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Cobalt(II)-catalyzed atom/group transfer reaction

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Title:
Cobalt(II)-catalyzed atom/group transfer reaction stereoselective carbene and nitrene transfer reactions
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English
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Ruppel, Joshua V
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University of South Florida
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Subjects / Keywords:
Porphryin
Catalysis
Cyclopropanation
Aziridination
Amination
Dissertations, Academic -- Chemistry -- Doctoral -- USF   ( lcsh )
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non-fiction   ( marcgt )

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Summary:
ABSTRACT: Metalloporphyrins have been shown to catalyze many fundamental and practically important chemical transformations, some of which represent the first demonstrations of these catalytic processes. The most notable examples include an assortment of atom/group transfer reactions, such as oxene, nitrene, and carbene transfers. Atom/group transfer reactions allow for the direct conversion of abundant and inexpensive alkenes and alkanes into value-added functional molecules. Previous reports from our group have shown that cobalt-porphyrin based carbene and nitrene transfer reactions are some of the most selective and practical catalytic systems developed for cyclopropanation and aziridination. Backed by a family of D₂-symmetric chiral cobalt porphyrins our group continues the development of stereoselective carbene and nitrene transfer reactions.Metal-catalyzed cyclopropanation of olefins with diazo reagents has attracted great research interest because of its fundamental and practical importance. The resulting cyclopropyl units are recurrent motifs in biologically important molecules and can serve as versatile precursors in organic synthesis. Supported by a family of D₂-symmetric chiral cobalt porphyrins, we have demonstrated the use of succimidyl diazoacetate as carbene source for a highly diastereo- and enantioselective cyclopropanation process. The resulting cyclopropyl succinimdyl esters are highly reactive and serve as valuable synthons for generating cyclopropylcarboxamides. We have also developed the first cobalt-porphyrin based intramolecular cyclopropanation, which is able to produce the resulting bicyclic lactones in high yields and enantioselectivity. Nitrene transfer reactions are also an attractive route to produce biologically and synthetically important molecules such as amines and aziridines.Although much progress has been made in nitrene transfer reactions utilizing N-(p-toluenesulfonyl) iminophenyliodinane (PhI=NTs) the nitrene source suffers from several drawbacks. Consequently, there has been growing interest in developing catalytic nitrene transfer reactions using alternate nitrene sources. To this end, we have utilized arylsulfonyl azides as nitrene source to explore their use in the development of a cobalt-porphyrin catalyzed enantioselective aziridination system. The cobalt catalyzed process can proceed under mild and neutral conditions in low catalyst loading without the need of other reagents, while generating nitrogen gas as the only byproduct. We have also explored the use of arylsulfonyl azides as nitrene source in a cobalt-catalyzed intramolecular C-H amination process.
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Dissertation (Ph.D.)--University of South Florida, 2008.
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by Joshua V. Ruppel.
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Cobalt(II)-Catalyzed Atom/Group Transfer Reactions: Stereoselective Carbene and Nitrene Transfer Reactions by Joshua V. Ruppel A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Department of Chemistry College of Arts and Sciences University of South Florida Major Professor: X. Peter Zhang, Ph.D. Jon Antilla, Ph.D. Roman Manetsch, Ph.D. Mark L. McLaughlin, Ph.D. Date of Approval: November 7, 2008 Keywords: porphyrin, catalysis, cycl opropanation, aziridination, amination Copyright 2008 Joshua V. Ruppel

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This work is dedicated to my friends a nd family for being supportive and patient while this work was in progress. I may ha ve missed the occasional (read: most) holidays and birthdays but my thoughts were always th ere, while my body wa s in the lab running another column. This is especially for Stephen and Jean Ann Ruppel for spending the time to raise me with a decent amount of stubbornness and intelligence. For driving me to the Honors Science Academy at Park Tutor High School everyday for a couple of months over the summer when I was in middle school, and suppor ting this thought I had in my head that instead of being a lawyer or a football player, I wanted to be a scientist.

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Acknowledgements I need to begin with thanking Dr. Peter Zhang for his guidance and mentorship over the last 5 years. Especially for pushing me to achieving my potential as a researcher and setting an example of dedication to science that is admirable. Dr. Jon Antilla has always been a good s ource of advice and insightful discussion on research and chemistry. I truly thank him fo r his support the last couple of years. Dr. Roman Manetsch and Dr Mark L. McLaughlin were kind enough to join my committee with knowing me only a short time. Si nce then I have been able to interact with them on several occasions and ha ve enjoyed their support and advice. Those that have the most direct influence over my work has been those that I have worked with over they years. My research career really began the summer of 2003 when I spent 3 months training under Dr. Guan-Y ung Gao, and I feel that experience has shaped my whole graduate career and I th ank him for his patience and support while I found my “hands”. I also need to thank th e many people I have worked with over the years especially Dr. Ying Chen, Dr. Jess Jones, Jeremiah Harden, and Matt Smith. Lastly, I need to thank my lab mate and fr iend Kimberly B. Fields. I can’t possibly put into words for how grateful I am to ha ve had her support in and out of the lab (as painful as it might have been at times). I also need to thank and acknowledge the support and generosity of the Bliss family. I hope that I can repay their kindness in full.

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i Table of Contents List of Tables iv List of Figures vi List of Spectra viii Abstract xii Chapter 1. Developments in Cobalt-Cat alyzed Carbene and Nitrene Transfer Reactions 1 1.1. Introduction 1 1.2. Carbene Transfer: Enantioselective Cyclopropanation 2 1.2.1. Cobalt Salen Catalysts 3 1.2.2. Cobalt Aldiminato Catalysts 5 1.2.3. Cobalt Porphyrin Catalysts 8 1.2.4. Other Supporting Ligands 13 1.2.5. Mechanism 16 1.3. Nitrene Transfer: Aziridination and Amination 17 1.3.1. Cobalt Porphyrin Catalyzed Aziridination 18 1.3.2. Cobalt Porphyrin Catalyzed C–H Amination 20 1.3.3. Mechanism 22 1.4. Conclusions 23

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ii Chapter 2. Cobalt-Catalyzed En antioselective Intramolecular Cyclopropanation of Allylic Diazoacetates 24 2.1. Introduction 24 2.2. Enantioselective Intr amolecular Cyclopropanation 26 2.3. Mechanism of Co(II)-Porphyrin Catalyzed Intramolecular Cyclopropanation 32 2.4. Conclusions 34 Chapter 3. Asymmetric Cobalt-Catalyzed Cyclopropanation with Succinimidyl Diazoacetate: General Synthesis of Optically Active Cyclopropyl Carboxamides 35 3.1. Introduction 34 3.2. Diastereoand Enantioselective Cyclopropanation with Succinimidyl Diazoacetate 37 3.3. Post-Derivitization Approach for th e Synthesis of Optically Active Cyclopropyl Carboxamides 43 3.4. Conclusions 45 Chapter 4. Cobalt-Catalyzed Olefin Azir idination with Arylsulfonyl Azides 46 4.1. Introduction 46 4.2. Hydrogen Bonded Catalyst Design 47 4.3. Enantioselective Aziridinati on of Arylsulfonyl Azides 52 4.4. Conclusions 59 Chapter 5. Cobalt-Catalyzed Intramolecu lar C–H Amination with Arylsulfonyl Azides 60

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iii 5.1. Introduction 60 5.2. Intramolecular C–H Amination with Arylsulfonyl Azides 61 5.3. Conclusions 67 Chapter 6. Experimental Procedur es and Compound Characterization 69 6.1. General Considerations 69 6.2. Supporting Information for Chapter 2 70 6.3. Supporting Information for Chapter 3 76 6.4. Supporting Information for Chapter 4 90 6.5. Supporting Information for Chapter 5 103 Chapter 7 Spectral Data 111 7.1. Spectral Data for Chapter 2 111 7.2. Spectral Data for Chapter 3 129 7.3. Spectral Data for Chapter 4 168 7.4. Spectral Data for Chapter 5 201 References 215 Peer Review Publications by Author 224 About the Author End Page

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iv List of Tables Table 1.1. [ Co( MPAC )] Catalyzed Cyclopropana tion with Axial Donor Ligands. 6 Table 1.2. Enantioselectiv e Cyclopropanation of Styrene Derivatives with Various Co(II)-Aldiminato Catalysts 8 Table 1.3. Diastereoand Enantiosele ctive Cyclopropanation of Olefins by [Co( P1 )]. 12 Table 1.4. Aziridinatio n of Different Olefins by [Co(TDClPP)]. 19 Table 1.5. [Co(TDClPP)]-Catalyzed Amination with Bromamine-T. 21 Table 2.1. Intramolecular Cyclopropana tion by Chiral Cobalt(II) Porphyrins. 28 Table 2.2. Intramolecular Cyclopropanation with [Co( P1 )] in Various Solvents. 29 Table 2.3. Enantioselec tive Intramolecular Cyclopropanation with [Co( P1 )] Under Various Conditions. 30 Table 2.4. [Co( P1 )]-Catalyzed Enantioselective Intramolecular Cyclopropanation of Allylic Diazoacetates. 32 Table 3.1. Asymmetric Cyclopropanati on of Styrene with Succinimidyl Diazoacetate by D2-Symmetric Chiral Coba lt(II) Porphyrins. 40 Table 3.2. [Co(P1)]-Catalyzed Diastereoand Enantioselective Cyclopropanation of Different Alkenes with Succinimidyl Diazoacetate. 42 Table 3.3. Synthesis of Chiral Cyclopropanecarboxamides. 44 Table 4.1. Aziridination of Styrene with Arylsulfonyl Azides with Different Cobalt(II) Porphyrins. 48

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v Table 4.2. [Co( P7 )]-Catalyzed Aziridination of Styrene with Arylsulfonyl Azides. 50 Table 4.3. Aziridination of Aromatic Olefins by [Co( P7 )]. 51 Table 4.4. Aziridination of Aromatic Olefins with 64c by [Co( P7 )]. 52 Table 4.5. Additive Effects of Asymmetric Aziridination. 54 Table 4.6. Asymmetric Aziridination by D2-Symmetric Chiral Cobalt(II) Porphyrins. 56 Table 4.7. [Co( P6 )]-Catalyzed Asymmetric Aziridination of Styrene. 57 Table 4.8. Asymmetric Aziridinatio n of Aromatic Olefins by [Co( P7 )]. 58 Table 5.1. C–H Amination of 69a Catalyzed by Metalloporphyrins. 62 Table 5.2. C–H Amination of 69a Catalyzed by Cobalt(II) Porphyrins. 64 Table 5.3. [Co(TPP)]-Catalyzed In tramolecular C–H Amination. 65 Table 5.4. Fiveand Six-Membered Ri ng Formation via Intramolecular C–H Amination Catalyzed by Cobalt Porphyrins. 67 Table 6.1. Crystal data and structure refinement for 56b 78

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vi List of Figures Figure 1.1. Co(III)-Salen Catalyzed Cyclopropanation. 3 Figure 1.2. Co(II)-Salen Catalyzed Cyclopropanation. 4 Figure 1.3. Cyclopropanation Utilizing a Co(II)-Salen Catalyst Baring a (NMI) Pendent Group. 4 Figure 1.4. Intramolecular Cyclopropanati on Utilizing a Co(II)-Salen Catalyst. 5 Figure 1.5. Cyclopropanation of Styren e with Chiral Co(II)-Catalyst 16 9 Figure 1.6. Synthesis of D2-Symmetric Chiral Porphyrins and their Cobalt Complexes. 10 Figure 1.7. Stereoselective Cyclopropanation with D2-Symmetric Chiral Co(II)-Porphyrin Complexes. 11 Figure 1.8. Cyclopropanation of Diazosulfones with [Co( P6 )]. 13 Figure 1.9. Cyclopropanation of -Nitrodiazoacetate with [Co( P1 )]. 13 Figure 1.10. Salen-Based Dicobalt Catalyzed Cyclopropanation. 14 Figure 1.11. Cyclopropanation with a Co(II)-Pincer Type Ligand. 15 Figure 1.12. Cyclopropanation with Vitamin B12 as Catalyst. 16 Figure 1.13. Proposed Mechanism of C obalt Catalyzed Cyclopropanation. 17 Figure 1.14. Common Nitrene Sources. 18 Figure 1.15. Aziridination of Styrene Derivatives with DPPA by [Co(TPP)]. 20 Figure 1.16. Asymmetric Aziridinat ion with DPPA by [Co(P1)]. 20 Figure 1.17. Imine Formation from Catalytic Amination of Benzylic C–H Bonds 21

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vii Figure 1.8. Proposed Mechanism of C obalt-Catalyzed Nitrene Transfer. 23 Figure 2.1. Intramolecular Cyclopropanation with Allylic Diazoacetates. 24 Figure 2.2. Intramolecular Cyclopropan ation in the synthesis of (+)Ambruticin S. 25 Figure 2.3. Intramolecular Cyclopropanati on with Various Metal-Complexes. 26 Figure 2.4. Structures of D2-Symmetric Chiral C obalt(II) Porphyrins. 27 Figure 2.5. Stereospecificity of [Co( P1 )]-Catalyzed Intramolecular Cyclopropanation. 33 Figure 2.6. Proposed Mechanism fo r the Non-stereospecific [Co( P1 )]Catalyzed Intramolecular Cyclopropanation. 34 Figure 3.1. Synthetic Routes to Chiral Cyclopropanecarboxamides 36 Figure 3.2. Intramolecular C–H Insertion with Diazoacetamides. 36 Figure 3.3. Examples of Important Bi ologically Active Chiral Cyclopropyl Carboxamides. 37 Figure 3.4. Structures of D2-Symmetric Chiral C obalt(II) Porphyrins. 38 Figure 4.1. Cobalt-Catalyzed Olefin Azir idination with Arylsulfonyl Azides. 47 Figure 4.2. Structures of C obalt(II) Porphyrin Catalysts 47 Figure 4.3. Structures of D2-Symmetric Chiral Cobalt(II) Porphyrins 53 Figure 5.1. Catalytic Intramolecular C–H Amination of Arylsulfonyl Azides 61 Figure 5.2. Structures of Me talloporphyrin Catalysts. 63 Figure 6.1. Carbon Assignments for the and -Anomer of 57i 90

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viii List of Spectra Spectra 6.1.1. 1H and 13C NMR for 10a 111 Spectra 6.1.2. GC/MS Spectra for 10a 112 Spectra 6.1.3. 1H and 13C NMR for 10b 113 Spectra 6.1.4. GC/MS Spectra for 10b 114 Spectra 6.1.5. 1H and 13C NMR for 10c 115 Spectra 6.1.6. GC/MS Spectra for 10c 116 Spectra 6.1.7. 1H and 13C NMR for 10d 117 Spectra 6.1.8. GC/MS Spectra for 10d 118 Spectra 6.1.9. 1H and 13C NMR for 10e 119 Spectra 6.1.10. GC/MS Spectra for 10e 120 Spectra 6.1.11. 1H and 13C NMR for 10f 121 Spectra 6.1.12. GC/MS Spectra for 10f 122 Spectra 6.1.13. 1H and 13C NMR for 10g 123 Spectra 6.1.14. GC/MS Spectra for 10g 124 Spectra 6.1.15. 1H and 13C NMR for 10h 125 Spectra 6.1.16. GC/MS Spectra for 10h 126 Spectra 6.1.17. 1H and 13C NMR for 10i 127 Spectra 6.1.18. GC/MS Spectra for 10i 128 Spectra 6.2.1. 1H and 13C NMR for 56a 129

