 mL). The crude material was
transferred to a separatory funnel and washed with sodium bicarbonate (100 mL) and brine (3 x
100 mL). The crude material was concentrated again in vacuo to yield an oil. The oil was
dissolved in a minimum amount of DCM (~ 50 mL) and purified by silica gel chromatography
(gradient ethyl acetate: hexanes 1:9 to 1:4 to 1:3) to yield the product as an oil (24.2 g, 83 %).
Spectroscopic data matches that reported for this compound.168 1H NMR (500 MHz) (CDCl3)
(amide rotamers) δ: 8.26 (2H, d, J = 9.5 Hz), 8.13 (2H, d, J = 9.5 Hz), 5.56 (1H, br s), 4.60 –
4.46 (1H, m), 3.83 – 3.67 (5H, m), 2.62 – 2.50 (1H, m), 2.44 (1H, br d, J = 14.0 Hz), 1.45 (9H,
m). 13C NMR (125 MHz) (CDCl3) (amide rotamers) δ: 172.3, 172.1, 163.9, 163.8, 153.9, 153.6,
150.6, 135.0, 130.8, 130.8, 128.8, 128.6, 123.5, 123.4, 80.5, 80.5, 74.5, 73.4, 64.4, 62.9, 57.7,
57.4, 52.5, 52.3, 52.2, 52.1, 36.4, 35.5, 28.3, 28.2. Crystal Structure:

125

Table 9.1: Bond Lengths and Bond Angles for Compound III.10
Bond Angles
O1
O1
O2
O3
O4
O5
O5
O6
O7
O7
O8
N1
N1
N1
N2
C1
C1

C1
C5
C5
N2
N2
C14
C15
C14
C12
C13
C12
C2
C3
C14
C9
C2
C4

Bond Lengths
C5
C14
C12
C3
C14
C14
O3
O3
O4
O1
O1
C2
N1
N1
N1
C12
C1

1.466(2)
1.333(2)
1.204(2)
1.219(2)
1.220(2)
1.341(3)
1.475(3)
1.208(3)
1.329(3)
1.447(3)
1.202(3)
1.468(3)
1.452(3)
1.354(3)
1.472(2)
1.513(3)
1.516(3)

126

O1
O5
O7
N1
N1
N1
N2
N2
N2
C1
C1
C1
C2
C3
C3
C3
C4

C1
C15
C13
C2
C2
C3
O4
C9
C9
C2
C4
C4
C1
C4
C12
C4
C3

117.03(13)
120.1(2)
116.1(2)
112.80(16)
120.48(18)
125.87(17)
123.76(16)
117.71(14)
118.53(13)
106.22(15)
107.92(16)
104.71(15)
103.50(17)
101.66(17)
112.05(17)
113.47(15)
102.91(16)

Table 9.1 (cont’d)
C3
C3
C5
C6
C6
C7
C8
C9
C10
C15
C15
C15

C4
C12
C6
C7
C11
C8
C9
C10
C11
C16
C17
C18

O1
O2
O2
C7
C11
C11
C8
C7
C8
C8
C10
C11
C10
O7
O8
O8
O5
O6
O6
O5
O5
O5
C17
C17
C18

1.536(3)
1.530(3)
1.497(2)
1.401(2)
1.390(2)
1.384(2)
1.387(2)
1.390(2)
1.383(2)
1.521(3)
1.515(6)
1.516(4)

C5
C5
C5
C6
C6
C6
C7
C8
C9
C9
C9
C10
C11
C12
C12
C12
C14
C14
C14
C15
C15
C15
C15
C15
C15

C6
O1
C6
C5
C5
C7
C6
C9
N2
C10
N2
C9
C6
C3
O7
C3
N1
O5
N1
C16
C17
C18
C16
C18
C16

111.88(14)
124.55(16)
123.57(15)
121.66(14)
117.65(14)
120.69(15)
119.87(15)
118.13(14)
118.62(14)
123.06(16)
118.31(14)
118.14(14)
120.10(14)
109.75(17)
124.67(19)
125.58(19)
110.08(19)
126.64(19)
123.2(2)
110.39(18)
101.6(3)
108.82(19)
110.6(2)
112.4(3)
112.5(3)

Figure 9.38: Compound III.11a

tert-butyl (2S,4S)-4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (III.11a). To a
250 mL roundbottom flask containing a stir bar was added 1-(tert-butyl) 2-methyl (2S,4S)-4-((4nitrobenzoyl)oxy)pyrrolidine-1,2-dicarboxylate (7.2 g, 18.2 mmol). THF was added (100 mL),

127

the reaction vessel was sealed with a septa, flushed with nitrogen, and cooled to 0 oC in an icewater bath. Stirring commenced and lithium borohydride solution was added dropwise (45 mL of
a 2.0 M solution in THF, 90.0 mmol). As per the procedure, the reaction was allowed to warm to
room temperature and stir for 40 hours. The reaction mixture was quenched by cooling to 0 oC in
an ice-water bath and adding saturated aqueous ammonium chloride. The quenched reaction
mixture was concentrated in vacuo to yield the crude material, which was dissolved in ethyl
acetate (150 mL) and partitioned with water (100 mL). The organic layer was washed with brine
(2 x 100 mL) and concentrated in vacuo. The crude product was purified by silica gel
chromatography (1:3 ethyl acetate: hexanes) to yield the pure product as a white solid (2.6 g, 66
%). Spectroscopic data matches that reported for this compound.169 1H NMR (500 MHz)
(CDCl3) (amide rotamers) δ: 4.30 (1H, t, J = 5.0, 5.0 Hz), 4.08 (1H, dd, J = 10.0, 2.0 Hz), 4.03
(1H, br s), 3.60 – 3.44 (5H, m), 2.35 (1H, br s), 1.86 (1H, br s), 1.46 (9H, s). 13C NMR (125
MHz) (CDCl3) (amide rotamers) δ: 155.7, 80.8, 69.8, 69.0, 64.7, 63.9, 58.4, 58.2, 56.8, 38.2,
37.5.
Figure 9.39: Compound III.11

tert-butyl (2S,4S)-4-hydroxy-2-((tosyloxy)methyl)pyrrolidine-1-carboxylate (III.11). To a
250 mL roundbottom flask containing tert-butyl (2S,4S)-4-hydroxy-2(hydroxymethyl)pyrrolidine-1-carboxylate (2.6 g, 11.9 mmol) and a stir bar was added DCM
(150 mL) followed by pyridine (1.85 mL, 1.81 g, 23.0 mmol). The reaction vessel was sealed
with a septa, flushed with nitrogen, and cooled to 0 oC in an ice-water bath. In a separate reaction
vessel, tosyl chloride (2.66 g, 14.0 mmol) was dissolved in DCM (30 mL) and added dropwise to

128

the stirring solution of DCM and the cis-diol. The reaction mixture was allowed to warm to room
temperature and stirred overnight. The following day, the reaction mixture was transferred to a
separatory funnel and washed with dilute HCl (50 mL of a 10 % v/v solution of HCl in water).
The organic layer was dried over sodium sulfate and concentrated in vacuo to yield the crude
product as a white solid. The crude product was purified by silica gel chromatography (1:1 ethyl
acetate: hexanes, Rf = 0.55) to yield the product as a white solid (1.4 g, 32 %). 1H NMR (500
MHz) (CDCl3) (amide rotamers) δ: 7.78 (2H, br d), 7.34 (2H, br d), 4.40 – 4.18 (3H, m), 4.04
(2H, br d), 3.55 – 3.47 (1H, m), 3.31 (1H, br d), 2.45 – 2.43 (3H, m), 2.39 – 2.26 (1H, m), 2.03 –
2.01 (1H, m), 1.43 – 1.38 (9H, m). 13C NMR (125 MHz) (CDCl3) (amide rotamers) δ: 154.5,
154.1, 145.2, 144.9, 132.7, 130.0, 129.9, 127.9, 127.7, 80.3, 80.0, 70.6, 70.4, 70.0, 69.8, 55.5,
55.2, 55.1, 36.5, 35.9, 34.6, 28.3, 21.6, 21.6. HRMS calc’d for [M+Na] = 394.1301, observed =
394.1301. IR (NaCl, DCM): 3428, 2976, 1690, 1676, 1598, 1401, 1365, 1257, 1115, 1002, 835,
736, 665, 554. M.P. = 108 oC.
Figure 9.40: Compound III.12a

tert-butyl (2S,4S)-4-((tert-butyldiphenylsilyl)oxy)-2-((tosyloxy)methyl)pyrrolidine-1carboxylate (III.12a). To a 250 mL roundbottom flask containing a stir bar was added tert-butyl
(2S,4S)-4-hydroxy-2-((tosyloxy)methyl)pyrrolidine-1-carboxylate (1.4 g, 3.7 mmol) and DCM
(50 mL). Stirring commenced and imidazole was added (0.204 g, 3.0 mmol), followed by DMAP
(0.120 g, 1.0 mmol) and TBDPSCl (0.808 mL, 0.849 g. 3.1 mmol). On addition of the silyl
chloride, a white precipitate formed. The rreation mixture was allowed to stir overnight. The

129

following day the reaction mixture was transferred to a separatory funnel and extracted with 10
% HCl (30 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to
yield the crude product as an oil. The crude material was purified by silica gel chromatography
(1:4 ethyl acetate:hexanes, Rf = 0.7) to yield the pure product as a clear oil that solidified on
standing (2.1 g, 92 %). 1H NMR (500 MHz) (CDCl3) (amide rotamers) δ: 7.29 (2H, d, J = 8.5
Hz), 7.65 – 7.62 (3H, m), 7.45 – 7.38 (8H, m), 4.35 – 4.21 (1H, m), 3.96 – 3.74 (3H, m), 3.54 –
3.27 (2H, m), 2.49 (4H, s), 2.24 – 2.07 (2H, m), 1.44 – 140 (9H, m), 1.06 – 1.02 (9H, m). 13C
NMR (125 MHz) (CDCl3) (amide rotamers) δ: 146.9, 141.6, 135.7, 135.6, 135.6, 133.1, 130.2,
129.9, 127.8, 127.7, 127.0, 71.0, 28.4, 28.2, 26.8, 26.6, 21.8, 18.9. HRMS calc’d for [M+Na] =
632.2478, observed = 632.2482. IR (NaCl, DCM): 3121, 2922, 1684, 1458, 1364, 1097, 922,
820, 765, 655.
Figure 9.41: Compound III.12

tert-butyl (2S,4S)-2-(azidomethyl)-4-hydroxypyrrolidine-1-carboxylate (III.12). To a 100
mL roundbottom flask containing a stir bar was added tert-butyl (2S,4S)-4-((tertbutyldiphenylsilyl)oxy)-2-((tosyloxy)methyl)pyrrolidine-1-carboxylate (2.1 g, 3.4 mmol)
followed by DMF (30 mL). Stirring commenced and to the reaction mixture was added sodium
azide (5.0 g, 77.0 mmol). The reaction vessel was sealed with a septa and flushed with argon.
The reaction mixture was heated to 70 o C overnight. The following day, the reaction mixture
was quenched with the addition of ethyl acetate (150 mL). The reaction mixture was transferred
to a separatory funnel and washed with water (4 x 100 mL) and brine (100 mL). The organic
layer was dried over sodium sulfate and concentrated in vacuo to yield the crude product as an

130

oil. This material was purified by silica gel chromatography (1:3 ethyl acetate:hexanes) to yield
the pure product as a clear oil (1.3 g, 79 %). 1H NMR (500 MHz) (CDCl3) (amide rotamers) δ:
7.65 – 7.62 (4H, m), 746 – 7.38 (6H, m), 4.76 (1H, d, J = 8.5 Hz), 4.33 – 4.24 (1H, m), 3.97 –
3.69 (3H, m), 3.46 – 3.24 (2H, m), 2.09 – 1.63 (2H, m), 1.43 (9H, s), 1.06 (9H, s). 13C NMR (125
MHz) (CDCl3) (amide rotamers) δ: 156.9, 135.7, 135.6, 133.4, 133.1, 129.9, 129.9, 127.8, 127.7,
80.3, 71.0, 68.2, 59.6, 55.2, 37.5, 28.4, 26.8, 18.9. HRMS calc’d for [M+H] = 481.2635,
observed = 481.2607. IR (NaCl, DCM): 3074, 2933, 2099, 1668, 1540, 1405, 1341, 1255, 1165,
1109, 1036, 909.
Figure 9.42: Compound III.13a

(S)-2-(1-((benzyloxy)carbonyl)pyrrolidin-2-yl)acetic acid (III.13a). To a 500 mL
roundbottom flask containing a stir bar was added benzyl (S)-2-((tosyloxy)methyl)pyrrolidine-1carboxylate (17.3 g, 44.4 mmol), DMF (50 mL), and KCN (5.12 g, 80.0 mmol). The reaction
vessel was sealed and flushed with argon. Stirring commenced and the reaction vessel was
heated to 70 oC overnight. The following day, the crude material was partitioned between ethyl
acetate (200 mL) and water (100 mL). The organic layer was washed with water (100 mL) and
brine (200 mL). The aqueous layers were combined and treated with KMnO4 (until the solution
maintained a purple color) to destroy any unreacted cyanide. The organic layer was dried over
sodium sulfate and concentrated in vacuo to yield the crude product as a brown oil. The crude
material was purified by silica gel chromatography (1:1 ethyl acetate: hexanes) to yield the

131

purified product as a clear oil (10.2 g, 94 %). The product, benzyl (S)-2(cyanomethyl)pyrrolidine-1-carboxylate, was added to a 500 mL roundbottom flask with a stir
bar, acetic acid (50 mL) and concentrated HCl (50 mL). Stirring commenced, and the reaction
vessel was heated to reflux overnight. The following day, the reaction vessel was cooled to room
temperature, transferred to a separatory funnel and extracted with ether (200 mL). The organic
layer was discarded and the aqueous layer was diluted to 400 mL with water. Dioxane was added
to the reaction mixture with a stir bar. Stirring commenced and sodium carbonated was added
until the reaction mixture was basic (by pH paper). To the stirring mixture was added Cbz-Cl
(6.0 mL, 7.14 g, 42.0 mmol) and the reaction mixture was stirred overnight. The following day,
the reaction mixture was transferred to a separatory funnel and extracted with ethyl acetate (200
mL). The crude reaction mixture was made acidic by addition of concentrated HCl and extracted
with ethyl acetate (4 x 150 mL). The organic layers were combined, dried over sodium sulfate,
and concentrated in vacuo to yield the pure product as a clear oil (7.2 g, 62 %). Spectroscopic
data matches that reported for this compound.170 1H NMR (500 MHz) (CDCl3) (amide rotamers)
δ: 10.55 (1H, br s), 7.37 – 7.31 (5H, m), 5.15 – 5.11 (2H, m), 4.26 – 4.21 (1H, m), 3.44 – 3.41
(2H, m), 3.06 – 2.82 (1H, m), 2.2 – 2.37 (1H, m), 2.13 – 2.07 (1H, m), 1.90 – 1.80 (3H, m). 13C
NMR (125 MHz) (CDCl3) (amide rotamers) δ: 176.7, 176.5, 154.9, 154.7, 136.6, 128.5, 128.4,
128.3, 128.1, 127.9, 127.8, 66.8, 54.3, 53.8, 46.8, 46.5, 39.0, 38.4, 31.4, 30.8, 23.5, 22.7.

132

Figure 9.43: Compound III.13

benzyl (S)-2-(2-(benzyloxy)-2-oxoethyl)pyrrolidine-1-carboxylate (III.13). To a 100 mL
roundbottom flask containing a stir bar was added (S)-2-(1-((benzyloxy)carbonyl)pyrrolidin-2yl)acetic acid (0.865 g, 3.2 mmol) followed by DCM (20 mL). Stirrinng commenced and to the
reaction mixture was added TEA (0.835 mL, 0.606 g, 6.0 mmol) followed by EDCI (0.684 g, 3.6
mmol), benzyl alcohol (0.311 mL, 0.324 g, 3.0 mmol), and DMAP (0.120 g, 1.0 mmol). The
reaction mixture was allowed to stir overnight. The following day the reaction mixture was
transferred to a separatory funnel and washed with 10 % HCl (20 mL) and sodium bicarbonate
(30 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to yield the
crude product as a yellow oil. The crude product was purified by silica gel chromatography (1:3
ethyl acetate: hexanes, Rf = 0.65) to yield the pure product as a clear oil (0.746 g, 66 %). 1H
NMR (500 MHz) (CDCl3) (amide rotamers) δ: 7.36 – 7.30 (10H, m), 5.14 – 5.07 (2H, m), 4.28 –
4.23 (1H, m), 3.46 – 3.39 (2H, m), 3.06 – 2.83 (1H, m), 2.44 – 2.36 (1H, m), 2.11 – 2.04 (2H,
m), 1.89 – 1.75 (3H, m). 13C NMR (125 MHz) (CDCl3) (amide rotamers) δ: 171.2, 171.0, 154.6,
136.9, 136.7, 135.9, 135.7, 128.5, 128.5, 128.4, 128.2, 128.2, 128.1, 127.9, 127.8, 6.8, 66.6, 66.2,
54.5, 54.0, 46.7, 46.4, 39.3, 38.3, 31.3, 30.5, 23.5, 22.7. HRMS calc’d for [M+H] = 354.1705,
observed = 354.1716. IR (NaCl, DCM): 3030, 2961, 1732, 1697, 1410, 1210, 742, 697.

133

Figure 9.44: Compound III.14

benzyl (S)-2-(2-(benzylamino)-2-oxoethyl)pyrrolidine-1-carboxylate (III.14). To a 100 mL
roundbottom flask containing a stir bar was added (S)-2-(1-((benzyloxy)carbonyl)pyrrolidin-2yl)acetic acid (0.984 g, 3.7 mmol) followed by DCM (20 mL). Stirrinng commenced and to the
reaction mixture was added TEA (1.10 mL, 0.808 g, 8.0 mmol) followed by EDCI (0.798 g, 4.2
mmol), benzylamine (0.436 mL, 0.428 g, 4.0 mmol), and DMAP (0.120 g, 1.0 mmol). The
reaction mixture was allowed to stir overnight. The following day the reaction mixture was
transferred to a separatory funnel and washed with 10 % HCl (20 mL) and sodium bicarbonate
(30 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to yield the
crude product as a yellow oil. The crude product was purified by silica gel chromatography (1:1
ethyl acetate: hexanes, Rf = 0.25) to yield the product as an oil the solidifies on standing (0.524
g, 40 %). 1H NMR (500 MHz) (CDCl3) (amide rotamers) δ: 7.33 – 7.19 (10H, m), 6.46 – 5.67
(1H, m), 5.19 – 5.01 (2H, m), 4.44 – 4.29 (2H, m), 4.19 – 4.12 (1H, m), 3.44 – 3.35 (2H, m),
2.75 – 2.60 (1H, m), 2.43 – 1.79 (5H, m). 13C NMR (125 MHz) (CDCl3) (amide rotamers) δ:
170.6, 170.3, 155.1, 154.6, 138.3, 136.7, 128.6, 128.5, 128.0, 127.7, 127.4, 127.3, 66.8, 66.7,
55.7, 54.9, 46.8, 46.5, 43.4, 41.4, 40.8, 31.1, 30.7, 23.6, 22.8. HRMS calc’d for [M+H] =
353.1865, observed = 353.1873. IR (NaCl, DCM): 3307, 3062, 2953, 1699, 1646, 1547, 1453,
1312, 1211, 1003, 917, 749, 698.

134

Figure 9.45: Compound III.15

benzyl (S)-2-((2-phenylacetoxy)methyl)pyrrolidine-1-carboxylate (III.15). To a 100 mL
roundbottom flask containing a stir bar was added benzyl (S)-2-(hydroxymethyl)pyrrolidine-1carboxylate (0.789 g, 3.35 mmol), followed by DCM (20 mL). The reaction vessel was sealed,
flushed with nitrogen, and stirring commenced. To the stirring mixture was TEA (0.835 mL,
0.606 g, 6.0 mmol) via syringe followed by EDCI (0.646 g, 3.4 mmol), phenylacetic acid (0.476
g, 3.5 mmol) and DMAP (0.120 g, 1.0 mmol). The reaction mixture was stirred overnight. The
following day the reaction mixture was transferred to a separatory funnel and washed with 10 %
HCl (20 mL) and sodium bicarbonate (30 mL). The organic layer was dried over sodium sulfate
and concentrated in vacuo to yield the crude product as a yellow oil. The crude material was
purified by silica gel chromatography (1:3 ethyl acetate: hexanes, Rf = 0.45) to yield the pure
product as a clear oil (0.454 g, 38 %). 1H NMR (500 MHz) (CDCl3) (amide rotamers) δ: 7.36 –
7.26 (10H, m), 5.13 (2H, s), 4.25 – 4.07 (3H, m), 3.61 (2H, d, J = 19.5 Hz), 3.48 – 3.28 (2H, m),
1.95 – 1.87 (1H, m), 1.79 – 1.74 (3H, m). 13C NMR (125 MHz) (CDCl3) (amide rotamers) δ:
171.3, 154.9, 154.8, 136.8, 136.6, 133.9, 133.8, 129.2, 128.6, 128.5, 128.4, 128.0, 127.9, 127.8,
127.1, 127.0, 67.0, 66.7, 65.2, 64.6, 56.0, 55.4, 47.0, 46.5, 41.4, 41.3, 28.6, 27.7, 23.7, 22.9.
HRMS calc’d for [M+H] = 354.1705, observed = 354.1717. IR. (NaCl, DCM): 2955, 1736,
1699, 1412, 1356, 1254, 1179, 957, 725, 699.

135

Figure 9.46: Compound III.16

benzyl (S)-2-((2-phenylacetamido)methyl)pyrrolidine-1-carboxylate (III.16). To a 100 mL
roundbottom flask containing a stir was added benzyl (S)-2-(aminomethyl)pyrrolidine-1carboxylate (0.90 mL, 1.01 g, 4.35 mmol), followed by DCM (20 mL). Stirring commenced and
to the reaction mixture was added TEA (0.975 mL, 0.707 g, 7.0 mmol) followed by EDCI (0.950
g, 5.0 mmol), phenylacetic acid (0.584 g, 4.3 mmol), and DMAP (0.120 g, 1.0 mmol). The
reaction vessel was sealed with a septa, flushed with nitrogen, and allowed to stir overnight. The
following day, the reaction mixture was transferred to a separatory funnel and washed with 10 %
HCl (20 mL) followed by sodium bicarbonate (50 mL). The organic layer was dried over sodium
sulfate and concentrated in vacuo to yield the crude product as a yellow oil. The crude material
was purified by silica gel chromatography (1:1:0.05 ethyl acetate: hexanes: methanol, Rf = 0.15)
to yield the pure product as a clear oil (1.12 g, 73 %). 1H NMR (500 MHz) (CDCl3) (amide
rotamers) δ: 7.38 – 7.15 (10H, m), 7.22 – 6.95 (1H, m), 5.07 (2H, s), 3.99 – 3.96 (1H, m), 3.64 –
3.32 (5H, m), 3.23 – 3.18 (1H, m), 1.98 – 1.76 (3H, m), 1.69 – 1.65 (1H, m). 13C NMR (125
MHz) (CDCl3) (amide rotamers) δ: 171.4, 156.5, 136.5, 135.1, 129.4, 129.2, 128.8, 128.7, 128.7,
128.5, 128.4, 128.0, 127.8, 127.0, 126.8, 67.0, 66.4, 57.0, 46.8, 45.6, 45.1, 43.9, 42.3, 29.3, 24.1,
23.8. HRMS calc’d for [M+H] = 353.1865, observed = 353.1884. IR (NaCl, DCM): 3335, 2983,
1700, 1650, 1560, 1409, 1335, 1248, 1099, 988, 919, 855, 800.

136

Figure 9.47: Compound III.17

(S)-(1-((benzyloxy)carbonyl)pyrrolidin-2-yl)methyl 4,5-dibromo-1H-pyrrole-2-carboxylate
(III.17). To a 50 mL roundbotto flask containing a stir bar was added benzyl (S)-2(hydroxymethyl)pyrrolidine-1-carboxylate (0.235 g, 1.0 mmol) followed by DCM (5 mL).
Stirring commenced and to the reaction mixture was added 4,5-dibromo-2-carboxylic acid (0.266
g, 1.0 mmol), EDCI (0.290 g, 1.1 mmol), TEA (0.420 mL, 0.303 g, 3.0 mmol), and DMAP
(0.012 g, 0.1 mmol). The reaction vessel was sealed, flushed with nitrogen, and allowed to stir
overnight. The following day the reaction mixture was transferred to a separatory funnel and
extracted with 10 % HCl (5 mL) and saturated sodium bicarbonate solution (10 mL). The organic
layer was dried over sodium sulfate and concentarated in vacuo to yield the crude product as a
red oil. This material was dissolved in a minimum amount of DCM and purified by silica gel
chromatography (3:7 ethyl acetate: hexanes, Rf = 0.25) to yield the pure product as a yellow oil
(0.112 g, 20 %). 1H NMR (500 MHz) (CDCl3) (amide rotamers) δ: 10.30 – 9.52 (1H, m), 7.35 –
7.30 (5H, m), 6.88 – 6.81 (1H, m), 5.21 – 5.04 (2H, m), 4.31 – 4.13 (3H, m), 3.51 – 3.48 (2H,
m), 2.07 – 1.77 (4H, m), 1.29 – 1.22 (1H, m). 13C NMR (125 MHz) (CDCl3) (amide rotamers) δ:
159.3, 158.7, 155.9, 154.9, 136.5, 128.5, 128.0, 127.8, 123.8, 117.8, 117.7, 106.6, 100.5, 67.0,
65.9, 65.2, 56.1, 55.5, 46.9, 46.6, 29.7, 28.6, 27.3, 23.8, 23.0. HRMS calc’d for [M+H] =
484.9712, observed = 484.9715. IR (NaCl, DCM): 3418, 2961, 1701, 1671, 1450, 1287, 1180,
976, 857, 767, 733, 684.