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ix Spectra 6.2.2. HPLC Spectra for 56a 130 Spectra 6.2.3. 1H and 13C NMR for 56b 131 Spectra 6.2.4. HPLC Spectra for 56b 132 Spectra 6.2.5. 1H and 13C NMR for 56c 133 Spectra 6.2.6. HPLC Spectra for 56c 134 Spectra 6.2.7. 1H and 13C NMR for 56d 135 Spectra 6.2.8. HPLC Spectra for 56d 136 Spectra 6.2.9. 1H and 13C NMR for 56e 137 Spectra 6.2.10. HPLC Spectra for 56e 138 Spectra 6.2.11. 1H and 13C NMR for 56f 139 Spectra 6.2.12. HPLC Spectra for 56f 140 Spectra 6.2.13. 1H and 13C NMR for 56g 141 Spectra 6.2.14. HPLC Spectra for 56g 142 Spectra 6.2.15. 1H and 13C NMR for 56h 143 Spectra 6.2.16. HPLC Spectra for 56h 144 Spectra 6.2.17. 1H and 13C NMR for 56i 145 Spectra 6.2.18. HPLC Spectra for 56i 146 Spectra 6.2.19. 1H and 13C NMR for 56j 147 Spectra 6.2.20. HPLC Spectra for 56j 148 Spectra 6.2.21. 1H and 13C NMR for 56k 149 Spectra 6.2.22. HPLC Spectra for 56k 150 Spectra 6.2.23. 1H and 13C NMR for 56l 151 Spectra 6.2.24. HPLC Spectra for 56l 152

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x Spectra 6.2.25. 1H and 13C NMR for 57a 153 Spectra 6.2.26. HPLC Spectra for 57a 154 Spectra 6.2.27. 1H and 13C NMR for 57b 155 Spectra 6.2.28. HPLC Spectra for 57b 156 Spectra 6.2.29. 1H and 13C NMR for 57c 157 Spectra 6.2.30. HPLC Spectra for 57c 158 Spectra 6.2.31. 1H and 13C NMR for 57d 159 Spectra 6.2.32. HPLC Spectra for 57d 160 Spectra 6.2.33. 1H and 13C NMR for 57e 161 Spectra 6.2.34. HPLC Spectra for 57e 162 Spectra 6.2.35. 1H and 13C NMR for 57f 163 Spectra 6.2.36. 1H and 13C NMR for 57g 164 Spectra 6.2.37. 1H and 13C NMR for 57h 165 Spectra 6.2.38. 1H and 13C NMR for 57i 166 Spectra 6.2.39. 1H and 13C NMR for 57j 167 Spectra 6.3.1. 1H NMR for P7 168 Spectra 6.3.2. 1H and 13C NMR for 65aa 169 Spectra 6.3.3. HPLC Specta for 65aa 170 Spectra 6.3.4. 1H and 13C NMR for 65ba 171 Spectra 6.3.5. HPLC Spectra for 65ba 172 Spectra 6.3.6. 1H and 13C NMR for 65ca 173 Spectra 6.3.7. 1H and 13C NMR for 65da 174 Spectra 6.3.8. HPLC Spectra for 65da 175

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xi Spectra 6.3.9. 1H and 13C NMR for 65ea 176 Spectra 6.3.10. HPLC Spectra for 65ea 177 Spectra 6.3.11. 1H and 13C NMR for 65fa 178 Spectra 6.3.12. HPLC Spectra for 65fa 179 Spectra 6.3.13. 1H and 13C NMR for 65ga 180 Spectra 6.3.14. 1H and 13C NMR for 65eb 181 Spectra 6.3.15. HPLC Spectra for 65eb 182 Spectra 6.3.16. 1H and 13C NMR for 65ec 183 Spectra 6.3.17. HPLC Spectra for 65ec 184 Spectra 6.3.18. 1H and 13C NMR for 65ed 185 Spectra 6.3.19. HPLC Spectra for 65ed 186 Spectra 6.3.20. 1H and 13C NMR for 65ee 187 Spectra 6.3.21. HPLC Spectra for 65ee 188 Spectra 6.3.22. 1H and 13C NMR for 65ef 189 Spectra 6.3.23. HPLC Spectra for 65ef 190 Spectra 6.3.24. 1H and 13C NMR for 65eg 191 Spectra 6.3.25. HPLC Spectra for 65eg 192 Spectra 6.3.26. 1H and 13C NMR for 65eh 193 Spectra 6.3.27. HPLC Spectra for 65eh 194 Spectra 6.3.28. 1H and 13C NMR for 65ei 195 Spectra 6.3.29. HPLC Spectra for 65ei 196 Spectra 6.3.30. 1H and 13C NMR for 65ej 197 Spectra 6.3.31. 1H and 13C NMR for 65cb 198

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xii Spectra 6.3.32. 1H and 13C NMR for 65ce 199 Spectra 6.3.33. 1H and 13C NMR for 65cf 200 Spectra 6.4.1. 1H and 13C NMR for 70a 201 Spectra 6.4.2. 1H and 13C NMR for 70b 202 Spectra 6.4.3. 1H and 13C NMR for 70c 203 Spectra 6.4.4. 1H and 13C NMR for 70d 204 Spectra 6.4.5. 1H and 13C NMR for 70e 205 Spectra 6.4.6. 1H and 13C NMR for 70f 206 Spectra 6.4.7. 1H and 13C NMR for 70g 207 Spectra 6.4.8. 1H and 13C NMR for 70h 208 Spectra 6.4.9. 1H and 13C NMR for 70i 209 Spectra 6.4.10. 1H and 13C NMR for 70j 210 Spectra 6.4.11. 1H NMR for 70ka + 70kb 211 Spectra 6.4.12. 1H and 13C NMR for 70ka 212 Spectra 6.4.13. 1H NMR for 70la + 70lb 213 Spectra 6.4.14. 1H and 13C NMR for 70a 214

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xiii Cobalt(II)-Catalyzed Atom/Group Transfer Reactions: Stereoselective Carbene and Nitrene Transfer Reactions Joshua V. Ruppel ABSTRACT Metalloporphyrins have been shown to catalyze many fundamental and practically important chemical transforma tions, some of which represent the first demonstrations of these catalytic processe s. The most notable examples include an assortment of atom/group transfer reactio ns, such as oxene, nitrene, and carbene transfers. Atom/group transfer reactions a llow for the direct conversion of abundant and inexpensive alkenes and alkanes into value-a dded functional molecules. Previous reports from our group have shown that cobalt-por phyrin based carbene and nitrene transfer reactions are some of the most selective a nd practical catalytic systems developed for cyclopropanation and aziridina tion. Backed by a family of D2-symmetric chiral cobalt porphyrins our group continues the development of stereoselective carbene and nitrene transfer reactions. Metal-catalyzed cyclopropana tion of olefins with diazo reagents has attracted great research interest because of its fundame ntal and practical importance. The resulting cyclopropyl units are recurrent motifs in biol ogically important molecules and can serve as versatile precursors in organic sy nthesis. Supported by a family of D2-symmetric

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xiv chiral cobalt porphyrins, we have demonstrat ed the use of succimidyl diazoacetate as carbene source for a highly diastereoand enantioselective cyclopropanation process. The resulting cyclopropyl succ inimdyl esters are highly reac tive and serve as valuable synthons for generating cyclopropylcarboxamides. We have also developed the first cobalt-porphyrin based intramolecular cycl opropanation, which is able to produce the resulting bicyclic lactones in hi gh yields and enantioselectivity. Nitrene transfer reactions are also an at tractive route to produ ce biologically and synthetically important molecules such as amines and aziridin es. Although much progress has been made in nitrene transfer reactions utilizing [N-(p-toluenesulfonyl) imino]phenyliodinane (PhI=NTs) the nitrene source suffers from several drawbacks. Consequently, there has been growing interest in developi ng catalytic nitrene transfer reactions using alternat e nitrene sources. To this end, we have utilized arylsulfonyl azides as nitrene source to explore their use in the development of a cobalt -porphyrin catalyzed enantioselective aziridination system. The cobalt catalyzed process can proceed under mild and neutral conditions in low catalyst loading without the need of other reagents, while generating nitrogen gas as the only byprod uct. We have also explored the use of arylsulfonyl azides as nitrene source in a c obalt-catalyzed intramolecular C–H amination process.

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1 Chapter 1 Developments in Cobalt-Catalyzed Ca rbene and Nitrene Transfer Reactions 1.1. Introduction Carbene and nitrene transfer reactions ha ve been reviewed extensively and have been very active fields of resear ch over the last several decades.1-2 Previous reviews focus their attention on the “usual” metal ions capable of mediating carbene and nitrene transfer reactions, such as ruthenium3-4, rhodium5-6, and copper7-8. Effective catalytic systems have been developed that achieve hi gh levels of diastereoand enantioselective control with the use of these metals in both carbene and nitrene systems.3-8 In recent reviews, cobalt has always taken its place in ch apters titled “Other metal catalysts.” This is not due to the inab ility of cobalt complexe s to effectively cataly ze atom/group transfer reactions or their inability to induce accepta ble levels of stereocontrol, but as a consequence of the relatively recent insurgen ce of research dedicated to cobalt catalyzed carbene and nitrene transfer reactions. This review is intended to highlight cobalt’s catalytic ability in carbene and nitrene tran sfer reactions, such as cyclopropanation and aziridination. Special emphasis will be pl aced on the advances in enantioselective catalysis for cyclopropanation a nd the development of cobalt catalyzed aziridination, as well as, the related amination products resul ting from those nitrene transfer reactions. The current proposed mechanisms of bot h cobalt-catalyzed cyclopropanation and aziridination/amination reactions will also be discussed.

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2 1.2. Carbene Transfer: Cyclopropanation The fundamental and practical importance of cyclopropanes in synthetic organic chemistry is well demonstrated.9 Currently, the metal-mediated decomposition of diazo reagents and their subsequent reaction with olef ins constitute the most direct route to the synthesis of these smallest all carbon ring syst ems. Prior to the development of catalytic systems able to decompose diazo reagen ts, the Simmons-Smith Reaction was the predominate method of gene rating cyclopropane products.1 At that time, the asymmetric synthesis of cyclopropanes required chiral st arting materials or starting materials which contained chiral auxiliarie s to generate products with modest enantiocontrol.1d Presently, the cyclopropanation of olefins with diazo reagents employing chiral metal complexes provides the advantage of using achiral reagen ts and inducing chirality directly from the chiral catalysts to generate th e optically enriched products. The first enantioselective cobalt catalyzed system was first published in 1978.10 This catalytic system employed a camphor ba sed ligand and required as little as 1 mol % of catalyst. The catalytic system gene rated cyclopropanes in excellent yields, good enantioselectivities (up to 80% optical purit y), and was effective with several diazo reagents, although it was solely limited to terminal olefins. This pioneering work by Nakamura and Ot suka demonstrated that chiral cobalt catalysts could effectively achieve high levels of enantiocontrol. This work set the standard by which all subsequent cobalt-cat alyzed cyclopropanation systems would be evaluated against for the cycl opropanation of styrene with -diazoacetates, such as ethyl diazoacetate (EDA) or t -butyl diazoacetate ( t -BDA). The results published in this

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3 seminal work demonstrated that cobalt catalyst s were equally as effective as their Cu, Ru, and Rh counterparts. 1.2.1. Cobalt Salen Catalysts In 1997, Katsuki used the salen ligand as a scaffold for the development of a series of Co(II)and Co(III)-catalysts that could effectively decompose t -butyl diazoacetate ( t -BDA) and generate cyclopropanes from styrene and other aryl olefins.11 The most effective of these catalysts could generate cyclopropanes with high trans diastereoand enantiosel ectivity (Figure 1.1). Figure 1.1. Co(III)-Salen Catalyzed Cyclopropanation. Katsuki followed that work with a second generation of salen cat alysts that were designed to be cis selective while also allowing for high enantiocontrol. These Co(II)catalysts were sterically more encumbered and employed the use of the additive Nmethylimidazole (NMI) as their 5th coordinate ligand. The positiv e additive effect of an axial donor ligand increased both the stereoselectivity as well as the yi eld of the reaction, while retaining high asymmetr ic induction (Figure 1.2).12

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4 Figure 1.2. Co(II)-Salen Catalyzed Cyclopropanation. Following the success of Co(II)-salen complex 5 a catalyst was designed which incorporated a pendent N-methylimidazole unit to further exploit the use of this axial donor ligand effect. This new generation of cat alyst still generated excellent selectivities as demonstrated by Co-salen complex 5 (Figure 1.3); however, it s catalytic efficiency was significantly improved as a result of solvent effects. Toluene was found to give superior yields and stereosele ctivity in comparison with the previous solvent of choice, tetrahydrofuran.13 N N O O Co Ph + t -BDA Ph Ph 5mol%Co(II)-Salen 6 Toluene,RT,24h >99%Yield cis:trans 99:1 97%ee:-%ee N N 1a 2 Ph CO2t -Bu 4 6 Figure 1.3. Cyclopropanation Utilizing a Co(II)-Sale n Catalyst Baring a (NMI) Pendent Group.

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5 Continued development of Katsuki’s Co-s alen catalyzed cyclopropanation system further demonstrated the utility of this catalytic process through the intramolecular cyclopropanation of allylic diaz oacetates. This catalytic system proved very substrate dependent as the allylic substituent greatly a ffected the reactivity and selectivity of the catalytic system. Despite its lack of substrate scope, the model substrate 7 generated the bicyclic product in up to 97% ee (Figure 1.4).14 N N O O Co R R 5mol%Co(II)-Salen THF,RT,24h, 1equiv.NMI 8 :R=Me 9 :R=H O Ph O CHN2 O O H H Ph H 8 :67%yield,97%ee 9 :75%yield,95%ee 7a 10a Figure 1.4. Intramolecular Cyclopropanation Utilizing a Co(II)-Salen Catalyst. Katsuki and co-workers were able to de velop a cobalt-catalyzed system capable of generating the cyclopropane product more efficiently a nd selectively than the prior work of Nakamura and Otsuka. Their development of a cis selective catalyst remains one of the few systems able to obtain the atypical cis -conformation in high diastereomeric excess. 1.2.2. Cobalt Aldiminato Catalysts Previously mentioned in Katsuki’s Co(II) -salen catalytic system, the use of an axial donor ligand for cobalt(II )-catalyzed cyclopropanation was first demonstrated on a

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6 structurally similar catalyst by Yamada in 1999. A series of donor ligands, which included NMI ( 12a ), were screened for their effect on the standard cyclopropanation reaction of styrene with t -BDA. Among those screened, N-methylimidazole ( 12a ) was found to be the superior additi ve for increasing the reaction yield and selec tivity of the cyclopropanation reactions in reference to those performed without additive (Table 1.1).15 Table 1.1. [ Co( MPAC )] Catalyzed Cyclopropanation with Axial Donor Ligands. Ph + t -BDA Ph CO2t -Bu 5mol% 11 10mol%Additive 12a-d entryaadditive yield(%)btrans:ciscee(%, trans )d1None 6276:24 74 2 N N 3 N N Ph 4 N NH 5 N 94 85 27 50 76:24 77:23 73:27 72:28 84 84 80 82 aReactionconditions:5mol%of 11 ,5.0mmolofstyrene,1.0mmolof t -BDA,and10mol%ofadditiveinTHFat25oCunderN2for2hrs.bIsolatedyield.cDeterminedbyGCand/orNMRanalysis.dDetermined bychiralHPLC. Ph Ph N N O O O O Co 11: [Co (MPAC )] 1a2 4 12a 12b 12c 12d

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7 Yamada and co-workers continued their work on cobalt-aldiminato catalysis by synthesizing and evaluating several catalysts and testing them for efficacy regarding the standard cyclopropanation r eaction of styrene with t -BDA. Results indicated that typically catalysts that have substituents with increased steric bulk off the ethylene diamine bridge and the addition of a bulky pendent ester group could increase both product yield and selectivity in comp arison to the reaction catalyzed by 12 (Table 1.2, entries 1-2). These catalysts were further i nvestigated through the evaluation of styrene derivatives with various elec tronic and steric environments which to a large extent generated the cyclopropanated pr oducts in excellent yields a nd enantioselectivities (Table 1.2, entries 3-6).16