137

Figure 9.48: Compound III.18

(S)-pyrrolidin-2-ylmethyl 2-phenylacetate (III.18). To a 500 mL roundbottom flask containing
benzyl (S)-2-((2-phenylacetoxy)methyl)pyrrolidine-1-carboxylate (2.43 g, 6.9 mmol) was added
ethyl acetate (200 mL) and 10 % palladium on carbon (2.3 g). Stirring commenced and a
hydrogen was applied to the reaction mixture with a balloon affixed to the roundbottom flask.
The reaction stirred for 18 hours at which time the balloon was removed, the reaction mixture
was filtered through celite and concentrated in vacuo to yield the product as a clear oil which
required no further purification (1.43 g, 94 %). 1H NMR (500 MHz) (CDCl3) δ: 7.36 – 7.26 (5H,
m), 5.07 (1H, br s), 4.25 (1H, dq, J = 12.5, 5.0, 2.0 Hz), 3.71 – 3.66 (3H, m), 3.60 – 3.55 (2H,
m), 3.47 – 3.42 (1H, m), 2.08 – 2.01 (1H, m), 1.95 – 1.79 (2H, m), 1.60 – 1.54 (1H, m). 13C
NMR (125 MHz) (CDCl3) δ: 172.4, 134.2, 128.9, 128.7, 127.0, 67.5, 61.6, 48.4, 42.4, 28.3, 24.4.
HRMS calc’d for [M+H] = 220.1337, observed = 220.1334. IR (NaCl, DCM): 3413, 2884, 1636,
1436, 1301, 1181, 1048, 1003.
Figure 9.49: (S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid

(S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid. To a 250 mL flask containing a stir
bar and (S)-2-(pyrrolidin-2-yl)acetic acid (1.05 g, 8.1 mmol) was added a 1:1 mixture of
dioxane/aqueous sodium carbonate (50 mL total, containing 2.62 g/25.0 mmol sodium
carbonate). The solid dissolved and stirring commenced. To the stirring mixture was added solid

138

Boc anhydride (2.18 g, 10.0 mmol), and the reaction mixture was allowed to stir overnight. The
following day, the crude mixture was transferred to a separatory funnel and washed with ethyl
acetate (100 mL). The organic layer was discarded and the aqueous layer was made acidic by the
addition of conc. HCl (until pH ~ 2 by pH paper). The aqueous layer was extracted with ethyl
acetate (3 x 50 mL). The organic layers were combined, dried over sodium sulfate, and
concentrated in vacuo to yield the product as a yellow solid (1.9 g, 93 %) which needed no
further purification. 1H NMR (500 MHz) (CDCl3) (amide rotamers) δ: 11.36 (1H, br s), 4.14 –
4.10 (1H, br s), 3.33 (2H, br s), 2.98 – 2.79 (1H, m), 2.31 (1H, dd, J = 15.5, 9.5 Hz), 2.09 – 2.02
(1H, m), 1.86 – 1.75 (3H, m), 1.43 (9H, br s). 13C NMR (125 MHz) (CDCl3) (amide rotamers) δ:
176.7, 176.5, 154.6, 154.4, 79.9, 79.8, 53.8, 46.6, 46.1, 39.1, 38.8, 31.3, 30.9, 28.5, 28.4, 28.2,
23.4, 22.7. HRMS calc’d for [M+H] = 230.1392, observed = 230.1344.
Figure 9.50: Compound IV.1a

-

1H-indole-3-carbohydrazide (IV.1a). To a 25 mL roundbottom flask containing a stir bar was
added methyl-3-indole carboxylate (3.22 g, 18 mmol) and 15 mL hydrazine hydrate (~15 %
water). Stirring commenced and a reflux condenser was attached to the flask. The reaction
mixture was heated to reflux overnight. Shortly after reaching reflux, all solid dissolved. The
next day the reaction mixture was cooled to room temperature and a solid precipitates. The solid
was filtered and washed with water and dried in vacuo to yield the product (1.93 g, 61 %).
Spectroscopic data matches that reported for this compound.171 1H NMR (500 MHz) (d6-DMSO)
δ: 11.57 (1H, br s), 9.15 (1H, s), 8.13 (1H, d, J = 8 Hz), 7.96 (1H, s), 7.41 (1H, d, J = 8 Hz), 7.15

139

– 7.07 (2H, m), 4.33 (2H, br s). 13C NMR (125 MHz) (d6-DMSO) δ: 165.6, 136.4, 127.5, 126.5,
122.2, 121.3, 120.7, 112.2, 109.4. Melting point = 228 – 230o C.
Figure 9.51: Compound IV.1

1H-indole-3-carbonyl azide (IV.1). To a 50 mL roundbottom containing a stir bar was added
1H-indole-3-carbohydrazide (1.69 g, 9.6 mmol). To this was added 15 mL glacial acetic acid.
Stirring commenced and the solid dissolved in the roundbottom. In a 50 mL Erlenmeyer flask
was placed sodium nitrite (1.92 g, 28.9 mmol) and 5 mL water. After the sodium nitrite dissolved
it was added dropwise to the 1H-indole-3-carbohydrazide/acetic acid solution. During the
addition an exotherm was observed, followed by the precipitation of a solid and towards the end
of the addition an orange vapor evolved. The reaction mixture was allowed to stir at room
temperature for 20 minutes, at which time it was poured into HCl (1000 mL of a 5 % v/v
solution) and stirred for an additional 20 minutes. The solid was collected by filtration,
transferred to a roundbottom flask and dried under vaccum to yield the product (1.17 g, 65 %).
Spectroscopic data matches that reported for this compound.171 1H NMR (500 MHz) (d6-DMSO)
δ: 12.15 (1H, s), 8.19 (1H, d, J = 3 Hz), 8.05 (1H, m), 7.52 – 7.50 (1H, m), 7.26 – 7.22 (2H, m).
C NMR (125 MHz) (d6-DMSO) δ: 167.7, 137.3, 135.1, 125.8, 123.6, 122.6, 120.8, 113.2,

13

108.3. Melting point = 132o C (violent decomposition).

140

Figure 9.52: Compound IV.2

1-benzyl-3-(1H-indol-3-yl)urea (IV.2). To a 25 mL roundbottom flask containing a stir bar was
added 1H-indole-3-carbonyl azide (1.10 g, 5.9 mmol), followed by toluene (30 mL), and
anhydrous benzyl amine (2.0 mL, 1.96 g, 18 mmol). A reflux condenser was attached to the
roundbottom and the reaction mixture was heated to reflux for 3 hours. During approximately the
first 30 minutes of this period, the azide dissolved and the reaction mixture turned dark red. At
approximately 90 minutes, a solid began to precipitate. When the 3 hour period was up, the
reaction mixture was cooled to room temperature and the product was filtered and washed with
toluene (twice with 10 mL). This product was dried under vacuum to a constant weight, yielding
the product (1.49 g, 95 %). The product can be recrystallized by dissolving in acetone and adding
ethyl acetate until a precipitate is observed, but this does not affect the resultant NMR spectra. 1H
NMR (500 MHz) (d6-DMSO) (amide rotamers) δ: 10.63 (1H, s), 8.24 (1H, s), 7.48 (1H, d, J = 8
Hz), 7.41 – 7.34 (1H, m), 7.33 – 7.29 (5H, m), 7.24 – 7.22 (1H, m), 7.04 – 6.95 (1H, m), 6.49
(1H, t, J = 6.0, 5.5 Hz), 4.31 (2H, d, J = 6 Hz). 13C NMR (125 MHz) (d6-DMSO) (amide
rotamers) δ: 156.2, 141.1, 140.9, 134.2, 128.7, 128.6, 128.2, 127.6, 127.5, 127.0, 127.0, 126.6,
122.2, 121.6, 121.4, 120.7, 118.3, 117.5, 116.2, 112.2, 111.8, 43.4, 42.2. HRMS [M+H] calc’d =
266.1293, observed = 266.1295. IR (NaCl, DCM): 3424, 2999, 2914, 2021, 1669, 1652, 1436,
1314, 1217. M.P. = 124 – 128o C. Crystal structure:

141

Table 9.2: Bond Angles and Bond Lengths for IV.2

Bond Lengths
Atom
O1
N1
N1
N2
N2
N3
N3
C2
C3
C4
C4

Atom
C1
C1
C3
C1
C10
C2
C5
C3
C4
C5
C9

Length/Å
1.2362(17)
1.3652(18)
1.4200(18)
1.3481(18)
1.4523(19)
1.375(2)
1.375(2)
1.355(2)
1.438(2)
1.408(2)
1.397(2)

142

Atom
C5
C6
C7
C8
C10
C11
C11
C12
C13
C14
C15

Atom
C6
C7
C8
C9
C11
C12
C16
C13
C14
C15
C16

Length/Å
1.395(2)
1.372(3)
1.398(3)
1.376(2)
1.510(2)
1.386(2)
1.387(2)
1.400(3)
1.367(3)
1.374(3)
1.383(2)

Table 9.2 (cont’d)
Bond Angles
Atom
C1
C1
C5
O1
O1
N2
C3
N1
C2
C2
C5
C9
C9
N3
N3

Atom
N1
N2
N3
C1
C1
C1
C2
C3
C3
C3
C4
C4
C4
C5
C5

Atom
C3
C10
C2
N1
N2
N1
N3
C4
N1
C4
C3
C3
C5
C4
C6

Angle/˚
122.68(13)
122.13(14)
109.05(14)
122.46(13)
123.10(13)
114.44(13)
109.52(14)
125.79(14)
126.70(14)
107.48(13)
106.22(13)
134.39(14)
119.38(14)
107.69(13)
130.50(15)

Atom
C6
C7
C6
C9
C8
N2
C12
C12
C16
C11
C14
C13
C14
C15

Atom
C5
C6
C7
C8
C9
C10
C11
C11
C11
C12
C13
C14
C15
C16

Atom
C4
C5
C8
C7
C4
C11
C10
C16
C10
C13
C12
C15
C16
C11

Angle/˚
121.81(15)
117.40(17)
121.53(16)
121.28(17)
118.55(16)
114.09(14)
120.11(16)
118.57(16)
121.27(14)
120.1(2)
120.50(19)
119.68(19)
120.4(2)
120.76(18)

Figure 9.53: Compound IV.3a

Palau’chlor (IV.3a). To a 500 mL roundbottom flask containing a stir bar was added (in the
order listed) S-methyl isothiourea hemisulfate (20.0 g, 72.0 mmol), sodium carbonate (15.2 g,
144.0 mmol), TBAB (0.92 g, 2.85 mmol), DCM (100 mL), and water (80 mL). Stirring
commenced and the reaction vessel was cooled in an ice water bath. To this mixture was added
aqueous sodium hydroxide (25 %, 8.6 g in 40 mL water), followed by methyl chloroformate
dropwise (25 mL, 30.7 g, 325.0 mmol). The reaction mixture was stirred for one hour at 0 oC and
two hours at room temperature. The remaining white solid that persisted was dissolved by adding
excess DCM (100 mL) and stirring vigorously. The reaction mixture was stirred for an additional

143

two hours at room temperature, at which point it was transferred to a separatory funnel and
partitioned. The organic layer was washed with water and dried over sodium sulfate. The organic
layer was concentrated in vacuo to yield bis-carboxymethyl-S-methylisothiourea hemisulfate as a
white solid (16.5 g, 56 %). M.P. = 86 oC.
To a 500 mL roundbottom flask containing a stir bar was added bis-carboxymethyl-Smethylisothiourea hemisulfate (14.0 g, 80.0 mmol) and methanol (370 mL). Stirring commenced
and ammonia was added (30 mL of a 7.0 N solution of ammonia in methanol). The reaction was
allowed to stir overnight. The following day the reaction mixture was concentrated in vacuo to a
white solid. M.P. = over 300 oC. The crude material was carried on to the next step.
To a 250 mL roundbottom flask containing a stir bar was added bis-carboxymethyl
guanidine (12.7 g, 72.0 mmol) followed by 150 mL DCM. The suspension was stirred at room
temperature for 10 minutes, at which time t-butyl hypochlorite was added (8.0 mL). After 10
minutes, an additional portion of t-butyl hypochlorite (1 mL). The suspension cleared shortly
after. The reaction was allowed to proceed for one hour at room temperature, at which time it
was concentrated in vacuo to yield the product as a free-flowing white solid (14.2 g, 95 % yield).
Spectroscopic data matches that reported for this compound.172 1H NMR (500 MHz) (CDCl3) δ:
9.82 (1H, br s), 8.09 (1H, br s), 3.86 (3H, s), 3.78 (3H, s). 13C NMR (125 MHz) (CDCl3) δ:
152.9, 150.6, 149.1, 54.0, 53.2. M.P. = 103 oC.
Figure 9.54: Compound IV.3

1,4-dibenzyl-2,5-di(1H-indol-3-yl)-1,2,4,5-tetrazinane-3,6-dione (IV.3). To a vial containing

144

1-benzyl-3-(1H-indol-3-yl)urea (0.026 g, 0.10 mmol) was added d4-methanol (1.0 mL), followed
by TBHP (0.020 mL of a 5.0 M solution). The reaction mixture was transferred to an NMR tube
for monitoring. Crystals began to form during the course of the reaction. The reaction mixture
was left in the NMR tube overnight. The following day, it was observed that more crystals had
grown. The d4-methanol was decanted from the NMR tube, and the crystals were dried by
heating the NMR tube with a heat gun. The crystals were redissolved in d6-DMSO (0.8 mL) and
analyzed by NMR. The irreproducibility of this reaction precluded complete characterization; the
structure reported is based on available data. 1H NMR (500 MHz) (d6-DMSO) δ: 7.47 (1H, d, J =
8.0 Hz), 7.40 (1H, s), 7.34 – 7.28 (5H, m), 7.24 (1H, m), 7.06 (1H, t, J = 7.5 Hz), 6.96 (1H, t, J =
7.5 Hz), 4.30 (2H, s). 13C NMR (125 MHz) (d6-DMSO) δ: 156.1, 141.1, 143.0, 128.7, 127.5,
127.0, 121.6, 118.3, 117.4, 116.0, 111.7, 43.2. HRMS = calc’d for [C16H15N3O, negative ion
mode] = 264.1137, observed = 264.1133.
Figure 9.55: Compound IV.4

tert-butyl 3-(3-benzylureido)-1H-indole-1-carboxylate (IV.4). To a 50 mL roundbottom flask
containing a stir bar was added 1-benzyl-3-(1H-indol-3-yl)urea (0.250 g, 1.0 mmol) and
acetonitrile (3 mL). Stirring commenced and Boc anhydride was added (0.261 g, 1.2 mmol),
followed by DMAP (0.012 g, 01 mmol). The reaction mixture was allowed to stir overnight. The
following day the reaction was concentrated in vacuo and purified by silica gel chromatograpy
(3:7 ethyl acetate: hexanes) to yield the product as a clear oil (0.102 g, 27 %). The
irreproducibility of this reaction precluded complete characterization; the structure reported is

145

based on available data. 1H NMR (500 MHz) (CD3OD) δ: 8.13 (1H, br d, J = 7.0 Hz), 7.82 (1H,
br s), 7.54 (1H, d, J = 8.0 Hz), 7.34 – 7.22 (6H, m), 4.43 (2H, s), 1.66 (9H, s). 13C NMR (125
MHz) (CD3OD) δ: 156.6, 149.8, 139.4, 128.1, 126.9, 126.7, 124.4, 122.0, 119.9, 116.7, 114.7,
112.1, 83.2, 43.3, 27.0.
Figure 9.56: Compound IV.5

tert-butyl (3aS,8bS)-8b-(3-benzylureido)-2-(3-nitrophenyl)-3-(phenylsulfonyl)-2,3,3a,8btetrahydro-4H-oxazolo[4,5-b]indole-4-carboxylate (IV.5). To a test tube was added tert-butyl
3-(3-benzylureido)-1H-indole-1-carboxylate (0.102 g, 0.27 mmol) and CD3OD (0.5 mL). To a
separate test tube was added 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (0.097 g, 0.32 mmol).
These solutions were combined and placed in an NMR tube. The reaction was monitored by
NMR and allowed to proceed overnight. The following day, crystals had precipitated in the
NMR tube. The CD3OD was decanted and the NMR tube was briefly heated with a heat gun (to
evaporate excess solvent). d6-DMSO (0.8 mL) was added to the NMR tube and the spectra
reported was obtained. The irreproducibility of this reaction precluded complete characterization;
the structure reported is based on available data. 1H NMR (500 MHz) (d6-DMSO) δ: 8.16 (1H, t,
J = 2.0 Hz), 8.06 (1H, d, J = 7.5 Hz), 7.96 (1H, ddd, J = 10.0, 2.5, 1.0 Hz), 7.81 (1H, d, J = 7.5),
7.49 – 7.45 (2H, m), 7.39 – 7.31 (5H, m), 7.29 – 7.21 (3H, m), 7.08 – 6.99 (5H, m), 6.68 (1H, s),
5.86 (1H, s), 4.47 (1H, dd, J = 15.0 Hz, 5.5 Hz), 4.32 (1H, dd, J = 15.0 Hz, 5.5 Hz), 1.48 (9H, s).

146

Figure 9.57: Compound IV.6

methyl 1-benzyl-1H-indole-3-carboxylate (IV.6). To a 50 mL roundbottom flask containing a
stir bar was added methyl-indole-3-carboxylate (3.5 g, 20 mmol). The reaction vessel was sealed
and flushed with nitrogen, and anhydrous DMF was added by syringe (20 mL). Stirring
commenced until the solid had dissolved. The septum was removed and sodium hydride (60 %
dispersion in oil, 1.12 g, 28 mmol) was added in one portion. The septum was replaced and the
reaction vessel was flushed again with nitrogen. As the sodium hydride dissolved, gas evolved
and the reaction mixture turned dark brown. After 30 minutes, benzyl bromide (3 mL, 4.44 g, 26
mmol) was added dropwise. The reaction was allowed to continue for 2 hours, at which time it
was opened to the air and water was added (5 mL, dropwise). The reaction mixture was
transferred to a separatory funnel and partitioned between ethyl acetate (50 mL) and water (50
mL). The organic layer was washed with water (3 x 50 mL), dried over sodium sulfate, and
concentrated in vacuo. The crude product was purified by column chromatography (1:4 ethyl
acetate:hexanes) to yield the product (3.9 g, 74 %). Spectroscopic data matches that known for
this compound.173 1H NMR (500 MHz) (CDCl3) δ: 8.15 (1H, d, J = 7 Hz), 7.86 (1H, s), 7.35 –
7.23 (6H, m), 7.16 (2H, d, J = 2H), 5.17 (2H, s), 3.92 (3H, s). 13C NMR (125 MHz) (CDCl3) δ:
165.4, 136.7, 135.8, 134.5, 129.0, 128.1, 127.0, 126.7, 122.9, 122.0, 121.7, 110.3, 107.5, 51.0,
50.7. M.P. = 104o C.

147

Figure 9.58: Compound IV.7

1-benzyl-1H-indole-3-carbohydrazide (IV.7). To a 100 mL roundbottom flask containing a stir
bar was added methyl 1-benzyl-1H-indole-3-carboxylate, followed by DMF (4 mL anhydrous)
and hydrazine (98 %, 15 mL). This mixture was heated to reflux overnight. On cooling to room
temperature the next day the reaction mixture solidified. The solid was transferred to a filter,
washed with water (4 x 50 mL), and dried in vacuo to yield the product (3.49 g, 89 %). 1H NMR
(500 MHz) (d6-DMSO) δ: 9.19 (1H, br s), 8.13 (1H, d, J = 7.5 Hz), 8.08 (1H, s), 7.50 (1H, d, J =
7.5 Hz), 7.42 – 7.10 (6H, m), 5.43 (2H, s), 4.35 (2H, br s). 13C NMR (125 MHz) (d6-DMSO) δ:
165.1, 144.5, 137.8, 136.4, 131.0, 129.1, 128.0, 127.6, 127.0, 122.5, 121.6, 121.1, 111.0, 109.1,
49.4. HRMS [M+H] calc’d = 266.1293, observed = 266.1293. Melting point = 141 – 143o C.
Figure 9.59: Compound IV.7a

1-benzyl-1H-indole-3-carbonyl azide (IV.7a). To a 100 mL roundbottom flask containing a stir
bar was added 1-benzyl-1H-indole-3-carbohydrazide (3.49 g, 13 mmol) followed by glacial
acetic acid (20 mL). Stirring commenced and the solid dissolved. In a separate flask, sodium
nitrite (1.5 g, 26 mmol) was dissolved in water (10 mL). The aqueous sodium nitrite was added
dropwise to the vigorously stirring mixture of in acetic acid over a period of 15 minutes. Early in
the addition an exotherm was observed, followed by the formation of a precipitate and the

148

thickening of the reaction mixture. At the end of the addition an orange gas evolved. The
reaction mixture was stirred at room temperature for 20 minutes, at which time it was poured
into dilute HCl (250 mL of a 5 % v/v solution) and stirred for an additional 20 minutes. At the
end of this period, the product was filtered and the solid was dried under vacuum to yield the
product (3.15 g, 90 %). 1H NMR (500 MHz) (d6-DMSO) δ: 8.44 (1H, s), 8.06 (1H, m) 7.58 (1H,
m) 7.34 – 7.24 (7H, m), 5.53 (2H, s). 13C NMR (125 MHz) (d6-DMSO) δ: 167.4, 137.9, 137.2,
137.1, 129.1, 128.2, 127.8, 126.5, 123.7, 123.0, 121.1, 112.2, 107.7, 50.2. IR (NaCl, DCM):
3002, 2916, 2148, 1655, 1522, 1438, 1315, 1230, 1171. M.P. = 110 – 111o C (decomposition, gas
evolution).
Figure 9.60: Compound IV.8

1-benzyl-3-(1-benzyl-1H-indol-3-yl)urea (IV.8). To a 250 mL roundbottom flask containing a
stir bar was added 1-benzyl-1H-indole-3-carbonyl azide (2.24 g, 8.1 mmol) and toluene (100
mL, dried over molecular sieves). Stirring commences and the reaction mixture was heated to
reflux for 30 minutes, at which point all the solid had dissolved. To this mixture benzyl amine
(anhydrous) was added by syringe (1.65 mL, 1.60 g, 15 mmol). The reaction mixture was
removed from the heat source and allowed to cool to room temperature. During this period a
sand-like precipitate formed. Once cool the reaction mixture was filtered with a fritted funnel
and washed with toluene (2 x 20 mL). The product thus obtained was dried in vacuo (1.33 g, 45
%). 1H NMR (500 MHz) (d6-DMSO) δ: 8.42 (1H, s), 7.56 (1H, s), 7.52 (1H, d, J = 8.0 Hz), 7.40
(1H, d, J = 9.5 Hz), 7.34 – 7.16 (10H, m), 7.09 (1H, app t, J = 8.0 Hz), 6.99 (1H, app t, J = 8.0

149

Hz), 6.54 (1H, t, J = 6.5 Hz), 5.32 (2H, s), 4.30 (2H, d, J = 6.0 Hz). 13C NMR (125 MHz) (d6DMSO) δ: 155.9, 141.0, 138.9, 134.0, 128.9, 128.7, 127.7, 127.5, 127.5, 127.1, 122.0, 121.5,
118.5, 117.8, 116.4, 110.3, 49.3, 43.4. HRMS [M+H] calc’d = 356.1763, observed = 356.1756.
IR (NaCl, DCM): 3428, 2998, 2913, 1682, 1556, 1313, 1223, 1044, 953. M.P. = 185 oC.
Figure 9.61: Compound IV.9

1,3-dibenzyl-1-(cyclopent-1-en-1-yl)urea (IV.9). To a 100 mL roundbottom flask containing a
stir bar was added sodium sulfate (5.0 g, 35 mmol) and anhydrous DCM (50 mL). The reaction
vessel was sealed with a septa and flushed with nitrogen. To the mixture was added
cyclopentanone (5.0 mL, 4.07 g, 56.5 mmol) via syringe, followed by anhydrous benzyl amine
(1.53 mL, 1.51 g, 14.2 mmol) via syringe. The reaction mixture was allowed to stir overnight.
The following day the reaction mixture was filtered (fritted funnel) and concentrated to a yellow
oil on a rotary evaporator. The crude product was concentrated in vacuo for 24 hours to remove
excess cyclopentanone, yielding the product as a yellow oil (2.4 g, 100%). To a 100 mL
roundbottom flask containing N-cyclopentylidene-1-phenylmethanamine (2.54 g, 14.6 mmol)
was added anhydrous DCM (50 mL) and a stir bar. The reaction vessel was sealed with a septa
and flushed with nitrogen. To the reaction mixture was added benzyl isocyanate (1.8 mL, 1.94 g,
14.6 mmol) via syringe. The reaction was allowed to continue overnight. The next day the
reaction was concentrated to dryness in vacuo to yield the product as a red oil (4.1g, 100 %). 1H
NMR (500 MHz) (CDCl3) δ: 7.37 – 7.23 (10H, m), 5.46 (1H, app t, J = 2.0 Hz), 5.42 (1H, br t, J
= 5.0 Hz), 4.72 (2H, s), 4.49 (2H, d, J = 5.5 Hz), 2.38 – 2.35 (2H, m), 2.32 – 2.28 (2H, m), 1.87

150

(2H, quintet, J = 7.5 Hz). 13C NMR (125 MHz) (CDCl3) δ TMS: 156.5, 143.1, 139.6, 138.9,
128.6, 128.4, 128.3, 127.6, 127.4, 127.4, 127.1, 127.1, 126.9, 124.1, 49.8, 44.7, 44.1, 32.3, 30.2,
22.0. HRMS calc’d for [M+H] = 307.1810, observed = 307.1814. IR (NaCl, DCM): 3350, 3061,
2949, 1650, 1585, 1038.
Figure 9.62: Compound V.1

1-(phenylsulfonyl)-1H-indole-3-carbaldehyde (V.1). To a 250 mL roundbottom flask
containing a stir bar was added (in the sequence described) indole-3-carboxaldehyde (1.45 g,
10.0 mmol), DCM (75 mL), tetrabutylammonium hydrogen sulfate (0.170 g, 0.50 mmol), freshly
ground NaOH (0.440 g, 11.0 mmol), and water (50 mL). The reaction vessel was cooled to 0 oC
in an ice-water bath and stirred at this temperature for 30 minutes. At this time, phenylsulfonyl
chloride (1.4 mL, 1.94 g, 11.0 mmol) was added dropwise. The reaction was allowed to proceed
for 3 hours, at which time it was transferred to a separatory funnel and partitioned. The organic
layer was washed with water (100 mL) and subsequently dried over sodium sulfate and
concentrated in vacuo to a solid. The crude product was dissolved in a minimum amount of
DCM and purified by silica gel chromatography (1:4 ethyl acetate: hexanes). The purified
product was obtained as a white solid (1.4 g, 58 %). Spectroscopic data matches that reported for
this compound.173 1H NMR (500 MHz) (CDCl3) δ: 10.10 (1H, s), 8.26 (2H, m), 7.99 – 7.96 (3H,
m), 7.63 – 7.60 (1H, m), 7.53 – 7.50 (2H, m), 7.44 – 7.36 (2H, m). 13C NMR (125 MHz)
(CDCl3) δ: 185.3, 137.3, 136.1, 135.2, 134.7, 129.7, 127.1, 126.4, 126.2, 125.1, 122.6, 122.5,
113.2. M.P. = 154 o C.

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Figure 9.63: Compound V.1a

(1-(phenylsulfonyl)-1H-indol-3-yl)methanol (V.1a). To a 250 mL roundbottom containing a
stir bar was added 1-(phenylsulfonyl)-1H-indole-3-carbaldehyde (1.4 g, 4.9 mmol) and methanol
(100 mL). The reaction vessel was heated until the starting material dissolved. To the reaction
mixture was added sodium borohydride (0.226 g, 6.0 mmol). The reaction was allowed to
proceed at room temperature for 2 hours. At this time the crude reaction mixture was
concentrated to a white solid on a rotary evaporator and purified by silica gel chromatography
(2:3 ethyl acetate: hexanes). The purified product was obtained as a white solid (1.4g, 100 %).
Spectroscopic data matches that reported for this compound.174 1H NMR (500 MHz) (CDCl3) δ:
8.01 (1H, dt, J = 8.0 Hz, 1.0 Hz), 7.91 – 7.89 (2H, m), 7.63 – 7.61 (1H, m), 7.56 – 7.52 (2H, m),
7.46 – 7.43 (2H, m), 7.37 – 7.33 (1H, m), 7.28 – 7.25 (2H, m), 4.83 (2H, s). 13C NMR (125
MHz) (CDCl3) δ: 138.1, 135.4, 133.8, 129.3, 126.8, 125.1, 123.7, 123.4, 122.4, 119.9, 113.7,
57.1. M.P. = 81 o C.
Figure 9.64: Compound V.2

(1-(phenylsulfonyl)-1H-indol-3-yl)methyl hydrazinecarboxylate (V.2). To a 100 mL flask
containing a stir bar was added (1-(phenylsulfonyl)-1H-indol-3-yl)methanol (1.4 g, 4.8 mmol),
followed by acetonitrile (50 mL). Stirring commenced, and CDI was added (2.43 g, 15 mmol),

152

and the reaction vessel was sealed and flushed with nitrogen. To the reaction mixture was added
hydrazine (98 %, 0.630 mL, 0.640 g, 20 mmol). The reaction mixture was allowed to stir at room
temperature overnight. The following day, the reaction mixture was concentrated in vacuo to
yield the crude product which was purified by silica gel chromatography (1:1 ethyl acetate:
hexanes, Rf = 0.13) to yield the pure product as a white solid (0.900 g, 54 %) 1H NMR (500
MHz) (CDCl3) δ: 7.99 (1H, d, J = 8.5 Hz), 7.91 (2H, m), 7.64 (1H, s), 7.60 – 7.54 (2H, m), 7.48
– 7.45 (2H, m), 7.37 – 7.34 (1H, m), 7.29 – 7.26 (3H, m), 5.97 (1H, br s), 5.28 (2H, s), 3.76 (2H,
br s). 13C NMR (125 MHz) (CDCl3) δ: 158.4, 138.0, 135.1, 133.9, 129.4, 129.3, 126.8, 125.6,
125.1, 123.5, 119.7, 117.5, 113.6, 58.8. HRMS calc’d for [C15H12NO2S]+ = 270.0583, observed
= 270.0623. IR (NaCl, DCM): 3415, 3355, 1698, 1636, 1506, 1447, 1367, 1121, 1058. M.P. =
110 o C.
Figure 9.65: Compound V.3

(1-(phenylsulfonyl)-1H-indol-3-yl)methyl 2-(2,4-dichlorobenzoyl)hydrazine-1-carboxylate
(V.3). To a 50 mL roundbottom flask containing a stir bar was added (1-(phenylsulfonyl)-1Hindol-3-yl)methyl hydrazinecarboxylate (0.700 g, 2.0 mmol). The reaction vessel was sealed
with a septa and flushed with nitrogen. To this was added (in the sequence listed) THF (20 mL)
via syringe, TEA (0.417 mL, 0.303 g, 3.0 mmol), and 2,4-dichlorobenzoyl chloride (0.308 mL,
0.459 g, 2.20 mmol, dissolved in 2 mL THF). The reaction mixture turned cloudy on addition of
2,4-dichlorobenzoyl chloride. The reaction was allowed to stir for 30 minutes at room
temperature, at which time TLC analysis revealed the starting material to be consumed (1:1 ethyl

153

acetate: hexanes). The reaction was quenched with the addition of water (5 mL), and transferred
to a separatory funnel where it was partitioned with DCM (40 mL). The organic layer was dried
over sodium sulfate and concentrated on a rotary evaporator to a white solid. The crude product
was purified by silica gel chromatography (1:1 ethyl acetate: hexanes, Rf = 0.75) to yield the
product as a white solid (1.1 g, 95 %). 1H NMR (500 MHz) (CDCl3) δ: 8.16 (1H, br s), 7.96 (1H,
d, J = 8.0 Hz), 7.88 (2H, d, J = 8.0 Hz), 7.65 (1h, s), 7.56 (1H, d, J = 7.0 Hz), 7.51 (1H, t, J = 7.0
Hz), 7.42 (3H, app t, J = 7.0 Hz), 7.33 (1H, t, J = 7.5 Hz), 7.25 (2H, br s), 7.11 (1H, br s). 13C
NMR (125 MHz) (CDCl3) δ: 165.0, 155.9, 137.9, 137.8, 135.0, 134.0, 132.1, 131.5, 130.3, 130.2
129.3, 129.2, 127.5, 126.8, 125.9, 125.2, 123.6, 119.7, 117.0, 113.6, 59.6. HRMS calc’d for
[M+Na] = 540.0164, observed = 540.0176. IR (NaCl, DCM): 3447, 3350, 1652, 1590, 1373,
1175, 1122. M.P. = 139 o C.
Figure 9.66: Compound V.4

1-tosyl-1H-indole (V.4). To a 250 mL roundbottom flask containing a stir bar was added indole
(5.9 g, 50.0 mmol) and aqueous NaOH (24 g, 60.0 mmol, NaOH in 50 mL water). Stirring
commenced and toluene was added (75 mL), followed by TBAB (1.6 g, 4.9 mmol). To this
mixture was added tosyl chloride (9.65 g, 50.0 mmol). After stirring for 2 hours at room
temperature, TLC analysis (1:5 ethyl acetate: hexanes) revealed starting material was still
present. To push the reaction to completion, an additional portion of NaOH (1.4 g, 35.0 mmol)
and tosyl chloride (0.646g, 3.4 mmol). The reaction was allowed to stir overnight.
The following day, the reaction mixture was transferred to a separatory funnel and
partitioned. The organic layer was washed with water (50 mL), dried over sodium sulfate, and

154

concentrated to dryness on a rotary evaporator. The crude product was dissolved in a minimal
amount of DCM and purified by column chromatography (1:9 ethyl acetate: hexanes) to yield the
product as a white solid (6.9 g, 51 %). Spectroscopic data matches that reported for this
compound.175 1H NMR (500 MHz) (CDCl3) δ: 8.02 (1H, d, J = 8.5 Hz), 7.78 (2H, d, J = 8.5 Hz),
7.59 (1H, d, J = 4.0 Hz), 7.47 (1H, d, J = 7.0 Hz), 7.33 (1H, t, J = 8.0 Hz), 7.27 – 7.20 (3H, m),
6.67(1H, d, J = 3.5 Hz), 2.33 (3H, s). 13C NMR (125 MHz) (CDCl3) δ: 144.9, 135.2, 134.7,
130.7, 129.8, 126.8, 126.3, 124.5, 123.2, 121.3, 113.5, 109.0, 21.5. M.P. = 82 oC.
Figure 9.67: Compound V.5a

2-methyl-1H-imidazole-1-sulfonyl azide hydrochloride (V.5a). To a 1000 mL roundbottom
flask containing a stir bar was added acetonitrile (450 mL) and sodium azide (32.5 g, 500.0
mmol). The reaction vessel was cooled to 0 oC in an ice water bath and stirring commenced. Ad
addition funnel with a pressure equalizing vent was added to the roundbottom flask, and was
charged with a mixture of freshly distilled sulfuryl chloride (40.0 mL, 67.0 g, 500.0 mmol) and
acetonitrile (50 mL). The sulfuryl chloride/acetonitrile solution was added dropwise to the
acetonitrile/sodium azide solution over a period of 40 minutes. The addition funnel was removed
and the reaction vessel was sealed with a septa and flushed with nitrogen. The reaction was
allowed to continue overnight. The following day, the reaction mixture was cooled to 0 oC in an
ice water bath and 2-methylimidazole (82.1 g, 500.0 mmol) was added in portions. The reaction
was allowed to warm to room temperature and stirred for 6 hours. At this time water was added
(250 mL), followed by ethyl acetate (250 mL). The mixture was allowed to stir at room
temperature for 15 minutes. The mixture was transferred to a separatory funnel and the layers

155

were partitioned. The aqueous layer was extracted with ethyl acetate (250 mL per extraction for
3 extractions). The organic layers were combined and washed twice with saturated sodium
bicarbonate (300 mL per extraction). The organic layer was dried over sodium sulfate and placed
in a 2000 mL beaker with a stir bar. The beaker was cooled to 0 oC in an ice water bath and a
solution of acetyl chloride in ethanol (54.0 mL, 750.0 mmol in 170 mL ethanol) was added
dropwise over 30 minutes. Towards the end of addition a solid formed. The reaction mixture was
allowed to stir for an additional 30 minutes at which time the solid was collected by filtration
(over a fritted funnel) and washed twice with dry diethyl ether. The solid was transferred to a 500
mL roundbottom flask and dried in vacuo to yield the product as a white crystalline solid (35.8 g,
32 % yield. Spectroscopic data matches that known for this compound.176 1H NMR (500 MHz)
(CD3OD) δ: 8.07 (1H, d, J = 2.0 Hz), 7.67 (1H, d, J = 2.5 Hz), 2.88 (3H, s). 13C NMR (125
MHz) (CD3OD) δ: 148.8, 121.4, 119.1, 11.8. M.P. = 103 oC.
Figure 9.68: Compound V.5

1-(azidosulfonyl)-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate (V.5). The
free-base of 2-methyl-1H-imidazole-1-sulfonyl azide hydrochloride was generated by dissolving
11.4 g (51.3 mmol) of the HCl salt in 100 mL saturated sodium bicarbonate and extracting twice
with ethyl acetate (100 mL per extraction). The organic layers were combined, dried over sodium
sulfate, and concentrated in vacuo to yield the free base as a clear oil (8.8 g, 47.0 mmol, 92 %
yield). To the free base was added anhydrous diethyl ether (200 mL), followed by a stir bar. The
reaction vessel was sealed with a septa and flushed with nitrogen. The reaction vessel was cooled
to 0 oC in an ice water bath and methyl triflate (6.9 mL, 10.0 g, 61.0 mmol) was added dropwise.

156

After 4 hours the product was collected by filtration (fritted funnel) and washed with diethyl
ether to yield the pure product (15.9 g, 88 % yield). Spectroscopic data matches that known for
this compound.176 1H NMR (500 MHz) (CD3OD) δ: 8.09 (1H, d, J = 2.0 Hz), 7.73 (1H, d, J = 2.5
Hz), 3.94 (3H, s), 2.88 (3H, s). 13C NMR (125 MHz) (CD3OD) δ: 148.5, 123.1, 121.6, 120.3,
119.0, 35.1, 10.4. M.P. = 72 oC.
Figure 9.69: Compound V.8

(1S,2R,4S,5R)-1-(anthracen-9-ylmethyl)-2-((S)-hydroxy(quinolin-4-yl)methyl)-5vinylquinuclidin-1-ium chloride (V.8). To a 100 mL roundbottom containing a stir bar was
added conchonine (1.0 g, 3.4 mmol) and 9-chloromethylanthracene (0.780 g, 3.44 mmol). To this
reaction mixture was added toluene (40 mL). The reaction mixture was heated to reflux for 4
hours, during which time a solid precipitates. The solid is filtered on a fritted funnel and
dissolved in chloroform (80 mL). Any remaining solid is filtered away, and petroleum ether was
added to the filtrate, which caused the pure product to precipitate. This product was collected by
filtration and remaining solvent was removed in vacuo. The pure product is isolated as an offwhite solid (0.537 g, 32 %).177 HRMS calc’d for [M-Cl] = 485.2593, observed = 485.2601. M.P.
= 220 o C.

157

Figure 9.70: Compound V.6

O-benzoyl-N-benzylhydroxylamine (V.6). To a 250 mL roundbottom containing a stir bar was
added DCM (80 mL) and benzyl amine (1.75 mL, 1.71 g, 16.0 mmol). Stirring commenced and
the reaction vessel was cooled to 0 oC in an ice water bath. Saturated aqueous sodium
bicarbonate solution was added (40 mL). To the reaction mixture was added benzoyl peroxide
(3.87 g, 16.0 mmol, 70 % benzoyl peroxide 30 % water, corrected for actual amount of benzoyl
peroxide). The reaction was stirred for 1.5 hours at 0 oC, at which time it was transferred to a
separatory funnel. The layers were partitioned and the aqueous layer was washed with DCM (50
mL). The organic layers were dried over sodium sulfate and concentrated in vacuo to yield the
crude product as an oil. The crude product was purified by silica gel chromatography (1:9 ethyl
acetate: hexanes) to yield the product as a clear oil (1.9 g, 53 %). Spectroscopic data matches that
reported for this compound.178 8.06 – 7.99 (2H, m), 7.57 (1H, m), 7.57 – 7.30 (8H, m), 4.27 (2H,
s). 13C NMR (125 MHz) (CDCl3) δ: 166.8, 150.4, 135.7, 133.3, 132.0, 129.9, 129.3, 128.9,
128.7, 128.6, 128.5, 128.2, 127.9, 127.0, 56.7.
Figure 9.71: Compound V.7

(S)-1-benzyl-3-(4-bromophenyl)-2-tosyldiaziridine (V.7).To a 50 mL roundbottom containing
a stir bar was added O-benzoyl-N-benzylhydroxylamine (1.0 g, 4.4 mmol) and toluene (40 mL).
To this mixture was added (in the order described) potassium phosphate tribasic (1.80 g, 8.8

158

mmol), followed by (1S,2R,4S,5R)-1-(anthracen-9-ylmethyl)-2-((S)-hydroxy(quinolin-4yl)methyl)-5-vinylquinuclidin-1-ium chloride (0.020 g, 0.04 mmol), and N-(4bromobenzylidene)-4-methylbenzenesulfonamide (1.2 g, 3.3 mmol). The reaction vessel was
sealed and flushed with argon for 5 minutes. The reaction was transferred to the cold room, and
was stirred at 4 oC for 3 days. At the end of this period a precipitate had formed. The crude
reaction was filtered and concentrated in vacuo to a yellow oil. The crude material was purified
by silica gel chromatography (gradient 1:1 to 1:0 DCM: hexanes) to yield the product as a white
solid (0.644 g, 45 %). Spectroscopic data matches that reported for this compound.178 1H NMR
(500 MHz) (CDCl3) δ: 7.70 (2H, d, J = 8.5 Hz), 7.56 (2H, dd, J = 7.0, 2.0 Hz), 7.39 (2H, d, J =
2.0 Hz), 7.16 – 7.14 (3H, m), 7.09 – 7.06 (2H, m), 6.91 (2H, d, J = 7.0 Hz), 4.85 (1H, s), 3.29
(2H, app quartet, J = 24.0, 13.0 Hz), 2.41 (3H, s). 13C NMR (125 MHz) (CDCl3) δ: 145.0, 135.5,
132.4, 131.7, 130.7, 129.7, 129.4, 129.1, 128.1, 128.8, 128.4, 128.1, 127.1, 124.1, 62.7, 56.1,
21.7. HRMS calc’d for [M+Na] = 465.0248, observed = 465.0238. M.P. = 114 – 116 o C.
Figure 9.72: Compound V.9

(E)-buta-1,3-dien-1-ylbenzene (V.9). To an oven dried 100 mL roundbottom flask containing a
stir bar was added methyl triphenylphosphonium bromide (2.9 g, 7.2 mmol). The reaction vessel
was sealed with a septa and flushed with nitrogen. To this vessel was added THF (25 mL);
stirring commenced and the reaction vessel was cooled to 0 oC in an ice water bath. To this
mixture was added LiHMDS dropwise via syringe (8.5 mL, 8.5 mmol, 1.0 M in hexanes). The
reaction mixture turned yellow on addition of LiHMDS and was removed from the ice water
bath. The reaction was allowed to continue at room temperature until all remaining methyl

159

triphenylphosphonium bromide dissolved (~ 45 minutes). At the point trans-cinnamaldehyde
(1.1 mL, 1.15 g, 8.4 mmol) was added dropwise. The reaction mixture was allowed to stir
overnight.
The following day, the reaction was quenched with methanol (5 mL) and concentrated to
an oily solid on a rotary evaporator. Hexanes was added (30 mL) to the crude product, which
caused a white precipitate to form. The solid was separated by filtration (fritted funnel) and the
filtrate was concentrated again to an oil on a rotary evaporator. Hexanes was added again, and
charcoal was added. The charcoal solution was filtered through a pad of silica gel, which was
washed with hexanes. The filtrate and washings were combined and concentrated in vacuo to
yield the product as an oil (0.822 g, 75 %). Spectroscopic data matches that reported for this
compound.179 1H NMR (500 MHz) (CDCl3) δ: 7.42 (2H, d, J = 7.0 Hz), 7.34 – 7.31 (2H, m),
7.25 – 7.23 (1H, m), 6.80 (1H, dd, J = 16.0, 10.0 Hz), 6.59 – 6.48 (2H, m), 5.35 (1H, d, J = 16.5
Hz), 5.19 (1H, d, J = 10.0 Hz). 13C NMR (500 MHz) (CDCl3) δ: 137.1, 137.1, 132.8, 129.6,
128.6, 127.6, 126.4, 117.6.
Figure 9.73: Compound V.10a

1-tosyl-1H-indole-3-carboxaldehyde (V.10a). To a 500 mL roundbottom flask containing a stir
bar was added (in the order specified) indole-3-carboxaldehyde (2.0 g, 13.8 mmol), benzene (50
mL), aqueous NaOH (30 % w/v, 50 mL), and tosyl chloride (2.8 g, 14.4 mmol). Vigorous
stirring commenced, followed by the addition of tetrabutylammonium bromide (0.44 g, 0.138
mmol). The reaction was stirred for 30 minutes at room temperature, at which time it was
transferred to a separatory funnel and partitioned. The organic layer was washed with water (50
160

mL) and dried over sodium sulfate. The crude reaction mixture was concentrated to an oil on a
rotary evaporator. The crude product was purified by recrystallization by dissolving the oil in a
minimum amount of DCM and adding hexanes until a white precipitate formed. The solid was
filtered and washed with hexanes. Remaining solvent was removed by drying in vacuo to yield
the product as a white solid (2.6 g, 63 %). Spectroscopic data matches that reported for this
compound.180 1H NMR (500 MHz) (CDCl3) δ: 10.09 (1H, s), 8.25 – 8.23 (2H, m), 7.94 (1H, d, J
= 8.5 Hz), 7.85 (2H, d, J = 8.5 Hz), 7.40 (1H, t, J = 7.5 Hz), 7.36 (1H, t, J = 7.5 Hz) 7.29 (2H, d,
J = 8.0 Hz) 2.37 (3H, s). 13C NMR (500 MHz) (CDCl3) δ: 185.3, 146.1, 136.2, 135.1, 134.3,
130.3, 127.2, 126.3, 126.2, 125.0, 122.6, 122.3, 113.2, 21.6. M.P. = 138 o C.
Figure 9.74: Compound V.10

1-tosyl-3-vinyl-1H-indole (V.10). To a 100 mL roundbottom flask containing a stir bar was
added methyl triphenylphosphonium bromide (1.7 g, 4.8 mmol). The reaction vessel was sealed
and flushed with nitrogen. To the vessel was added THF (40 mL) via syringe. Stirring
commenced, and LiHMDS was added dropwise via syringe (5.5 mL, 5.5 mmol, 1.0 M in
hexanes). The reaction mixture was stirred at room temperature until the solid dissolved (~ 2
hours). At this time, 1-tosyl-1H-indole-carboxaldehyde was added dropwise (1.2 g, 3.9 mmol,
dissolved in 5 mL THF). On addition of the aldehyde, the reaction mixture turned red. The
reaction was allowed to proceed overnight.
The following day, the reaction mixture was quenched with water (5 mL) and transferred
to a separatory funnel. To the mixture was added brine (50 mL) and ether (100 mL), followed by
extraction. The layers were separated and the aqueous layer was washed with ether a second time
161

(50 mL). The organic layers were combined and washed with brine, dried over sodium sulfate,
and concentrated in vacuo to yield the crude product as an oil. The crude product was purified by
silica gel chromatography (1:19 ethyl acetate: hexanes) to yield the crude product as a tan solid
(0.500 g, 44 %). Spectroscopic data matches that reported for this compound.180 1H NMR (500
MHz) (CDCl3) δ: 8.00 (1H, d, J = 4.0 Hz), 7.78 – 7.74 (3H, m), 7.61 (1H, s), 7.36 – 7.32 (1H,
m), 7.29 – 7.26 (1H, m), 7.26 – 7.21 (2H, m), 6.77 (1H, dd, J = 18.0 Hz, 11.5 Hz), 5.80 (1H, d, J
= 18.0 Hz), 5.36 (1H, d, J = 12.0 Hz), 2.34 (3H, s). 13C NMR (500 MHz) (CDCl3) δ: 145.0,
135.4, 135.1, 129.9, 128.9, 127.5, 126.8, 124.9, 124.0, 123.5, 120.9, 120.4, 115.3, 113.7, 21.5.
M.P. = 101 o C.
Figure 9.75: Compound VI.1

1-tosylindoline-2-carboxylic acid (VI.1). To a 250 mL roundbottom flask containing a stir bar
was added indoline-2-carboxylic acid (5.0 g, 30.0 mmol), followed by water (150 mL). Stirring
commenced, and potassium carbonate was added (9.10 g, 66 mmol). The potassium carbonate
was allowed to dissolve (~ 5 minutes), and tosyl chloride was added (6.08 g, 32.0 mol). The
reaction mixture was allowed to stir overnight.
The following day all solids had dissolved, leaving a brown solution. The reaction
mixture was cooled to 0 oC in an ice water bath and 100 mL DCM was added. While stirring,
concentrated HCl was added until the aqueous layer was acidic (pH ~ 2 by pH paper). The
reaction mixture was warmed to room temperature and stirred for 5 minutes. The reaction
mixture was transferred to a separatory funnel and partitioned. The aqueous layer was extracted
with an additional portion of DCM (100 mL). The organic layers were combined and dried over

162

sodium sulfate and concentrated to dryness on a rotary evaporator to yield a brown solid.
Residual solvent was removed in vacuo to yield the product as a brown solid (8.2 g, 83 %).
Spectroscopic data matches that reported for this compound.181 1H NMR (500 MHz) (CDCl3) δ:
8.81 (1H, br s), 7.66 – 7.60 (3H, m), 7.24 – 7.22 (3H, m), 7.08 7.02 (2H, m), 4.79 (1H, app
quartet, J = 9.5, 5.0 Hz), 3.19 (2H, t, J = 4.5 Hz), 2.37 (3H, s). 13C NMR (125 MHz) (CDCl3) δ:
175.32, 144.7, 140.9, 133.9, 129.8, 129.6, 128.2, 127.3, 125.0, 124.8, 116.0, 62.0, 32.6, 21.5.
M.P. = 186 o C.
Figure 9.76: Compound VI.2

benzyl (1-tosylindolin-2-yl)carbamate (VI.2). To a 250 mL roundbottom flask containing a stir
bar was added 1-tosylindoline-2-carboxylic acid (7.9 g, 25 mmol). To this vessel was added THF
(100 mL) and stirring commenced while cooling the vessel to 0 oC in an ice water bath. To this
mixture was added TEA (3.7 mL, 2.52 g, 26 mmol), followed by ethyl chloroformate (2.5 mL,
2.81 g, 26 mmol). A solid precipitated, and after 10 minutes of stirring an solution of aqueous
sodium azide was added (19.5 g, 300 mmol in 50 mL water) in one portion. This mixture was
was allowed to stir for 30 minutes at to 0 oC. The reaction mixture was transferred to a
separatory funnel and extracted with ethyl acetate three times (100 mL per extraction). The
organic layers were combined, dried over sodium sulfate, and concentrated to a red oil on a
rotary evaporator (behind a blast shield). The oil was dried in vacuo for 10 minutes to remove
residual solvent. The oil was dissolved in anhydrous toluene (100 mL) and heated on an oil bath.
Bubbles evolved after 2 minutes and stopped after 10 minutes (presumably nitrogen gas). To the
reaction mixture was added benzyl alcohol (4.2 mL, 4.36 g, 40.0 mmol), and the reaction

163

mixture was heated to an internal temperature of 60 oC (direct measurement of solution by
thermometer) overnight.
The following day the reaction was cooled to room temperature and a small amount of
solid was filtered from the crude reaction mixture on a fritted funnel. The reaction mixture was
concentrated to dryness as a black solid. The crude product was purified by silica gel
chromatography (3:7 ethyl acetate: hexanes) to yield the product as a white solid (5.5 g, 52 %).
1

H NMR (500 MHz) (CDCl3) (amide rotamers) δ: 7.70 – 7.64 (2H, m), 7.36 – 7.34 (6H, m), 7.24

– 7.18 (3H, m), 7.08 – 7.01 (2H, m), 5.92 – 5.89 (1H, br m), 5.50 (1H, br s), 5.14 (2H, q, J =
17.0, 12.5 Hz), 4.71 (1H, s), 3.20 (1H, dd, J = 17.0, 8.5 Hz), 2.89 (1H, br d, J = 17.0 Hz), 2.36
(3H, s). 13C NMR (500 MHz) (CDCl3) (amide rotamers) δ: 154.9, 144.3, 140.8. 140.5, 136.0,
134.8, 129.7, 129.6, 128.8, 128.5, 128.5, 128.2, 128.1, 128.0, 127.6, 127.3, 127.2, 126.9, 125.0,
124.4, 115.5, 69.6, 67.0, 65.3, 36.9, 21.5. HRMS calc’d for [M – H] = 421.1222, observed =
421.1222. IR (NaCl, DCM): 1749, 1716, 1635, 1521, 1436, 1260. M.P. = 66 – 70o C.
Figure 9.77: Compound VI.3a

tosyl-L-proline (VI.3a). To a 250 mL roundbottom flask containing a stir bar was added Lproline (10.26 g, 89 mmol) and water (100 mL). Stirring commenced, and sodium carbonate was
added (20.21 g, 196 mmol). After bubbles ceased to evolve, tosyl chloride was added (19.06 g,
100 mmol) and the reaction was allowed to stir overnight.
The following day, DCM was added (100 mL) and the reaction was cooled to 0 oC in an
ice water bath. Concentrated HCl was added until the aqueous layer was acidic (pH ~ 2 by pH
paper). The reaction mixture was transferred to a separatory funnel and washed with water. The

164

aqueous layer was extracted with DCM (100 mL). The organic layers were combined, dried over
sodium sulfate, and concentrated in vacuo to yield the pure compound as an oil (21.1 g, 88 %).
Spectroscopic data matches that reported for this compound.182 1H NMR (500 MHz) (CDCl3) δ:
7.75 (2H, 2, J = 8.5 Hz), 7.29 (2H, d, J = 8.0 Hz), 7.09 (1H, br s), 4.20 (1H, q, J = 8.0, 4.5 Hz),
3.54 – 3.50 (1H, m), 3.18 (1H, q, J = 15.5, 4.0 Hz), 2.39 (3H, s), 2.10 – 2.06 (1H, m), 1.94 – 1.88
(2H, m), 1.63 – 1.60 (1H, m). 13C NMR (125 MHz) (CDCl3) δ: 176.9, 143.7, 134.3, 129.7, 127.6,
127.5, 61.2, 48.9, 30.8, 24.6, 21.5.
Figure 9.78: Compound VI.3

benzyl (S)-(1-tosylpyrrolidin-2-yl)carbamate (VI.3). To a 500 mL roundbottom flask
containing a stir bar was added tosyl-L-proline (18.9 g, 70.0 mmol). To this vessel was added
THF (150 mL) and stirring commenced while cooling the vessel to 0 oC in an ice-water bath. To
this mixture was added TEA (9.75 mL, 7.07 g, 70 mmol), followed by isobutyl chloroformate
(9.15 mL, 9.51 g, 70 mmol). A solid precipitated, and after 10 minutes of stirring an solution of
aqueous sodium azide was added (65.0 g, 1.0 mol in 200 mL water) in one portion. This mixture
was stirred for 30 minutes at to 0 oC. The reaction mixture was transferred to a separatory funnel
and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried over
sodium sulfate, and concentrated in vacuo to a red oil. The oil was dissolved in toluene (100 mL)
and heated on an oil bath. Gas evolved after 2 minutes and stopped after 10 minutes (presumably
nitrogen gas). To the reaction mixture was added benzyl alcohol (12.0 mL, 12.5 g, 70.0 mmol),
and the reaction mixture was heated to an internal temperature of 60 oC (direct measurement of
solution by thermometer) overnight.

165

The following day, the reaction mixture was cooled to room temperature and
concentrated on a rotary evaporator. The oil was triturated by adding a minimal amount of ethyl
acetate and hexanes and concentrated in vacuo. The solid was washed with ethyl acetate (2 x 50
mL) and dried in vacuo to yield the pure product (5.27 g, 18 %). 1H NMR (500 MHz) (CDCl3)
(amide rotamers) δ: 7.78 – 7.71 (2H, m), 7.37 – 7.26 (7H, m), 5.31 (2H, s), 5.15 – 5.11 (2H, m),
3.57 (1H, br s), 3.08 (1H, m), 2.42 (3H, app s), 1.91 – 1.66 (4H, m). 13C NMR (125 MHz)
(CDCl3) (amide rotamers) δ: 155.0, 143.8, 143.7, 136.2, 134.3, 129.8, 129.7, 129.7, 128.7, 128.7,
128.5, 128.3, 128.1, 128.1, 127.6, 126.9, 67.9, 67.7, 66.7, 66.3, 65.3, 48.6, 33.9, 22.9, 22.8, 21.5.
HRMS calc’d for [M+Na] = 397.1198, observed = 397.1197. IR (NaCl, DCM): 3467, 1648,
1539, 1455, 1238. M.P. = 134 – 136 o C.
Figure 9.79: Compound VI.4a

4-methoxybenzenesulfonamide (VI.4a). To a 250 mL roundbottom flask containing a stir bar
was added 100 mL saturated NH4OH and p-methoxybenzene sulfonyl chloride (7.28 g, 37.8
mmol). Stirring commenced. Within 1 hour most of the starting material had dissolved, and a
solid began to form, creating a cloudy solution. The reaction was allowed to proceed overnight.
The following day, the reaction mixture was filtered (fritted funnel) and washed with water three
times (50 mL per wash). The product was obtained as a white crystalline powder and dried in
vacuo to remove residual solvent (5.6 g, 79 %). Spectroscopic data matches that reported for this
compound.183 1H NMR (500 MHz) (d6-DMSO) δ: 7.74 (2H, d, J = 8.5 Hz), 7.20 (2H, br s), 7.07

166

(2H, d, J = 9.5), 3.81 (3H, s). 13C NMR (125 MHz) (d6-DMSO) δ: 162.0, 136.6, 128.1, 114.4,
56.0. M.P. = 108 oC.
Figure 9.80: Compound VI.4b

dimethyl (4-methoxyphenyl)sulfonylcarbonimidodithioate (VI.4b). To a 100 mL
roundbottom flask containing a stir bar was added 4-methoxybenzenesulfonamide (5.3 g, 28.8
mmol) and DMF (23 mL). The reaction vessel was cooled to 0 oC in an ice-water bath. Stirring
commenced, and to this mixture was added (in the sequence indicated) sodium hydroxide (2.1
mL of a 20.0 M solution, 42.0 mmol) and carbon disulfide (1.07 mL, 17.8 mmol). The mixture
was stirred for 15 minutes, at which time sodium hydroxide (1.0 mL of a 20.0 M solution, 20.0
mmol) was added, followed by carbon disulfide (0.54 mL, 9.0 mmol). The reaction mixture was
stirred for an additional 15 minutes, at which time sodium hydroxide (1.0 mL of a 20.0 M
solution, 20.0 mmol) and carbon disulfide (0.54 mL) addition was repeated. This mixture was
stirred for 20 minutes at 0 oC and 2 hours at room temperature. At this time, the reaction vessel
was cooled to 0 oC in an ice-water bath and dimethyl sulfate was added dropwise (6.1 mL, 8.11
g, 65 mmol). On addition of dimethyl sulfate the reaction turns yellow. The reaction vessel was
warmed to room temperature and stirred for 3 hours. After this time period, the reaction vessel
was again cooled to 0 oC and water was added (40 mL). The reaction mixture was stirred
vigorously for 1 hour. During this time an orange solid forms. After the 1 hour period has
elapsed, the solid is filtered (fritted funnel) and washed with water twice (50 mL per wash). The
crude solid is transferred to a 100 mL roundbottom flask and methanol is added (60 mL). The

167

reaction vessel is heated until the solid dissolves, at which time the vessel is allowed to cool to
room temperature. Crystals precipitate and are collected with a fritted funnel and washed twice
with methanol (20 mL per wash). To obtain a second crop, the filtrates are combined and placed
in a 250 mL roundbottom, sealed with a septa and placed in - 20 oC overnight. The combined
crops are dried in vacuo to obtain the pure compound (3.24 g, 39 %). Spectroscopic data matches
that reported for this compound.184 1H NMR (500 MHz) (CDCl3) δ: 7.92 (2H, d, J = 8.5 Hz),
6.97 (2H, d, J = 8.5 Hz), 3.86 (3H, s), 2.52 (6H, s). 13C NMR (125 MHz) (CDCl3) δ: 184.0,
163.0, 132.3, 129.4, 113.9, 55.6, 16.4. M.P. = 77 o C.
Figure 9.81: Compound VI.4c

methyl N'-(4-methoxyphenyl)sulfonylcarbamimidothioate (VI.4c). To a 50 mL roundbottom
flask containing a stir bar was added dimethyl (4-methoxyphenyl) sulfonylcarbonimidodithioate
(2.71 g, 9.3 mmol). To the vessel was added methanol (10 mL) and ammonia (2.5 M in
methanol, 2.5 mL, 10 mmol). The reaction vessel was sealed with a septa and stirring
commenced while the reaction vessel was heated to 50 oC in an oil bath for 1 hour. At this time
an aliquot was removed and concentrated in vacuo to a white solid. 1H NMR revealed ~ 95 %
conversion to product. To drive the reaction to completion, ammonia in methanol (2.5 M, 1.0
mL, 2.5 mmol) was added. The vessel was sealed and heated to 50 oC for another hour. The
solvent was removed on a rotary evaporator and the product was dried in vacuo to yield the
product as a white solid (2.41 g, 99 %). Spectroscopic data matches that reported for this
compound.185 1H NMR (500 MHz) (CDCl3) δ: 7.87 (2H, d, J = 8.5 Hz), 6.96 (2H, d, J = 8.5 Hz),

168

3.87 (3H, s), 2.37 (3H, s). 13C NMR (125 MHz) (CDCl3) δ: 168.6, 162.6, 133.8, 128.4, 113.9,
55.5, 14.0. M.P. = 148 o C.
Figure 9.82: Compound VI.4

methyl (4-methoxyphenyl)sulfonyl)carbonochloridoimidothioate (VI.4). To a 100 mL
roundbottom flask containing a stir bar was added dimethyl (4-methoxyphenyl)sulfonylcarbonimidodithioate (2.0 g, 6.9 mmol). DCM was added to the reaction vessel (50 mL).
The reaction vessel was sealed, flushed with nitrogen, and stirring commenced. To the reaction
mixture was added sulfuryl chloride (1.10 mL, 1.84 g, 13.7 mmol) dropwise via syringe. After
the addition of sulfuryl chloride the reaction was heated to 40 oC in an oil bath for 3 hours. At 3
hours, the vessel was opened and the reaction mixture was analyzed by TLC (3:7 ethyl acetate:
hexanes), which revealed the consumption of all starting material. The crude reaction mixture
was concentrated in vacuo to yield a solid which was purified by silica gel chromatography (3:7
ethyl acetate: hexanes) to yield the pure product was a solid (1.9 g, 99 %). Spectroscopic data
matches that reported for this compound.18 1H NMR (500 MHz) (CDCl3) δ: 7.87 (2H, d, J = 8.5
Hz), 6.96 (2H, d, J = 9.0 Hz), 3.87 (3H, s), 2.37 (3H, s). 13C NMR (125 MHz) (CDCl3) δ: 168.6,
162.6, 133.8, 128.4, 113.9, 55.5, 14.0. M.P. = 74 o C.
Figure 9.83: Compound VI.5

169

methyl N-((4-methoxyphenyl)sulfonyl)indoline-1-carbimidothioate (VI.5). To a 50 mL
roundbottom flask containing a stir bar was added methyl (4-methoxyphenyl)sulfonyl)-carbon
chloridothiolate (1.28 g, 4.6 mmol), followed by DCM (15 mL). Stirring commenced, and
indoline was added dropwise (0.471 mL, 0.500 g, 4.2 mmol). Before TEA could be added, the
reaction solidified (~ 10 seconds after indoline addition). The reaction vessel was sealed with a
septa and flushed with nitrogen. To the solid mixture was added TEA (0.702 mL, 0.509 g, 5.0
mmol) via syringe. The reaction mixture was allowed to stir overnight.
The following day the reaction was concentrated in vacuo to yield the crude product as a
yellow solid. The crude product was dissolved in a minimal amount of DCM and purified by
silica gel chromatograpy (3:7 ethyl acetate: hexanes, Rf = 0.20). to yield the purified product as a
tan crystalline solid (1.05 g, 67 %). 1H NMR (500 MHz) (CDCl3) δ: 7.95 – 7.92 (2H, m), 7.58
(1H, d, J = 7.5 Hz), 7.18 (1H, d, J = 7.0 Hz), 7.02 – 6.94 (4H, m), 4.31 (2H, t, J = 8.0 Hz), 3.88
(3H, s), 3.13 (2H, t, J = 8.0 Hz), 2.75 (3H, s). 13C NMR (125 MHz) (CDCl3) δ: 162.1, 161.9,
141.7, 135.7, 133.7, 128.5, 127.1, 125.2, 125.1, 117.7, 113.7, 55.5, 53.2, 27.5, 18.3. HRMS
calc’d for [M+H] = 363.0837, observed = 363.0838. IR: (NaCl, DCM): 2930, 2840, 1506, 1390.
M.P. = 139 o C. Crystal Structure:

170

171

Table 9.3: Bond Lengths and Bond Angles for Compound VI.5
Bond Lengths
Atom
Atom
S1
C1
S1
C10
S2
O2
S2
O3
S2
N1
S2
C11
O1
C14
O1
C17
N1
C1
N2
C1
N2
C2
N2
C9
C2
C3

Length/Å
1.7710(17)
1.805(2)
1.4412(13)
1.4375(13)
1.6019(15)
1.7613(18)
1.363(2)
1.428(2)
1.309(2)
1.344(2)
1.487(2)
1.425(2)
1.526(3)

Bond Angles
Atom
Atom
C1
S1
O2
S2
O2
S2
O3
S2
O3
S2
O3
S2
N1
S2
C14
O1
C1
N1
C1
N2
C1
N2
C9
N2
N1
C1
N1
C1
N2
C1
N2
C2
C4
C3
C5
C4
C5
C4

Atom
C10
N1
C11
O2
N1
C11
C11
C17
S2
C2
C9
C2
S1
N2
S1
C3
C2
C3
C9

Angle/°
102.95(8)
113.88(8)
107.08(8)
117.28(8)
108.49(8)
107.60(8)
101.06(8)
116.43(14)
128.56(12)
123.06(14)
126.94(14)
109.71(14)
127.24(13)
118.91(15)
113.83(12)
105.23(15)
104.55(15)
129.26(18)
119.90(19)

The law of cosines, c2 = a2 + b2 – 2ab[cos(C)], was used to determine the length between N1 and
C3 as 5.266 angstroms. The same law of cosines was used to determine the length of the
hypothetical guanidine nitrogen from N2 as 1.984 angstroms. Considering the nitrogen that
would be forming the ring is at most 2 angstroms away from N2 and the carbon bonding partner
is 5 angstroms away, the likelihood of forming the desired bond was too low to pursue.