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8 Table 1.2. Enantioselective Cyclopropanation of Styrene Derivatives with Various Co(II)-Aldiminato Catalysts. 5mol%Co(II)-Catalyst 10mol%NMI Mes Mes N N O O O O O O Co Mes Mes N N O O O O O O Co Ar CO2t -Bu 4 Ar + t -BDA 1 2 13 14 entryaolefin yield(%)btrans:ciscee(%, trans )d1 3 4 5 6 aReactionconditions:5mol%ofcatalyst,5.0mmolofstyrene,1.0mmolof t -BDA,and10mol%ofadditiveinTHFat25oCunderN2for2hrs. 9790:1096 93 90:1096 85 87:13 96 95 87:13 96 4747:53 99 Cl MeO cat. 9991:996 13 14 13 13 13 13 2 1.2.3. Cobalt Porphyrin Catalysts Independently in 2003, the research groups of Cenini and Zhang reported the use of cobalt(II) tetraphenylporphyrin ([Co(TPP) ]) as an effective catalyst for the cyclopropanation of diazoacetates. These initi al results provided the first evidence that cobalt porphyrins could be used as catalysts for cyclopropanation.17 Although the diastereoselectivity was limited in both catalytic systems, both groups were able to

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9 demonstrate that changes to the substituents on the porphyrin ring system would effect the selectivity. Subsequent investigations by both research groups lead to the use of porphyrins with chiral substituents at the meso positions. These catalysts generated limited asymmetric induction, because the chiral subun its had conformations that provided little effect on the environment near th e metal center, or active site.18 On the other hand, chiral substituents attached at the ortho -aryl positions provided the first significant enantioselectivities ge nerated by a cobalt-porphyrin catalyzed system (Figure 1.5).17a + EDA Ph CO2Et 2mol% 16 Toluene,80oC,12h N NH N HN O O O O O O O O *R *R R* R* R* R* *R *R O O CH3 O CH3 H3C R*= 73%yield trans:cis 36:64 77%ee( cis ) Ph 1a 15 17 16 Figure 1.5. Cyclopropanation of Styrene w ith Chiral Co(II)-Catalyst 16 In 2004, Zhang reported the synthesis and evaluation of a new class of D2symmetric chiral cobalt(II) porphyrins as cy clopropanation catalysts. These chiral porphyrins were synthesized in a modular ap proach using palladium catalyzed crosscoupling reactions which allowed for the pr oduction of a diverse collection of ligands with varied steric and electronic effects (Fig ure 1.6). The versatility of this modular chiral cobalt porphyrin catalyst construction is a result of both the selection of chiral

PAGE 27

10 substituents at the ortho -aryl postitions and the non-chiral aryl groups that can be used to further tune the electronic and steric envi ronment around the metal center (Figure 1.6). By changing the chiral amide, each of the 4 possible isomers produced from the cyclopropanation of styrene with t -BDA can be selectively accessed (Figure 1.7).19 N NH N HN R R Br Br Br Br O NH2 *R Pd(OAc)2/Xantphos Cs2CO3 N NH N HN R R NH NH HN HN O O O O R* *R *R R* CoCl2 2,6-lutidine N N N N R R NH NH HN HN O O O O R* *R *R R* Co NH NH HN HN O O O O *R *R R* R* Co 18 19 20 N N N N HN HN O O NH NH O O H H H H Co 20a :[Co( P1 )] N N N N HN HN O O NH NH O O Co 20f :[Co( P6 )] MeO OMe OMe MeO O O O O N N N N HN HN O O NH NH O O H H H H Co 20b :[Co( P2 )] OMe MeO OMe MeO H H H H N N N N HN HN O O NH NH O O H H H H Co 20e :[Co( P5 )] O O O N N N N HN HN O O NH NH O O H H H H OMe MeO MeO OMe Co 20c :[Co( P3 )] N N N N HN HN O O NH NH O O H H H H OMe MeO MeO OMe Co 20d :[Co( P4 )] OMe MeO OMe MeO O Figure 1.6. Synthesis of D2-Symmetric Chiral Porphyrins and their Cobalt Complexes.

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11N N N N NH NH HN HN O O O O R* *R *R R* Co + t -BDA CO2t -Bu CO2t -Bu CO2t -Bu CO2t -Bu cis-(1S,2R): 4c cis-(1R,2S): 4d trans-(1R,2R): 4a trans-(1S,2S): 4bH H H H H H H H Expected(S) O H2N (R) O H2N (R) O H2N OMe (S) O H2N OMe >99:1dr 95%ee 37:63dr 96%ee 38:62dr 96%ee t -Bu t -Bu t -Bu t -Bu 1 2 20a,c (S) -20a (R) -20a (R) -20c (S) -20c Figure 1.7. Stereoselective Cyclopropanation with D2-Symmetric Chiral Co(II)Porphyrin Complexes. After its cyclopropanation de but in 2004, the [Co(P1)] catalyst has demonstrated efficiency over a remarkable scope of substrates, includi ng styrene derivatives20 as well as electron-deficient olefins21 (Table 1.3). For this catalytic system, the greatest positive ligand effects were observed with the use of N,N-dimethylaminopyridine (DMAP) as the axial donor ligand. A axial donor ligands were previously demonstrated in both Yamada and Katsuki’s cobalt-catalyzed systems to in crease the selectivity of the cyclopropanation products.12,15 Recently, the Zhang group has shown that the use of D2-symmetric chiral cobaltporphyrins allow for the employment of othe r diazo compounds as efficient carbene sources, such as diazosulfones (Figure 1.8). When utilizing diazosu lfones as the carbene

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12 precursors, cyclopropanation catalyst [Co(P6)] explo its potential hydrogen bonding interactions between the assu med cobalt-carbene sulfonyl group and the amide functional groups on the porphyrin ligand. This leads to a more rigid and polar chiral environment that promotes and stabilizes the carbene in termediate formed from the decomposition of the diazosulfones and results in increased selectivity.22 Table 1.3. Diastereoand Enantioselective Cyclopropanation of Olefins by [Co( P1 )]. + t -BDA R CO2t -Bu 1mol%[Co( P1 )] 0.5equivDMAP entryaolefin yield(%)btrans:ciscee(%, trans )d1 2 3 4 aReactionconditions:1mol%ofcatalyst,1.0equivofolefin,1.2equivof t -BDA,and0.5equivofDMAPintolueneat25oCunderN2for20hrs.cDeterminedbyGC.dDeterminedbychiralGCorHPLC.eChlorobenzene wasusedassolvent. 84>99:195 69 98:291 86 98:2 96 7497:3 84 Cl MeO Olefin F F F F F 5eEtO O 9299:191 6eH2N O 77 99:197 7eEt O 8199:194 8eNC 83 76:24 93 2 4

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13 Figure 1.8. Cyclopropanation of Di azosulfones with [Co( P6 )]. Zhang and co-workers have expanded th e scope of their chiral cobalt(II)porphyrin catalyzed cyclopropanation sy stems further through the use of acceptor/acceptor diazo reagents. Specifically, -nitrodiazoacetate in the presence of [Co( P1 )] could generate the atypical Z -substituted cyclopropanes in high yields and excellent enantioselec tivities (Figure 1.9).23 These highly valuable Z-substituted nitrocyclopropanes can be easily converted into -amino acid derivatives through the reduction of the nitro group. Figure 1.9. Cyclopropanation of -Nitrodiazoacetate with [Co( P1 )]. 1.2.4. Other Supporting Ligands Several less developed catalysts have b een employed for the cyclopropanation of olefins by diazo compounds. Among these cata lysts, Co(II)phthalocyanine, which is

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14 similar to porphyrins in structure, produ ces the racemic cyclopropane products in moderate to high yields.24 No information concerning the stereoselectivity of these reactions was reported. Inspired by Katsuki’s work with Co-salen catalysts for cyclopropanation, Gao has developed a dinuculear cobalt catalyst ba sed upon the salen scaffold (Figure 1.10).25 Although the dicobalt system is not as eff ective as the salen ligands developed by Katsuki, it does provide a basis for futu re dinuclear systems employed for carbene transfer reactions. N N O O Co N N Co N N O O Co N N 5mol%CoupledSalenComplex DCM,RT 74%yield trans:cis 69:31 78%ee( trans ) 90%yield trans:cis 72:28 86%ee( trans ) + EDA Ph 1a 15 Ph CO2Et 17 25 26 Figure 1.10. Salen-Based Dicobalt Catalyzed Cyclopropanation. Recently, the research group of Gade developed a pincer type ligand for enantioselective catalysis. The catalytic activity of these new ligands were evaluated in the cyclopropanation of styr ene with ethyl diazoacetate and produced the corresponding cyclopropanes in high yields with excellent diastereoand high enantioselectivities (Figure 1.11).26

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15 Figure 1.11. Cyclopropanation with a Co(II)-Pincer Type Ligand. Prior to the Zhang group’s work using D2-symmetric chiral porphyrin ligands, they employed the use of the naturally occurring vitamin B12 derivative aquocobalamin. Inspired by nature’s use of porphyrin like ring structures in the active sites of many enzymes capable of highly selective transformations, vitamin B12 was chosen as a potential catalyst for cyclopropanation. Th is cobalt(III) catalyst proved to be a cisselective catalyst, although it generated only modest enantioselectivities (Figure 1.12).27 The modest enantioselectivities are not that unexpected as the chiral substituents are on the periphery of the corrin ring system and w ould have a limited inductive effect near the metal center, as previously observed with the meso -substituted porphyrin catalysts evaluated by the groups of Cenini and Zhang.17a,18

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1688%yield trans:cis 39:61 54%ee:64%ee + EDA Ph CO2Et 2mol%B12( 28 ) Ph 1a 15 17 N N N N CH3 CONH2 CH3 CH3 CH3 CONH2 CONH2 H2NOC H H2NOC O HN O P H O O O O OH N N CONH2 Co R 28 :VitaminB12R=HO•HCl HO Figure 1.12. Cyclopropanation with Vitamin B12 as Catalyst. 1.2.5. Mechanism The mechanism of cyclopropanation via diazo reagent decomposition is thought to proceed via carbene formation followed by th e interaction of the olefin to produce the cyclopropane product. I nvestigations into the nature of the cobalt-carbene intermediate were undertaken by Yamada through the use infrared spectroscopy and computational studies. The results of these experiments concluded that the r eaction of the diazo compound with the cobalt complex 30 results in a surplus of a single electron that is delocalized between the carbene carbon and the carbonyl unit re sulting in the cobalt(III)carbene complex 32 (Figure 1.13).28 This information is comb ined with the established use of a axial donor ligand ( L ) in cobalt(II)-catalyzed cycl opropanation and the following mechanism is proposed (Figure 1.13).

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17 Co L Co Co L Co L N2 H O OR N2 H O OR R' R' O OR L AxialLigand( L ) + 293031 32 Figure 1.13. Proposed Mechanism of Cobalt Catalyzed Cyclopropanation. 1.3. Nitrene Transfer: Aziridination and Amination In comparison to cobalt-catalyzed cyclopropanation, the analogous aziridination is in its infancy in terms of research and de velopment. The current field of aziridination and the related amination pr ocess is dominated by Ru4, Rh6, and Cu8 catalytic systems. As is the case with diazo reagents for cyclopropanation, the analogous aziridination process has been dominated by one class of nitr ene source. The typica l nitrene source for aziridination has become [N-( p -toluenesulfonyl)imino]phe nyliodinane (PhI=NTs) reagent.29 In light of its many drawbacks such as limited shelf-life, limited solubility in organic solvents, commercial una vailability, and generation of an equivalent of PhI as by product, much research has been devoted to the in situ generation of PhI=NTs and its related derivatives.4d,6b,8a,30 Aside from these traits, PhI=NTs has become the nitrene source of choice for many nitrene transfer reactions. Cobalt-cata lyzed systems have successfully provided a platform for the explor ation of other nitrene sources that have previously been ignored in favor of PhI= NTs, such as bromamine/chloramine-T and organic azides as nitren e sources (Figure 1.14).

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18 Figure 1.14. Common Nitrene Sources. Much like aziridination, C–H amination employs PhI=NTs and in situ variants as the primary nitrene source in many catalytic systems.4a,6a,6c-d,6f C–H amination can occur in competition to the aziridination process when an appropriate activated C–H bond is present on an olefin.4c As a result, the cobalt catalyzed amination process has been developed in parallel to aziri dination including the use of a lternate nitrene sources such as bromamine/chloramine-T and organic azides. Currently, porphyrin ligands are leadi ng the development of both these cobalt catalyzed systems. This is not entirely su rprising as some of th e first examples of aziridination and amination reactions were explored with metalloporphyrins as catalysts.31 1.3.1. Cobalt Porphyrin Catalyzed Aziridination The first practical and efficient coba lt-catalyzed aziridination system was published by Zhang in 2005. This catalytic system employs the commercially available [Co(TDClPP)] as catalyst with bromamineT as the nitrene source. Unlike most aziridination systems, olefins were used as limiting reagents. The racemic Nsulfonylated aziridines were pr oduced from a wide variety of aromatic and aliphatic amines in good to high yields (Table 1.4).32

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19 Table 1.4. Aziridination of Different Olefins by [Co(TDClPP)]. NS O O Na Br 34a :Bromamine-T + Olefin [Co(TDClPP)]5mol% CH3CN,25oC,18h NTs R entryaolefin yield(%)b1 2 3 4 5 aReactionconditions:5mol%of[Co(TDClPP)],1.0equivofolefin,2 equivofbromamine-TinCH3CN25oCunderN2for18h.bIsolatedyield.ccis:trans=9:91.dcis:trans=47:53.ecis:trans=8:92.fcis:trans=58:42. 83 70 product NTs NTs NTs 33 NTs NTs R R R R NTs n n R=Me:94cR=Ph:92dR=Me:87eR=Ph:94fn=1:61 n=2:66 n=3:79 NTs 56 6 7 8 9 10 11 36 R=Me R=Ph R=Me R=Ph n=1 n=2 n=3 Zhang and co-workers continued to deve lop their cobalt-catalyzed aziridination through the employment of the commerci ally available diph enylphosphoryl azide (DPPA) as the nitrene source. Preliminary work catalyzed by [Co(TPP)] demonstrated that DPPA could be used to generate the racemic N-phosphorylate aziridines in moderate

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20 to good yields (Figure 1.15).33 Unfortunately, DPPA proved be a nitrene source that was more limited in scope than bromamine-T. The cobalt porphyrin ca talyzed system which utilizes DPPA as the nitrene source is confin ed to terminal aromatic olefins and requires an excess of olefin for efficient catalysis. Figure 1.15. Aziridination of Styrene Deriva tives with DPPA by [Co(TPP)]. However, unlike the bromamine-T system, the nitrene source DPPA has been developed into one of the firs t examples of cobalt-cataly zed asymmetric aziridination. The D2-symmetric chiral porphyrins, which were also demonstrated as potent catalysts for asymmetric cyclopropanation, and generated the aziridine products in moderate yields and enantioselectivities (Figure 1.16).34 Figure 1.16. Asymmetric Aziridination with DPPA by [Co(P1)]. 1.3.2. Cobalt Porphyrin Catalyzed C–H Amination Cenini first demonstrated the use of ar yl azides as suitable nitrene sources for cobalt-catalyzed amination. This process ge nerates the amine produc t exclusively when a 3o benzylic C–H bond is present. Secondary and primary C–H bonds generate mixtures of amine and imine products through subsequent reactions of the amines with a second equivalent of the azide (Figure 1.17).35

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21 Figure 1.17. Imine Formation from Catalytic Amination of Benzylic C–H Bonds Table 1.5. [Co(TDClPP)]-Catalyzed Am ination with Bromamine-T. The Zhang group observed amination side products when substrates that had a benzylic C–H bonds were employed in the aforementioned bromamine-T aziridination system.32 The amine products could be generated in moderate yields and were selectively generated at benzylic positions (Table 1.5).36 Although, the amine product was isolated

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22 without presence of the imine side-product in other substrates (Table 1.5 entries 1-2 and 4), the imine product was generate d exclusively with substrate 39c (Table 1.5, entry 3). 1.3.3. Mechanism Very little has been published concerni ng the mechanism of cobalt-catalyzed nitrene transfer reactions. Previous i nvestigations into th e mechanism of coppermediated aziridination reactions gave ri se to a proposed mechanism involving a Cu(I)/Cu(III) catalytic cycle.2d,37 This proposed copper-med iated nitrene transfer catalytic cycle combined with the analogous proposed mechanism of cobalt-catalyzed cyclopropanation28 can be utilized to propose a mechan istic pathway for cobalt-catalyzed nitrene transfer reactions, sin ce the mechanism is likely to follow that of the analogous carbene transfer process of cy clopropanation (Figure 1.18). The interaction of the cobalt-complex 29 with the nitrene source could generate the cobalt-nitrene radical species 44 and the subsequent inter action of an olefin or activated C–H bond would then give rise to the aziridination or amination products, respectively. The results published by Zhang in the cobalt-porphyrin catalyzed aziridination of olefins with bromamineT provides evidence for a cobalt-nitrene intermediate that undergoe s a ring closing step in a non-stereospecific nature.32 Unfortunately, the cobalt-catalyzed aziridin ation with DPPA was limited to terminal olefins and as a result neither the stereospecificity of the r eaction could be determined nor could the comparison with the bromamine-T system be made. The lack of an asymmetric report using bromamine-T as the nitrene source by the Zhang group while DPPA as the nitrene source has provided the first examples of an asymmetric cobalt-catalyzed aziridination de monstrates the very unique properties of

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23 these two catalytic systems. This provides ev idence that the choice of the nitrene sources examined will play a significant roll in the future development and understanding of cobalt-catalyzed nitren e transfer reactions. Co Co Z=N2orNaBr N R N R R' N R' Z or or Ar R' H Ar R' HN R 44 29 Figure 1.18. Proposed Mechanism of CobaltCatalyzed Nitrene Transfer. 1.4. Conclusions Cobalt-catalyzed cyclopropanation and azi ridination have enjoyed a resurgence of interest and research in the past 15 years. The current developments have generated some of the most general and selective exam ples of cyclopropanation catalytic systems published, highlighted by the cobalt-catalyzed systems of Katsuki and Zhang. Although the cobalt-catalyzed aziridination and amination systems have not reached the selectivity and scope of their carbene counterparts, alte rnative nitrene sources will allow for the continued development and improvement of these catalytic systems.