172

Figure 9.84: Compound VI.6

methyl 1-tosylindoline-2-carboxylate (VI.6). To a 500 mL roundbottom flask containing a stir
bar was added 1-tosylindoline-2-carboxylic acid (7.70 g, 28.5 mmol) and methanol (200 mL).
Stirring commenced and the reaction mixture was cooled to 0 oC in an ice water bath. Thionyl
chloride was added dropwise (11.4 g, 96.0 mmol, 7.0 mL). Once addition was complete, the
reaction vessel was attached to a reflux condenser and placed in a heating mantle. The reaction
mixture was heated to reflux overnight. The following day the reaction mixture was concentrated
to approximately half the original volume in vacuo. Ethyl acetate (100 mL) and water (100 mL)
was added to the reaction vessel and the crude reaction mixture was transferred to a separatory
funnel. The aqueous layer was separated and the organic layer was washed with saturated
sodium bicarbonate (100 mL) followed by brine (100 mL). The organic layer was dried over
sodium sulfate and concentrated in vacuo to yield the pure product as a brown solid (7.70 g, 82
% yield). Spectroscopic data matches that reported for this compound.41 1H NMR (500 MHz)
(CDCl3) δ: 7.69 – 7.66 (2H, m), 7.58 (1H, d, J = 8.0 Hz), 7.23 – 7.19 (3H, m), 7.06 – 6.99 (2H,
m), 4.79 (1H, quartet, J = 8.5, 5.5 Hz), 3.80 (3H s), 3.21 – 3.16 (1H, m), 3.11 – 3.07 (1H, m),
2.37 (3H, s). 13C NMR (125 MHz) (CDCl3) δ: 171.6, 144.4, 141.3, 134.5, 129.7, 129.5, 128.1,
127.3, 124.8, 124.3, 115.6, 62.2, 52.9, 33.0, 21.5. M.P. = 67 o C.
Figure 9.85: Compound VI.7a

(1-tosylindolin-2-yl)methanol (VI.7a). To a 500 mL roundbottom flask containing a stir bar

173

was added methyl 1-tosylindoline-2-carboxylate (7.70 g, 23.0 mmol), followed by THF (100
mL). The reaction vessel was sealed, flushed with nitrogen, and cooled to 0 oC in an ice-water
bath. Stirring commenced and lithium borohydride was added dropwise (26.0 mmol, 13.0 mL of
a 2.0 M solution in THF). The reaction was allowed to warm to room temperature and continued
overnight. The following day, the reaction was quenched by the addition of saturated ammonium
chloride (10.0 mL) and concentrated to approximately half the original volume in vacuo. The
crude reaction mixture was transferred to a separatory funnel and partitioned between ethyl
acetate and water (by adding 100 mL of each to the separatory funnel). The aqueous layer was
extracted with an additional portion of ethyl acetate (50 mL). The organic layers were dried over
sodium sulfate and concentrated in vacuo to yield the crude product as an oil. The crude material
was purified by silica gel chromatography (1:4 ethyl acetate: hexanes, Rf = 0.42) to yield the
final product as a yellow solid (5.50 g, 78 % yield). Spectroscopic data matches that reported for
this compound.187 1H NMR (500 MHz) (CDCl3) δ: 7.69 (1H, d, J = 8.0 Hz), 7.52 (2H, app
quartet, J = 6.5, 1.5 Hz), 7.25 – 7.15 (3H, m), 7.04 – 7.03 (2H, m), 4.31 – 4.26 (1H, m), 3.72
(2H, br s), 2.79 (1H, dd, J = 16.0, 9.5 Hz), 2.63 (16.0, 3.5 Hz), 2.45 (1H, br s), 2.35 (3H, s). 13C
NMR (125 MHz) (CDCl3) δ: 144.2, 141.2, 134.3, 132.0, 129.6, 127.8, 127.1, 125.1, 117.6, 65.5,
63.5, 31.2, 21.5. IR (NaCl, DCM): 3483, 1636, 1349, 1091, 1041. M.P = 111 oC.
Figure 9.86: Compound VI.7

(1-tosylindolin-2-yl)methyl sulfamate (VI.7). To an oven dried 100 mL roundbottom flask
containing a stir bar was added chlorosulfonyl isocyanate (5.08 g, 36.3 mmol, 3.10 mL) via

174

syringe. The reaction vessel was sealed with a septa and flushed with nitrogen. The reaction
vessel was cooled to 0 oC in an ice-water bath and 95 % formic acid was added dropwise (1.65 g,
1.35 mL, 36.3 mmol). Vigorous bubbling was observed and the reaction mixture became a white
solid during the acid addition. After the addition of formic acid was complete, anhydrous
acetonitrile was added (10 mL) via syringe, and the white solid dissolved. The reaction vessel
was allowed to warm to room temperature and stirred for 8 hours.
In a separate 50 mL oven dried roundbottom flask was added (1-tosylindolin-2-yl)
methanol (5.0 g, 16.5 mmol). The reaction vessel was sealed and dimethylacetamide was added
(25 mL). The vessel containing the chlorosulfonyl isocyanate/formic acid mixture was again
cooled to 0 oC in an ice water bath and the (1-tosylindolin-2-yl) methanol/dimethyl formamide
solution was added via cannula. The reaction mixture was stirred overnight.
The following day the reaction mixture was quenched by the addition of water (30 mL).
The crude product was transferred to a separatory funnel and diluted with ethyl acetate (300 mL).
The organic layer was washed 5 times with water (400 mL per wash) and three times with brine
(200 mL per wash). The organic layer was dried over sodium sulfate and concentrated in vacuo
to a white foam. The crude product was purified by silica gel chromatography (3:7 ethyl acetate:
hexanes, Rf = 0.21) to yield the pure product as a tan powder (3.7 g, 59 %). 1H NMR (500 MHz)
(CDCl3) δ: 7.63 (1H, d, J = 8.5 Hz), 7.53 (2H, d, J = 8.5 Hz), 7.25 – 7.16 (3H, m), 7.05 – 7.04
(2H, m), 5.18 (2H, br s), 4.55 (1H, app quartet, J = 9.5, 2.5 Hz), 4.36 (1H, dd, J = 6.0, 5.25 Hz),
4.25 (1H, dd, J = 7.0, 5.5 Hz), 2.87 – 2.74 (2H, m), 2.35 (3H, s). 13C NMR (125 MHz) (CDCl3)
δ: 144.5, 140.8, 133.9, 131.0, 129.8, 128.1, 127.1, 125.4, 125.3, 117.3, 71.5, 59.9, 31.2, 21.5.
HRMS calc’d for [M+H] = 383.0735, observed = 383.0738. IR (NaCl, DCM): 3391, 3298, 1636,

175

1352, 1166, 1091, 814. M.P. = 127 o C.
Figure 9.87: Compound VI.10a

2,2,2-trichloroethyl (bis(methylthio)methylene)sulfamate (VI.10a). To a 100 mL
roundbottom flask containing a stir bar was added 2,2,2-trichloroethoxysulfamate (6.85 g, 30.0
mmol) and DMF (23 mL). The reaction vessel was cooled to 0 oC in an ice-water bath. Stirring
commenced, and to this mixture was added (in the sequence indicated) sodium hydroxide (2.1
mL of a 20.0 M solution, 42.0 mmol) and carbon disulfide (1.07 mL, 17.8 mmol). The mixture
was stirred for 15 minutes, at which time sodium hydroxide (1.0 mL of a 20.0 M solution, 20.0
mmol) was added, followed by carbon disulfide (0.7 mL, 0.882 g, 11.5 mmol). The reaction
mixture was stirred for an additional 15 minutes, at which time the sodium hydroxide and carbon
disulfide addition was repeated (1.0 mL 20.0M NaOH and 0.7 mL carbon disulfide). This
mixture was stirred for 20 minutes at 0 oC and 2 hours at room temperature. At this time, the
reaction vessel was cooled to 0 oC in an ice-water bath and dimethyl sulfate was added dropwise
(6.1 mL, 8.11 g, 65 mmol). On addition of dimethyl sulfate the reaction turns yellow. The
reaction vessel was warmed to room temperature and stirred for 3 hours. After this time period,
the reaction vessel was again cooled to 0 oC and water was added (40 mL). The reaction mixture
was stirred vigorously for 1 hour. During this time an orange solid forms. After the 1 hour period
has elapsed, the solid was filtered and washed with water (2 x 50 mL). The crude solid is
transferred to a 100 mL roundbottom flask and methanol is added (60 mL). The reaction vessel
was heated until the solid dissolves, at which time the vessel is allowed to cool to room
temperature. Crystals precipitate and are collected through filtration (fritted funnel) and washed

176

twice with methanol (20 mL per wash). To obtain a second crop of crystals, the filtrates are
combined and placed in a 250 mL roundbottom, sealed with a septa and placed in - 20 oC
overnight. The combined crops are dried in vacuo to obtain the pure compound (3.93 g, 40 %).
Spectroscopic data matches that reported for this compound.150 1H NMR (500 MHz) (CDCl3) δ:
4.75 (2H, s), 2.63 (6H, s). 13C NMR (125 MHz) (CDCl3) δ: 189.8, 93.2, 79.2, 16.6. M.P. = 62 o
C.
Figure 9.88: Compound VI.10

2,2,2-trichloroethyl-(amino(methylthio)methylene)sulfamate (VI.10). To a 25 mL
roundbottom flask containing a stir bar was added 2,2,2-trichloroethyl
(bis(methylthio)methylene)sulfamate (2.2 g, 6.6 mmol) and methanol (10 mL). The reaction
vessel was sealed with a septa and wrapped with parafilm. The sealed vessel was immersed in an
oil bath heated to 50 oC. After immersion in the oil bath, ammonia was added by syringe (2 ml of
4.0 M solution in methanol, 8.0 mmol). The reaction was heated to 50 oC for 90 minutes, at
which time it was removed from the oil and allowed to cool to room temperature. The reaction
mixture was concentrated to a solid on a rotary evaporator and residual solvent was removed in
vacuo to yield the pure product as a solid (2.01 g, 100 %). Spectroscopic data matches that
reported for this compound.150 1H NMR (500 MHz) (CDCl3) δ: 4.69 (2H, s), 2.47 (3H, s). 13C
NMR (125 MHz) (CDCl3) δ: 171.7, 93.5, 78.7, 14.2. M.P. = 90 o C.

177

Figure 9.89: 2,2,2-trichloroethyl-(chloro(methylthio)methylene)sulfamate

2,2,2-trichloroethyl-(chloro(methylthio)methylene)sulfamate. To a 25 mL roundbottom flask
containing a stir bar was added 2,2,2-trichloroethyl(bis(methylthio)methylene)sulfamate (1.51 g,
4.51 mmol) followed by DCM (5 mL). The reaction vessel was sealed, flushed with nitrogen and
stirring commenced, after which sulfuryl chloride was added via syringe (0.903 mL, 1.50 g, 11.2
mmol). The reaction was stirred for 6 hours at room temperature, at which time the reaction
mixture was concentrated in vacuo to yield the crude product as a yellow solid. The crude
product was purified by silica gel chromatography (gradient 1:9 to 1:5 ethyl acetate: hexanes) to
yield the product as a white solid (1.39 g, 98 % yield). Spectroscopic data matches that reported
for this compound.150 1H NMR (500 MHz) (CDCl3) δ: 4.78 (2H, s), 2.56 (3H, s). 13C NMR (125
MHz) (CDCl3) δ: 166.4, 92.7, 79.5, 18.3. M.P. = 62 oC.
Figure 9.90: Compound VI.9

2,2,2-trichloroethyl carbamoyl(2,3-dihydro-1H-inden-2-yl)sulfamate (VI.9). To a 100 mL
roundbottom flask containing a stir bar was added 2-indanol (0.900 g, 6.7 mmol) followed by
2,2,2-trichloroethyl carbamoylsulfamate (2.0 g, 7.4 mmol), followed by triphenylphosphine (1.93
g, 7.4 mmol). The vessel was sealed with a septa and flushed with nitrogen. To the sealed vessel
was added THF via syringe (20 mL), followed by dropwise addition of diethylazidicarboxylate

178

(1.05 mL, 1.28 g, 7.4 mmol). The reaction mixture was allowed to stir overnight. The following
day, the crude reaction mixture was concentrated in vacuo. The crude product was purified by
multiple rounds of silica gel chromatography (gradient ethyl acetate: hexanes gradient 1:9 – 1:5 –
1:3) to yield the pure product as a white solid (1.1 g, 43 %). 1H NMR (500 MHz) (CDCl3) δ:
7.26 – 7.20 (4H, m), 6.99 (1H, br s), 5.68 (1H, quintet, J = 3.5 Hz), 5.46 (1H, br s), 4.70 (2H, s),
3.34 (2H, dd, J = 17.0, 5.5 Hz), 3.20 (2H, dd, J = 17.0, 2.0 Hz). 13C NMR (125 MHz) (CDCl3) δ:
159.9, 139.6, 127.1, 124.7, 93.7, 80.6, 78.5, 39.5. HRMS calc’d for [M – H] = 384.9589,
observed = 384.9583. IR (NaCl, DCM): 3459, 3353, 1626, 1541, 1455, 1339, 1179, 1089, 1018,
853, 746. M.P. = 58 oC.
Figure 9.91: Compound VI.11

2,2,2-trichloroethyl-(amino((2,3-dihydro-1H-inden-2-yl)amino)methylene)sulfamate
(VI.11). To a 25 mL roundbottom flask containing a stir bar was added 2-aminoindan (0.860
mL, 0.897 g, 6.6 mmol), followed by 2,2,2-trichloroethyl(amino(methylthio)methylene)sulfamate (1.97 g, 6.6 mmol). To the reaction mixture was added
water (7 mL). The reaction vessel was sealed with a septa and wrapped with parafilm. The
reaction vessel was immersed in an oil bath heated to 105 oC for 4 hours. After 1.5 hours, all the
organic material had formed a brown layer on the underneath the aqueous layer. At 4 hours, the
reaction vessel was removed from the oil bath and cooled to room temperature. DCM was added
(20 mL), and the reaction mixture was heated with a heat gun to dissolve the crude reaction in
the DCM. The crude mixture was transferred to a separatory funnel and partitioned. The aqueous
layer was extracted once with DCM (20 mL). The organic layers were combined, dried over

179

sodium sulfate, and concentrated in vacuo to a purple oil. The crude material was dissolved in a
minimum amount of DCM and purified by silica gel chromatograpy (gradient 1:4 to 3:7 ethyl
acetate: hexanes, Rf = 0.12) to obtain the product as tan needles (1.4 g, 55 %). 1H NMR (500
MHz) (CDCl3) δ: 7.26 – 7.18 (4H, m), 6.06 (3H, br s), 4.57 (3H, s), 3.33 (2H, d, J = 10.0 Hz),
2.89 (2H, d, J = 15.5 Hz). 13C NMR (125 MHz) (CDCl3) δ: 156.4, 127.2, 124.8, 94.0, 78.1, 52.8,
39.7. HRMS = calc’d for [M – H] = 383.9749, observed = 383.9738. IR (NaCl, DCM): 3460,
3352, 2945, 1717, 1635, 1540, 1310, 1018. M.P. = 119 o C.
Figure 9.92: Compound VII.1a

1-((benzyloxy)carbonyl)piperidine-2-carboxylic acid (VII.1a). To a 100 mL roundbottom
containing a stir bar was added piperidine-2-carboxylic acid (1.29 g, 10.0 mmol) followed by a
water: dioxane mixture (40 mL of a 1:1 mixture). Stirring commenced and sodium carbonate was
added (2.41 g, 23.0 mmol). Gas evolved; once the evolution had ceased most of the solid had
dissolved. To this stirring mixture was added Cbz-Cl (1.7 mL, 2.04 g, 12.0 mmol) dropwise. The
reaction mixture was allowed to stir overnight. The following day, the reaction mixture was
concentrated to approximately half-volume in vacuo. This mixture was transferred to a
separatory funnel and extracted with DCM (50 mL). This extract was discarded. In the
separatory funnel, the aqueous layer was acidified by addition of concentrated HCl until the
aqueous layer was acidic (pH ~ 2 by pH paper). The acidified aqueous layer was extracted 3
times with DCM (50 mL per extraction). The organic layers were combined and dried over
sodium sulfate and concentrated in vacuo to yield the pure product as a clear oil (2.3 g, 88 %).

180

Spectroscopic data matches that reported for this compound.192 1H NMR (500 MHz) (CDCl3) δ:
10.08 (1H, br s), 7.37 -7.31 (5H, m), 5.16 (2H, m), 5.01 – 4.90 (1H, app d), 4.10 (1H, app d),
3.10 – 2.97 (1H, m), 2.25 (1H, dd, J = 27.5, 12.5 Hz), 1.73 – 1.63 (3H, m), 1.47 – 1.23 (2H, m).
C NMR (125 MHz) (CDCl3) δ: 177.6, 177.5, 156.7, 155.9, 136.4, 128.4, 128.0, 127.8, 67.5,

13

67.4, 54.3, 54.1, 41.9, 41.7, 26.6, 26.5, 24.6, 24.4, 20.7, 20.6.
Figure 9.93: Compound VII.1

1-benzyl 2-(3-phenylpropyl) piperidine-1,2-dicarboxylate (VII.1). To a 250 mL roundbottom
flask containing a stir bar was added 1-((benzyloxy)carbonyl)piperidine-2-carboxylic acid (2.3 g,
8.8 mmol), followed by DCM (40 mL). To the reaction vessel was added (in the order listed)
EDCI (1.72 g, 9.0 mmol), TEA (1.4 mL, 1.01 g, 10.0 mmol), and DMAP (0.245 g, 2 .0 mmol).
The reaction vessel was sealed and flushed with nitrogen. Stirring commenced and 3-phenyl-1propanol was added via syringe (1.22 mL, 1.22 g, 9.0 mmol). The reaction was allowed to
proceed overnight. The following day, the reaction was transferred to a separatory funnel in
which it was washed with water (50 mL), dilute HCl (50 mL 0.5 M HCl), saturated aqueous
sodium bicarbonate (50 mL) and brine. The crude product was dried over sodium sulfate and
concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography
(1:4 ethyl acetate: hexanes, Rf = 0.30) to yield the pure product as a clear oil (1.5 g, 44 %). 1H
NMR (500 MHz) (CDCl3) (amide rotamers) δ : 7.35 – 7.13 (10H, m), 5.16 – 5.13 (2H, m), 4.97
– 4.85 (1H, m), 4.15 – 4.05 (3H, m), 3.10 – 2.94 (1H, m), 2.68 – 2.61 (2H, m), 2.27 – 2.19 (1H,
m), 1.98 – 1.89 (2H, m), 1.71 – 1.62 (3H, m), 1.47 – 1.41 (1H, m), 1.29 – 1.21 (1H, m). 13C
NMR (125 MHz) (CDCl3) (amide rotamers) δ: 171.6, 156.5, 155.4, 141.0, 136.6, 128.4, 128.4,

181

127.9, 127.8, 126.0, 67.3, 67.2, 64.3, 54.6, 54.4, 41.9, 41.8, 32.0, 26.8, 26.7, 24.7, 24.5, 20.7,
20.6. HRMS calc’d for [M+H] = 382.2018, observed = 382.2044. IR (NaCl, DCM): 3028, 2943,
2860, 1737, 1710, 1454, 1417, 1336, 1255, 1255, 1203, 1163, 1090, 1044.
Figure 9.94: Compound VII.2a

3-phenylpropyl piperidine-2-carboxylate (VII.2a). To a 250 mL roundbottom flask containing
a stir bar was added 1-benzyl 2-(3-phenylpropyl) piperidine-1,2-dicarboxylate (1.5 g, 3.9 mmol)
followed by ethanol (100 mL) and 10 % palladium on carbon (100 mg). Stirring commenced,
and a balloon containing hydrogen was affixed to the reaction vessel. Hydrogen gas was applied
to the ethanol/palladium mixture in this manner and the reaction was allowed to stir overnight.
The following day, the balloon was removed and the crude reaction mixture was concentrated in
vacuo to a dark oil. The crude was redissolved in ethyl acetate and filtered through celite. The
filtrate was concentrated in vacuo to yield an oil. The crude material was purified through silica
gel chromatography (1:4:0.01 ethyl acetate: hexanes: methanol, Rf = 0.57) to yield the product as
a clear oil (0.533 g, 54 %). 1H NMR (500 MHz) (CDCl3) δ: 7.28 – 7.25 (2H, m), 7.19 – 7.15
(3H, m), 4.17 – 4.08 (2H, m), 3.32 (1H, dd, J = 9.5, 3.5 Hz), 3.06 (1H, dt, J = 12.0, 4.0 Hz), 2.69
– 2.61 (3H, m), 1.99 – 1.93 (4H, m), 1.79 – 1.76 (1H, m), 1.57 – 1.40 (4H, m). 13C NMR (125
MHz) (CDCl3) δ: 173.5, 141.1, 128.4, 128.3, 126.0, 64.0, 58.6, 45.7, 32.1, 30.1, 29.2, 25.8, 24.1.
HRMS calc’d for [M+H] = 248.1651, observed = 248.1658. IR (NaCl, DCM): 3501, 1735, 1454,
1184, 1055, 744.

182

Figure 9.95: Compound VII.2

3-phenylpropyl 1-(2-oxo-2-phenylacetyl)piperidine-2-carboxylate (VII.2). To a 250 mL
roundbottom flask containing 3-phenylpropyl piperidine-2-carboxylate (1.0 g, 4.0 mmol) was
added DCM (20 mL). The reaction vessel was sealed with a septa, flushed with nitrogen, and
cooled to 0 oC. To the stirring mixture was added 2-oxo-2-phenacetyl chloride (1.00 g, 6.0
mmol) dropwise via syringe. Immediately after the acid chloride addition, TEA (1.01 g, 10.0
mmol) was added dropwise. The reaction mixture was allowed to stir overnight. The next day,
the reaction mixture was concentrated to approximately 20 % original volume and a white solid
precipitated. The crude reaction mixture was purified by silica gel chromatography (1:3 ethyl
acetate: hexanes, Rf = 0.50) to yield the product as an opaque oil (1.3 g, 85 %). 1H NMR (500
MHz) (CDCl3) δ: 8.05 – 7.96 (2H, m), 7.65 – 7.57 (1H, m), 7.52 – 7.45 (2H, m), 7.31 – 7.10
(5H, m), 5.42 (1H, d, J = 5.5 Hz), 4.65 – 4.08 (3H, m), 3.50 (1H, br d, J = 13.0 Hz), 3.24 (1H, td,
J = 15.0, 15.0, 3.5 Hz), 3.01 (0.1 H, td, J = 10.0, 10.0, 2.5 Hz), 2.73 (2H, t, J = 7.5 Hz), 2.59 (0.3
H, t, J = 7.0 Hz), 2.39 – 2.36 (1H, m), 2.21 – 2.01 (2H, m), 1.91 – 1.70 (3H. m), 1.61 – 1.34 (4H,
m). 13C NMR (125 MHz) (CDCl3) δ: 191.7, 191.3, 170.4, 170.1, 167.4, 166.7, 140.8, 140.7,
134.8, 133.1, 133.0, 129.9, 129.7, 129.0, 128.8, 128.5, 128.5, 128.4, 128.3, 126.1, 126.1, 64.9,
56.6, 51.6, 44.2, 39.2, 32.1, 32.0, 30.2, 30.0, 27.3, 26.3, 24.8, 24.4, 21.2, 21.0. HRMS calc’d for
[M+H] = 380.1862, observed = 380.1862. IR (NaCl, DCM): 3029, 2947, 1734, 1683, 1647,
1446, 1224, 1162.

183

Figure 9.96: Compound VII.3a

3-(3,4,5-trimethoxyphenyl)propan-1-ol (VII.3a). To an oven dried roundbottom flask
containing a stir bar was added freshly distilled THF (150 mL). The reaction vessel was
immersed in an ice water bath, sealed with a septa, and flushed with nitrogen for 15 minutes
while stirring. The septa was removed and LAH was added slowly (1.70 g, 45.0 mmol). The
vessel was sealed and flushed with nitrogen for 10 minutes. To the reaction mixture was added
dropwise via syringe 3,4,5-trimethoxycinnamic acid (9.94 g, 42.0 mmol, dissolved in 80 mL
THF). Vigorous bubbling was observed. The reaction was allowed to warm to room temperature
and continued overnight. The next day, the reaction mixture was cooled to 0 oC in an ice water
bath and methanol was added dropwise until no gas evolution was observed. After this,
concentrated HCl was added dropwise until no gas evolution was observed. The reaction mixture
was removed from the ice bath and stirred at room temperature for 20 minutes. The crude
reaction mixture was concentrated in vacuo to approximately one-third the original volume and
transferred to a separatory funnel. To the crude was added water (100 mL) and DCM (100 mL).
The reaction mixture was partitioned and extracted with DCM (4 x 50 mL per extraction). The
organic layers were combined and concentrated in vacuo to yield an orange oil that was purified
through silica gel chromatography (1:1 ethyl acetate: hexanes, Rf = 0.24) to yield the product as
an oil (4.4 g, 46 %). Occasionally the reduction of the allylic alcohol was incomplete, yielding
approximately 10 % (by 1H NMR integration) of the allylic alcohol. This impurity can easily be
converted to the alkane through catalytic hydrogenation (hydrogen balloon over 10 % palladium
on carbon in ethyl acetate). This step was performed as needed. Spectroscopic data matches that

184

reported for this compound.188 1H NMR (500 MHz) (CDCl3) δ: 6.42 (2H, s), 3.85 (3H, s), 3.82
(6H, s), 3.69 (2H, t, J = 6.5 Hz), 2.66 (2H, t, J = 7.0 Hz), 1.92 – 1.88 (2H, m), 1.51 (1H, br s).
C NMR (125 MHz) (CDCl3) δ: 153.1, 137.6, 136.0, 105.2, 62.2, 60.8, 56.0, 34.3, 32.5.

13

Figure 9.97: Compound VII.3

1-benzyl 2-(3-(3,4,5-trimethoxyphenyl)propyl) (R)-piperidine-1,2-dicarboxylate (VII.3).
To a 50 mL roundbottom flask containing a stir bar was added (R)-1-((benzyloxy)carbonyl)piperidine-2-carboxylic acid (purchased from Sigma, 0.258 g, 1.0 mmol) was added
DCM (10 mL) followed by TEA (0.306 mL, 0.222 g, 2.2 mmol), EDCI (0.209 g, 1.1 mmol), 3(3,4,5-trimethoxyphenyl)propan-1-ol (0.226 g, 1.0 mmol), and DMAP (0.012 g, 0.10 mmol). The
reaction vessel was sealed, flushed with nitrogen, and stirred overnight. The following day, the
reaction mixture was transferred to a separatory funnel and washed with water (50 mL). The
organic layer was separated, dried over sodium sulfate, and concentrated in vacuo to yield the
product as an oil. The crude material was purified by silica gel chromatograpy (1:3 ethyl acetate:
hexanes, Rf = 0.22) to obtain the pure product as a clear oil (0.189 g, 40 % yield). 1H NMR (500
MHz) (CDCl3) (amide rotamers) δ: 7.36 – 7.30 (5H, m), 6.43 – 6.37 (2H, m), 5.16 – 5.14 (2H,
m), 4.98 – 4.87 (1H, m), 4.18 – 4.05 (3H, m), 3.88 – 3.83 (9H, m), 3.12 – 2.89 (1H, m), 2.65 –
2.56 (2H, m), 2.27 – 2.21 (1H, m), 1.99 – 1.89 (2H, m), 1.72 – 1.63 (3H, m), 1.48 – 1.40 (1H,
m), 1.31 – 1.23 (1H, m). 13C NMR (125 MHz) (CDCl3) (amide rotamers) δ: 172.8, 171.6, 156.5,
153.1, 153.1, 136.7, 136.5, 136.3, 128.5, 128.4, 128.2, 128.0, 127.9, 127.8, 127.7, 105.2, 105.2,
105.1, 67.3, 67.2, 66.8, 64.3, 64.2, 63.8, 60.8, 60.4, 56.0, 56.0, 54.7, 54.4, 41.9, 41.8, 36.1, 32.6,

185

32.4, 31.3, 30.3, 30.2, 26.7, 24.7, 24.5, 20.7, 20.7, 20.5, 14.2. HRMS calc’d for [M+H] =
472.2335, observed = 472.2337. IR (NaCl, DCM): 2943, 1727, 1704, 1591, 1504, 1452, 1421,
1335, 1245, 1128, 1016.
Figure 9.98: Compound VII.4a

1-((benzyloxy)carbonyl) (S)-piperidine-2-carboxylic acid (VII.4a). To a 100 mL roundbottom
containing a stir bar was added (S)-piperidine-2-carboxylic acid (0.500 g, 3.8 mmol) followed by
a 1:1 mixture of water: dioxane (20 mL). Stirring commenced and sodium carbonate was added
(0.525 g, 5.0 mmol). Gas evolved; once the evolution had ceased most of the solid had dissolved.
To this stirring mixture was added Cbz-Cl (0.325 mL, 0.391 g, 2.3 mmol) dropwise. The reaction
mixture was allowed to stir overnight. The following day, the reaction mixture was concentrated
to approximately half-volume on a rotary evaporator. This mixture was transferred to a
separatory funnel and extracted with DCM (50 mL). This extract was discarded. In the
separatory funnel, the aqueous layer was acidified by addition of concentrated HCl until the
aqueous layer was acidic (pH ~ 2 by pH paper). The acidified aqueous layer was extracted with
DCM (3 x 50 mL). The organic layers were combined and dried over sodium sulfate and
concentrated in vacuo to yield the pure product as a clear oil (0.904 g, 89 %). Spectroscopic data
matches that reported for this compound.192 1H NMR (500 MHz) (CDCl3) (amide rotamers) δ:
10.08 (1H, br s), 7.37 -7.31 (5H, m), 5.16 (2H, m), 5.01 – 4.90 (1H, app d), 4.10 (1H, app d),
3.10 – 2.97 (1H, m), 2.25 (1H, dd, J = 27.5, 12.5 Hz), 1.73 – 1.63 (3H, m), 1.47 – 1.23 (2H, m).
C NMR (125 MHz) (CDCl3) (amide rotamers) δ: 177.6, 177.5, 156.7, 155.9, 136.4, 128.4,

13

128.0, 127.8, 67.5, 67.4, 54.3, 54.1, 41.9, 41.7, 26.6, 26.5, 24.6, 24.4, 20.7, 20.6.

186

Figure 9.99: Compound VII.4

1-benzyl 2-(3-(3,4,5-trimethoxyphenyl)propyl) (S)-piperidine-1,2-dicarboxylate (VII.4). To
a 100 mL roundbottom flask containing a stir bar was added (S)-2-piperidine carboxylic acid
(0.250 g, 1.9 mmol), followed by a water: dioxane mixture (10 mL of a 1:1 mixture). Stirring
commenced and sodium carbonate was added (0.630 g, 6.0 mmol), followed by Cbz-Cl (0.328
mL, 0.391 g, 2.3 mmol). The reaction mixture was stirred at room temperature for 48 hours.
After this time, the reaction mixture was transferred to a separatory funnel and made acidic by
the dropwise addition of concentrated HCl (pH ~ 2 measured by pH paper). The acidified
reaction mixture was extracted with DCM (3 x 20 mL). The organic layers were combined, dried
over sodium sulfate, and concentrated to dryness in vacuo to yield the crude product as a clear oil
(0.432 g, 91 %). The crude mixture was carried on to the following step.
To a 50 mL roundbottom flask containing a stir bar was added 1-benzyl 2-(3-(3,4,5trimethoxyphenyl)propyl) (S)-piperidine-1,2-dicarboxylate (0.432 g, 1.7 mmol) was added DCM
(10 mL) followed by TEA (0.696 mL, 0.505 g, 5.0 mmol), EDCI (0.380 g, 2.0 mmol), 3-(3,4,5trimethoxyphenyl)propan-1-ol (0.384 g, 1.7 mmol), and DMAP (0.024 g, 0.20 mmol). The
reaction vessel was sealed, flushed with nitrogen, and stirred overnight. The following day, the
reaction mixture was transferred to a separatory funnel and washed with water (50 mL). The
organic layer was separated, dried over sodium sulfate, and concentrated in vacuo to yield the
product as an oil. The crude material was purified by silica gel chromatograpy (1:3 ethyl acetate:
hexanes, Rf = 0.22) to obtain the pure product as a clear oil (0.527 g, 66 % yield). 1H NMR (500

187

MHz) (CDCl3) (amide rotamers) δ: 7.36 – 7.30 (5H, m), 6.43 – 6.37 (2H, m), 5.16 – 5.11 (2H,
m), 4.98 – 4.86 (1H, m), 4.18 – 4.05 (3H, m), 3.86 – 3.83 (9H, m), 3.12 – 2.89 (1H, m), 2.65 –
2.56 (2H, m), 2.27 – 2.12 (1H, m), 2.07 – 1.89 (2H, m), 1.72 – 1.63 (2H, m), 1.48 – 1.40 (1H,
m), 1.31 – 1.22 (1H, m). 13C NMR (125 MHz) (CDCl3) (amide rotamers) δ: 171.6, 153.1, 136.7,
136.5, 136.2, 128.4, 128.0, 127.7, 105.2, 67.3, 67.2, 64.3, 64.2, 60.8, 56.0, 54.7, 54.4, 41.9, 32.4,
30.3, 30.2, 26.7, 24.7, 24.5, 20.7, 20.6. HRMS calc’d for [M+H] = 472.2335, observed =
472.2333. IR (NaCl, DCM): 2942, 1735, 1703, 1590, 1504, 1420, 1334, 1128, 1014.
Figure 9.100: Compound VII.5

1-benzyl 2-(3-(3,4,5-trimethoxyphenyl)propyl)piperidine-1,2-dicarboxylate (VII.5). To a 250
mL roundbottom flask containing a stir bar and 1-((benzyloxy)carbonyl)piperidine-2-carboxylic
acid (5.6 g, 20.0 mmol) was added DCM (100 mL). Stirring commenced and the following
reagents were added in the order listed: TEA (4.2 mL, 3.0 g, 30.0 mmol), EDCI (4.20 g, 22.0
mmol), DMAP (0.248 g, 2.0 mmol), and 3-(3,4,5-trimethoxyphenyl)propan-1-ol (4.47 g, 19.8
mmol, dissolved in 10 mL DCM). The reaction mixture was sealed with a septa, flushed with
nitrogen, and allowed to proceed overnight. The following day, the reaction mixture was
transferred to a separatory funnel and extracted with water. The organic layer was dried over
sodium sulfate and concentrated in vacuo to yield the crude product. This material was purified
by silica gel chromatography (1:3 ethyl acetate: hexanes, Rf = 0.22) to yield the pure product as a
clear oil (4.7 g, 50 %). 1H NMR (500 MHz) (CDCl3) (amide rotamers) δ: 7.35 – 7.25 (5H, m),
6.39 – 6.36 (2H, m), 5.15 – 5.10 (2H, m), 4.97 – 4.85 (1H, m), 4.17 – 4.04 (3H, m), 3.83 – 3.82

188

(9H, m), 3.10 – 2.94 (1H, app dt), 2.40 – 2.55 (2H, m), 1.98 – 1.88 (2H, m), 1.71 – 1.62 (3H, m),
1.47 – 1.39 (1H, m), 1.29 – 1.21 (1H, m). 13C NMR (125 MHz) (CDCl3) (amide rotamers) δ:
171.6, 153.1, 136.7, 136.5, 136.1, 128.4, 127.9, 127.7, 105.2, 67.3, 67.2, 64.2, 60.8, 56.0, 54.6,
54.4, 41.9, 32.4, 30.3, 26.7, 24.7, 24.5, 20.7, 20.6. HRMS calc’d for [M+Na] = 494.2155,
observed = 494.2157. IR (NaCl, DCM): 2941, 1736, 1701, 1589, 1508, 1336, 1164, 1011, 981.
Figure 9.101: Compound VII.6a

1-(methoxycarbonyl)piperidine-2-carboxylic acid (VII.6a). To a 50 mL roundbottom flask
containing a stir bar was added racemic pipecolic acid (1.29 g, 10.0 mmol) and water (10 mL)
followed by 2N aqueous sodium hydroxide (0.933 g, 20.0 mmol in 10 mL water). Stirring
commenced and methyl chloroformate was added (0.847 mL, 1.03 g, 11.0 mmol). The reaction
mixture was allowed to stir overnight. The following day the reaction was quenched with the
addition of concentrated HCl (until pH ~ 2 by pH paper) and extracted twice with ethyl acetate
(30 mL per extraction). The organic layers were dried over sodium sulfate and concentrated to
dryness in vacuo to yield the crude product as a clear oil. The crude material was purified by
silica gel chromatography (1:1 ethyl acetate: hexanes) to yield the pure produce as a clear oil
(1.09 g, 58 %). Spectroscopic data matches that reported for this compound.193 1H NMR (500
MHz) (CDCl3) (amide rotamers) δ: 9.65 (1H, br s), 4.90 (1H, app d), 4.04 (1H, app dd), 3.72
(3H, app d), 3.06 – 2.94 (1H, m), 2.25 (1H, br t, J = 15.0 Hz), 1.73 – 1.64 (3H, m), 1.44 – 1.27
(2H, m). 13C NMR (125 MHz) (CDCl3) (amide rotamers) δ: 177.5, 177.4, 157.3, 156.6, 54.3,
54.0, 53.0, 41.8, 41.6, 26.7, 26.5, 24.6, 24.4, 20.6.

189

Figure 9.102: Compound VII.6

1-methyl 2-(3-(3,4,5-trimethoxyphenyl)propyl) piperidine-1,2-dicarboxylate (VII.6). To a 50
mL roundbottom flask was added 1-(methoxycarbonyl)piperidine-2-carboxylic acid (1.09 g, 5.8
mmol) followed by DCM (20 mL). Stirring commenced and to the reaction mixture was added
the following (in the order listed): EDCI (1.14 g, 6.0 mmol) and DMAP (0.122 g, 1.0 mmol).
The reaction vessel was sealed with a septa and flushed with nitrogen. To the stirring reaction
mixture was added via syringe (in the order listed): TEA (1.4 mL, 1.01 g, 10.0 mmol) followed
by 3-(3,4,5-trimethoxyphenyl)propan-1-ol (1.17 g, 5.1 mmol dissolved in 5.0 mL DCM). The
reaction mixture was allowed to stir overnight. The following day, the reaction was quenched by
the addition of water (20 mL) and partitioned in a separatory funnel. The organic layer was dried
over sodium sulfate and concentrated to dryness in vacuo to yield the crude product as an oil.
The crude material was purified by silica gel chromatograpy (1:2 ethyl acetate: hexanes, Rf =
0.42) to yield the pure product as a clear oil. 1H NMR (500 MHz) (CDCl3) (amide rotamers) δ:
6.39 (2H, s), 4.95 – 4.80 (1H, m), 4.17 – 4.11 (2H, m), 3.87 – 3.82 (9H, m), 3.72 – 3.70 (3H, m),
3.08 – 2.92 (1H, m), 2.62 (2H, br t, J = 7.0 Hz), 2.25 – 2.23 (1H, m), 1.96 (2H, quintet, J = 7.0
Hz), 1.72 – 1.63 (4H, m), 1.44 – 1.42 (1H, br m), 1.29 – 1.21 (1H, m). ). 13C NMR (125 MHz)
(CDCl3) (amide rotamers) δ: 171.7, 15.1, 136.7, 136.2, 105.2, 64.2, 60.8, 56.0, 54.3, 52.8, 41.8,
32.4, 30.3, 26.7, 24.7, 24.5, 20.7. HRMS calc’d for [M+H] = 396.2022, observed = 396.2019. IR
(NaCl, DCM): 2944, 1735, 1699, 1652, 1448, 1242.

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Figure 9.103: Compound VII.7a

1-tosylpiperidine-2-carboxylic acid (VII.7a). To a 50 mL roundbottom flask containing a stir
bar was added racemic pipecolic acid (1.29 g, 10.0 mmol) followed by water (30 mL). Stirring
commenced and sodium carbonate was added (2.62 g, 25.0 mmol), followed by tosyl chloride
(2.09 g, 11.0 mmol). The reaction mixture was allowed to stir overnight. The following day the
reaction mixture was made acidic by the addition of conc. HCl (until pH ~ 2 by pH paper) and
extracted twice with DCM (30 mL per extraction). The organic layer was dried over sodium
sulfate and concentrated in vacuo to yield the product as a white solid. The crude material was
purified by silica gel chromatography (1:1 ethyl acetate: hexanes) to yield the product as a white
solid (1.1 g, 38 %). Spectroscopic data matches that reported for this compound.194 1H NMR
(500 MHz) (CDCl3) δ: 7.67 (2H, d, J = 2.0 Hz), 7.26 (2H, d, J = 2.0 Hz), 4.76 (1H, br d, J = 5.0
Hz), 3.72 (1H, br d, J = 11.5 Hz), 3.19 (1H, td, J = 13.0 Hz, 2.5 Hz), 2.40 (3H, s), 2.13 (1H, br d,
J = 13.5 Hz), 1.74 – 1.60 (3H, m), 1.44 – 1.25 (2H, br m). 13C NMR (125 MHz) (CDCl3) δ:
177.0, 143.4, 136.9, 129.5, 127.1, 54.7, 42.5, 27.4, 24.4, 21.5, 20.0. M.P. = 108 oC.
Figure 9.104: Compound VII.7

3-(3,4,5-trimethoxyphenyl)propyl 1-tosylpiperidine-2-carboxylate (VII.7). To a 50 mL
roundbottom flask was added 1-(methoxycarbonyl)piperidine-2-carboxylic acid (1.13 g, 3.9
mmol) followed by DCM (20 mL). Stirring commenced and to the reaction mixture was added

191

the following (in the order listed): EDCI (0.764 g, 4.0 mmol) and DMAP (0.122 g, 1.0 mmol).
The reaction vessel was sealed with a septa and flushed with nitrogen. To the stirring reaction
mixture was added via syringe (in the order listed): TEA (0.835 mL, 0.606 g, 6.0 mmol)
followed by 3-(3,4,5-trimethoxyphenyl)propan-1-ol (0.829 g, 3.6 mmol dissolved in 5.0 mL
DCM). The reaction mixture was allowed to stir overnight. The following day, the reaction was
quenched by the addition of water (20 mL) and partitioned in a separatory funnel. The organic
layer was dried over sodium sulfate and concentrated to dryness in vacuo to yield the crude
product as an oil. The crude material was purified by silica gel chromatograpy (1:2 ethyl acetate:
hexanes, Rf = 0.19) to yield the pure product as a clear oil. 1H NMR (500 MHz) (CDCl3) δ: 7.67
(2H, d, J = 8.5 Hz), 7.22 (2H, d, J = 7.5 Hz), 6.38 (2H, s), 4.75 (1H, br d, J = 4.0 Hz), 4.07 –
3.96 (2H, m), 3.88 (6H, s), 3.82 (3H, s), 3.73 – 3.70 (1H, m), 3.23 (1H, dt, J = 13.0, 13.0, 3.0
Hz), 2.59 (2H, t, J = 7.0, 7.0 Hz), 2.38 (3H, s), 2.14 – 2.10 (1H, m), 1.90 – 1.84 (2H, m), 1.76 –
1.61 (3H, m), 1.46 – 1.42 (1H, m), 1.32 – 1.26 (1H, m). 13C NMR (125 MHz) (CDCl3) δ: 170.8,
153.3, 153.1, 143.1, 138.1, 137.1, 136.6, 136.2, 129.4, 127.2, 127.1, 105.2, 64.3, 60.8, 65.1, 56.0,
55.0, 48.3, 42.5, 32.4, 30.1, 27.7, 24.6, 21.5, 20.0. HRMS calc’d for [M+H] = 492.2056,
observed = 492.2055. IR (NaCl, DCM): 3062, 2942, 1735, 1652, 1590, 1507, 1421, 1337, 1240,
1157, 1128.
Figure 9.105: Compound VII.8a

((benzyloxy)carbonyl)-L-proline (VII.8a). To a 100 mL roundbottom flask containing a stir bar
was added L-proline (1.15 g, 10.0 mmol), followed by a 1:1 water: dioxane mixture (20 mL).
Stirring commenced and sodium carbonate (2.41 g, 23.0 mmol) was added in one portion. After

192

gas ceased to evolve, Cbz-Cl was added dropwise (1.7 mL, 1.2 g, 12.0 mmol). The reaction was
allowed to stir overnight. The following day, the reaction mixture was transferred to a separatory
funnel and extracted with ether twice (50 mL per extraction). The aqueous layer was acidified
with concentrated HCl (pH ~ 2 by pH paper) and extracted three times with ethyl acetate (50 mL
per extraction). The organic layer was dried over sodium sulfate and concentrated in vacuo to
yield the product as a clear oil (2.5 g, 100 %). The crude material is suitable for use, but an
analytical sample was prepared by purification through silica gel chromatography (elute in 1:4
ethyl acetate: hexanes). Spectroscopic data matches that reported for this compound.195 1H NMR
(500 MHz) (CDCl3) (amide rotamers) δ: 8.76 (1H, br s), 7.38 – 7. 26 (5H, m), 5.22 – 5.14 (2H,
m), 4.41 (1H, doublet of quartets, J = 24.5, 8.0, 4.5 Hz), 3.65 – 3.45 (2H, m), 2.32 – 1.88 (4H,
m)

C NMR (125 MHz) (CDCl3) (amide rotamers) δ: 178.2, 176.2, 155.9, 154.4, 136.4, 136.2,

13

128.5, 128.4, 128.1, 127.9, 127.6, 67.5, 67.1, 59.3, 58.6, 46.9, 46.6, 30.9, 29.2, 24.3, 23.4.
Figure 9.106: Compound VII.8

1-benzyl 2-(3-phenylpropyl) (S)-pyrrolidine-1,2-dicarboxylate (VII.8). To a 250 mL oven
dried roundbottom flask containing a stir bar was added ((benzyloxy)carbonyl)-L-proline (2.50 g,
10.0 mmol), followed by DCM (100 mL). Stirring commenced, and to the reaction mixture was
added (in the order listed) TEA (1.7 mL, 1.21 g, 12.0 mmol), EDCI (2.0 g, 11.0 mmol), DMAP
(0.244 g, 0.2 mmol), and 3-phenyl-1-propanol (1.49 g, 1.49 mL, 11.0 mmol). The reaction vessel
was sealed and flushed with nitrogen and allowed to react overnight. The following day, the
reaction mixture was transferred to a separatory funnel and extracted with water (once, 100 mL).
The crude reaction mixture was concentrated on a rotary evaporator and purified through silica

193

gel chromatography (1:4 ethyl acetate: hexanes, Rf = 0.33) to yield the pure product as a clear oil
(2.1 g, 57 %). 1H NMR (500 MHz) (CDCl3) (amide rotamers) δ: 7.39 – 7.12 (10H, m), 5.20 –
5.07 (2H, m), 4.43 – 4.34 (1H, m), 4.19 – 4.14 (1H, m), 4.07 – 3.97 (1H, m), 3.70 – 3.45 (2H,
m), 2.74 – 2.67 (1H, m), 2.58 (1H, t, J = 7.5 Hz), 2.30 – 2.18 (1H, m), 2.03 – 1.81 (5H, m). 13C
NMR (125 MHz) (CDCl3) (amide rotamers) δ: 181.3, 172.8, 172.6, 154.3, 141.1, 140.9, 136.7,
136.5, 128.5, 128.4, 128.4, 128.3, 128.3, 127.9, 127.9, 127.8, 127.8, 126.0, 126.0, 125.8, 109.2,
67.0, 66.9, 64.3, 64.3, 62.3, 59.3, 58.9, 46.9, 46.4, 34.2, 32.0, 32.0, 31.9, 30.9, 30.2, 30.0, 29.9,
29.8, 26.8, 24.3, 23.5. HRMS calc’d for [M+H] = 368.1826, observed = 368.1862. IR (NaCl,
DCM): 2955, 1743, 1705, 1652, 1416, 1119, 1088, 746.
Figure 9.107: Compound VII.9

1-benzyl 2-(3-(3,4,5-trimethoxyphenyl)propyl) (S)-pyrrolidine-1,2-dicarboxylate (VII.9). To
a 100 mL roundbottom flask containing ((benzyloxy)carbonyl)-L-proline (1.59 g, 6.4 mmol) was
added a stir bar and DCM (50 mL). The reaction mixture was stirred and the following reagents
were added in the order listed: EDCI (1.33 g, 7.0 mmol), DMAP (0.122 g, 1.0 mmol), and TEA
(1.01 g, 10.0 mmol). The reaction vessel was sealed and flushed with nitrogen. To the stirring
mixture was added 3-(3,4,5-trimethoxyphenyl)propan-1-ol (1.44 g, 6.4 mmol) via syringe
dissolved in DCM (10 mL). The reaction was allowed to stir overnight. The following day, the
reaction was quenched with water (50 mL), transferred to a separatory funnel and partitioned.
The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material
was purified by silica gel chromatography (1:3 ethyl acetate: hexanes, Rf = 0.51) to yield the

194

pure product as a clear oil (1.3 g, 42 % yield). 1H NMR (500 MHz) (CDCl3) (amide rotamers) δ:
7.36 – 7.24 (5H, m), 6.39 – 6.34 (2H, app d), 5.19 – 5.06 (2H, m), 4.38 (1H, ddd, J = 19.5, 15.5,
3.5 Hz), 4.19 – 4.00 (2H, m), 3.84 – 3.80 (9H, m), 3.66 – 3.47 (2H, m), 2.62 (1H, t, J = 7.5 Hz),
2.51 (1H, t, J = 8.0 Hz), 2.28 – 2.20 (1H, m), 2.02 – 1.80 (5H, m). 13C NMR (125 MHz) (CDCl3)
(amide rotamers) δ: 172.8, 172.7, 154.8, 154.2, 153.1, 153.1, 136.9, 136.7, 136.6, 136.5, 136.1,
136.1, 128.4, 128.3, 127.9, 127.8, 127.7, 105.2, 105.1, 66.9, 66.9, 64.3, 64.2, 60.8, 59.3, 58.9,
56.0, 46.9, 46.4, 32.3, 32.3, 31.0, 30.3, 30.1, 29.9, 24.3, 23.5. HRMS calc’d for [M+H] =
368.1862, observed = 368.1869. IR (NaCl, DCM): 2961, 2839, 1734, 1647, 1593, 1507, 1419,
1126, 911.
Figure 9.108: Compound VII.10a

1-(methoxycarbonyl) (S)-piperidine-2-carboxylic acid (VII.10a). To a 50 mL roundbottom
flask containing a stir bar was added (S)-pipecolic acid (0.250 g, 1.9 mmol) and water (5 mL)
followed by 2N aqueous sodium hydroxide (0.200 g, 5.0 mmol in 5 mL water). Stirring
commenced and methyl chloroformate was added (0.160 mL, 0.198 g, 2.1 mmol). The reaction
mixture was allowed to stir overnight. The following day the reaction was quenched with the
addition of concentrated HCl (until pH ~ 2 by pH paper) and extracted twice with ethyl acetate
(30 mL per extraction). The organic layers were dried over sodium sulfate and concentrated to
dryness in vacuo to yield the crude product as a clear oil. The crude material was purified by
silica gel chromatography (1:1 ethyl acetate: hexanes) to yield the pure produce as a clear oil
(0.238 g, 66 %). Spectroscopic data matches that reported for this compound.193 1H NMR (500

195

MHz) (CDCl3) (amide rotamers) δ: 9.65 (1H, br s), 4.90 (1H, app d), 4.04 (1H, app dd), 3.72
(3H, app d), 3.06 – 2.94 (1H, m), 2.25 (1H, br t, J = 15.0 Hz), 1.73 – 1.64 (3H, m), 1.44 – 1.27
(2H, m). 13C NMR (125 MHz) (CDCl3) (amide rotamers): 177.5, 177.4, 157.3, 156.6, 54.3, 54.0,
53.0, 41.8, 41.6, 26.7, 26.5, 24.6, 24.4, 20.6.
Figure 9.109: Compound VII.10

1-methyl 2-(3-(3,4,5-trimethoxyphenyl)propyl) (S)-piperidine-1,2-dicarboxylate (VII.10).
To a 50 mL roundbottom flask was added 1-(methoxycarbonyl) (S)-piperidine-2-carboxylic acid
(0.238 g, 1.32 mmol) followed by DCM (10 mL). Stirring commenced and to the reaction
mixture was added the following (in the order listed): EDCI (0.304 g, 1.6 mmol) and DMAP
(0.060 g, 0.5 mmol). The reaction vessel was sealed with a septa and flushed with nitrogen. To
the stirring reaction mixture was added via syringe (in the order listed): TEA (0.350 mL, 0.252 g,
2.5 mmol) followed by 3-(3,4,5-trimethoxyphenyl)propan-1-ol (0.293 g, 1.3 mmol dissolved in
3.0 mL DCM). The reaction mixture was allowed to stir overnight. The following day, the
reaction was quenched by the addition of water (10 mL) and partitioned in a separatory funnel.
The organic layer was dried over sodium sulfate and concentrated to dryness in vacuo to yield
the crude product as an oil. The crude material was purified by silica gel chromatograpy (1:2
ethyl acetate: hexanes, Rf = 0.42) to yield the pure product as a clear oil (0.222 g, 44 %). 1H
NMR (500 MHz) (CDCl3) (amide rotamers) δ: 6.39 (2H, s), 4.95 – 4.80 (1H, m), 4.17 – 4.11
(2H, m), 3.87 – 3.82 (9H, m), 3.72 – 3.70 (3H, m), 3.08 – 2.92 (1H, m), 2.62 (2H, br t, J = 7.0
Hz), 2.25 – 2.23 (1H, m), 1.96 (2H, quintet, J = 7.0 Hz), 1.72 – 1.63 (4H, m), 1.44 – 1.42 (1H, br

196

m), 1.29 – 1.21 (1H, m). ). 13C NMR (125 MHz) (CDCl3) (amide rotamers) δ: 171.7, 15.1, 136.7,
136.2, 105.2, 64.2, 60.8, 56.0, 54.3, 52.8, 41.8, 32.4, 30.3, 26.7, 24.7, 24.5, 20.7. HRMS calc’d
for [M+H] = 396.2022, observed = 396.2019. IR (NaCl, DCM): 2944, 1735, 1699, 1652, 1448,
1242.
Figure 9.110: Compound VII.11a

1-(isobutoxycarbonyl) (S)-piperidine-2-carboxylic acid (VII.11a). To a 50 mL roundbottom
flask containing a stir bar was added (S)-pipecolic acid (0.250 g, 1.9 mmol) and water (5 mL)
followed by 2N aqueous sodium hydroxide (0.200 g, 5.0 mmol in 5 mL water). Stirring
commenced and isobutyl chloroformate was added (0.275 mL, 0.285 g, 2.1 mmol).The reaction
mixture was allowed to stir overnight. The following day, the reaction was quenched by the
addition of concentrated HCl (until the mixture was pH ~ 2 by pH paper) and extracted with
ethyl acetate (2 x 25 mL). The organic layers were combined, dried over sodium sulfate, and
concentrated in vacuo to yield the crude product as an oil. The crude material was purified by
filtering through a plug of silica gel (1:2 ethyl acetate: hexanes) to yield the pure product as a
clear oil which solidifies on standing (0.302 g, 69 %). 1H NMR (500 MHz) (CDCl3) (amide
rotamers) δ: 10.31 (1H, br s), 4.91 (1H, br d), 4.05 (1H, br d), 3.92 – 3.82 (2H, m), 3.07 – 2.95
(1H, m), 2.25 (1H, br t, J = 14.0 Hz), 1.98 – 1.90 (1H, m), 1.74 – 1.65 (3H, m), 1.46 – 1.40 (1H,
m), 1.36 – 1.28 (1H, m), 0.92 (6H, dd, J = 21.0, 7.0 Hz). 13C NMR (125 MHz) (CDCl3) (amide
rotamers) δ: 177.7, 177.5, 156.9, 156.2, 71.9, 71.8, 54.2, 54.0, 41.7, 41.5, 27.9, 26.7, 26.5, 24.6,
24.4, 20.7, 20.6, 19.0. HRMS calc’d for [M – H] = 228.1241, observed = 228.1233. IR (NaCl,

197

DCM): 3095, 2960, 2874, 1744, 1704, 1667, 1470, 1434, 1386, 1259, 1167, 1044, 973. M.P. =
67 oC.
Figure 9.111: Compound VII.11

1-isobutyl 2-(3-(3,4,5-trimethoxyphenyl)propyl) (S)-piperidine-1,2-dicarboxylate (VII.11).
To a 100 mL roundbottom flask containing a stir bar was added 1(isobutoxycarbonyl)piperidine-2-carboxylic acid (0.302 g, 1.32 mmol) followed by DCM (10
mL). To this solution was added 3-(3,4,5-trimethoxyphenyl)propan-1-ol (0.316 g, 1.4 mmol
dissolved in 2 mL DCM). Stirring commenced and the following reagents were added in the
order listed: EDCI (0.304 g, 1.6 mmol), TEA (0.350 mL, 0.252 g, 2.5 mmol) and DMAP (0.06 g,
0.50 mmol). The reaction vessel was sealed, flushed with nitrogen, and allowed to stir overnight.
The following day, the reaction mixture was transferred to a separatory funnel and washed with
water (50 mL). The organic layer was dried with sodium sulfate and concentrated in vacuo to
yield the crude product as an oil. This material was purified by silica gel chromatography (1:3
ethyl acetate: hexanes, Rf = 0.32) to yield the pure product as a clear oil (0.301 g, 52 % yield). 1H
NMR (500 MHz) (CDCl3) (amide rotamers) δ: 6.39 (2H, s), 4.95 – 4.83 (1H, br d), 4.17 – 3.91
(4H, m), 3.90 – 3.82 (9 H, m), 3.09 – 2.93 (1H, br dt), 2.62 (2H, br t, J = 7.0 Hz), 2.25 – 2.22
(1H, m), 1.99 – 1.89 (3H, m), 1.74 – 1.64 (3H, m), 1.45 – 1.43 (1H, m), 1.30 – 1.22 (1H, m),
0.94 – 0.88 (6H, m). 13C NMR (125 MHz) (CDCl3) (amide rotamers) δ: 171.8, 171.8, 156.8,
156.2, 153.1, 136.7, 136.2, 105.2, 71.7, 71.6, 64.3, 64.2, 60.8, 56.0, 54.5, 54.3, 41.7, 32.4, 30.3,

198

30.3, 27.9, 26.8, 26.7, 24.7, 24.5, 20.8, 20.6, 19.0. HRMS calc’d for [M+H] = 438.2492,
observed = 438.2494. IR (NaCl, DCM): 2948, 1735, 1701, 1591, 1457, 1421, 1292, 1016.
Figure 9.112: Compound VII.12a

2-(3,4,5-trimethoxyphenyl)ethan-1-ol (VII.12a). To a 250 mL roundbottom flask was added a
stir bar and freshly distilled THF (100 mL). The reaction vessel was cooled in an ice-water bath
and stirring commenced. LAH (1.11 g, 30.0 mmol) was added in portions. The reaction vessel
was sealed with a septa and flushed with nitrogen. In a separate vessel 3,4,5trimethoxyphenylacetic acid (4.52 g, 20.0 mmol) was dissolved in THF (30 mL), and was added
dropwise to the LAH/THF solution. The reaction was allowed to warm to room temperature and
proceed overnight. The following day, the reaction vessel was cooled in an ice-water bath and
the reaction was quenched with water (until gas no longer evolved) and concentrated HCl (~ 1
mL). The reaction mixture was partitioned between ethyl acetate (200 mL) and water (100 mL).
The organic layer was dried over sodium sulfate and concentrated in vacuo to yield the crude
product as a clear, yellow oil. The crude material was purified with silica gel chromatography
(1:1 ethyl acetate: hexanes) to yield the final product as a yellow oil that solidified on standing
(2.9 g, 68 %). Spectroscopic data matches that reported for this compound.197 1H NMR (500
MHz) (CDCl3) δ: 6.45 (2H, s), 3.87 – 3.83 (11H, m), 2.81 (2H, t, J = 7.0, 7.0 Hz). 13C NMR (125
MHz) (CDCl3) δ: 153.2, 136.5, 134.2, 105.8, 63.5, 60.8, 56.0, 39.5. M.P. = 40 oC.