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24 Chapter 2 Cobalt-Catalyzed Enantiosel ective Intramolecular Cyclopropanation of Allylic Diazoacetates 2.1. Introduction Metal-mediated decomposition of diazo r eagents in the presence of olefins has proven to be an efficien t route to cyclopropanes.1 These carbocycles represent a class of compounds that have found numerous fundamental and practical applic ations in synthesis and medicine.9 The intramolecular cyclopropanation of allylic diazo reag ents (Figure 2.1) provides a means to access a wealth of structures that have proven to be highly useful in synthetic chemistry,9a, as in the synthesis of (+)-ambruticin S ( 48 )38 and carboxycyclopropyl glycines.39 Figure 2.1. Intramolecular Cyclopropanation with Allylic Diazoacetates. Kirkland’s use of a dirhodium catalyzed intramolecular cyclopropanation of an allylic diazoacetate ( 45 ) and subsequent ring opening of the resulting bicyclic lactone 46 provided the key step in the in stallation of the cyclopropane ring in the synthesis of (+)ambructitin S ( 48 ), a potent antifungal (Figure 2.2).38 The syntheses of

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25 carboxycyclopropyl glycines employ a similar strategy utilizing allylic diazoacetamides.39 Figure 2.2. Intramolecular Cyclopropanation in the synthesis of (+)-Ambruticin S. A number of outstanding metal-catalyzed systems have been reported to achieve high levels of selectivity for the decompos ition of allylic diazo reagents into these valuable bicyclic structures (Figure 2.1).3a,14,26,40 The work of Doyle and co-workers with chiral dirhodium catalysts have proven to be one of the most selective methods for generating excellent enantioselectivities over a range of substrates, but is limited in effectiveness when more st erically demanding substrat es are used (Figure 2.3).40b-e The research groups of Katsuki and Che-Ming Ch e have demonstrated the ability of cobaltsalens and ruthenium-porphyrins to be cap able catalysts for the intramolecular cyclopropanation process with aryl substitu ted allylic diazo reagents (Figure 2.3).3a,14 Continuing research efforts in this field aim at developing a catalytic system that is capable of effecting high selectivity over a broad range of substrates.

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26 Rt O O N2 O Rc O [MLn] Rc Rt H H 7 10 N O Rh Rh N O N O O N CO2Me Doyle 49 :[Rh2(5S-MEPY)4] N N N N Ru L L Che 50 :[Ru(Por*)(CO)(EtOH)] N N Co O O Katsuki 9 :Co(II)-Salen Figure 2.3. Intramolecular Cyclopropanation with Various Metal-Complexes. 2.2. Enantioselective Intramolec ular Cyclopropanation Utilizing a family of cobalt(II) complexes of D2-symmetric chir al porphyrins (Figure 2.4)19a, our research group has developed one of the most selective and general asymmetric intermolecular cyclopropanation catalytic processes.19-23 The ability of these unique chiral cobalt(II) porphyrin complexes to effectively decompose diazo reagents in the presence of a broad range olefins to generate high diaste reoand enantioselectivities has provided a platform to develop the first chiral cobalt(II) porphyrin catalytic process for intramolecular cyclopropanation.

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27 N N N N HN HN O O NH NH O O H H H H Co 20a :[Co( P1 )] N N N N HN HN O O NH NH O O Co 20f :[Co( P6 )] MeO OMe OMe MeO O O O O N N N N HN HN O O NH NH O O H H H H Co 20b :[Co( P2 )] OMe MeO OMe MeO H H H H N N N N HN HN O O NH NH O O H H H H Co 20e :[Co( P5 )] O O O N N N N HN HN O O NH NH O O H H H H OMe MeO MeO OMe Co 20c :[Co( P3 )] N N N N HN HN O O NH NH O O H H H H OMe MeO MeO OMe Co 20d :[Co( P4 )] OMe MeO OMe MeO O Figure 2.4. Structures of D2-Symmetric Chiral Cobalt(II) Porphyrins. This family of D2-symmetric chiral porphyrins (F igure 2.4) was evaluated for its ability to catalyze the intramolecular cyclopropanation process with substrate 7a and produced the desired bicyclic product 10a Employing [Co( P1 )] as catalyst we found the intramolecular cyclopropanation process proceeds efficiently with moderate enantioselectivity (Table 2.1, entry 1). As seen in previous intermolecular cyclopropanation systems, the use of an axia l donor ligand, such as DMAP, has a positive trans effect and results in an increase in enantioselectivity (Table 2.1, entry 2).19b The results demonstrated significant de pendence on the bulky nature of the ligand. For example, sterically more encumbered [Co( P2 )] catalyzed the reaction with a slightly lower yield and enantioselectivity than [Co( P1 )]. Catalysts with considerably more sterically encumbered ligand designs ([Co( P3 P6 )]) were unable to effectively generate the bicyclic produc t (Table 2.1, entries 4-7).

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28 Table 2.1. Intramolecular Cyclopropanation by Chiral Cobalt(II) Porphyrins. entrya[Co(Por*)]byield(%)dee(%)e[Co( P1 )] [Co( P2 )] [Co( P3 )] [Co( P4 )] [Co( P6 )] 3 53 --4 75 68 [Co( P5 )]21 -7 5 6 2 1 [Co( P1 )] 9240 --66 -7 --aReactionconditions:Performedat25oCfor24hwithMeCNassolvent using2mol%ofcatalyst;[substrate]=0.2M.bSeeFigure2.4.c0.5 equivofadditive.dIsolatedyield.eDeterminedbychiralGC. Ph O O N2 O H O [Co( Por* )] H Ph H H additivec-DMAP DMAP DMAP DMAP DMAP DMAP 7a 10a Upon the discovery of [Co( P1 )] as the most capable catalyst, several solvents were evaluated for their effect on the selec tivity and efficiency of the intramolecular cyclopropanation process. The catalytic syst em could proceed under a variety of solvent conditions including: coordinating solvents (Table 2.2, entries 1-2), a broad range of polarities from highly polar ethyl acetate to non-polar hexanes (Table 2.2, entries 3-4), as well as aromatic and chlorina ted solvents (Table 2.2, entrie s 5-8). The disparity in enantioselectivities was very minimal over th is broad range of solvent characteristics; however the efficiency of th e reaction diminished when th e strongly coordinating solvent THF was used as well as the non-polar hexanes which was like ly due to poor solubility.

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29 Upon achieving these results, DCM was selected as the solvent due to these conditions providing the greatest enantioselectivity whil e retaining a moderate to high yield. Table 2.2. Intramolecular Cyclopropanation with [Co( P1 )] in Various Solvents. aReactionconditions:Performedat25oCfor24hwith0.5 equivofDMAPand2mol%ofcatalyst;[substrate]=0.2M.bIsolatedyield.cDeterminedbychiralGC. Ph O O N2 O H O [Co( P1 )] DMAP(0.5equiv) H Ph H H entryasolvent yield(%)bee(%)cPhCl 7561 6 Hexanes31 65 4 1 75 68 2 1967 5 Toluene 6662 8 DCE 53 3 EtOAc 7464 58 7 DCM 7072 MeCN THF 7a10a The importance of DMAP as the axial ligand was investigat ed by evaluating the equivalency requirements of the a dditive. It was shown that a decrease or increase in the amount of DMAP led to lower yi elds and little difference in the enantioselectivity (Table 2.3, entries 1-3). The decrease in yield is most likely a resu lt of the equilibrium shifting from the catalytically active 5-coordinate cobalt complex to either the 6-coordinate species that lacks an open c oordination site or to the less reactive 4-coordinate species without DMAP. As expected, de creasing the temperature to 0 oC led to a decrease in yield and a slight increase in enantioselectiv ity; similarly, increasi ng the temperature led to the opposite trend (Table 2.3, entries 4-5) Increasing the reaction time led to an

PAGE 47

30 increase in yields as expe cted, although a negligible dr op in enantioselectivity was observed (Table 2.3, entry 6). An increase or decrease in catalyst loading led to the corresponding increase or decrease in the yiel d of the desired product with a negligible effect on the enantioselectiv ity (Table 2.3, entry 7-8). Table 2.3. Enantioselective Intramolecular Cyclopropanation with [Co( P1 )] Under Various Conditions. aReactionconditions:PeformedinthepresenceofDMAPand[Co( P1 )]; [substrate]=0.2M.bIsolatedyield.cDeterminedbychiralGC. Ph O O N2 O H O [Co( P1 )] DCM H Ph H H entryayield(%)bee(%)c1 70 72 DMAP (equiv) time(h) temp(oC) 0.5 24 25 [Co(P1)] (mol%) 2% 2 57 68 0.25 24 25 2% 3 5069 0.75 24 25 2% 437 76 0.5 24 0 2% 5 7664 0.5 24 40 2% 68267 0.54825 2% 775 68 0.5 24 25 5% 8 54 69 0.5 24 25 1% 7a 10a The use of [Co( P1 )] with a substoichiometric am ount of DMAP as the axial donor ligand was evaluated with several trans -allylic substrates to probe the scope and effectiveness of the catalytic intramolecular cyclopropanation pr ocess. A series of aryl substituted allylic diazoacetates with vary ing electronic and steric properties were evaluated with [Co( P1 )] for their ability to form the bicyclic products. The p -methyl and o -methyl substitutions dramatically increased both the yields and enantioselectivity, with 84% and 78% ee, respectfu lly (Table 2.4, entry 2-3). The sterically demanding p -tertiary

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31 butyl group led to a noticeable decrease in en antioselectivity while generating a moderate yield (Table 2.4, entry 4). Both electron-dona ting and electron-wit hdrawing groups were well tolerated demonstrating the lack of sensitiv ity to electronic effects (Table 2.4, entries 5-6). The heteroaromatic 2-substituted fura n substrate was also well tolerated, although a decrease in enantioselectivity was observed (Table 2.4, entry 7). Disubstituted allylic diazoacetates proved to be ex cellent substrates for the intramolecular cyclopropanation process with [Co( P1 )] generating excellent yields and enantioselectivities at both room temperature and 40 oC (Table 2.4, entry 8-9). Interestingly, the use of a cis -substituted allylic diazoacetate 7j in the presence of [Co( P1 )] and with DMAP as the axial donor li gand generated the product in decreased yield and enantioselectivity, but wi th the same conformation as the trans -substituted substrate 7a (Table 2.4, entries 1 and 10). This result indicates the intramolecular cyclopropanation system proceeds through a non-stereospecific step-wise pathway.

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32 Table 2.4. [Co( P1 )]-Catalyzed Enantiose lective Intramolecular Cyclopropanation of Allylic Diazoacetates. entryayield(%)bee(%)cRt9 90(86)e35(62)e70(76)e72(64)ep -MeOC6H470 88 9478 o -CH3C6H4p -tBuC6H426 76 77 63 2-furan p -BrC6H483 84 1 5 p -CH3C6H484 95 2 35 20 H 10 RcH H C6H5CH3CH3C6H5H H H H H 86(>99)e79(79)eC6H58 CH37 6 4 3aReactionconditions:Performedat25oCfor24husing2mol%of[Co( P1 )] with0.5equivofDMAPinDCM;[substrate]=0.2M.bIsolatedyield.cDeterminedbychiralGC.dSignofopticalrotation.eReactionsperformedat 40oC. Rt O O N2 O Rc O [Co( P1 )] Rc Rt H H [ ]d(+) (+) (+) (+) (+) (+) (+) (+) (+) (+) 7a-j 10a-i DiazoProduct 7a 7b 7c 7d 7e 7f 7g 7h 7i 7j 10a 10b 10c 10d 10e 10f 10g 10h 10i 10a 2.3. Mechanism of Co(II)-Porphyrin Catalyzed Intramolecular Cyclopropanation The observation of a non-ste reospecific product is indi cative of a radical based mechanism. Although the radical nature of cobalt(II) carbene intermediates have been established by Yamada and co-workers,28 further investigation of the catalytic system shows this mechanism is highly dependant upon the use of an axial donor ligand, in this case DMAP. When the cis -substituted substrate 7j is decomposed in the presence of [Co(P1)] without DMAP, a mixture of dias teromers are isolat ed, representing the stereospefic , 10j and non-sterospecific , 10a products (Figure 2.5). The

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33 mixture of products observed for both the re actions, with and wit hout DMAP, leads to interesting mechanistic implications. Figure 2.5. Stereospecificity of [Co( P1 )]-Catalyzed Intramolecular Cyclopropanation. The interaction of the allylic diazoacet ate with the cobalt-complex liberates nitrogen gas and generates the cobalt-carbene species. Presumably, when an axial donor ligand, such as DMAP, is used, this cobalt ca rbene species forms the 6-coordinate species 53 The resulting carbene-cobalt-DMAP comple x is stable enough that the subsequent interaction with the olefin allows for the fo rmation of the benzylic radical intermediate 54 and through a slow ring closi ng step is able to produce , 10a Conversely, the absence of the axial donor ligand, DMAP, produces a more reactive intermediate, the benzylic radical 52 and results in a fast ring clos ing step and generates both the stereospecific , 10j product and , 10a confirmation (Figure 2.5). This phenomenon has also been observed with the Ru-porphyr in intramolecular cyclopropanation system of Che-Ming Che a nd coworkers, who observed a mixture of the , 10j and , 10a diastereomers when 7j was employed in their system.3a CheMing Che also attributes this observation to a probable step-wise mechanism. It is worth noting that this observation was not made in the Rh2-catalytic intramolecular cyclopropanation system of Doyle when the same 7j substrate was utilized.40b

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34 Figure 2.6. Proposed Mechanism for the Non-stereospecific [Co( P1 )]-Catalyzed Intramolecular Cyclopropanation. O O N2 Ph 7j Co L Co Co L Co L O O L AxialLigand( L ) DMAP Ph Co L O O Ph , 10a O O Ph O O Ph Co O O Ph Co O O Ph O O N2 Ph 7j , 10a , 10j 29 30 31 51 52 53 54 slow fast O O Ph + 2.4. Conclusions The chiral cobalt(II)-porphyrin complex [Co( P1 )] was shown to be an effective catalyst for the intramolecular cyclopropanati on of allylic diazoacetates. Further studies are needed to develop a catalytic system th at will enjoy excell ent selectivity over a broader range of substrates. Continued inves tigations into the use of axial donor ligands and their effect on the selectivity and mech anism of this reaction are warranted.

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35 Chapter 3 Asymmetric Cobalt-Catalyzed Cyclopropana tion with Succinimidyl Diazoacetate: General Synthesis of Optically Active Cyclopropyl Carboxamides 3.1. Introduction The importance of cyclopropanes in numerous fundamental and practical applications has stimulated an interest in the stereoselective synthesis of these carbocycles.9 Metal catalyzed asymmetric cycl opropanation of olefins with diazo reagents constitutes the most direct and general approach for the construction of cyclopropane derivatives.1 A number of outstanding chiral catalysts have been used to achieve high diastereoand enantioselectivity for several classes of cyclopropanation reactions, most of which have employed diazoacetates.3,5,7 Ongoing endeavors in asymmetric cyclopropanation are aimed at further expanding the substrate scope to include different types of olefins with various kinds of carbe ne sources, including different classes of diazo reagents.

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36 R + N2 H O N R1 R2 R + N2 H O O N O O R O O N O O N R2 H R1 R O N R1 R2 [LnM] [LnM] 1 1 55 56 58 57 Figure 3.1. Synthetic Routes to Chiral Cyclopropanecarboxamides. In contrast to the large body of excelle nt results achieved with diazoacetates,3,5,7 diazoacetamides have not been successfu lly employed for asymmetric intermolecular cyclopropanation (Figure 3.1). Except for the Rh2-based intramolecular reactions reported by Doyle and co-coworker40b,d the majority of the published reports using diazoacetamides are non-asymmetric systems.41 The absence of effective intermolecular asymmetric cyclopropanations with diazoacet amides may be attributed to two major factors: (i) the inherent low reactivity of the resulting metalcarbene intermediate due to reduced electrophilicity and incr eased steric hindrance, and (ii) complications resulting from competitive intramolecula r C–H insertion (Figure 3.2).42 N2 H O N R1 R2 [LnM] H O N R1 R2 N2 H O N R [LnM] N O R H 58a 58b 59 60 H H Figure 3.2. Intramolecular C–H Insertion with Diazoacetamides.

PAGE 54

37 Inspired by their important biomed ical applications (Figure 3.3),43 a postderivatization approach was a pplied to the synthesis of chiral cyclopropyl carboxamides 57 in enantioenriched forms through the re action of preformed cyclopropyl chiral building blocks 56 with various amines (Figure 3.1) Utilizing a cobalt-catalyzed asymmetric cyclopropanation process with succinimidyl diazoacetate ( 55 : N2CHCO2Su),44 in the presence of olefins generate s the cyclopropane products in high yields and excellent diastereoand enantioselectivities. As a result of the high reactivity of hydroxysuccinimide esters, the cyclopr opyl products could serve as convenient synthons for the general preparation of chiral amides through reacti ons with a range of different amines, and without loss of pre-es tablished enantiomeric purity (Figure 3.1). N H O O OEt Br N O S OTBDMS O O CO2H N O N O Ph S H H 61 HIV-1 ReverseTranscriptaseInhibitor 62 Antibacterial -LactamseInhibitor 63 MemoryImpairment ProlylEndopeptidaseInhibitor Figure 3.3. Examples of Important Biologi cally Active Chiral Cyclopropyl Carboxamides. 3.2. Diastereoand Enantioselective Cy clopropanation with Succinimidyl Diazoacetate The well-defined cobalt(II) complexes of D2symmetric chiral porphyrins ([Co( Por* )])19a have emerged as a class of e ffective catalysts for asymmetric cyclopropanation r eactions with both electron-sufficient20 and electron-deficient21 olefins using diazoacetates, diazosulfones22, and -nitro-diazoacetates.23 Among this family of

PAGE 55

38 ([Co( Por* )]), a group of six derivatives [Co( P1 – P6 )] (Figures 3.4), possess diverse electronic, steric, and chiral environments, were evaluated as potential catalysts for asymmetric cyclopropanation of styr ene with the sterically bulky N2CHCO2Su (Table 3.1). N N N N HN HN O O NH NH O O H H H H Co 20a :[Co( P1 )] N N N N HN HN O O NH NH O O Co 20f :[Co( P6 )] MeO OMe OMe MeO O O O O N N N N HN HN O O NH NH O O H H H H Co 20b :[Co( P2 )] OMe MeO OMe MeO H H H H N N N N HN HN O O NH NH O O H H H H Co 20e :[Co( P5 )] O O O N N N N HN HN O O NH NH O O H H H H OMe MeO MeO OMe Co 20c :[Co( P3 )] N N N N HN HN O O NH NH O O H H H H OMe MeO MeO OMe Co 20d :[Co( P4 )] OMe MeO OMe MeO O Figure 3.4. Structures of D2-Symmetric Chiral Cobalt(II) Porphyrins. As a practical attribute of [Co( Por* )]-catalyzed cyclopropan ation, these reactions were carried in a one-pot fashion with styr ene as the limiting reag ent, and without the occurrence of common diazo di merization side reaction. Upon examination of the results (Table 3.1), it was evident that the steric bulk iness of the carbene source played a role in the differences observed between these cat alysts. For example, no reactions were observed with the more sterically encumbered catalysts [Co( P4 )], [Co( P5 )], and [Co( P6 )] (Table 3.1, entries 4–6). Furthermore, th e yields of the desired cyclopropane 56a when sterically unhindered catalysts [Co( P1 )], [Co( P2 )], and [Co( P3 )] were employed

PAGE 56

39 correlated well with the liga nd environment (Table 3.1, entr ies 1–3). For these reactions, outstanding diastereoselectiv ities were achieved, with trans 56a produced as the sole diastereomer. While the best enantioselectivity was attained by [Co( P2 )], the use of [Co( P1 )] afforded the best yield in addition to high enantioselectiv ity. Reduction of the N2CHCO2Su from 1.5 to 1.2 equivalents gave similarly high diastereoand enantioselectivity for the [Co( P1 )]-catalyzed reaction, but re sulted in decreased yields (Table 1, entries 1 and 7). As demonstrated previously, a positive trans effect on enantioselectivity was observed upon additi on of DMAP (Table 1, entries 7–9). Although selectivity was not affected by lowering the catalyst loadi ng or reducing the reaction time, a decrease in the overall product yiel d was observed (Table 1, entries 10 and 11). Finally, toluene seemed to be the solvent of choice as the use of other solvents, such as chlorobenzene, led to lower yields and decr eased enantioselectivities (Table 1, entry 12).

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40 Table 3.1. Asymmetric Cyclopropanation of Styren e with Succinimidyl Diazoacetate by D2-Symmetric Chiral Cobalt(II) Porphyrins. + N2 H O O N O O O O N O O [Co( Por* )] entrya[Co(Por*)]byield(%)cee(%)e[Co( P2 )] [Co( P3 )] [Co( P4 )] [Co( P5 )] [Co( P1 )] 3 10 0 -4 7096 [Co( P6 )] 0 74 7f5 6 2 1 [Co( P1 )] 8692 0 -63 -91aReactionconditions:Performedat25oCfor48hwithtoluene assolventusing5mol%ofcatalystwith1.0equivofstyrene and1.5equivofN2CHCO2Suinthepresenceof0.5equivof DMAP;[styrene]=0.25M.bSeeFigure3.4.cIsolatedyield.dDeterminedbyNMRorHPLC.eTransisomereewas determinedbychiralHPLC.f1.2equivofN2CHCO2Su.g24h.h2mol%.iPerformedinchlorobenzene. additive DMAP DMAP DMAP DMAP DMAP DMAP DMAP trans:cisd8f9f10f,g11f,h12f,i[Co( P1 )] [Co( P1 )] [Co( P1 )] [Co( P1 )] [Co( P1 )] NMI -DMAP DMAP DMAP 85 86 66 64 67 >99:01 >99:01 >99:01 --->99:01 >99:01 >99:01 >99:01 >99:01 >99:01 88 88 91 91 87 1a 55 56a Under the optimized reaction conditions different olefin substrates were subjected to catalytic cyclopropanation using N2CHCO2Su. As demonstrated in these select examples (Table 3.2), both electron-su fficient and electron-de ficient olefins could

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41 be successfully cyclopropanated by [Co( P1 )]. For example, asymmetric cyclopropanation of styrene derivatives beari ng various substituents, includ ing alkyl and halide groups as well as electron donating and withdraw ing groups, could be catalyzed by [Co( P1 )] to form the corresponding cyclopropanes 56a f in good yields with outstanding diastereoselectivities and excellent enantioselectivities (Table 3.2, entries 1, 3, 5, 7, 9 and 11). Further improvement in enantioselectivity was achieved uniformly for all these substrates when the relatively bulkier [Co( P2 )] was employed as the catalyst, albeit in lower yields (Table 3.2, entries 2, 4, 6, 8, 10, a nd 12). In addition, the Co-based catalytic process showed significant functional group tole rance as demonstrated with the reactions of acetoxyand nitrosubstituted styrenes to form 56g h (Table 3.2, entries 13 and 14). Due to the steric bulkiness of N2CHCO2Su, the catalytic system was less efficient for large aromatic olefins as exemplified by the [Co( P1 )]-catalyzed cyclopropanation reaction of 2-vinylnaphthalene, offering 56i in low yield (Table 3.2, entry 15). In addition to aromatic olefins, the [Co( P1 )]/N2CHCO2Su-based system could also selectively cyclopropanate the challenging electron-deficient olefins, such as -unsaturated esters, amides, and ketones (Table 3.2, entries 16–18). It is worth noting that the cyclopropanes prepared from these olefins ( 56j l ) are highly electrophilic in nature and have proven to be valuable synthetic intermediates.45

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42 Table 3.2. [Co( P1 )]-Catalyzed Diastereoand Enan tioselective Cyclopropanation of Different Alkenes with Succinimidyl Diazoacetate. entryayield(%)bee(%)d7096 2f1 8692aReactionconditions:Performedat25oCfor48hwithtolueneassolventusing5mol% [Co( P1 )]with1.0equivofstyreneand1.5equivofN2CHCO2Sucinthepresenceof0.5 equivofDMAP;[styrene]=0.25M.bIsolatedyield.cDeterminedbyNMRorHPLC.dTrans isomereewasdeterminedbychiralHPLC.eSignofopticalrotation.f[Co( P2 )]ascatalyst.g[1R,2R]absoluteconfigurationbyX-raycrystalstructuralanalysisandopticalrotation. trans:cisc>99:01 >99:01 [ ]e(-) (-) 4f3 71 96 9095 >99:01 98:02 (-)g(-)g8198 8097 >99:01 >99:01 (-) (-) 6f5 75 97 71 95 >99:01 99:01 (-) (-) 8f7 10f9 12f11 4892 6690 >99:01 >99:01 (-) (-) 3094 77 90 >99:01 >99:01 (-) (-) 13 14 15 16 17 18 71 91 >99:01 (-) 5092 >99:01 (-) 3391 99:01 (-) 5789 >99:01 (-) 5296 >99:01 (-) 55 91 >99:01 (-) CO2Su cyclopropane CO2Su CO2Su t -Bu CO2Su MeO CO2Su Cl CO2Su F3C CO2Su AcO CO2Su O2N CO2Su O CO2Su O CO2Su O N Et Me Me O CO2Su Me 56a 56b 56c 56d 56e 56f 56g 56h 56i 56j 56k 56l

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43 3.3. Post-Derivitization Approach for the Synt hesis of Optically Active Cyclopropyl Carboxamides With the established availability of enantioenriched succinimidyl cyclopropyl carboxylate derivatives through the [Co( P1 )]-catalyzed asymmetric cyclopropanation with N2CHCO2Su, the potential application of these derivatives as chiral building blocks for the synthesis of cyclopropyl carboxamides (Figure 3.1) was subsequently explored. Using [ 1R, 2R ]56a as a representative synthon, a ra nge of different amines were examined for the post-derivatiz ation synthetic approach (Tab le 3.3). Both aliphatic and aromatic amines reacted with 56a smoothly, affording the desired cyclopropyl carboxamides with retention of configuration (Table 3.3, 57a and 57b ). The transformation of 56a into the corresponding primary amide using ammonia also occurred in high yield and without loss of di astereoand enantiose lectivity (Table 3.3, 57c ). Cyclic amines such as pyrrolidine and morpholine could also be effectively converted to the corresponding amides in high yields with complete preservation of the stereochemistry (Table 3.3, 57d and 57e ). Owing to the mild and neutral reaction conditions, the post-derivatization approach was able to tolerate a number of different functional groups as exemplified by the reactions with chiral -amino acids such as methyl ( S )-phenylalaninate as well as chiral -amino alcohols such as ( S )-phenylalaninol and ( R )-valinol (Table 3.3, 57f 57g and 57h ). The resulting multi-functional cyclopropyl amides, bearing three stereogenic centers, could be isolated as single diastereomers in good to excellent yields. To further demonstrate the utility of this approach, [ 1R, 2R ]56a was allowed to react with the unprot ected tripeptide [ S ]H2N-Gly-Gly-Ala-COOH and D-glucosamine at

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44 room temperature in a mixture of wate r and THF (Table 3.3 ). The corresponding cyclopropyl carboxamides were isolated as single diaste reomers in 60% and 47% yield, respectfully, without affecting the hy droxylic and carboxylic functionalities. Table 3.3. Synthesis of Chiral Cyclopropanecarboxamides. O O N O O aReactionconditions:Performedat25oCinTHFopentoairfor30min;Isolatedyields;de determinedbyNMRorHPLC;eedeterminedbychiralHPLC.b24h.cNH3/Dioxane(1.0M).dIsolatedassinglediastereomer.ePerformedinTHF:H2O:Et3N(1:1:0.05).f1h.gIsolateda mixtureofanomers : (2:1). N H R1 R2 O N R1 R2 25oC 56a [-1R,2R] 92%ee >99%de 57[1R,2R]a O N C6H13 H O N H 57a -[1R,2R] 92%yield 88%ee >99%de OMe 57b -[1R,2R]b62%yield 89%ee >99%de O N H H 57c -[1R,2R]c93%yield 92%ee >99%de O N 57d -[1R,2R] 93%yield 92%ee >99%de O N 57e -[1R,2R] 93%yield 92%ee >99%de O N H 57f -[1R,2R,3S]d,e,f66%yield O O OMe O N H OH O N H OH O N H O N H O O O CH3 OH O 57g -[1R,2R,3S]d93%yield 57h -[1R,2R,3R]d54%yield 57j -[1R,2R,3S]b,d,e60%yield 57i -[1R,2R,3R]e,f,g47%yield HO OH HO OH 1 2 2 1 3 3 3 3 3

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45 3.4. Conclusions We have shown that the succinimidyl cy clopropyl carboxylate derivatives can be generated in excellent diastereoand enan tioselectivities throu gh a broad range of terminal olefins utilizing [Co( P1 )] and [Co( P2 )] as catalysts. We have also shown that the use of succinimidyl cyclopropyl carboxylate derivatives can be used as a convenient synthons to produce the corre sponding cyclopropyl carboxam ides under mild conditions with excellent functional group tolerance without loss of the pre-established enantiomeric purity. The analogous transformation utilizing cycloprop yl esters generated from EDA or t -BDA would require heating and possibly long reaction times to generate the cyclopropyl carboxamide derivatives. This c ould lead to loss of the pre-established enantiomeric purity through epimerizati on. Many amines could require the transformation of the ester to an acid chloride so that a sufficiently electrophilic carbon would be available for the reaction, limiting th e efficiency of the reaction and introducing harsh reaction conditions.