199

Figure 9.113: Compound VII.12

1-benzyl 2-(3,4,5-trimethoxyphenethyl) (S)-piperidine-1,2-dicarboxylate (VII.12). To a 500
mL roundbottom flask containing a stir bar and (S)-1-((benzyloxy)carbonyl)piperidine-2carboxylic acid (0.386 g, 1.5 mmol) was added DCM (10 mL). Stirring commenced, and in the
order listed was added TEA (0.417 mL, 0.303 g, 3.0 mmol), EDCI (0.323 g, 1.7 mmol), DMAP
(0.060 g, 0.50 mmol), and 2-(3,4,5-trimethoxyphenyl)ethan-1-ol (0.318 g, 1.5 mmol). The
reaction vessel was sealed, flushed with nitrogen, and allowed to stir overnight. The following
day, the reaction mixture was quenched with water (10 mL) and partitioned in a separatory
funnel. The organic layer was dried over sodium sulfate and concentrated in vacuo to a yellow
oil. The crude product was purified by silica gel chromatography (1:3 ethyl acetate: hexanes) to
yield the product as a clear oil (0.145 g, 21 %). 1H NMR (500 MHz) (CDCl3) (amide rotamers)
δ: 7.37 – 7.29 (5H, m), 6.41 (2H, d, J = 14.0 Hz), 5.16 – 5.10 (2H, m), 4.95 – 4.82 (1H, m), 4.38
– 4.29 (2H, m), 4.09 – 3.99 (1H, m), 3.84 (6H, app d, J = 3.5 Hz), 3.81 (3H, app d, J = 5.0 Hz),
3.00 – 2.80 (3H, m), 2.17 (1H, t, J = 16.0 Hz), 1.67 – 1.56 (3H, m), 1.43 – 1.38 (1H, m), 1.55 –
1.10 (1H, m). 13C NMR (125 MHz) (CDCl3) (amide rotamers) δ: 171.6, 171.6, 156.5, 155.9,
153.2, 136.6, 136.6, 133.2, 133.1, 128.4, 128.0, 127.8, 105.7, 67.3, 67.1, 65.5, 65.4, 60.8, 56.0,
54.6, 54.4, 41.8, 41.7, 35.4, 35.3, 26.7, 24.6, 24.4, 20.6, 20.5. HRMS calc’d for [M+Na] =
480.1998, observed = 480.2011. IR (DCM, NaCl): 1746, 1697, 1597, 1421, 1362, 1190, 1022.

200

Figure 9.114: Compound VII.13

1-benzyl 2-(3,4,5-trimethoxybenzyl) piperidine-1,2-dicarboxylate (VII.13). To a 100 mL
roundbottom flask containing a stir bar was added 1-((benzyloxy)carbonyl)piperidine-2carboxylic acid (0.435 g, 1.6 mmol), followed by DCM 1 mL). The reaction mixture was stirred
and the following reagents were added (in the order listed): TEA (0.417 mL, 0.303 g, 3.0 mmol),
EDCI (0.342 g, 1.8 mmol), and DMAP (0.060 g, 0.50 mmol). Stirring commenced and the
reaction vessel was sealed with a septa and flushed with nitrogen. To this mixture was added
3,4,5-trimethoxybenzyl alcohol (0.273 mL, 0.336 g, 1.7 mmol, dissolved in 2.0 mL DCM) via
syringe. The reaction mixture was allowed to stir overnight. The following day, the reaction
mixture was transferred to a separatory funnel and extracted with water (50 mL) and brine (50
mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to yield the
crude product as a clear oil. The crude material was purified by silica gel chromatograpy (1:3
ethyl acetate: hexanes, Rf = 0.28) to yield the final product as a clear oil (0.371 g, 50 %). 1H
NMR (500 MHz) (CDCl3) (amide rotamers) δ: 7.35 – 7.25 (5H, m), 6.55 – 6.52 (2H, m), 5.15 –
4.89 (5H, m), 4.14 – 4.03 (1H, m), 3.83 – 3.82 (9H, m), 3.11 – 2.96 (1H, m), 2.28 – 2.21 (1H,
m), 1.70 – 1.41 (4H, m), 1.28 – 1.22 (1H, m). 13C NMR (125 MHz) (CDCl3) (amide rotamers) δ:
171.5, 156.4, 155.9, 153.3, 137.7, 136.5, 131.4, 131.2, 128.4, 128.4, 128.0, 127.7, 127.6, 104.9,
104.8, 67.3, 67.2, 66.8, 60.8, 56.1, 54.7, 54.4, 41.9, 41.8, 26.7, 24.7, 24.5, 20.7, 20.6. HRMS
calc’d for [M+Na] = 466.1842, observed = 466.1845. IR (NaCl, DCM): 2941, 1734, 1699, 1592,
1457, 1420, 1242, 1192, 1127.

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Figure 9.115: Compound VII.14a

(R)-1-((benzyloxy)carbonyl)piperidine-3-carboxylic acid (VII.14a). To a 100 mL
roundbottom flask containing a stir bar was added (R)-3-pipecolic acid (1.0 g, 7.7 mmol)
followed by 1,4-dioxane (10 mL) and water (10 mL). Stirring commenced and sodium carbonate
was added (2.1 g, 20.0 mmol) followed by Cbz-Cl (1.20 mL, 1.44 g, 8.5 mmol). The reaction
mixture was stirred overnight. The following day the reaction was quenched by the addition of
HCl (36 mmol HCl 10 mL of a 3.6 M solution). The reaction mixture was transferred to a
separatory funnel and extracted with ethyl acetate (3 x 20 mL per extraction). The organic layers
were combined, dried over sodium sulfate, and concentrated in vacuo to yield the crude product
as an oil. This material was dissolved in a 1:1 mixture of ethyl acetate: hexanes and passed
through a plug of silica gel to yield the crude product as a an oil that on standing turns into a
waxy, white solid (1.74 g, 84 %). 1H NMR (500 MHz) (CDCl3) (amide rotamers) δ: 7.38 – 7.29
(5H, m), 5.17 – 5.10 (2H, m), 4.27 – 4.15 (1H, m), 3.97 (1H, dt, J = 9.5, 3.5, 3.5 Hz), 3.17 – 3.06
(1H, m), 2.96 – 2.90 (1H, m), 2.51 (1H, br s), 2.10 – 2.07 (1H, m), 1.74 – 1.65 (2H, m) 1.50 (1H,
br s). 13C NMR (125 MHz) (CDCl3) (amide rotamers): 178.8, 155.2, 136.6, 128.5, 128.0, 127.9,
67.2, 45.4, 44.1, 40.9, 27.0, 24.0. HRMS calc’d for [M+H] = 264. 1236, observed = 264.1259;
calc’d for [M+Na] = 286. 1055, observed = 286. 1058. IR (NaCl, DCM): 3435, 2953, 1732,
1697, 1473, 1291, 1150, 1078. M.P. = 97 oC.

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Figure 9.116: Compound VII.14

1-benzyl 3-(3-(3,4,5-trimethoxyphenyl)propyl) (R)-piperidine-1,3-dicarboxylate (VII.14). To
a 100 mL roundbottom flask containing (R)-1-((benzyloxy)carbonyl)piperidine-3-carboxylic acid
(0.542 g, 2.0 mmol) was added a stir bar followed by DCM (15 mL), EDCI (0.414 g, 2.2 mmol),
TEA (0.696 mL, 0.505 g, 5.0 mmol), DMAP (0.060 g, 0.5 mmol), and 3-(3,4,5trimethoxyphenyl)propan-1-ol (0.461 g, 2.0 mmol). The reaction mixture was stirred overnight.
The reaction mixture was transferred to a separatory funnel and washed with dilute HCl (10 mL
5 % HCl v/v) followed by saturated aqueous sodium bicarbonate (20 mL). The organic layer was
dried over sodium sulfate and concentrated in vacuo. The crude material was purified by silica
gel chromatography (1:2 ethyl acetate: hexanes) to yield the product as a clear oil (0.453 g, 48
%). 1H NMR (500 MHz) (CDCl3) (amide rotamers) δ: 7.36 – 7.30 (5H, m), 6.39 (2H, s), 5.16 –
5.11 (2H, m), 4.28 – 3.90 (4H, m), 3.84 – 3.82 (9H, m), 3.15 – 3.04 (1H, m), 2.95 – 2.90 (1H,
m), 2.62 (2H, br t, J = 7.0 Hz), 2.08 – 2.05 (1H, m), 1.97 – 1.92 (2H, m), 1.72 – 1.62 (2H, m),
1.50 (1H, br s). 13C NMR (125 MHz) (CDCl3) (amide rotamers): 173.2, 155.1, 153.1, 136.8,
136.7, 136.2, 128.5, 128.0, 127.8, 105.2, 67.1, 63.9, 60.8, 56.0, 45.7, 44.2, 41.3, 32.5, 30.2, 27.2,
24.3. HRMS calc’d for [M+H] = 472.2335, observed = 472.2331. IR (NaCl, DCM): 2491, 1733,
1698, 1589, 1420, 1237, 1127.

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Figure 9.117: Compound VII.15

1-benzyl 2-(3-phenylpropyl) (S)-piperidine-1,2-dicarboxylate (VII.15). To a 50 mL
roundbottom flask containing a stir bar was added 1-((benzyloxy)carbonyl) (S)-piperidine-2carboxylic acid (0.523 g, 1.98 mmol), followed by DCM (20 mL). To the reaction vessel was
added (in the order listed) EDCI (0.45 g, 2.5 mmol), TEA (0.696 mL, 0.505 g, 5.0 mmol), and
DMAP (0.060 g, 0.50 mmol). The reaction vessel was sealed and flushed with nitrogen. Stirring
commenced and 3-phenyl-1-propanol was added via syringe (0.258 mL, 0.258 g, 1.9 mmol). The
reaction was allowed to proceed overnight. The following day, the reaction was transferred to a
separatory funnel in which it was washed with water (10 mL), dilute HCl (10 mL 0.5 M HCl),
saturated aqueous sodium bicarbonate (20 mL) and brine. The crude product was dried over
sodium sulfate and concentrated to dryness in vacuo. The crude product was purified by silica
gel chromatography (1:4 ethyl acetate: hexanes, Rf = 0.30) to yield the pure product as a clear oil
(0.276 g, 38 %). 1H NMR (500 MHz) (CDCl3) (amide rotamers) δ: 7.35 – 7.13 (10H, m), 5.16 –
5.13 (2H, m), 4.97 – 4.85 (1H, m), 4.15 – 4.05 (3H, m), 3.10 – 2.94 (1H, m), 2.68 – 2.61 (2H,
m), 2.27 – 2.19 (1H, m), 1.98 – 1.89 (2H, m), 1.71 – 1.62 (3H, m), 1.47 – 1.41 (1H, m), 1.29 –
1.21 (1H, m). 13C NMR (125 MHz) (CDCl3) (amide rotamers) δ: 171.6, 156.5, 155.4, 141.0,
136.6, 128.4, 128.4, 127.9, 127.8, 126.0, 67.3, 67.2, 64.3, 54.6, 54.4, 41.9, 41.8, 32.0, 26.8, 26.7,
24.7, 24.5, 20.7, 20.6. HRMS calc’d for [M+H] = 382.2018, observed = 382.2044. IR (NaCl,
DCM): 3028, 2943, 2860, 1737, 1710, 1454, 1417, 1336, 1255, 1255, 1203, 1163, 1090, 1044.

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Figure 9.118: Compound VII.16a

(S)-2-(propoxycarbonyl)piperidin-1-ium chloride (VII.16a). To a 100 mL roundbottom flask
containing a stir bar was added (S)-pipecolic acid (0.250 g, 1.9 mmol) and 1-propanol (40 mL).
Stirring commenced and thionyl chloride was added to the mixture dropwise (0.5 mL). A reflux
condenser was attached to the flask and the reaction mixture was heated to reflux overnight. The
following day the reaction mixture was cooled to room temperature and concentrated in vacuo to
approximately 20 % original volume. To this mixture was added diethyl ether (40 mL). The
reaction mixture turned white and solid began to form. The crude mixture was placed placed in a
– 20 oC freezer overnight. The following day the solid was filtered and washed with ether. The
solid material was dried under vaccum to yield the pure product as a white solid (0.269 g, 68 %).
1

H NMR (500 MHz) (d6-DMSO): 9.69 (1H, br s), 9.37 (1H, br s), 4.16 – 4.07 (2H, m), 4.04 (1H,

dd, J = 11.0, 3.5 Hz), 3.20 (1H, br d, J = 12.5 Hz), 2.87 (1H, td, J = 11.5, 3.0 Hz), 2.07 – 2.04
(1H, m), 1.72 – 1.52 (7H, m), 0.89 (3H, t, J = 8.0 Hz).

13

C NMR (125 MHz) (d6-DMSO): 169.2,

67.4, 55.9, 43.7, 26.0, 21.8, 21.6, 21.4, 10.6. HRMS calc’d for [M-Cl] = 172.1338, observed =
172.1333. IR (NaCl, DCM): 1653, 1558, 1456, 1373, 1226.M.P. = 162 oC.
Figure 9.119: Compound VII.16

1-benzyl 2-propyl (S)-piperidine-1,2-dicarboxylate (VII.16). To a 50 mL roundbottom flask
containing a stir bar was added (S)-2-(propoxycarbonyl)piperidin-1-ium chloride (0.220 g, 1.06

205

mmol) followed by dioxane (2 mL) and water (2 mL). Stirring commenced and sodium
carbonate was added as a solid (0.315 g, 3.0 mmol), followed by Cbz-Cl (0.170 mL, 0.204 g, 1.2
mmol). The reaction mixture was stirred at rom temperature overnight. The following day the
reaction was quenched by the addition of HCl (24.0 mmol, 2 mL conc. HCl and 8 mL distilled
water). The reaction mixture was transferred to a separatory funnel and extracted with ethyl
acetate (3 x 15 mL per extraction). The crude material was concentrated in vacuo to yield an oil,
which was purified by silica gel chromatography (1:2 ethyl acetate: hexanes) to yield the pure
product as a clear oil (0.266 g, 75 %). 1H NMR (500 MHz) (CDCl3) (amide rotamers) δ: 7.36 –
7.30 (5H, m), 5.17 – 5.09 (2H, m), 4.95 – 4.83 (1H, m), 4.13 – 4.03 (3H, m), 3.10 – 2.94 (1H,
m), 2.27 – 2.19 (1H, m), 1.70 – 1.58 (5H, m), 1.46 – 1.40 (1H, m), 1.29 – 1.21 (1H, m), 0.94 –
0.88 (3H, m). 13C NMR (125 MHz) (CDCl3) (amide rotamers): 171.7, 171.6, 156.5, 155.9, 136.6,
128.5, 128.4, 127.9, 127.7, 67.2, 67.1, 66.6, 54.6, 54.4, 41.8, 41.8, 26.8, 26.7, 24.7, 24.5, 21.9,
20.7, 20.6, 10.4. HRMS calc’d for [M+H] = 306.1705, observed = 306.1708. IR (NaCl, DCM):
2979, 1698, 1669, 1540, 1419.
Figure 9.120: Compound VII.17

1-benzyl 2-(3-phenylpropyl) (R)-pyrrolidine-1,2-dicarboxylate (VII.17). To a 100 mL
roundbottom flask containing a stir bar and ((benzyloxy)carbonyl)-D-proline (purchased from
Sigma; 2.1 g, 8.4 mmol) was added DCM (50 mL). Stirring commenced and the following
reagents were added (in the order listed) EDCI (1.71 g, 9.0 mmol), TEA (2.52 mL, 2.02 g, 20.0
mmol), DMAP (0.120 g, 0.1 mmol) and 3-phenyl-1-propanol (0.952 mL, 0.952 g, 7.0 mmol).
The reaction vessel was sealed with a septa and flushed with nitrogen. Stirring commenced and

206

the reaction was allowed to proceed overnight. The following day, the reaction mixture was
transferred to a separatory funnel and washed with water (50 mL) and brine (50 mL). The crude
material was concentrated in vacuo to yield an oil which was dissolved in a minimum amount of
DCM and purified by silica gel chromatography (1:4 ethyl acetate:hexanes) to yield the product
as a clear oil (1.8 g, 59 %). 1H NMR (500 MHz) (CDCl3) (amide rotamers) δ: 7.39 – 7.12 (10H,
m), 5.20 – 5.07 (2H, m), 4.39 (1H, ddd, J = 29.0, 7.0, 3.5 Hz), 4.18 – 4.15 (1H, m), 4.06 – 3.98
(1H, m), 3.69 – 3.0 (1H, m), 3.58 – 3.49 (1H, m), 2.69 (1H, t, J = 8.0, 8.0 Hz), 2.58 (1H, t, J =
7.5, 7.5 Hz), 2.28 – 2.09 (1H, m), 2.04 – 1.81 (5H, m). 13C NMR (125 MHz) (CDCl3) (amide
rotamers) δ: 172.8, 172.6, 154.8, 154.3, 141.1, 140.9, 136.7, 136.5, 128.4, 128.4, 128.3, 128.3,
127.9, 127.9, 127.8, 127.8, 126.0, 126.0, 67.0, 66.9, 64.3, 64.0, 59.3, 58.9, 46.9, 46.4, 32.0, 31.9,
30.9, 30.2, 30.0, 29.9, 24.3, 23.5. HRMS calc’d for [M+Na] = 390.1681, observed = 390.1696.
IR (NaCl, DCM): 2955, 1743, 1706, 1452, 1414, 1352, 1194, 1118, 1028, 748.
Figure 9.121: Compound VII.18

1-benzyl 2-phenethyl (S)-pyrrolidine-1,2-dicarboxylate (VII.18). To a 100 mL roundbottom
flask containing a stir bar and ((benzyloxy)carbonyl)-L-proline (2.3 g, 9.2 mmol) was added
DCM (50 mL). Stirring commenced and the following reagents were added (in the order listed)
EDCI (2.18, 11.5 mmol), TEA (2.52 mL, 2.02 g, 20.0 mmol), DMAP (0.120 g, 0.1 mmol) and 2phenylethanol (0.976 mL, 0.976 g, 8.0 mmol). The reaction vessel was sealed with a septa and
flushed with nitrogen. Stirring commenced and the reaction was allowed to proceed overnight.
The following day, the reaction mixture was transferred to a separatory funnel and washed with
water (50 mL) and brine (50 mL). The crude material was concentrated in vacuo to yield an oil

207

which was dissolved in a minimum amount of DCM and purified by silica gel chromatography
(gradient 1:9 to 1:4 ethyl acetate: hexanes) to yield the product as a clear oil (0.985 g, 33 %). 1H
NMR (500 MHz) (CDCl3) (amide rotamers) δ: 7.40 – 7.14 (11H, m), 5.24 – 5.01 (3H, m), 4.48 –
4.31 (2H, m), 4.27 – 4.17 (1H, m), 3.66 – 3.43 (2H, m), 2.96 (1H, t, J = 7.0, 7.0 Hz), 2.81 (1H, t,
J = 7.0, 7.0 H), 2.25 – 1.81 (5H, m). 13C NMR (125 MHz) (CDCl3) (amide rotamers): 172.7,
172.5, 154.8, 154.2, 137.6, 137.4, 136.7, 136.6, 128.9, 128.8, 128.5, 128.4, 128.4, 128.4, 128.3,
128.2, 128.1, 128.0, 127.9, 127.9, 127.8, 127.8, 127.8, 126.6, 126.5, 67.0, 66.9, 66.9, 66.9, 66.8,
66.7, 65.4, 65.3, 59.2, 58.9, 46.9, 46.9, 46.4, 46.3, 35.0, 34.8, 30.9, 29.8, 24.3, 24.2, 23.5, 23.4.
HRMS calc’d for [M+Na] = 376.1525, observed = 376.1525. IR (NaCl, DCM): 3063, 2956,
1744, 1708, 1586, 1453, 1415, 1352, 1277, 1172, 1088, 999, 749, 699.
Figure 9.122: Compound VII.19

dibenzyl (S)-pyrrolidine-1,2-dicarboxylate (VII.19). To a 100 mL roundbottom flask
containing a stir bar was added benzyl-L-prolinate (purchased from Alfa Aesar, 0.858 g, 4.4
mmol) followed by DCM (20 mL). The vessel was sealed with a septa and flushed with nitrogen.
To the stirring reaction mixture was added TEA (0.835 mL, 0.606 g, 6.0 mmol) and Cbz-Cl
(0.580 mL, 0.697 g, 4.1 mmol). The reaction mixture was allowed to stir overnight. The
following day the reaction mixture was transferred to a separatory funnel and extracted with
dilute HCl (20 mL of 5 % HCl v/v) and saturated sodium bicarbonate solution (20 mL). The
organic layer was dried over sodium sulfate and concentrated in vacuo to yield the crude product.
The crude material was purified by silica gel chromatography (1:2 ethyl acetate: hexanes, Rf =
0.4) to yield the product as a clear oil (0.724 g, 51 %). 1H NMR (500 MHz) (CDCl3) (amide

208

rotamers) δ: 7.38 – 7.23 (10H, m), 5.24 – 5.12 (2H, m), 5.09 – 5.00 (2H, m), 4.48 – 4.38 (1H, m),
3.67 – 6.57 (1H, m), 3.55 – 3.46 (1H, m), 2.29 – 2.19 (1H, m), 2.05 – 1.86 (3H, m). 13C NMR
(125 MHz) (500 MHz) (CDCl3) (amide rotamers) δ: 172.6, 172.4, 154.9, 154.2, 136.7, 136.5,
135.7, 135.5, 128.5, 128.4, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.9, 127.8, 127.7, 67.0,
66.9, 66.8, 66.7, 59.2, 58.9, 46.9, 46.4, 30.9, 29.9, 24.3, 23.5. HRMS for [M+H] = 340.1549,
observed = 340.1549. IR (NaCl, DCM): 2957, 1744, 1704, 1652, 1416, 1275, 1168, 1087, 986,
697.
Figure 9.123: Compound VII.20

3-phenylpropyl tosyl-L-prolinate (VII.20). To a 50 mL roundbottom flask containing a stir bar
was added 3-phenylpropyl L-prolinate (0.471 g, 2.0 mmol) followed by DCM (10 mL), and TEA
(0.417 mL, 0.303 g, 3.0 mmol). To this mixture was added tosyl chloride dissolved in DCM
(0.399 g, 2.1 mmol dissolved in 3.0 mL DCM). On addition a white precipitate was formed, and
the reaction was allowed to stir overnight. The following day, the reaction mixture was
transferred to a separatory funnel and extracted wth dilute HCl (20 mL of 5 % HCl v/v) followed
by saturated aqueous sodium bicarbonate (30 mL). The organic layer was dried over sodium
sulfate and concentrated in vacuo. The crude product was purified by silica gel chromatography
(1:3 ethyl acetate: hexanes, Rf = 0.40) to yield the purified product as a clear oil (0.742 g, 96 %).
1

H NMR (500 MHz) (CDCl3) δ: 7.77 (2H, d, J = 8.0 Hz), 7.31 – 7.28 (4H, m), 7.21 – 7.19 (3H,

m), 4.31 (1H, dd, J = 8.5, 3.0 Hz), 4.18 – 4.10 (2H, m), 3.52 – 3.48 (1H, m), 3.35 – 3.30 (1H, m),
2.70 (2H, t, J = 7.5 Hz), 2.42 (3H, s), 2.06 – 1.94 (5H, m), 1.80 – 1.75 (1H, m). 13C NMR (125
MHz) (CDCl3) δ: 172.1, 143.5, 141.0, 135.3, 129.6, 128.4, 127.5, 126.0, 64.6, 60.5, 48.4, 32.0,

209

30.9, 30.1, 24.6, 21.5. HRMS calc’d for [M+H] = 388.1583, observed = 388.1593. IR (NaCl,
DCM): 1652, 1540, 1277, 1094.
Figure 9.124: Compound VII.21

2-benzyl 1-(3-phenylpropyl) (S)-pyrrolidine-1,2-dicarboxylate (VII.21). (S)-2-((benzyloxy)
carbonyl)pyrrolidin-1-ium chloride was purchased and the free base was generated by dissolving
the acid salt in water (3.0 g, 12.4 mmol dissolved in 10 mL distilled water) and adding sodium
carbonate (2.1 g, 20.0 mmol). The aqueous layer was extracted with ethyl acetate (3 x 15 mL).
The organic layers were dried over sodium sulfate and concentrated in vacuo to yield the
product, benzyl-L-prolinate (2.41 g, 95 %), as a clear oil. To a 10 mL roundbottom flask
containing a stir bar was added benzyl-L-prolinate (1.10 g, 5.4 mmol) followed by DCM (25
mL). Stirring commenced and 4-phenylbutanoyl chloride was added dropwise (1.0 g, 5.4 mmol)
and TEA (1.67 mL, 1.21 g, 12.0 mmol). An exotherm was observed and a white precipitate was
formed. The reaction was allowed to stir overnight. The following day the reaction mixture was
transferred to a separatory funnel and washed with dilute HCl (10 mL 5 % HCl v/v) followed by
saturated aqueous sodium bicarbonate (20 mL). The organic layer was dried over sodium sulfate
and concentrated in vacuo. The crude material was purified by silica gel chromatography (1:2
ethyl acetate: hexanes, Rf = 0.25) to yield the pure product as a clear oil (1.12 g, 59 %). 1H NMR
(500 MHz) (CDCl3) (amide rotamers) δ: 7.38 – 7.30 (7H, m), 7.29 – 7.13 (3H, m), 5.22 – 5.12
(2H, m), 4.57 – 4.31 (1H, m), 3.66 – 3.53 (1H, m), 3.44 – 3.39 (1H, m), 2.68 (1H, t, J = 7.5 Hz),
2.62 – 2.37 (1H, m), 2.37 – 2.11 (3H, m), 2.06 – 1.86 (5H, m). 13C NMR (125 MHz) (CDCl3)

210

(amide rotamers) δ: 172.2, 171.6, 141.7, 135.7, 128.7, 128.6, 128.5, 128.5, 128.4, 128.3, 128.2,
128.1, 125.8, 67.1, 66.7, 59.4, 58.7, 46.9, 46.3, 35.1, 35.1, 33.4, 33.4, 31.4, 29.1, 26.1, 26.0, 24.7,
22.5. HRMS calc’d for [M+H] = 352.1913, observed = 352.1947. IR (NaCl, DCM): 2859, 1733,
1698, 1506, 1455, 1420, 1396, 1127.
Figure 9.125: Compound VII.22a

(E)-4-(3,4,5-trimethoxyphenyl)but-3-enoic acid (VII.22a). To a 250 mL roundbottom flask
containing a stir bar was added (2-carboxyethyl)triphenylphosphonium bromide (11.3 g, 27.2
mmol) followed by DMF (20 mL). The reaction vessel was sealed with a septa and flushed with
nitrogen. The reaction mixture was heated to aid in the dissolution of the phosphonium salt.
After the salt was dissolved, the reaction vessel was cooled to 0 oC in an ice-water bath, opened
to the atmosphere, and sodium hydride (2.18 g, 28 mmol, of a 60 % dispersion in oil) was added
in portions. Gas evolved and the reaction vessel was re-sealed under nitrogen. In a separate
vessel 3,4,5-trimethoxybenzaldehyde (5.4 g, 27.5 mmol) was dissolved in DMF (20 mL). The
aldehyde/DMF solution was added dropwise to the sodium hydride/phosphonium salt solution.
Once addition was complete, the reaction vessel was heated to 50 oC in an oil bath overnight.
The following day the reaction mixture was poured into ice-water (200 mL). This solution was
extracted with hexanes (1 x 200 mL) and ethyl acetate (1 x 200 mL). The solution was made
acidic by the addition of HCl (50 mL of 5 % HCl v/v) and extracted with ethyl acetate (2 x 100
mL). The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to
yield a yellow oil. This material was dissolved in a minimum amount of ethyl acetate and filtered

211

through a plug of silica gel. This material was concentrated in vacuo to yield a yellow oil which
was ultimately purified by silica gel chromatography (1:3 ethyl acetate: hexanes, Rf = 0.2) to
yield the product as a yellow solid (2.10 g, 31 %). Spectroscopic data matches that reported for
this compound.198 1H NMR (500 MHz) (CDCl3) δ: 6.60 (2H, s), 6.45 (1H, d, J = 16.0 Hz), 6.23 –
6.17 (1H, m), 3.87 (6H, s), 3.84 (3H, s), 3.30 (2H, dd, J = 7.0, 1.0 Hz). 13C NMR (125 MHz)
(CDCl3) δ: 177.4, 153.3, 137.8, 133.9, 132.3, 120.2, 103.3, 60.9, 56.1, 56.0, 37.8. M.P. = 72 oC.
Figure 9.126: Compound VII.22b

4-(3,4,5-trimethoxyphenyl)butanoic acid (VII.22b). To a 250 mL roundbottom flask
containing a stir bar was added (E)-4-(3,4,5-trimethoxyphenyl)but-3-enoic acid (2.05 g, 8.1
mmol). Ethyl acetate (100 mL) was added, followed by 10 % palladium on carbon (1.2 g).
Stirring commenced and a balloon containing hydrogen was affixed to the roundbottom flask and
a hydrogen atmosphere was applied to the reaction mixture. The reaction stirred overnight and
the following day was filtered through celite and concentrated in vacuo to yield the pure product
(2.07 g, 99 %) as a gray solid. 1H NMR (500 MHz) (CDCl3) δ: 6.39 (2H, s), 3.91 (1H, d, J = 8.0
Hz), 3.84 (6H, s), 3.81 (3H, s), 2.61 (2H, t, J = 8.0 Hz), 2.39 (2H, t, J = 7.5 Hz), 1.96 (2H,
quintet, J = 7.5 Hz).