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46 Chapter 4 Cobalt-Catalyzed Olefin Aziridinat ion with Arylsulfonyl Azides 4.1. Introduction Metal-catalyzed olefin azir idination is a fundamentally and practically important chemical process that is receiving an increasing amount of research attention.2 The resulting aziridines are key elements in many biologically and pharmaceutically interesting compounds and serve as valu able synthons for the preparation of functionalized amines.46 The greatest progress in catalytic aziridi nation has been made utilizing PhI=NTs and related iminoiodane derivatives.4,6,8 Since the introduction of PhI=NTs as a nitrene source, considerable progress has been made in metal-catalyzed olefin aziridination with notable developments with the use of in situ generation of PhI=NTs and variants.4d,6b,8a,30 Despite these advances, the continued search for alternative nitrene sources is warranted as the use of PhI=NTs has been met with several difficulties. Besides its short shelf life and poor solubility in common solvents, the ca talytic process generates a stoichiometric amount of PhI as byproduct from the decomposition of PhI=NTs. In view of their similarity to diazo reagen ts for carbene transfer processes, azides may have the potential to serv e as a general class of nitren e precursors in metal-mediated nitrene transfer reactions, including aziridinati on (Figure 4.1). In addition to their wide availability and ease of synthesis, azide-base d nitrene transfer reac tions would generate

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47 nitrogen gas as the only byproduct. Despite th ese attributes, only a few catalytic systems have been developed, both non-asymmetric and asymmetric, that can effectively catalyze the aziridination process.2e,4a-b,37,47,48 Figure 4.1. Cobalt-Catalyzed Olefin Aziridin ation with Arylsulfonyl Azides. 4.2. Hydrogen Bonding Guided Catalyst Design We have reported a catalytic cobalt-porphyr in based system for the aziridination of olefins with azides, specifi cally diphenylphosporyl azide (DPPA).33 It was shown that [Co(TPP)] (Figure 4.2) could catalyze olefin aziridinati on with the commercially available DPPA as the nitrene source, l eading to the formation of N-phosphorylated aziridines. Recently, this work was expa nded to employ chiral cobalt porphyrins as catalysts which allowed for modest enantioselectivities.34 Figure 4.2. Structures of Cobalt(II) Porphyrin Catalysts In an attempt to expand the scope of the catalytic process to other azides, it was found that [Co(TPP)] was a poor catalyst choice for olefin aziridinat ion with arylsulfonyl azides as the nitrene sources. The desired aziridines 65a-c were obtained in 11-24%

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48 yields from the reaction of styrene with common azides 64a-c (Table 4.1). Similarly, Co(TDClPP)] (Figure 4.2), which was shown to be an effective catalyst for azidination30 and amination34 with bromamine-T, produced the desired product in trace amounts for each azide screened (Table 4.1). Table 4.1. Aziridination of Styrene with Arylsulfonyl Azides with Different Cobalt(II) Porphyrins. 65aa 65ba 65ca + S O O Ar N3 N SO2 A r [Co( Por )] N S O O N S O O OMe N S O O N H O 18% 24% <10% <10% <10% <10% 94% 88% 98% entryaaziridine [Co(TPP)][Co(TDClPP)][Co( P7 )] 1 2 3 aReactionconditions:Performedat40oCfor18hwithC6H5Classolventusing 2mol%ofcatalystinthepresenceof4MS;styrene:azide=5:1;[azide]=0.2M. 64a-c 65aa-ca As part of our efforts to develop a co balt-porprhyin based catalytic system, we developed a new cobaltporphryin catalyst, [Co( P7 )] (Figure 4.2), to exploit potential hydrogen bonding interactions between the a ssumed cobalt-nitrene sulfonyl group and the amide functional groups on the porphyrin ligand. [Co( P7 )] was shown to be a highly active catalyst for the aziridination of aroma tic olefins with various arylsulfonyl azides, forming the corresponding aziridines in exce llent yields under mild conditions. Under

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49 the same conditions used as the afor ementioned reactions by [Co(TPP)] and [Co(TDClPP)], we found th at employment of [Co( P7 )] resulted in a dramatic improvement of the catalytic aziridination (Table 4.1). Th e desired aziridines were obtained in 88-98% yields, which suppor ts the hydrogen bon ding catalyst design. In addition to azides 64a-c that contain p -methyl, p -methoxy, and p -acetamide groups (Table 4.2, entries 1-3), [Co( P7 )] could effectively ac tivate a wide range of arylsulfonyl azides (Table 4.2). Th e use of arylsulfonyl azides having p -cyano, p -nitro, and o -nitro substituents afforded the correspondin g aziridines in excellent yields as well (Table 4.2, entries 4-6). The [Co( P7 )]-catalytic system could also accommodate the much bulkier naphthalene-1-sulfonyl azide to produce the resulting aziridine product in 97% yield (Table 4.2, entry 7). It was found that the [Co( P7 )] system could be applied to various combinations of olefins and azides. Using azide 64e as the nitrene source, various styrene derivatives as well as 2-vinylnapththalene coul d be aziridinated in high to ex cellent yields (Table 4.3). While most of the reactions we re carried out with 5 equivale nts of olefin, the catalytic process could also be operated with olefin as limiting reagent albeit with a slight decrease in yield (Table 4.3, entries 1-2, 5-6, 8). To further demonstrate the utility of [Co( P7 )], azide 64c was also employed as the nitrene s ource for the aziridination of various aromatic olefins and produced the aziridi nes in excellent yields (Table 4.4).

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50 Table 4.2. [Co( P7 )]-Catalyzed Aziridination of St yrene with Arylsulfonyl Azides. + S O O Ar N3 N SO2 A r N S O O N S O O OMe N S O O N H O 94 88 98 entryaaziridine yield(%)b1 2 3 azide SO2N3 SO2N3 MeO SO2N3 HN O SO2N3 NC SO2N3 O2N SO2N3 NO2 SO2N3 N S O O CN N S O O NO2 N S O O N S O O O2N 4 5 6 7 88 97 96 97 aReactionConditions:PerformedinC6H5Clfor18hat40oCinthe presenceof4MSusing2mol%of[Co( P7 )];styrene:azide=5:1;[azide]= 0.2M.bIsolatedyields. [Co( P7 )] 64a-g 65aa-ga 65aa 65ba 65ca 65da 65ea 65fa 65ga 64a 64b 64c 64d 64e 64f 64g

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51 Table 4.3. Aziridination of Aromatic Olefins by [Co( P7 )]. entryaaziridine yield(%)b1 2 azide N S O O NO2 aReactionConditions:PerformedinC6H5Clfor18hat40oCinthe presenceof4MSusing2mol%of[Co( P7 )];olefin:azide=5:1;[azide]= 0.2M.bIsolatedyields.colefin:azide=1:1.2. olefin 64e 64e 97 (90)c N S O O NO2 89 (83)c 3 64e N S O O NO2 89 4 64e N S O O NO2 88 5 64e N S O O NO2 98 (97)ct -Bu t -Bu 6 64e N S O O NO2 94 (83)cCl Cl 7 64e N S O O NO2 96 Br Br 8 64e N S O O NO2 95 (90)cF F 9 64e N S O O NO2 96 F3C F3C 10 64e N S O O NO2 75 65ea 65eb 65ec 65ed 65ee 65ef 65eg 65eh 65ei 65ej

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52 Table 4.4. Aziridination of Aromatic Olefins with 64c by [Co( P7 )]. entryaaziridine yield(%)b1 2 azide N S O O NHC(O)Me aReactionConditions:PerformedinC6H5Clfor18hat60oCinthe presenceof4MSusing2mol%of[Co( P7 )];olefin:azide=5:1;[azide]= 0.2M.bIsolatedyields. olefin 64c 64c 98 N S O O NHC(O)Me 83 3 64c N S O O NHC(O)Me 84 t -Bu t -Bu 4 64c N S O O NHC(O)Me 93 Cl Cl 65ca 65cb 65ce 65cf 4.3. Enantioselective Aziridinat ion of Arylsulfonyl Azides The hydrogen bonded catalyst design, whic h led to the development of [Co( P7 )] as an effective catalyst for olefin aziridina tion with arylsulfonyl azides, provides a basis for the employment of D2-symmetric chiral porphyrins, which have shown to be very effective catalysts for cyclopropanation,19-23 for the development of a cobalt-based enantioselective aziridination system. The D2-symmetric porphyrins (Figure 4.3) developed by our group employ the use of a quadruple amidation reac tion to install the chiral amides to the ortho -phenyl positions of the core tetraphenylporphyrin ring system in much the same way that [Co( P7 )] was synthesized.19a Not only does this reaction install the chiral groups in an orientation that allows for significant asymmetric induction, as shown by our results in cyclopropanation,19-23 but it also forms th e same basic ligand

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53 structure as [Co( P7 )], which allows for potenti al hydrogen bonding between the porphyrin ligand’s amide functional groups and the sulfonyl groups of the proposed metal-nitrene complex. The convenient modul ar design of the chir al cobalt-porphyrin allows us to develop this asymmetric coba lt-catalyzed olefin aziridination reaction. N N N N HN HN O O NH NH O O H H H H Co 20a :[Co( P1 )] N N N N HN HN O O NH NH O O Co 20f :[Co( P6 )] MeO OMe OMe MeO O O O O N N N N HN HN O O NH NH O O H H H H Co 20b :[Co( P2 )] OMe MeO OMe MeO H H H H N N N N HN HN O O NH NH O O H H H H Co 20e :[Co( P5 )] O O O N N N N HN HN O O NH NH O O H H H H OMe MeO MeO OMe Co 20c :[Co( P3 )] N N N N HN HN O O NH NH O O H H H H OMe MeO MeO OMe Co 20d :[Co( P4 )] OMe MeO OMe MeO O Figure 4.3. Structures of D2-Symmetric Chiral Cobalt(II) Porphyrins. In the initial screening of select D2-symmetric chiral cobalt(II) porphyrins, [Co( P1 )] and [Co( P4 )] (Figure 4.3), demonstrated that the aziridination of styrene with azide 64e could be generated in moderate yiel ds and enantioselectivities (Table 4.5, entries 1-2). Catalyst [Co( P4 )] was chosen to screen a series of additives for increases in catalytic efficiency and selec tivity. A slight positive additi ve effect on selectivity was previously demonstrated in the asymmetr ic aziridination of olefins with DPPA by [Co(P 1 )].32 It was shown that strongly donating ax ial ligands inhibite d the reaction from proceeding, including the use of a substoichi ometric amount of THF as additive (Table

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54 4.5, entries 1-6 and 8). The use of phthali mide and the common solvents, ethanol and methanol, led to decreases in yield with no significant change in asymmetric induction (Table 4.5, entries 7 and 9-10). Table 4.5. Additive Effects of Asymmetric Aziridination. entrya[Co(Por*)]byield(%)cee(%)d[Co( P4 )] [Co( P4 )] [Co( P4 )] [Co( P4 )] 3 ----4 44 61 [Co( P4 )] -5 6 2 1 [Co( P1 )] 9413 ------aReactionconditons:Performedat25oCfor18hinC6H5Clusing2 mol%ofcatalystinthepresenceof4MSand0.2equivofadditive; olefin:azide=5:1;[azide]=0.2M.bSeeFigure4.3.cIsolatedyield.dDeterminedbychiralHPLC. + [Co( Por* )] Additive (0.2equiv) SO2N3 O2N N S O O NO2 additive --DMAP PPh3NMI NBI [Co( P4 )] [Co( P4 )] [Co( P4 )] [Co( P4 )] 8 -3360 9 1065 10 7 41 61 -Phthalimide THF EtOH MeOH 64e 64ea Increasing the catalyst loading to 5 mol % and allowing for longer reaction times resulted in both increased yields and enantioselectivies with the use of [Co( P1 6 )] as catalysts (Table 4.6, entries 1-6). Of the cobalt-catalysts screened, [Co( P6 )] was shown to be the catalyst most capable of achieving respectable levels of enantioslectivity. In

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55 order to probe for conditions that would favor an increase in the enantioselectivity of the products when utilizing [Co( P6 )] as catalyst, the reaction was performed with decreased catalyst loading, temperature, and time. Unfo rtunately, none of thes e changes in reaction conditions provided the positive effect on enan tioselectivity that was desired; instead these conditions negatively effected the yi eld of the reaction (Table 4.6, entries 7-9). Further attempts to optimize the enantioselec tivity led to the scr eening of various noncoordinating solvents; however, none of the solvents screened showed a significant improvement in enantioselectiv ity and many yields were subs tantially diminished (Table 4.6 entries 10-15). The use of the non-halogena ted solvent ethyl acetate, deactivated the catalyst through potential axial coordination and resulted in the failure to produce the desired aziridine (Table 4.6, entry 16).

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56 Table 4.6. Asymmetric Aziridination by D2-Symmetric Chiral C obalt(II) Porphyrins. entrya[Co(Por*)]byield(%)cee(%)d[Co( P2 )] [Co( P3 )] [Co( P4 )] [Co( P5 )] 3 80 82 69 4 82 30 [Co( P6 )]68 5 6 2 1 [Co( P1 )] 9422 75 51 21 88aReactionconditions:Performedat25oCfor48hinC6H5Clusing 5mol%ofcatalystinthepresenceof4MS;olefin:azide=5:1; [azide]=0.2M.bSeeFigure4.3.cIsolatedyield.dDeterminedby chiralHPLC.e2mol%[Co(P6)].fPerformedat0oC.g18h. + [Co( Por* )] PhCl;4MS SO2N3 O2N N S O O NO2 solvent C6H5Cl C6H5Cl C6H5Cl C6H5Cl C6H5Cl C6H5Cl [Co( P6 )] [Co( P6 )] [Co( P6 )] [Co( P6 )] 12 65 67 89 13 41 81 [Co( P6 )] 22 14 15 11 10 [Co( P6 )] 2188 21 82 86 85 C6H5CH3C6H5CF31,2-C6H4Cl21,3-C6H4Cl2DCM 1,2-DCE [Co( P6 )] -16 -EtOAc [Co( P6 )]52 7e86 C6H5Cl [Co( P6 )]-8f-C6H5Cl [Co( P6 )]40 9g85 C6H5Cl 64e 65ea The cobalt-catalyzed system was eval uated against a number of arylsulfonyl azides containing various f unctional groups, such as p -methyl, p -methoxy, p -cyano, p nitro, and o -nitro groups, which led to large vari ations in yields although they all generated similar enantioselectivities (Table 4.7). Presumably, the similarity of the enantioselectivities is due to the activation and stabilization effect s resulting from the

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57 hydrogen bonding of the porphyrin ligand with the assumed coba lt-nitrene intermediate. These interactions allow for comparable as ymmetric inductions to be observed as a reflection of their structurally similar proposed intermediates. Table 4.7. [Co( P6 )]-Catalyzed Asymmetric Aziridination of Styrene. + S O O Ar N3 N SO2Ar [Co( P6 )] PhCl;4MS N S O O N S O O OMe 5 9 entryaaziridine yield(%)b1 2 azide SO2N3 SO2N3 MeO SO2N3 NC SO2N3 O2N SO2N3 NO2 N S O O CN N S O O NO2 N S O O O2N 3 4 5e44 68 <30aReactionConditions:PerformedinC6H5Clfor48hat25oCinthepresenceof4MS using5mol%of[Co( P6 )];styrene:azide=5:1;[azide]=0.2M.bIsolatedyields.cDeterminedbychiralHPLC.dSignofopticalrotation.eContaminatedbyazidestarting material. 86 88 ee(%)c87 88 70 64a-b,d-f 65aa-ba,da-fa 64a 64b 64d 64e 64f 65aa 65ba 65da 65ea 65fa [ ]d(-) (-) (-) (-) (-) Utilizing azide 64e as the nitrene source, it was demonstrated that various styrene derivatives as well as 2-vinylna pththalene could afford the azi ridines in moderate yields and good enantioselectivities with the use of [Co( P6 )] as catalyst (Table 4.8).