13

C NMR (125 MHz) (CDCl3) δ: 179.7, 153.1, 136.9, 136.1, 107.2, 105.3,

60.8, 56.2, 56.0, 35.4, 33.3, 26.2. HRMS calc’d for [M+H] = 255.1232, observed = 255.1237. IR
(NaCl, DCM): 3390, 2938, 1734, 1705, 1590, 1507, 1457, 1333, 1283, 1126. M.P. = 70 oC.

212

Figure 9.127: Compound VII.22

benzyl (S)-1-(4-(3,4,5-trimethoxyphenyl)butanoyl)piperidine-2-carboxylate (VII.22). To a
100 mL roundbottom flask containing a stir bar was added benzyl (S)-piperidine-2-carboxylate
(0.475 g, 2.1 mmol) and DCM (15 mL). Stirring commenced and 4-(3,4,5-trimethoxyphenyl)
butanoic acid was added (0.533 g, 2.1 mmol) as a solid, followed by EDCI (0.437 g, 2.3 mmol),
TEA (0.560 mL, 0.404 g, 4.0 mmol), and DMAP (0.060 g, 0.5 mmol). The reaction vessel was
sealed with a septa, flushed with nitrogen, and stirred overnight. The following day the reaction
mixture was transferred to a separatory funnel and washed with water (20 mL) and saturated
sodium bicarbonate solution (20 mL). The organic layer was dried over sodium sulfate and
concentrated in vacuo. The crude material was isolated as an oil and purified by silica gel
chromatography (1:2 ethyl acetate: hexanes, Rf = 0.2) to yield the pure product as a clear oil
(0.463 g, 48 %). 1H NMR (500 MHz) (CDCl3) (amide rotamers) δ: 7.37 – 7.29 (5H, m), 6.42 –
6.39 (2H, m), 5.45 (0.8 H, d, J = 5.0 H), 5.22 – 5.13 (2H, m), 4.58 – 4.54 (0.35 H, m), 3.85 –
3.82 (9H, m), 3.69 (1H, br d, J = 13.0 Hz), 2.66 – 2.54 (2H, m), 2.43 – 2.21 (3H, m), 2.01 – 1.91
(2H, m), 1.71 – 1.59 (4H, m), 1.45 – 1.23 (2H, m). 13C NMR (125 MHz) (CDCl3) (amide
rotamers): 172.9, 171.3, 153.0, 137.6, 136.0, 135.7, 128.6, 128.5, 128.2, 128.2, 128.0, 105.3,
105.2, 66.8, 60.8, 56.0, 51.9, 43.3, 35.7, 32.5, 26.6, 25.3, 20.9. HRMS calc’d for [M+H] =

213

456.2386, observed = 456.2387. IR (NaCl, DCM): 1736, 1645, 1588, 1455, 1353, 1319, 1238,
1126.
Figure 9.128: Compound VII.23

3-phenylpropyl L-prolinate (VII.23). To a 500 mL roundbottom containing 1-benzyl 2-(3phenylpropyl) (S)-pyrrolidine-1,2-dicarboxylate (2.51 g, 6.80 mmol) was added a stir bar and
ethyl acetate (200 mL). Stirring commenced and 10 % palladium on carbon was added (1.0 g).
The reaction vessel was affixed with a hydrogen balloon and hydrogen was applied to the stirring
reaction mixture. The reaction was allowed to proceed overnight, and on the following day the
balloon was removed and the crude material was filtered through celite. The organic layer was
transferred to a separatory funnel and washed with aqueous acid (50 mL of 5 % HCl v/v). The
aqueous layer was washed with ethyl acetate (100 mL). The aqueous layer was made basic by
addition of sodium carbonate (pH ~ 10 by pH paper) and was extracted with ethyl acetate (3 x 50
mL). The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to
yield the product as a clear oil. (1.21 g, 76 %). 1H NMR (500 MHz) (CDCl3) δ: 7.31 – 7.18 (5H,
m), 4.15 (2H, t, J = 7.0, 7.0 Hz), 3.76 (1H, dd, J = 5.5, 2.5 Hz), 3.11 – 3.06 (1H, m), 2.94 – 2.89
(1H, m), 2.70 (2H, t, J = 7.5, 7.5 Hz), 2.18 – 2.10 (2H, m), 2.01 – 1.96 (2H, m), 1.88 – 1.72 (3H,
m). 13C NMR (125 MHz) (CDCl3) δ: 175.5, 141.0, 128.4, 128.3, 126.0, 64.2, 59.8, 47.0, 32.1,
30.3, 30.2, 25.5. HRMS calc’d for [M+H] = 234.1494, observed = 234.1493. IR (NaCl, DCM):
3425, 1734, 1698, 1684, 1653, 1540, 1455, 1418, 1349, 1167.

214

Figure 9.129: Compound VII.24a

3-(3-methyl-3H-diazirin-3-yl)propanoic acid (VII.24a). To a 50 mL roundbottom flask
containing a stir bar was added an ammonia/methanol solution (7.0 M in ammonia, 15 mL).
Stirring commenced and the reaction vessel was sealed with a septa and flushed with argon. The
reaction vessel was cooled to 0 oC in an ice-water bath. To this solution was added dropwise
levulanic acid (1.32 mL, 1.50 g, 12.9 mmol, dissolved in 1.0 mL methanol). The reaction
mixture was stirred for 3 hours at 0 oC, at which time the ice-water bath was removed and
hydroxylamine-O-sulfonic acid (1.53 g, 15.0 mmol) was added as a solid. The reaction vessel
was resealed, flushed with argon, and allowed to stir overnight. The following day the reaction
mixture was filtered (a solid has precipitated) and concentrated in vacuo to yield 3-(3methyldiaziridin-3-yl)propanoic acid (100%) as a clear oil. This material was carried on to the
next step without additional purification. The 3-(3-methyldiaziridin-3-yl)propanoic acid was
dissolved in methanol (10.0 mL) and TEA was added (2.70 mL, 3.37 g, 33.0 mmol). Stirring
commenced and the reaction vessel was cooled to 0 oC in an ice-water bath. Iodine was added
until a purple color persisted. At that time, the reaction mixture was diluted with ethyl acetate (20
mL) and transferred to a separatory funnel. The organic layer was washed with 10 % HCl (10
mL) followed by sodium bisulfite (10 mL of a 10 % w/v solution) and finally with brine. The
organic layer was dried over sodium sulfate and concentrated in vacuo to yield the product as a
yellow oil (1.31 g, 85 %). Spectroscopic data matches that reported for this compound.199 1H
NMR (500 MHz) (CDCl3) δ: 2.23 (2H, t, J = 7.5 Hz), 1.72 (2H, t, J = 7.5 Hz), 1.04 (3H, s). 13C
NMR (125 MHz) (CDCl3) δ: 177.5, 29.3, 28.3, 25.0, 19.6.

215

Figure 9.130: Compound VII.24

3-phenylpropyl (3-(3-methyl-3H-diazirin-3-yl)propanoyl)-L-prolinate (VII.24). To a 50 mL
roundbottom flask containing a stir bar was added 3-(3-methyl-3H-diazirin-3-yl)propanoic acid
(0.322 g, 2.6 mmol) followed by DCM (10 mL), EDCI (0.608 g, 3.0 mmol), DMAP (0.060 g,
0.50 mmol) and TEA (0.835 mL, 0.606 g, 6.0 mmol). Stirring commenced, and 3-phenylpropyl
L-prolinate was added (0.629 g, 2.7 mmol). The reaction vessel was sealed with a septa, flushed
with nitrogen, and stirred overnight. The crude reaction mixture was transferred to a separatory
funnel and extracted with dilute HCl (50 mL of 5 % HCl v/v) and saturated aqueous sodium
bicarbonate (100 mL). The organic layer was dried over sodium sulfate and concentrated in
vacuo. The crude product was purified by silica gel chromatography (1:1 ethyl acetate: hexanes,
Rf = 0.30) to yield the pure product as a clear oil (0.544 g, 58 %). 1H NMR (500 MHz) (CDCl3)
(amide rotamers) δ:

13

C NMR (125 MHz) (CDCl3) (amide rotamers): 172.2, 170.0, 141.1, 128.5,

128.4, 128.3, 126.1, 125.9, 64.9, 64.3, 59.4, 58.7, 46.9, 46.4, 32.0, 31.4, 30.2, 30.1, 29.3, 29.2,
29.0, 28.5, 25.5, 24.7, 22.5, 20.0. Missing carbon at 72 ppm, see text for discussion. HRMS
calc’d for [M+H] = 344.1974, observed = 344.1971. IR (NaCl, DCM): 2055, 1733, 1651, 1558,
1396, 1174.

216

Figure 9.131: Compound VII.25

3-phenylpropyl (4-oxopentanoyl)-L-prolinate (VII.25). To a 100 mL roundbottom flask
containing a stir bar was added levulinic acid (0.307 mL, 0.348 g, 3.0 mmol) followed by DCM
(20 mL), EDCI (0.608 g, 3.2 mmol), TEA (1.39 mL, 1.01 g, 10.0 mmol), DMAP (0.120 g, 1.0
mmol) and 3-phenylpropyl L-prolinate (0.700 g, 3.0 mmol). The reaction mixture was stirred
overnight. The following day the reaction mixture was transferred to a separatory funnel and
washed with dilute HCl (10 mL 5 % HCl v/v) followed by sodium bicarbonate (30 mL). The
organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material was
purified by silica gel chromatography (1:1 ethyl acetate: hexanes Rf = 0.70) to yield the pure
product as a clear oil (0.988 g, 96 %). 1H NMR (500 MHz) (CDCl3, amide rotamers) δ: 7.30 –
7.26 (2H, m), 7.20 – 7.16 (3H, m), 4.54 – 4.47 (1H, m), 4.19 – 4.11 (2H, m), 3.69 – 3.64 (1H,
m), 3.62 – 3.55 (1H, m), 2.97 – 2.91 (1H, m), 2.72 – 2.62 (4H, m), 2.61 – 2.48 (1H, m), 2.31 –
1.90 (10H, m). 13C NMR (125 MHz) (CDCl3, amide rotamers): 207.7, 172.3, 170.4, 141.1,
128.5, 128.4, 128.4, 128.3, 126.1, 125.9, 64.9, 64.3, 59.4, 58.8, 46.9, 46.4, 38.1, 37.7, 32.0, 31.4,
30.2, 30.0, 29.3, 28.5, 24.7, 22.6. HRMS calc’d for [M+H] = 332.1862, observed = 332.1873. IR
(NaCl, DCM): 2955, 1699, 1652, 1558, 1456, 1419.

217

Figure 9.132: Compound VIII.1a

ethyl (4R,5R)-1-benzyl-2-(4-methoxyphenyl)-5-(4-nitrophenyl)-4-phenyl-4,5-dihydro-1Himidazole-4-carboxylate (VIII.1a). To a 250 mL roundbottom flask containing a stir bar was
added toluene (100 mL), followed by anhydrous benzylamine (3.26 mL, 3.19 g, 60.0 mmol),
followed by para-nitrobenzaldehyde (9.0 g, 60.0 mmol). The reaction mixture was heated to
reflux overnight using a Dean-Stark apparatus for the azeotropic removal of water. The
following day, the reaction mixture was cooled to room temperature and concentrated in vacuo
to yield the imine (14.4 g, 100 % yield) as an oil which was used in the next step without
purification.
In a separate 250 mL roundbottom flask containing a stir bar was added phenylglycine
(10.0 g, 66.0 mmol), followed by water (400 mL) and sodium carbonate (19.5 g, 186.0 mmol).
Stirring commenced and p-methoxybenzoyl chloride was added dropwise (11.8 g, 69.2 mmol,
dissolved in 200 mL 1,4-dioxane) and the reaction mixture was allowed to stir overnight. The
following day, the reaction mixture was made acidic by the addition of dilute HCl (dropwise
addition of 50 mL of 20 % v/v HCl), at which time a white solid precipitated. The crude product
was filtered and washed with ethyl ether, dissolved in ethyl acetate, washed with water (3 x 100
mL per extraction), dried over sodium sulfate and concentrated in vacuo to yield a white solid.

218

The crude product was purified by recrystallization (dissolve in a minimum amount of ethyl
acetate and heat, precipitate by adding hexanes) to yield the pure product as a white solid, which
was dried in vacuo to a constant weight (8.3 g, 44 %). The protected 2-phenylglycine (8.3 g, 32.1
mmol) was transformed to the corresponding azlactone by dissolving in DCM (200 mL) and
adding TFAA (4.8 mL, 7.2 g, 33.3 mmol). The reaction was stirred under nitrogen for 2 hours,
during which time a yellow color developed (diagnostic of the formation of the azlactone). After
this time, the reaction mixture was transferred to a separatory funnel and extracted twice with
saturated sodium bicarbonate (2 x, 50 mL per extraction). The crude azlactone was dried over
sodium sulfate and concentrated in vacuo to yield the crude product as a yellow solid.
In a 500 mL roundbottom flask with a stir bar the imine previously described (8.3 g, 31.0
mmol) was dissolved in anhydrous DCM (300 mL). To this mixture was added the protected
phenylglycine azlactone previously described (7.4 g, 31.0 mmol). Stirring commenced, and to
the reaction mixture was added freshly distilled TMSCl (5.04 mL, 4.32 g, 40.0 mmol) was
added. The reaction vessel was connected to a reflux condenser which was sealed with a septa
and flushed with nitrogen. The reaction mixture was heated to reflux overnight. The following
day, the reaction mixture was concentrated to dryness and 300 mL ethyl acetate was added. The
reaction vessel was cooled at 0 oC for 3 hours, at which time the precipitate was filtered and
washed with ethyl acetate and hexanes. The sand-like solid was dried in vacuo to yield the
imidazoline as the HCl salt (4.3 g, 27 % yield).
The imidazoline HCl salt (4.3 g, 8.4 mmol) was suspended in DCM (20 mL) in a 50 mL
roundbottom flask, followed by EDCI (1.80, 9.5 mmol), TEA (2.08 mL, 1.51 g, 15.0 mmol),
DMAP (0.120 g, 1.0 mmol), and ethyl alcohol (0.870 mL, 0.690 g, 15.0 mmol). The reaction
vessel was sealed with a septa, flushed with nitrogen, and allowed to stir overnight. The

219

following day, the reaction mixture was transferred to a separatory funnel and extracted with
water (25 mL). The organic layer was dried over sodium sulfate, concentrated in vacuo, and
purified by silica gel chromatography (2:3 ethyl acetate hexanes to 2:3:0.2 ethyl acetate:
hexanes: TEA) to yield the product as an orange solid (2.0 g, 44 %). Spectroscopic data matches
that reported for this compound.197 1H NMR (500 MHz) (CDCl3) δ: 8.22 (2H, dd, J = 10.0, 1.5
Hz), 7.77 (2H, dd, J = 10.0, 2.0 Hz), 7.69 – 7.67 (2H, m), 7.55 (2H, d, J = 8.5 Hz), 7.35 – 7.25
(3H, m), 7.11 – 7.06 (1H, m), 7.06 – 7.00 (4H, m), 6.72 (2H, d, J = 7.5 Hz), 4.91 (1H, s), 4.64
(1H, d, J = 16.0 Hz), 3.86 – 3.83 (4H, m), 3.74 – 3.70 (1H, m), 3.67 – 3.62 (1H, m), 0.828 (3H, t,
J = 6.5 Hz). 13C NMR (125 MHz) (CDCl3) δ: 170.5, 165.6, 161.5, 147.6, 146.3, 143.6, 135.9,
130.5, 128.9, 128.5, 128.2, 127.7, 127.6, 127.2, 126.5, 123.6, 122.0, 114.1, 83.1, 73.1, 61.3, 55.4,
49.7, 13.6.
Figure 9.133: Compound VIII.1

ethyl (4R,5R)-5-(4-aminophenyl)-1-benzyl-2-(4-methoxyphenyl)-4-phenyl-4,5-dihydro-1Himidazole-4-carboxylate (VIII.1) To a 250 mL roundbottom flask with a stir bar was added
ethyl (4R,5R)-1-benzyl-2-(4-methoxyphenyl)-5-(4-nitrophenyl)-4-phenyl-4,5-dihydro-1Himidazole-4-carboxylate (2.0 g, 3.7 mmol), followed by glacial acetic acid (50 mL). Stirring
commenced, and to the reaction mixture was added zinc dust (3.0 g, 46.0 mmol). An exotherm

220

was observed, and the reaction was allowed to continue for two hours. At this time, the reaction
mixture was filtered and the filter was washed with water. Water was added to the crude mixture
(100 mL) and solid sodium carbonate was added until no bubbles were observed (the product
collects as a solid on top of the aqueous layer once the mixture is sufficiently basic). The
aqueous layer was extracted with ethyl acetate (3 x 100 mL). The organic layers were dried over
sodium sulfate and concentrated in vacuo to yield the product as an orange solid which needed
no further purification (2.1 g, quantitative yield). Spectroscopic data match that reported for this
compound.197 1H NMR (500 MHz) (CDCl3) δ: 7.73 – 7.68 (4H, m), 7.32 – 7.26 (2H, m), 7.25 –
7.24 (1H, m), 7.15 – 7.04 (5H, m), 6.97 – 6.95 (2H, m), 6.75 (2H, d, J = 7.0 Hz), 6.66 (2H, d, J =
8.5 Hz), 4.79 (1H, s), 4.61 (1H, d, J = 15.5 Hz), 3.85 – 3.82 (4H, m), 3.78 – 3.63 (4H, m), 0.88
(3H, t, J = 6.5 Hz). 13C NMR (125 MHz) (CDCl3) δ: 171.1, 165.0, 161.0, 146.4, 144.4, 137.1,
130.3, 129.2, 128.3, 127.8, 127.5, 127.2, 127.1, 127.1, 126.9, 123.0, 114.9, 113.8, 82.4, 73.5,
60.9, 55.3, 48.4, 13.6.
Figure 9.134: Compound VIII.2

Biotin ethyl ester (VIII.2). To a 500 mL roundbottom flask containing a stir bar was added
biotin (5.0 g, 20.4 mmol) followed by ethanol (250 mL). The starting material did not dissolve,
but stirring commenced and the reaction mixture was cooled to 0 oC in an ice bath. Acetyl
chloride was added dropwise (2.0 mL, 2.2 g, 28.2 mmol). The ice bath was removed and the
reaction mixture was allowed to stir overnight. By the following day the biotin had dissolved,
indicating completion of the reaction. The reaction mixture was concentrated in vacuo to yield

221

the crude product as a white solid. The product was purified by dissolving the crude solid in a
minimum of acetone and precipitating with hexanes. The solid was filtered and dried in vacuo to
yield the pure product as a white solid (3.4 g, 59 % yield). Spectroscopic data matches that
reported for this compound.198 1H NMR (500 MHz) (CDCl3) δ: 5.90 (1H, br s), 5.48 (1H, br s),
4.50 (1H, dd, J = 10.0, 5.0 Hz), 4.30 (1H, dd, J = 7.5, 5.5 Hz), 4.11 (2H, quartet, J = 7.5 Hz),
3.17 – 3.13 (1H, m), 2.90 (1H, dd, J = 12.5, 4.5 Hz), 2.73 (1H, d, J = 12.5 Hz), 2.31 (2H, t, J =
7.5 Hz), 1.74 – 1.63 (4H, m), 1.49 – 1.40 (2H, m), 1.24 (3H, t, J = 8.0 Hz). 13C NMR (125 MHz)
(CDCl3) δ: 173.7, 163.6, 61.9, 60.3, 60.1, 55.4, 40.5, 33.9, 28.3, 28.2, 24.7, 14.2.
Figure 9.135: Compound VIII.3a

(4,4’)-DMT-Biotin ethyl ester (VIII.3a). To a 100 mL roundbottom flask was added a stir bar
and biotin ethyl ester (3.4 g, 11.7 mmol). The reaction vessel was sealed with a septa and flushed
with nitrogen. To the vessel was added anhydrous pyridine (50 mL). Stirring commenced, and on
complete dissolution of the solid (~ 5 minutes) the septa was removed and 4,4’-dimethoxytrityl
chloride was added (4.39 g, 13.0 mmol). The reaction mixture was stirred for 3 hours at which
time methanol was added (5.0 mL). The reaction mixture was concentrated in vacuo and
redissolved in DCM. The organic layer was washed with dilute HCl (80 mL of 5 % v/v HCl) and
saturated bicarbonate. The organic layer was dried over sodium sulfate and concentrated in
vacuo to yield the crude product as an oil. The crude material was purified by silica gel

222

chromatography (100 % DCM to 5 % methanol in DCM) to yield the pure product was a yellow
foam (3.4 g, 49 % yield). Spectroscopic data matches that reported for this compound.198 1H
NMR (500 MHz) (CDCl3) δ: 7.30 – 7.21 (5H, m), 7.17 – 7.11 (4H, m), 6.82 – 6.79 (4H, m), 5.81
(1H, br s), 4.36 – 4.33 (1H, m), 4.29 – 4.26 (1H, m), 4.18 – 4.08 (3H, m), 3.77 (6H, s), 3.10 –
3.06 (1H, m), 2.42 – 2.39 (1H, m), 2.28 – 2.22 (3H, m), 2.03 (1H, s), 1.64 – 1.55 (4H, m), 1.44 –
1.31 (2H, m), 1.25 (4H, td, J = 5.0, 5.0, 2.5 Hz). 13C NMR (125 MHz) (CDCl3) δ: 173.5, 171.1,
163.7, 161.6, 158.5, 158.3, 147.4, 143.7, 139.5, 135.8, 135.8, 131.3, 129.7, 129.1, 127.8, 127.7,
127.5, 127.0, 126.8, 113.1, 113.0, 112.8, 112.7, 81.3, 72.6, 65.3, 61.7, 60.3, 60.2, 60.2, 60.1,
59.8, 55.3, 55.2, 55.2, 54.2, 40.4, 39.0, 33.9, 33.9, 33.7, 28.6, 28.3, 28.2, 28.1, 24.7, 24.6, 24.5,
21.0, 14.2, 14.2.
Figure 9.136: Compound VIII.3

(4,4’)-DMT-Biotinol (VIII.3). To a 500 mL roundbottom flask containing (4,4’)-DMT-Biotin
ethyl ester (3.4 g, 5.8 mmol) was added a stir bar and THF (200 mL). Stirring commenced, and
the reaction vessel was cooled to 0 oC in an ice bath. Powdered LAH was added in portions
(0.985, 26.0 mmol). After addition was complete, the reaction vessel was sealed with a septa and
flushed with nitrogen. The reaction was allowed to warm to room temperature and proceed
overnight. The following day, the reaction was quenched with ethanol, water, and water
saturated with sodium sulfate. The crude reaction mixture was concentrated in vacuo to remove

223

ethanol and THF. The crude was transferred to a separatory funnel and extracted with ethyl
acetate (3 x 100 mL per extraction). The organic layer was dried over sodium sulfate and
concentrated in vacuo to yield the crude product as an oil. The crude was purified by silica gel
chromatography (100 % DCM to 5 % methanol in DCM) to yield the pure product as a white
solid (2.7 g, 89 %). Spectroscopic data matches that reported for this compound.198 1H NMR (500
MHz) (CDCl3) δ: 7.30 – 7.14 (9H, m), 6.84 – 6.80 (4H, m), 6.16 – 5.47 (1H, br m), 4.37 – 4.17
(2H, m), 3.79 (6H. s), 3.66 – 3.55 (2H, m), 3.13 – 3.01 (1H, m), 2.45 (1H, d, J = 12.5 Hz), 2.28
(1H, dd, J = 13.0, 4.5 Hz), 2.17 (1H, br s), 1.68 – 1.56 (3H, m), 1.55 – 1.45 (1H, m), 1.41 -1.38
(4H, m). 13C NMR (125 MHz) (CDCl3) δ: 158.3, 158.2, 143.7, 135.8, 135.7, 131.3, 129.9, 129.7,
129.1, 128.1, 127.8, 127.7, 127.7, 127.5, 126.9, 113.1, 112.9, 112.8, 72.7, 65.5, 61.6, 59.6, 55.4,
55.2, 55.2, 54.3, 40.4, 39.1, 32.0, 31.5, 29.0, 28.1, 25.6. HRMS calc’d for [M+Na] = 555.2293,
observed = 555.2294.
Figure 9.137: Compound VIII.4

prop-2-yn-1-yl (4R,5R)-1-benzyl-2,4,5-triphenyl-4,5-dihydro-1H-imidazole-4-carboxylate
(VIII.4). To a 250 mL roundbottom flask containing a stir bar was added toluene (100 mL),
followed by anhydrous benzylamine (3.26 mL, 3.2 g, 29.5 mmol), followed by benzaldehyde
(2.98 mL, 3.1 g, 29.5 mmol). The reaction mixture was heated to reflux overnight using a DeanStark apparatus for the azeotropic removal of water. The following day, the reaction mixture was
cooled to room temperature and concentrated in vacuo to yield the imine (6.3 g, 100 % yield) as

224

an oil which was used in the next step without purification. In a separate 250 mL roundbottom
flask containing a stir bar was added phenylglycine (10.0 g, 66.1 mmol), followed by aqueous
sodium hydroxide (1.0 N, 132 mL). Stirring commenced and benzoyl chloride was added
dropwise (8.4 mL, 10.2 g, 72.8 mmol, dissolved in 40 mL 1,4-dioxane) and the reaction mixture
was allowed to stir overnight. The following day, the reaction mixture was made acidic by the
addition of dilute HCl (dropwise addition of 50 mL of 20 % v/v HCl), at which time a white
solid precipitated. The crude product was dissolved in ethyl acetate, partitioned in a separatory
funnel, dried over sodium sulfate and concentrated in vacuo to yield a white solid. The crude
product was purified by recrystallization (dissolve in a minimum amount of 1:9 methanol:ethyl
acetate and heat, precipitate by adding hexanes) to yield the pure product as a white solid, which
was dried in vacuo to a constant weight (8.3 g, 49 %).
The N-benzoyl 2-phenylglycine (8.3 g, 32.1 mmol) was transformed to the corresponding
azlactone by dissolving in DCM (200 mL) and adding TFAA (4.8 mL, 7.2 g, 33.3 mmol). The
reaction was stirred under nitrogen for 2 hours, during which time a yellow color developed
(diagnostic of the formation of the azlactone). After this time, the reaction mixture was
transferred to a separatory funnel and extracted twice with saturated sodium bicarbonate (2 x, 50
mL per extraction). The crude azlactone was dried over sodium sulfate and concentrated in
vacuo to yield the crude product as a yellow solid.
In a 500 mL roundbottom flask with a stir bar the imine previously (6.3 g, 29.5 mmol)
described was dissolved in anhydrous DCM (300 mL). To this mixture was added the N-benzoyl
-phenylglycine azlactone previously described (7.0 g, 32.1 mmol). Stirring commenced, and to
the reaction mixture was added freshly distilled TMSCl (4.1 mL, 3.50 g, 32.4 mmol) was added.
The reaction vessel was connected to a reflux condenser which was sealed with a septa and

225

flushed with nitrogen. The reaction mixture was heated to reflux overnight. The following day,
the reaction mixture was concentrated to dryness and 300 mL ethyl acetate was added. The
reaction vessel was cooled at 0 oC for 3 hours, at which time the precipitate was filtered and
washed with ethyl acetate and hexanes. The sand-like solid was dried in vacuo to yield the
imidazoline as the HCl salt (7.7 g, 51 % yield).
The imidazoline HCl salt (1.40 g, 3.0 mmol) was suspended in DCM (20 mL) in a 50 mL
roundbottom flask, followed by EDCI (0.665 g, 3.5 mmol), TEA (1.25 mL, 0.909 g, 9.0 mmol),
DMAP (0.120 g, 1.0 mmol), and propargyl alcohol (0.290 mL, 0.280 g, 5.0 mmol). The reaction
vessel was sealed with a septa, flushed with nitrogen, and allowed to stir overnight. The
following day, the reaction mixture was transferred to a separatory funnel and extracted with
water (25 mL). The organic layer was dried over sodium sulfate, concentrated in vacuo, and
purified by silica gel chromatography (3:7 ethyl acetate hexanes to 1:1:0.1 ethyl acetate:
hexanes: TEA) to yield the product as an oil (0.646 g, 46 %). 1H NMR (500 MHz) (CDCl3) δ:
7.82 – 7.77 (4H, m), 7.52 – 7.50 (3H, m), 7.43 – 7.30 (8H, m), 7.15 – 7.07 (3H, m), 6.77 (2H, d,
J = 7.0 Hz), 4.95 (1H, s), 4.66 (1H, d, J = 16.0 Hz), 4.27 (1H, dd, J = 15.5, 2.5 Hz), 4.05 (1H, dd,
J = 15.5, 2.5 Hz), 3.86 (1H, d, J = 16.0 Hz), 2.24 (1H, t, J = 2.5 Hz). 13C NMR (125 MHz)
(CDCl3) δ: 170.1, 165.8, 143.5, 137.5, 136.5, 130.4, 128.8, 128.7, 128.6, 128.1, 127.6, 127.4,
127.2, 126.8, 83.0, 76.8, 74.6, 73.9, 52.4, 48.6. HRMS calc’d for [M+H] = 471.2073, observed =
471.2106. IR (NaCl, DCM): 3293, 3062, 2935, 2128, 1739, 1615, 1571, 1448, 1360, 1217, 1066,
731, 699.

226

Figure 9.138: Compound VIII.5

(1-(13-oxo-17-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-3,6,9-trioxa12-azaheptadecyl)-1H-1,2,3-triazol-4-yl)methyl (4R,5R)-1-benzyl-2,4,5-triphenyl-4,5dihydro-1H-imidazole-4-carboxylate (VIII.5). To a 25 mL roundbottom flask containing a stir
bar was added N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-5-((3aS,4S,6aR)-2oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide (“Azide-PEG3-Biotin conjugate”
purchased from Aldrich, 100 mg, 0.22 mmol) followed by DCM/2-propanol (3.0 mL of a 1:1
mixture) and prop-2-yn-1-yl (4R,5R)-1-benzyl-2,4,5-triphenyl-4,5-dihydro-1H-imidazole-4carboxylate (0.137 g, 0.29 mmol). Stirring commenced and water was added (3.0 ml) followed
by copper(II) sulfate pentahydrate (0.50 g, 0.20 mmol) and sodium ascorbate (0.099 g, 0.5
mmol). The organic layer turned brown and the reaction mixture was allowed to stir for 48 hours
at room temperature. The crude reation mixture was transferred to a separatory funnel and
partitioned. The aqueous layer was washed with DCM (1 x 5 mL), and the organic layers were
combined, dried over sodium sulfate filtered through celite (washed with DCM) and
concentrated in vacuo to yield the crude product as a tan foam (0.271 g). The crude material was
purified by silica gel chromatography (crude was dissolved in DCM and applied to a column
packed in 1:1:0.1 ethyl acetate:hexanes:TEA. The unreacted alkyne was eluted in this solvent
system. The product is eluted in 1:4 methanol:ethyl acetate, Rf = 0.1) to yield the pure product as
227

a clear oil (0.047 g, 23 %). 1H NMR (500 MHz) (CDCl3) δ: 7.75 – 7.70 (4H, m), 7.49 – 7.48
(3H, m), 7.32 – 7.26 (10H, m), 7.13 – 7.10 (1H, m), 7.07 – 7.04 (2H, m), 6.78 (1H, br s), 6.70
(2H, d, J = 7.0 Hz), 6.12 (1H, br s), 5.29 (1H, br s), 4.89 (1H, s), 4.79 – 4.58 (3H, m), 4.44 – 4.39
(3H, m), 4.26 – 4.24 (1H, m), 3.80 – 3.77 (3H, m), 3.52 – 3.47 (10H, m), 3.37 – 3.35 (2H, m),
3.12 – 3.07 (4H, m), 2.84 (1H, dd, J = 13.0, 4.0 Hz), 2.68 (1H, br d, J = 12.5 Hz), 2.12 (2H, t, J =
8.0 Hz), 1.71 – 1.56 (4H, m), 1.41 – 1.36 (7H, m). 13C NMR (125 MHz) (CDCl3) δ: 173.2, 165.8,
163.5, 142.0, 128.8, 128.7, 128.4, 128.1, 127.6, 127.5, 127.1, 126.7, 125.9, 125.3, 76.7, 73.8,
70.5, 70.3, 70.3, 70.0, 69.8, 69.2, 61.7, 60.0, 58.4, 55.4, 50.0, 48.6, 45.7, 40.5, 39.0, 35.7, 35.7,
28.0, 28.0, 25.4, 8.6. HRMS calc’d for [M+H] = 915.4227, observed = 915.4205. IR (NaCl,
DCM): 3478, 3405, 3391, 2098, 1645, 1450, 1353, 1240, 1179, 1096, 1029, 980, 699.
Figure 9.139: Compound VIII.6

Ethyl (4R,5R)-1-benzyl-2-(4-methoxyphenyl)-5-(4-(3-(3-methyl-3H-diazirin-3yl)propanamido)phenyl)-4-phenyl-4,5-dihydro-1H-imidazole-4-carboxylate (VIII.6). To a
roundbottom flask containing a stir bar and ethyl (4R,5R)-5-(4-aminophenyl)-1-benzyl-2-(4methoxyphenyl)-4-phenyl-4,5-dihydro-1H-imidazole-4-carboxylate (1.2 g, 2.3 mmol) was added
DCM (10 mL), EDCI (0.451 g, 2.3 mmol), TEA (0.696 mL, 0.505 g, 5.0 mmol), and DMAP
(0.060 g, 0.50 mmol). Stirring commenced, the reaction vessel was sealed with a septa and

228

flushed with nitrogen. To the stirring mixture was added 3-(3-methyl-3H-diazirin-3-yl)propanoic
acid (0.268 g, 2.2 mmol) dropwise. The reaction mixture was allowed to stir overnight. The
following day the reaction mixture was transferred to a separatory funnel and extracted with
dilute HCl (10 mL of a 5 % HCl v/v solution) followed by aqueous sodium bicarbonate (20 mL).
The organic layer was dried over sodium sulfate and concentrated in vacuo to yield the crude
product as an oil. The crude material was purified by silica gel chromatography (1:1:0.04 ethyl
acetate: hexanes: TEA) to yield the pure product as an orange oil (0.542 g, 40 %). 1H NMR (500
MHz) (CDCl3) δ: 8.03 (1H, br s), 7.72 – 7.70 (2H, m), 7.67 (2H, d, J = 8.0 Hz), 7.55 (2H, d, J =
8.5 Hz), 7.35 – 7.26 (6H, m), 7.14 – 7.11 (1H, m), 7.08 – 7.05 (2H, m), 6.99 – 6.96 (2H, m), 6.73
(2H, d, J = 7.5 Hz), 4.86 (1H, s), 4.62 (1H, d, J = 16.5 Hz), 3.85 (3H, s), 3.80 (1H, d, J = 15.5
Hz), 3.74 – 3.69 (1H, m), 3.68 – 3.63 (1H, m), 2.18 (2H, t, J = 7.5 Hz), 1.81 (2H, dt, J = 8.0, 8.0,
3.0 Hz), 1.05 (3H, s), 0.838 (3H, t, J = 7.5 Hz). 13C NMR (125 MHz) (CDCl3) δ: 170.9, 169.8,
165.3, 161.3, 143.9, 138.2, 136.6, 133.3, 130.3, 128.7, 128.4, 128.1, 127.5, 127.4, 127.1, 126.7,
119.8, 114.0, 82.3, 73.0, 61.0, 55.4, 48.6, 31.4, 297, 25.4, 19.9, 13.6. Missing carbon at 72 ppm,
see text for discussion. HRMS calc’d for [M+H] = 616.2924, observed = 616.2923. IR (NaCl,
DCM): 2089, 1696, 1632, 1507, 1473, 1396.
Figure 9.140: Compound VIII.7a

2-(4-bromophenyl)-1,3-dioxane (VIII.7a). To a 500 mL roundbottom flask containing a stir bar
was added p-bromobenzaldehyde (20.0 g, 108.0 mmol) followed by toluene (200 mL). Stirring
commenced, and to the reaction mixture was added 1,3-propane diol (10.2 mL, 10.6 g, 140.0

229

mmol) and tosyl acid (0.200 g, 1.0 mmol). The reaction mixture was heated to reflux overnight
in a Dean-Stark apparatus. The following day the reaction mixture was allowed to cool to room
temperature and extracted with sodium bicarbonate (100 mL) and brine. The organic layer was
dried over sodium sulfate and concentrated in vacuo to yield the product as a white solid (25.4 g,
98 %). Spectroscopic data matches that reported for this compound.199 1H NMR (500 MHz)
(CDCl3) δ: 7.50 – 7.49 (2H, m), 7.37 – 7.36 (2H, m), 5.46 (1H, s), 4.01 – 3.95 (2H, m), 2.26 –
2.17 (1H, m), 1.47 – 1.43 (1H, m). 13C NMR (125 MHz) (CDCl3): 137.7, 131.3, 127.8, 122.8,
100.8, 67.3, 25.6. M.P. = 72 oC.
Figure 9.141: Compound VIII.7

1-(4-(1,3-dioxan-2-yl)phenyl)-2,2,2-trifluoroethan-1-one (VIII.7). To a 500 mL oven dried
roundbottom flask containing 2-(4-bromophenyl)-1,3-dioxane (25.4 g, 105.0 mmol) was added
THF (300 mL) and a stir bar. The reaction vessel was sealed, flushed with nitrogen, and stirring
commenced and once all the solid had dissolved the reaction mixture was cooled to – 78 oC in a
dry ice-acetone bath. To the stirring mixture was added n-butyllithium dropwise (46.0 mL of a
2.5 M solution in hexanes). The reaction mixture was allowed to stir at – 78 oC for 30 minutes, at
which time ethyl trifluoroacetate was added dropwise (15.0 mL, 17.8 g, 126.5 mmol dissolved in
150 mL THF). The reaction mixture was allowed to stir at – 78 oC for 2 hours, at which time it
was allowed to warm to room temperature. The reaction was quenched with saturated
ammonium chloride (20.0 mL) and concentrated to ~ 20 % original volume in vacuo. The
remaining biphasic liquid was partitioned between ethyl acetate (200 mL) and water (100 mL).

230

The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to
yield the product as a waxy, white solid (15.5 g, 75 %). Spectroscopic data matches that reported
for this compound.199 1H NMR (500 MHz) (CDCl3) δ: 8.06 (2H, d, J = 8.5 Hz), 7.66 (2H, d, J =
8.5 Hz), 5.56 (1H, s), 4.17 (2H, dd, J = 11.5, 5.5 Hz), 4.02 (2H, dt, J = 13.0, 13.0, 2.5 Hz), 2.22
(1H, m), 1.49 (1H, dd, J = 13.0, 2.5 Hz). 13C NMR (125 MHz) (CDCl3) δ: 180.2 (q, 2JCF = 34.5),
145.8, 130.1, 130.1, 129.9, 126.8, 117.7 (q, 1JCF = 291.4), 100.1, 67.4, 25.6.
Figure 9.142: Compound VIII.8a

1-(4-(1,3-dioxan-2-yl)phenyl)-2,2,2-trifluoroethan-1-one O-methylsulfonyl oxime (VIII.8a).
To a 500 mL roundbottom containing a stir bar and 1-(4-(1,3-dioxan-2-yl)phenyl)-2,2,2trifluoroethan-1-one (15.5 g, 59.6 mmol) was added 300 mL of ethanol. Stirring commenced and
powdered sodium hydroxide (12.8 g, 321.0 mmol) was added, followed by hydroxylamine HCl
(22.3 g, 321.0 mmol). The reaction mixture was heated to reflux overnight. The following day,
the reaction mixture was cooled to room temperature, filtered, and concentrated in vacuo to yield
the product as a white solid (16.4 g, 100 %). The product was carried on to the next step with no
further purification. The oxime was dissolved in DCM (100 mL) and cooled to 0 oC in an icewater bath. Stirring commenced, and to the reaction mixture was added TEA (20.0 mL, 15.1 g,
150.0 mmol), DMAP (1.2 g, 10.0 mmol), and mesyl chloride (10.0 mL, 15.1 g, 133.8 mmol)
dropwise. The reaction mixture was allowed to warm to room temperature and stirred overnight.
The following day the reaction mixture was transferred to a separatory funnel and washed with
10 % HCl (200 mL), sodium bicarbonate (200 mL) and brine. The organic layer was dried over

231

sodium sulfate and concentrated in vacuo to yield the product mesylated oxime. The crude
material was purified by silica gel chromatography (1:4 ethyl acetate: petroleum ether) to yield
the product as a mixture of cis and trans isomers (20.1 g, 85 %). Spectroscopic data matches that
reported for this compound.199 1H NMR (500 MHz) (CDCl3) δ: 7.64 (2H, d, J = 8.5 Hz), 5.55
(1H, s), 4.28 (2H, dd, J = 10.5, 4.0 Hz), 4.01 (2H, dt, J = 10.5, 10.5, 1.5 Hz), 3.24 (3H, s), 2.22
(1H, m), 1.47 (1H, m). 13C NMR (125 MHz) (CDCl3) δ: 154.7, 142.4, 128.4, 126.6, 126.6, 126.5,
124.6, 119.5 (q, 1JCF = 274.1), 100.3, 100.2, 67.4, 37.3, 36.7, 36.6, 31.5, 25.6 5 (q, 2JCF = 34.7),
Figure 9.143: Compound VIII.8

3-(4-(1,3-dioxan-2-yl)phenyl)-3-(trifluoromethyl)-3H-diazirine (VIII.8). To a 250 mL
roundbottom flask containing 1-(4-(1,3-dioxan-2-yl)phenyl)-2,2,2-trifluoroethan-1-one Omethylsulfonyl oxime (20.1 g, 56.6 mmol) was added methanol (50 mL) and a stir bar. The
reaction vessel was sealed with a septa and flushed with nitrogen. Stirring commenced and the
reaction vessel was cooled to – 78 oC in a dry ice-acetone bath. To the stirring mixture was
added ammonia (7.0 M in methanol, 30.0 mL, 210.0 mmol). The reaction was allowed to warm
to room temperature and stir overnight. The following day the reaction mixture was concentrated
in vacuo to yield 3-(4-(1,3-dioxan-2-yl)phenyl)-3-(trifluoromethyl)diaziridine (15.5 g, 100 %) as
a yellow oil. Spectroscopic data matches that reported for this compound.199 1H NMR (500 MHz)
(CDCl3) δ: 7.53 (2H, d, J = 8.5 Hz), 7.21 (2H, d, J = 8.5 Hz), 5.51 (1H, s), 4.27 (2H, ddd, J =
11.0, 3.0, 1.0 Hz), 3.99 (2H, dt, 13.5, 13.5, 2.5 Hz), 2.27 – 2.17 (1H, m), 1.48 – 1.44 (1H, m). 13C

232

NMR (125 MHz) (CDCl3): 140.2, 129.4, 126.5, 126.4, 122.0 (q, 1JCF = 277.9), 100.5, 67.3, 28.3
(q, 2JCF = 38.8). 19F NMR δ: - 65.2.
Figure 9.144: Compound VIII.9

Ethyl (4R,5R)-1-benzyl-2-(4-methoxyphenyl)-4-phenyl-5-(4-(((Z)-4-(3-(trifluoromethyl)-3Hdiazirin-3-yl)benzylidene)amino)phenyl)-4,5-dihydro-1H-imidazole-4-carboxylate (VIII.9).
To a 250 mL roundbottom flask containing a stir bar and 3-(4-(1,3-dioxan-2-yl)phenyl)-3(trifluoromethyl)-3H-diazirine (0.900 g, 3.3 mmol) was added a 1:2 water:acetone mixture (40
mL) and Amberlyst-15 pellets (0.150 g). The reaction vessel was sealed, flushed with nitrogen,
and stirred at room temperature for 72 hours. At this time, the reaction mixture was transferred to
a separatory funnel and washed with DCM (20 mL x 1). The organic layer was dried over
sodium sulfate and transferred to a 100 mL roundbottom flask with a stir bar. The conversion of
the starting material to the product aldehyde, 4-(3-(trifluoromethyl)-3H-diazirin-3yl)benzaldehyde, was assumed to be 100 %, and quantity of material used in the next step was
based on this assumption.
Molecular sieves were added (4 angstrom pellets), followed by ethyl (4R,5R)-5-(4aminophenyl)-1-benzyl-2-(4-methoxyphenyl)-4-phenyl-4,5-dihydro-1H-imidazole-4-carboxylate
(1.5 g, 3.4 mmol). Stirring commenced and once the imidazoline had dissolved, sodium

233

triacetoxyborohydride (0.840 g, 4.0 mmol) was added in one portion. The reaction vessel was
sealed with a septa, flushed with nitrogen, and stirred overnight. The following day, the reaction
mixture was transferred to a separatory funnel and quenched with saturated sodium bicarbonate
(50 mL x 1). The organic layer was dried over sodium sulfate and concentrated in vacuo to yield
the crude product as an orange foam. The crude material was purified by silica gel
chromatography (3:7:0.01 ethyl acetate:hexanes:TEA, Rf = 0.3). Analytically pure material can
be obtained in this manner, but a small portion (50 mg) was purified by Autocolumn (product
eluted in 100 % ethyl acetate in a method that ramped from 5 % to 100 % ethyl acetate:hexanes,
method MG-9-67). The combined yield obtained was 200 mg (8 % from starting aldehyde) of
material as a yellow oil. 1H NMR (500 MHz) (CDCl3) δ: 8.49 (1H, s), 7.96 (2H, d, J = 8.0 Hz),
7.75 (4H, d, J = 8.5 Hz), 7.43 (2H, d, J = 8.0 Hz), 7.36 – 7.29 (5H, m), 7.24 (2H, d, J = 8.5 Hz),
7.15 – 7.06 (3H, m), 7.09 (2H, 9.0 Hz), 6.77 (2H, d, J = 7.5 H), 4.91 (1H, s), 4.67 (1H, d, J =
16.0 Hz), 3.87 (3H, s), 3.86 (1H, d, J = 16.0 Hz). 3.79 – 3.74 (1H, m), 3.72 – 3.65 (1H, m), 0.86
(3H, t, J = 6.5 Hz). 13C NMR (125 MHz) (CDCl3): 170.9, 165.2, 161.2, 158.7, 151.3, 144.2,
137.1, 136.7, 136.4, 132.0, 130.4, 129.1, 129.0, 128.4, 128.0, 127.4, 127.3, 127.2, 126.8, 126.7,
126.7, 123.0, 122.7, 120.9, 120.8 (q, 1JCF = 276.1), 113.9, 82.7, 73.4, 61.0, 55.3, 48.9, 13.6 (q,
2

JCF = 39.8). 19F NMR δ: – 64.8. HRMS calc’d for [M + H] = 702.2692, observed = 702.2680.

IR (NaCl, DCM): 3033, 2935, 2099, 1728, 1613, 1514, 1447, 1419, 1343, 1252, 1231, 1187,
1157, 1092, 1069, 1031, 938, 830, 737, 697.

234

APPENDIX

235

Figure 10.1: 1H and 13C Spectra of Compound II.4

236

Figure 10.2: 1H and 13C Spectra of Compound II.5a

237

Figure 10.3: 1H and 13C Spectra of Compound II.5b

238

Figure 10.4: gCOSY Spectra of Compound II.5b

239

Figure 10.5: gHMQC Spectra of Compound II.5b

240

Figure 10.6: 1H and 13C Spectra of Compound II.5

241

Figure 10.7: 1H and 13C Spectra of Compound II.11

242

Figure 10.8: 1H and 13C Spectra of Compound II.12

243

Figure 10.9: 1H and 13C Spectra of Compound II.13

244

Figure 10.10: 1H and 13C Spectra of Compound II.14

245

Figure 10.11: 1H and 13C Spectra of Compound II.15a

246

Figure 10.12: 1H and 13C Spectra of Compound II.15b

247

Figure 10.13: 1H and 13C Spectra of Compound II.16

248

Figure 10.14: 1H and 13C Spectra of Compound II.7

249

Figure 10.15: 1H and 13C Spectra of Compound II.7a

250

Figure 10.16: 1H and 13C Spectra of Compound II.17a

251

Figure 10.17: 1H and 13C Spectra of Compound II.6

252

Figure 10.18: 1H and 13C Spectra of Compound II.18

253

Figure 10.19: 1H and 13C Spectra of Compound II.19

254

Figure 10.20: 1H and 13C Spectra of Compound II.20a

255

Figure 10.21: 1H and 13C Spectra of Compound II.21a

256

Figure 10.22: 1H and 13C Spectra of Compound II.21

257

Figure 10.23: 1H and 13C Spectra of Compound II.22

258

Figure 10.24: 1H and 13C Spectra of Compound III.2a

259

Figure 10.25: 1H and 13C Spectra of Compound III.2b

260

Figure 10.26: 1H and 13C Spectra of Compound III.2

261

Figure 10.27: 1H and 13C Spectra of Compound III.3

262

Figure 10.28: gCOSY Spectra of Compound III.3

263

Figure 10.29: gHMQC Spectra of Compound III.3

264

Figure 10.30: 1H and 13C Spectra of Compound III.4a

265

Figure 10.31: 1H and 13C Spectra of Compound III.4

266

Figure 10.32: gCOSY Spectra of Compound III.4

267

Figure 10.33: gHMQC Spectra of Compound III.4

268

Figure 10.34: 1H and 13C Spectra of Compound III.5

269

Figure 10.35: 1H and 13C Spectra of Compound III.6a

270

Figure 10.36: 1H and 13C Spectra of Compound III.6

271

Figure 10.37: gCOSY Spectra of Compound III.6

272

Figure 10.38: gHMQC Spectra of Compound III.6

273

Figure 10.39: 1H and 13C Spectra of Compound III.7a

274

Figure 10.40: 1H and 13C Spectra of Compound III.7

275

Figure 10.41: 1H and 13C Spectra of Compound III.8

276

Figure 10.42: 1H and 13C Spectra of Compound III.9

277

Figure 10.43: 1H and 13C Spectra of Compound III.10

278

Figure 10.44: 1H and 13C Spectra of Compound III.11a

279

Figure 10.45: 1H and 13C Spectra of Compound III.11

280

Figure 10.46: gCOSY Spectra of Compound III.11

281

Figure 10.47: gHMQC Spectra of Compound III.11

282

Figure 10.48: 1H and 13C Spectra of Compound III.12a

283

Figure 10.49: 1H and 13C Spectra of Compound III.12

284

Figure 10.50: 1H and 13C Spectra of Compound III.13a

285

Figure 10.51: 1H and 13C Spectra of Compound III.13

286

Figure 10.52: 1H and 13C Spectra of Compound III.14

287

Figure 10.53: 1H and 13C Spectra of Compound III.15

288

Figure 10.54: 1H and 13C Spectra of Compound III.16

289

Figure 10.55: 1H and 13C Spectra of Compound III.17

290

Figure 10.56: 1H and 13C Spectra of Compound III.18

291

Figure 10.57: 1H and 13C Spectra of N-Boc-Homo-L-proline

292

Figure 10.58: 1H and 13C Spectra of Compound IV.1a

293

Figure 10.59: 1H and 13C Spectra of Compound IV.1

294

Figure 10.60: 1H and 13C Spectra of Compound IV.2.

295

Figure 10.61: gCOSY Spectra of Compound IV.2

296

Figure 10.62: gHMQC Spectra of Compound IV.2

297

Figure 10.63: 1H and 13C Spectra of Compound IV.3a

298

Figure 10.64: 1H and 13C Spectra of Compound IV.3

299

Figure 10.65: gHMQC Spectra of Compound IV.3

300

Figure 10.66: 1H and 13C Spectra of Compound IV.4

301

Figure 10.67: 1H Spectra of Compound IV.5

302

Figure 10.68: 1H and 13C Spectra of Compound IV.6

303

Figure 10.69: 1H and 13C Spectra of Compound IV.7

304

Figure 10.70: 1H and 13C Spectra of Compound IV.7a

305

Figure 10.71: 1H and 13C Spectra of Compound IV.8

306

Figure 10.72: 1H and 13C Spectra of Compound IV.9

307

Figure 10.73: gCOSY Spectra of Compound IV.9

308

Figure 10.74: gHMQC Spectra of Compound IV.9

309

Figure 10.75: 1H and 13C Spectra of Compound V.1

310

Figure 10.76: 1H and 13C Spectra of Compound V.1a

311

Figure 10.77: 1H and 13C Spectra of Compound V.2

312

Figure 10.78: 1H and 13C Spectra of Compound V.3

313

Figure 10.79: gHMQC Spectra of Compound V.3

314

Figure 10.80: 1H and 13C Spectra of Compound V.4

315

Figure 10.81: 1H and 13C Spectra of Compound V.5a

316

Figure 10.82: 1H and 13C Spectra of Compound V.5

317

Figure 10.83: 1H and 13C Spectra of Compound V.6

318

Figure 10.84: 1H and 13C Spectra of Compound V.7

319

Figure 10.85: 1H and 13C Spectra of Compound V.9

320

Figure 10.86: 1H and 13C Spectra of Compound V.10a

321

Figure 10.87: 1H and 13C Spectra of Compound V.10

322

Figure 10.88: 1H and 13C Spectra of Compound VI.1

323

Figure 10.89: 1H and 13C Spectra of Compound VI.2

324

Figure 10.90: gHMQC Spectra of Compound VI.2

325

Figure 10.91: 1H and 13C Spectra of Compound VI.3a

326

Figure 10.92: 1H and 13C Spectra of Compound VI.3

327

Figure 10.93: gHMQC Spectra of Compound VI.3

328

Figure 10.94: 1H and 13C Spectra of Compound VI.4a

329

Figure 10.95: 1H and 13C Spectra of Compound VI.4b

330

Figure 10.96: 1H and 13C Spectra of Compound VI.4c

331

Figure 10.97: 1H and 13C Spectra of Compound VI.4

332

Figure 10.98: 1H and 13C Spectra of Compound VI.5

333

Figure 10.99: 1H and 13C Spectra of Compound VI.6

334

Figure 10.100: 1H and 13C Spectra of Compound VI.7a

335

Figure 10.101: 1H and 13C Spectra of Compound VI.7

336

Figure 10.102: 1H and 13C Spectra of Compound VI.10a

337

Figure 10.103: 1H and 13C Spectra of Compound VI.10

338

Figure 10.104: 1H and 13C Spectra of 2,2,2-trichloroethyl(chloro(methylthio)methylene)sulfamate

339

Figure 10.105: 1H and 13C Spectra of Compound VI.9

340

Figure 10.106: 1H and 13C Spectra of Compound VI.11

341

Figure 10.107: gHMQC Spectra of Compound VI.11

342

Figure 10.108: 1H and 13C Spectra of Compound VII.1a

343

Figure 10.109: 1H and 13C Spectra of Compound VII.1

344

Figure 10.110: 1H and 13C Spectra of Compound VII.2a

345

Figure 10.111: 1H and 13C Spectra of Compound VII.2

346

Figure 10.112: gCOSY Spectra of Compound VII.2

347

Figure 10.113: gHMQC Spectra of Compound VII.2

348

Figure 10.114: 1H and 13C Spectra of Compound VII.3a

349

Figure 10.115: 1H and 13C Spectra of Compound VII.3

350

Figure 10.116: 1H and 13C Spectra of Compound VII.4a

351

Figure 10.117: 1H and 13C Spectra of Compound VII.4

352

Figure 10.118: 1H and 13C Spectra of Compound VII.5

353

Figure 10.119: gCOSY Spectra of Compound VII.5

354

Figure 10.120: gHMQC Spectra of Compound VII.5

355

Figure 10.121: 1H and 13C Spectra of Compound VII.6a

356

Figure 10.122: 1H and 13C Spectra of Compound VII.6

357

Figure 10.123: gHMQC Spectra of Compound VII.6

358

Figure 10.124: 1H and 13C Spectra of Compound VII.7a

359

Figure 10.125: 1H and 13C Spectra of Compound VII.7

360

Figure 10.126: gCOSY Spectra of Compound VII.7

361

Figure 10.127: 1H and 13C Spectra of Compound VII.8a

362

Figure 10.128: 1H and 13C Spectra of Compound VII.8

363

Figure 10.129: gCOSY Spectra of Compound VII.8

364

Figure 10.130: gHMQC Spectra of Compound VII.8

365

Figure 10.131: 1H and 13C Spectra of Compound VII.9

366

Figure 10.132: gCOSY Spectra of Compound VII.9

367

Figure 10.133: gHMQC Spectra of Compound VII.9

368

Figure 10.134: 1H and 13C Spectra of Compound VII.10a

369

Figure 10.135: 1H and 13C Spectra of Compound VII.10

370

Figure 10.136: 1H and 13C Spectra of Compound VII.11a

371

Figure 10.137: 1H and 13C Spectra of Compound VII.11

372

Figure 10.138: 1H and 13C Spectra of Compound VII.12a

373

Figure 10.139: 1H and 13C Spectra of Compound VII.12

374

Figure 10.140: 1H and 13C Spectra of Compound VII.13

375

Figure 10.141: 1H and 13C Spectra of Compound VI.14a

376

Figure 10.142: 1H and 13C Spectra of Compound VII.14

377

Figure 10.143: 1H and 13C Spectra of Compound VII.15

378

Figure 10.144: 1H and 13C Spectra of Compound VII.16a

379

Figure 10.145: 1H and 13C Spectra of Compound VII.16

380

Figure 10.146: 1H and 13C Spectra of Compound VII.17

381

Figure 10.147: 1H and 13C Spectra of Compound VII.18

382

Figure 10.148: gCOSY Spectra of Compound VII.18

383

Figure 10.149: gHMQC Spectra of Compound VII.18

384

Figure 10.150: 1H and 13C Spectra of Compound VII.19

385

Figure 10.151: 1H and 13C Spectra of Compound VII.20

386

Figure 10.152: 1H and 13C Spectra of Compound VII.21

387

Figure 10.153: 1H and 13C Spectra of Compound VII.22a

388

Figure 10.154: 1H and 13C Spectra of Compound VII.22b

389

Figure 10.155: 1H and 13C Spectra of Compound VII.22

390

Figure 10.156: gCOSY Spectra of Compound VII.22

391

Figure 10.157: gHMQC Spectra of Compound VII.22

392

Figure 10.158: 1H and 13C Spectra of Compound VII.23

393

Figure 10.159: 1H and 13C Spectra of Compound VII.24a

394

Figure 10.160: 1H and 13C Spectra of Compound VII.24

395

Figure 10.161: 1H and 13C Spectra of Compound VII.25

396

Figure 10.162: 1H and 13C Spectra of Compound VIII.1a

397

Figure 10.163: 1H and 13C Spectra of Compound VIII.1

398

Figure 10.164: 1H and 13C Spectra of Compound VIII.2

399

Figure 10.165: 1H and 13C Spectra of Compound VIII.3a

400

Figure 10.166: 1H and 13C Spectra of Compound VIII.3

401

Figure 10.167: 1H and 13C Spectra of Compound VIII.4

402

Figure 10.168: 1H and 13C Spectra of Compound VIII.5

403

Figure 10.169: gHMQC Spectra of Compound VIII.5

404

Figure 10.170: 1H and 13C Spectra of Compound VIII.6

405

Figure 10.171: 1H and 13C Spectra of Compound VIII.7a

406

Figure 10.172: 1H and 13C Spectra of Compound VIII.7

407

Figure 10.173: 1H and 13C Spectra of Compound VIII.8a

408

Figure 10.174: 1H and 13C Spectra of Compound VIII.8

409

Figure 10.175: 1H and 13C Spectra of Compound VIII.9

410

Figure 10.176: gHMQC Spectra of Compound VIII.9

411

Figure 10.177: 19F Spectra of Compound VIII.9

412

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