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58 Table 4.8. Asymmetric Aziridination of Aromatic Olefins by [Co( P7 )]. entryaaziridine yield(%)b1 2 azide N S O O NO2 aReactionConditions:PerformedinC6H5Clfor48hat25oCinthepresenceof4MS using5mol%of[Co( P6 )];olefin:azide=5:1;[azide]=0.2M.bIsolatedyields.cDeterminedbychiralHPLC.dSignofopticalrotation. Olefin 64e 64e 68 N S O O NO2 59 3 64e N S O O NO2 47 4 64e N S O O NO2 47 5 64e N S O O NO2 62 t -Bu t -Bu 6 64e N S O O NO2 63 Cl Cl 7 64e N S O O NO2 75 Br Br 8 64e N S O O NO2 74 F F 9 64e N S O O NO2 65 F3C F3C 10 64e N S O O NO2 57 ee(%)c88 81 80 85 78 82 86 88 76 ND 65ea 65eb 65ec 65ed 65ee 65ef 65eg 65eh 65ei 65ej [ ]d(-) (-) (-) (-) (-) (-) (-) (-) (-) (-)

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59 4.3. Conclusions We have developed a cobalt(II)-porphyr in based catalyst design which exploits the potential hydrogen bonding interactions of the porphyrin ligand with the proposed cobalt-nitrene intermediates generated from the use of arylsulfonyl azides as nitrene precusors. This discovery led to the implementation of a family of D2-symmetric chiral cobalt porphyrins for the assessment of their va lue as asymmetric aziridination catalysts. This investigation has revealed a very effective catalyst, [Co( P6 )], that could be employed for a variety of arylsulfonyl azides with aromatic olefins. Although currently limited in olefin substrate scope the development of other ar ylsulfonyl azides as nitrene sources will potentially further expand the substrate scope to include multi-substituted olefins and aliphatic olefins.

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60 Chapter 5 Cobalt-Catalyzed Intramolecular C–H Am ination with Arylsulfonyl Azides 5.1. Introduction Metal-mediated C–H amination reactions represent an important chemical process that can transform compounds with ubiquit ous C–H bonds into value added nitrogen containing molecules, such as amines.2,49 Significant research has been devoted to the use of PhI=NTs and related iminoiodane deriva tives as nitrene sources for the catalytic amination of C–H bonds.8c,50 Great efforts have been made to overcome several limitations associated with the use of hyperv alent iodine reagents, such as PhI=NTs, which include their instability and the generatio n of a full equivalent of ArI as byproduct. While the approach of in situ iminoiodane generation in the presence of a terminal oxidant has met with success recently, 4d,6b,8a,30 alternate nitrene sources, chloramineT,8c,51 bromamine-T,32,36,52 and tosyloxycarbamates53 have been actively pursued to improve catalytic nitrene transfer reactions including aziridination and C–H amination. Azides represent a broad class of co mpounds that have the potential to be considered as an ideal nitrene source for metal-mediated nitrene transfer reactions.2c,47 In addition to their ease of synt hesis and availability, azide-bas ed nitrene transfers generates nitrogen gas as the only byproduct. Despite th ese attributes, only a few catalytic systems have been developed that can effectively cat alyze the decomposition of azides for nitrene transfer reactions, specifically C–H aminati on. Notable examples include Co(Por)-based

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61 amination with aryl azides,4a,35 a Ru(Salen)-based aziridination, where amination is noted as a side product,4c and a dirhodium system capable of intramolecular amination of vinyl azides.6e As an extension of our previous work w ith Co(TPP)-based amination of benzylic C–H bonds with bromamine-T as the nitr ene source and inspired by the current developments with the use of arylsulfonyl azides as nitrene sources in catalytic aziridination, we have developed a Co-catal yzed intramolecular C–H amination process with azides as nitrene sources. Commercially available Co(TPP) was shown to be an effective catalytst for the intramolecular ni trene insertion of C–H bonds utilizing a broad range of arylsulfonyl azides and leading to the syntheses of the corresponding benzosultam derivatives (Figure 5.1), whic h have been found in various important applications.54 The Co-mediated process proceeds efficiently under mild conditions without the need for other additives, while ge nerating nitrogen gas as the only byproduct. R6 R5 R4 R3 S R2 R1 H O O N3 R6 R5 R4 R3 S R2 R1 O O NH [M(Por)] 6970 Figure 5.1. Catalytic Intramolecular C–H Amination of Arylsulfonyl Azides. 5.2. Intramolecular C–H Am ination with Arylsulfonyl Azides Using the commercially available 2,4,6triisopropylbenzenesulfonyl azide ( 69a ) as a model substrate, we first surveyed the potential catalytic activity of various metalloporphryins (Figure 5.2) toward intramolecular C–H amination (Table 5.1). The reactions were carried out with 2 mol % of metalloporphyrin at 80 oC overnight in

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62 chlorobenzene, which was previously identified as the solvent of choice for aziridination with arylsulfonyl azides a nd diphenylphosphoryl azides.33,34 It was evident that Co(II) was by far the most active metal ion for the intramolecular C–H amination using tetraphenylporphryin (TPP) as the supporti ng ligand, forming the desired benzosultam 70a in 96% yield (Table 5.1, entr y 5). Complexes of other first row transition metal ions supported by TPP produced no or only trace amounts of 70a (Table 5.1, entries 1-3, 6-8), with the exception of Fe(TPP)Cl that genera ted 11% yield of the desired product (Table 5.1, entry 4). Although not as effective as Co(II), Ru(TPP)(CO) could catalyze the amination reaction and generated the benzosultam 70a in 67% yield (Table 5.1, entry 9). Table 5.1. C–H Amination of 69a Catalyzed by Metalloporphyrins. S H O O N3 S O O NH [M(TPP)] Entrya[M(Por)]bYield(%)c 1 2 3 4 5 6 7 8 9 [V(TPP)Cl] [Cr(TPP)Cl] [Mn(TPP)Cl] [Fe(TPP)Cl] [Co(TPP)] [Ni(TPP)] [Cu(TPP)] [Zn(TPP)] [Ru(TPP)CO] 0 0 <5 11 96 0 0 0 67 aReactionconditions:PerformedinC6H5Clat80oC for18hand2mol%ofcatalystinthepresenceof5 molecularsieves;[substrate]=0.20M.bSeeFigure 5.2.cIsolatedyields. 69a 70a

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63 Figure 5.2. Structures of Metalloporphyrin Catalysts. With the superiority of the cobalt system established, several common porphyrins with differing electronic and steric properties were applie d to probe the ligand effect (Figure 5.2). While both Co(OEP) and Co (TMeOPP) could effectively catalyze the reaction (Table 5.2, entries 1-2), an increase in ligand steric hindrance and/or electron deficiency resulted in poor catalytic ac tivity (Table 5.2, entries 3-5). The Co(TPP)catalyzed reaction could also proceed well at lower temperatures, including room temperature (Table 5.2, entries 7-8), and in di fferent solvents (Table 5.2, entries 9-10). As expected, a decrease in catalyst loading from 2 mo l % to 0.5 mol % moderately decreased the yield and requi red longer reaction times a lthough there was no dramatic adverse effect on the catalytic process (Table 5.2, entries 11-12). Control experiments showed that no reaction was observed in the absence of catalyst (T able 5.2, entry 13).

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64 Table 5.2. C–H Amination of 69a Catalyzed by Cobalt(II) Porphyrins. S H O O N3 S O O NH [Co(Por)] entrya[M(Por)]bYield(%)d1 2 3 4 5 7 8 9 10 [Co(OEP)] [Co(TMeOPP)] [Co(TMP)] [Co(TPFPP)] [Co(TDClPP)] [Co(TPP)] [Co(TPP)] [Co(TPP)] [Co(TPP)] 86 93 30 8 5 95 91 91 85aReactionconditions:PerformedunderN2for18hinthepresenceof5 molecularsieves;[substrate]=0.20M.bSeeFigure5.2.cCatalystloading.dIsolatedyields.eCarriedoutfor42h. mol(%)csolvent temp(oC) 11 12 13 [Co(TPP)] [Co(TPP)] -88 92e0 0.0 0.5 0.5 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 C6H5Cl C6H5Cl C6H5Cl C6H5Cl C6H5Cl C6H5Cl C6H5Cl C6H5Cl C6H5Cl C6H5CH3CH2Cl26 [Co(TPP)] 96 2.0 C6H5Cl C6H5Cl 80 80 80 80 80 80 80 80 80 40 23 23 23 69a 70a The Co(TPP) catalytic system was found to be suitable for a broad range of arylsulfonyl azides (Table 5.3) Probing the reactivity of each arylsulfonyl azide substrate, the catalytic reactions were ev aluated at three separate temperatures: 80 oC, 40 oC, and room temperature. In addition to in tramolecular nitrene insertion into tertiary C– H bonds (Table 5.3, entries 1-2), secondary (T able 5.3, entries 3-4), and even primary (Table 5.3, entries 5-7) C–H bonds having vari ous aromatic substitution patterns could be effectively aminated. These substrates led to the selective formation of the corresponding five-membered heterocycles. Although they all could be intramol ecularly inserted in

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65 excellent yields at 80 oC, the reactivity pattern of the C–H bonds could be observed at lower temperatures and followed in the order of 3o > 2o > 1o (Table 5.3, entries 1-7). It is interesting to note that increases in aroma tic ring substitution led to higher-yielding formations of the aminated products (T able 5.3, entries 5-7) suggesting a positive buttressing effect of meta and paragroups on the nitrene insertion into ortho C–H bonds. Arysulfonyl azides containing electr on-withdrawing functional groups, such as bromo and nitro substituents could also be su ccessfully catalyzed (Tab le 5.3, entries 8-9). Table 5.3. [Co(TPP)]-Catalyzed Intram olecular C–H Amination. aReactionconditions:PerformedunderN2inC6H5Clfor18hwith2mol%of[Co(TPP)]inthe presenceof5molecularsie ves;[substrate]=0.20M.bIsolatedyields.eCarriedoutfor42h. NH S O O 80 40 Rt 96 95 91 NH S O O 80 40 Rt 94 82 72 NH S O O 80 40 Rt 90 54 19 NH S O O 80 40 Rt 91 57 40 NH S O O Br 80 40 Rt 93 77 46 S NH O O O2N 80 40 Rt 99 85 69 NH S O O 80 40 Rt 96 32 18 NH S O O 80 40 Rt 91 58 37 NH S O O 80 40 Rt 95 79 47 S O O NH 80 40 Rt 87 33 23 sultam temp(oC) sultam temp(oC) entryaentryayield(%)byield(%)b1 2 3 4 5 6 7 8 9 10 70a 70b 70c 70d 70e 70f 70g 70h 70i 70j

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66 The aforementioned C–H bond reactivity order of 3o > 2o > 1o in combination with the higher reactivity of the activated benzylic C–H bonds, resulted in the exclusive formation of five-membered ring struct ures in all the above cases where 1o and 3o or 1o and 2o C–H bonds coexist in the substrate (Table 5.3, entries 1-4 and 8-9). As in the other cases mentioned above (Table 5.3, entrie s 1-4 and 8-9), the exclusive high-yielding formation of five-membered spiroheterocyc lic product was observed from a substrate contained both 2o and 3o C–H bonds (Table 5.3, entry 10). However, when both fiveand six-member ed ring formations were observed an azide substrate containing two different 2o C–H bonds, such as benz ylic and non-benzylic types was employed. For example, Co(TPP)catalyzed intramolecula r C–H amination of azide 69k with an n-butyl group led to the production of six-membered 70kb as well as the five-membered 70ka (Table 5.4, entries 1-3). The ratio of 70ka to 70kb was determined to be 72:28, 68:32, and 67:33 at 80 oC, 40 oC, and room temperature, respectively. The increase in the ratio of 70ka to 70kb at elevated temperatures suggests the greater thermodynamic stability of the five -membered ring structure. Similarly, when 69l with an n-propyl group was used, both the five-membered 70la and six-membered 70lb were formed (Table 5.4, entries 4-6); howev er, the ratio of fiveto six-membered ring products was significantly lower than those of azide 69k Our preliminary results indicated that the ratio of fiveand six-membered ring fo rmation could be influenced sterically and electronically through the use of different por phyrin ligands. While a similar ratio of 70la to 70lb was obtained for Co(TMP)or Co(TMeOPP)-catalyzed reactions (Table 5.4, entries 7-8), the ratio was significan tly increased to 73:27 when Co(OEP) was used as cataly st (Table 5.4, entry 9).

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67 Table 5.4. Fiveand Six-Membered Ring Formation via Intramolecular C–H Amination Catalyzed by Cobalt Porphyrins. S C3H7 H O O N3 S O O NH [Co(Por)] entrya[Co(Por)]byield(%)d1 2 3 4 5 7 8 9 [Co(TPP)] [Co(TPP)] [Co(TPP)] [Co(TPP)] [Co(TPP)] [Co(TMP)] [Co(TMeOPP)] [Co(OEP)] 91 41 25 94 56 77 97 92aReactionconditions:PerformedinC6H5Clfor18hwith2mol%of[Co(Por)]in thepresenceof5molecularsieves;[substrate]=0.20M.bSeeFigure5.2.cRatioof5-and6-memberedringproductsdeterminedbyNMR.dCombined isolatedyields. temp(oC) 6 [Co(TPP)] 33 80 40 23 80 40 23 80 80 80 C4H11 C4H11 S O O C4H11 NH C2H5 C3H7 S C2H5 H O O N3 S O O NH [Co(Por)] C3H7 C3H7 S O O C3H7 NH CH3 C2H5 + + azidesultam 70ka + 70kb 70ka + 70kb 70ka + 70kb 70la + 70lb 70la + 70lb 70la + 70lb 70la + 70lb 70la + 70lb 70la + 70lb distributionc72+28 68+32 67+33 56+44 56+44 54+46 55+45 73+27 59+41 69k 69k 69k 69l 69l 69l 69l 69l 69l 69k 69l 70ka70kb 70la 70lb 5.3. Conclusion We have developed the first Co-based catalytic system for intramolecular C–H amination with azides. We have demonstrat ed that the commercially available Co(TPP) is an effective and general catalyst for in tramolecular C–H amination with arylsulfonyl azides. This catalytic proce ss generates the potentially valu able benzosultam derivatives

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68 in excellent yields. In addition to 1o, 2o, and 3o benzylic C–H bonds, non-benzylic C–H bonds can also be aminated. Continuing efforts are underway to identify suitable catalysts with high regioselectivity toward e ither fiveor six-membered ring formation. In addition, current research also includes th e use of chiral por phyrins as ligands to support a cobalt-based asymmetric C– H amination catalytic system.

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69 Chapter 6 Experimental Procedures and Compound Characterization 6.1. General Considerations All catalytic reactions we re performed under nitrogen in oven-dried glassware following standard Schlenk techniques unless otherwise specifically noted. Toluene was distilled under nitrogen from sodium benzophe none ketyl prior to use. Chlorobenzene and dichloromethane were dried over calcium hydride under nitrogen and freshly distilled before use. 4 molecular sieves were drie d in a vacuum oven prior to use. Chemicals were purchased from commercial sources and used without further purification unless specifically noted. Thin layer chromat ography was performed on Merck TLC plates (silica gel 60 F254). Flash column chromat ography was performed with Merck silica gel (60 , 230-400 mesh, 32-63 m). 1H NMR and 13C NMR were recorded on a Varian Inova400 (400 MHz) or a Varian Inova500 (500 MHz) with ch emical shifts reported relative to residual solvent. Infrared spectra were measur ed with a Nicolet Avatar 320 spectrometer with a Smart Miracle accessor y. HRMS data was obtained on an Agilent 1100 LC/MS/TOF mass spectrometer. HPLC measurements were carried out on a Shimadzu Prominence LC-20AT HPLC system with a SPD-N20A diode array detector. Enantiomeric excess was measured using eith er a Chiralcel OD-H or Chiralcel AD-H chiral HPLC column. Optical rotation was measured on a Rudolf Autopol IV polarimeter.

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70 6.2. Supporting Information for Chapter 2 An oven dried Schlenk tube, that was previously evacuated and backfilled with nitrogen gas, was charged with diazoacetate (0.2 mmol, if solid), catalyst, and DMAP. The Schlenk tube was then evacuated and b ack filled with nitrogen. The Teflon screw cap was replaced with a rubber septum and 0.5 ml portion of solvent was added followed by diazo (0.2 mmol, if liquid), and the remaini ng solvent (total 1 mL). The Schlenk tube was then purged with nitrogen for 1 minute and the rubber septum was replaced with a Teflon screw cap. The Schlenk tube was then placed in an oil bath for the desired time and temperature. Following completion of th e reaction, the reaction mixture was purified by flash chromatography. The fractions containing product were collected and concentrated by rotary evaporation to a fford the compound. In most cases, the product was visualized on TLC using the cerium ammonium molybdate (CAM) stain. O H O H H [1R-(l ;5 ,6 ]-6-Phenyl-3-oxabicyclo[3.1.0]hexan-2-one ( 10a ) was obtained using the general procedure in 70 % yield (24.3 mg). [ ]20 D = 61 (c = 2.05, CHCl3, 66%ee). Configuration drawn is based upon optical ro tation and comparison with literature.40b 1H NMR (400 MHz, CDC13): 7.31-7.21 (m, 3H), 7.05-7.04 (m, 2H), 4.45 (dd, J = 4.8, 9.6 Hz, 1H), 4.39 (d, J = 9.6 Hz, 1H), 2.53-2.49 (m, 1H), 2.33-2.30 (m, 2H). 13C NMR (100 MHz, CDC13): 174.9, 137.1, 128.7, 127.1, 125.9, 69.69, 29.34, 27.36, 26.12. IR (neat, cm-1): 2923 (C-H), 2852 (C-H), 1740 (C=O). HRMS (ESI): Calcd. for C11H11O2

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71 ([M+H]+) m/z 175.0759, Found 175.0765. GC/MS: Chiralde x G-TA (initial temperature: 150 oC; isothermal for 34 mins; temperature increased 5.0 oC per min to a final temperature of 180 oC): 72%ee; 19.7 min (major) 21.8 min (minor). [1R-(l ;5 ,6 ]-6para Methylphenyl-3-oxabicyclo[3.1.0]hexan-2-one ( 10b ) was obtained using the general proce dure in 95% yield (35.9 mg). [ ]20 D = 66 (c = 3.5, CHCl3). Configuration drawn by analogy based upon optical rotation with known compounds in literature.40b 1H NMR (400 MHz, CDC13): 7.11 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 4.45 (dd, J = 4.8, 9.6 Hz, 1H), 4.40 (d, J = 9.6 Hz, 1H), 2.51-2.48 (m, 1H), 2.32 (s, 3H), 2.30-2.29 (m, 2H). 13C NMR (100 MHz, CDC13): 175.1, 136.8, 134.1, 129.3, 125.8, 69.69, 29.12, 27.24, 25.94, 20.93. IR (neat, cm-1): 2979 (C-H), 2848 (C-H), 1766 (C=O). HRMS (ESI): Calcd. for C12H13O2 ([M+H]+) m/z 189.0915, Found 189.0919. GC/MS: Chiraldex G-TA (initial temperature: 150 oC; isothermal for 60 mins; temperature increased 4.0 oC per min to a final temperature of 180 oC; isothermal for 30 mins): 84%ee; 30.6 min (major) 33.2 min (minor). O H O H H [1R-(l ;5 ,6 ]-6ortho Methylphenyl-3-oxabicyclo[3.1.0]hexan-2-one ( 10c ) was obtained using the general proce dure in 94% yield (35.2 mg). [ ]20 D = 24 (c = 1.16, CHCl3). Configuration drawn by analogy based upon optical rotation with known

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72 compounds in literature.40b 1H NMR (400 MHz, CDC13): 7.19-7.13 (m, 3H), 6.95 (d, J = 6.8 Hz, 1H), 4.48 (dd, J = 4.8, 9.6 Hz, 1H), 4.43 (d, J = 9.6 Hz, 1H), 2.58-2.54 (m, 1H), 2.43 (s, 3H), 2.35-2.33 (m, 1H), 2.31-2.29 (m, 1H). 13C NMR (100 MHz, CDC13): 175.2, 137.5, 134.7, 130.2, 127.3, 126.1, 125.4, 69.68, 27.62, 25.99, 24.59, 19.55. IR (neat, cm-1): 2979 (C-H), 2904 (C-H), 1766 (C=O). HRMS (ESI): Calcd. for C12H13O2 ([M+H]+) m/z 189.0915, Found 189.0905. GC/MS: Chiralde x G-TA (initial temperature: 150 oC; isothermal for 60 mins; temperature increased 4.0 oC per min to a final temperature of 180 oC; isothermal for 30 mins): 78%ee; 25.0 min (major) and 26.9 min (minor). O H O H H t Bu [1R-(l ;5 ,6 ]-6para t-Butylphenyl-3-oxabicyclo[3.1.0]hexan-2-one ( 10d ) was obtained using the general proce dure in 76% yield (35.2 mg). [ ]20 D = 21 (c = 3.5, CHCl3). Configuration drawn by analogy based upon optical rotation with known compounds in literature.40b 1H NMR (400 MHz, CDC13): 7.33 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 4.45 (dd, J = 4.8, 9.6 Hz, 1H), 4.40 (d, J = 9.6 Hz, 1H), 2.532.49 (m, 1H), 2.33-2.31 (m, 2H), 1.30 (s, 9H). 13C NMR (100 MHz, CDC13): 175.3, 150.5, 134.4, 126.0, 125.9, 70.00, 34.76, 31.51, 29.38, 27.54, 26.29. IR (neat, cm-1): 2964 (C-H), 2868 (C-H), 1746 (C=O). HRMS (ESI): Calcd. for C15H19O2 ([M+H]+) m/z 231.1385, Found 231.1389. GC/MS: Chiraldex GTA (initial temperature: 150 oC;

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73 isothermal for 60 mins; temperature increased 4.0 oC per min to a final temperature of 180 oC; isothermal for 30 mins): 26%ee; 68.0 min (major) and 69.4 min (minor). [1R-(l ;5 ,6 ]-6para Methoxyphenyl-3-oxabicyclo[3.1.0]hexan-2-one ( 10e ) was obtained using the general proce dure in 88% yield (36.1 mg). [ ]20 D = 62 (c = 0.72, CHCl3). Configuration drawn by analogy based upon optical rotation with known compounds in literature.40b 1H NMR (400 MHz, CDC13): 7.00 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 4.45 (dd, J = 4.4, 9.6 Hz, 1H), 4.39 (d, J = 9.6 Hz, 1H), 2.492.46 (m, 1H), 2.29-2.25 (m, 2H). 13C NMR (100 MHz, CDC13): 175.1, 158.7, 129.0, 127.1, 114.1, 69.69, 55.29, 28.91, 27.18, 25.72. IR (neat, cm-1): 2927 (C-H), 2851 (C-H), 1760 (C=O). HRMS (ESI): Calcd. for C12H13O3 ([M+H]+) m/z 205.0864, Found 205.0868. GC/MS: Chiraldex G-TA (initial temperature: 150 oC; isothermal for 60 mins; temperature increased 4.0 oC per min to a final temperature of 180 oC; isothermal for 30 mins): 70%ee; 66.1 min (major) and 67.8 min (minor). O H O H H B r [1R-(l ;5 ,6 ]-6para Bromophenyl-3-oxabicyclo[3.1.0]hexan-2-one ( 10f ) was obtained using the general proce dure in 84% yield (42.3 mg). [ ]20 D = 54 (c = 0.70,

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74 CHCl3). Configuration drawn by analogy based upon optical rotation with known compounds in literature.40b 1H NMR (400 MHz, CDC13): 7.42 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.4 Hz, 2H), 4.45 (dd, J = 4.8, 9.6 Hz, 1H), 4.40 (d, J = 9.6 Hz, 1H), 2.522.48 (m, 1H), 2.31-2.26 (m, 2H). 13C NMR (100 MHz, CDC13): 174.5, 136.2, 131.8, 127.6, 120.9, 69.58, 28.69, 27.23, 26.09. IR (neat, cm-1): 2922 (C-H), 2852 (C-H), 1743 (C=O). HRMS (ESI): Calcd. for C11H10BrO2 ([M+H]+) m/z 252.9864, Found 252.9869. GC/MS: Chiraldex G-TA (i nitial temperature: 150 oC; isothermal for 60 mins; temperature increased 4.0 oC per min to a final temperature of 180 oC; isothermal for 30 mins): 83%ee; 75.9 min (major) and 79.3 min (minor). O H O H H O [1S-(l ;5 ,6 ]-6-Furyl-3-oxabicyclo[3.1.0]hexan-2-one ( 10g ) was obtained using the general procedure in 77 % yield (25.3 mg). [ ]20 D = 85 (c = 0.36, CHCl3). Configuration drawn by analogy based upon optical rotati on with known compounds in literature.40b 1H NMR (400 MHz, CDC13): 7.25 (d, J = 1.2 Hz, 1H), 6.29-6.27 (m, 1H), 6.12 (d, J = 3.2 Hz, 1H), 4.42 (dd, J = 4.8, 9.6 Hz, 1H), 4.36 (d, J = 9.6 Hz, 1H), 2.63-2.60 (m, 1H), 2.422.40 (m, 1H), 2.34-2.32 (m, 1H). 13C NMR (100 MHz, CDC13): 174.4, 149.9, 141.7, 110.6, 106.3, 69.28, 25.15, 24.03, 22.73. IR (neat, cm-1): 2979 (C-H), 2910 (C-H), 1762 (C=O). HRMS (ESI): Calcd. for C9H9O3 ([M+H]+) m/z 165.0551, Found 165.0549. GC/MS: Chiraldex G-TA (i nitial temperature: 150 oC; isothermal for 60 mins; temperature increased 4.0 oC per min to a final temperature of 180 oC): 63%ee; 8.8 min (major) and 9.8 min (minor).

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75O O H H (1S,5R,6R)-6-methyl-6-phenyl-3oxabicyclo[3.1.0]hexan-2-one ( 10h ) was obtained using the general procedure in 86% yield (32.5 mg). [ ]20 D = 71 (c = 0.46, CHCl3). Configuration drawn by analogy based upon opt ical rotation with known compounds in literature.40b 1H NMR (400 MHz, CDC13): 7.33-7.21 (m, 5H), 4.51 (dd, J = 5.2, 10.0 Hz, 1H), 4.34 (d, J = 10.0 Hz, 1H), 2.53-2.50 (m, 1H), 2.44-2.43 (m, 1H), 1.46 (s, 3H). 13C NMR (100 MHz, CDC13): 174.4, 143.3, 128.7, 127.2, 127.1, 66.54, 31.02, 30.63, 29.32, 15.59. IR (neat, cm-1): 2980 (C-H), 2902 (C-H), 1762 (C=O). HRMS (ESI): Calcd. for C12H13O2 ([M+H]+) m/z 189.0916, Found 189.0922. GC/MS: Chiraldex G-TA (initial temperature: 150 oC; isothermal for 60 mins; temperature increased 4.0 oC per min to a final temperature of 180 oC; isothermal for 30 mins): 79%ee; 16.9 min (minor) and 18.0 min (major). O O H H (1S,5R)-6,6-Dimethyl-3-oxab icyclo[3.1.0]hexan-2-one ( 10i ) was obtained using the general procedure in 35 % yield (9.0 mg). [ ]20 D = 67 (c = 0.15, CHCl3). Configuration drawn is based upon optical rotation and comparison with literature.40b 1H NMR (400 MHz, CDC13): 4.35 (dd, J = 5.6, 10.0 Hz, 1H), 4.15 (d, J = 10.0 Hz, 1H), 2.05-2.02 (m, 1H), 1.95-1.94 (m, 1H), 1.18 (s, 3H), 1.17 (s, 3H). 13C NMR (100 MHz, CDC13): 174.9, 66.52, 30.49, 30.02, 25.20, 14.40. IR (neat, cm-1): 2980 (C-H), 2902 (C-H), 1766

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76 (C=O). HRMS (ESI): Calcd. for C9H9O3 ([M+H]+) m/z 127.0759, Found 127.0748. GC/MS: Chiraldex G-TA (i nitial temperature: 150 oC; isothermal for 3 mins; temperature increased 5.0 oC per min to a final temperature of 180 oC; isothermal for 11 mins): 90%ee; 20.9 min (minor) and 22.3 min (major). 6.3. Supporting Information for Chapter 3 An oven dried Schlenk tube, that was previously evacuated and backfilled with nitrogen gas, was charged with succinimi dyl diazoacetate (0.37 mmol), catalyst (0.0125 mmol). The Schlenk tube was then evacuated and back filled with nitrogen. The Teflon screw cap was replaced with a rubber septum and 0.2 ml portion of solvent was added followed by styrene (0.25 mmol), and the rema ining solvent (total 1 mL). The Schlenk tube was then purged with nitrogen for 1 mi nute and the rubber septum was replaced with a Teflon screw cap. The Schlenk tube was then placed in an oil bath for the desired time and temperature. Following completion of th e reaction, the reaction mixture was purified by flash chromatography (hexanes:ethyl acetat e = 1:1). The fracti ons containing product were collected and concentrated by rotary evaporation to afford the compound. In most cases, the product was visual ized on TLC using the cerium ammonium molybdate (CAM) stain. 2,5-dioxopyrrolidin-1-yl 2-phe nylcyclopropanecarboxylate ( 56a ) was obtained using the general procedure in 86% yield (56.0 mg). [ ]20 D = -235 (c = 0.83, CHCl3). 1H NMR (400 MHz, CDC13): 7.31-7.22 (m, 3H), 7.13-7.11 (m, 2H), 2.82 (bs, 4H), 2.75-2.70 (m,

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77 1H), 2.15-2.11 (m, 1H), 1.80-1.75 (m, 1H), 1.61-1.56 (m, 1H). 13C NMR (100 MHz, CDC13): 169.0, 168.7, 138.3, 128.6, 127.1, 126.3, 28.23, 25.57, 20.87, 18.37. IR (neat, cm-1): 2980 (C-H), 2890 (C-H), 1800 (C=O), 1773 (C=O), 1732 (C=O). HRMS (ESI): Calcd. for C14H13NO4Na ([M+Na]+) m/z 282.07368, Found 282.07304. HPLC Chiralcel OD-H (80 hexanes:20 isopropanol @ 0.8 ml/min): 92%ee; 25 min (minor) and 29 min (major). 2,5-dioxopyrrolidin-1-yl 2-p-tolylcyclopropanecarboxylate ( 56b ) was obtained using the general procedure in 90% yield (61.7 mg). [ ]20 D = -296 (c = 1.00, CHCl3). 1H NMR (400 MHz, CDC13): 7.11 (d, J = 7.8 Hz, 2H), 7.03 (d, J = 7.8 Hz, 2H), 2.82 (bs, 4H), 2.74-2.69 (m, 1H), 2.32 (s, 3H), 2.12-2.08 (m, 1H), 1.78-1.73 (m, 1H), 1.59-1.54 (m, 1H). 13C NMR (100 MHz, CDC13): 169.1, 168.7, 136.7, 135.2, 129.2, 126.2, 28.03, 25.53, 20.78, 20.77, 18.23. IR (neat, cm-1): 2924 (C-H), 1783 (C=O), 1735 (C=O). HRMS (ESI): Calcd. for C15H19N2O4 ([M+NH4]+) m/z 291.13393, Found 291.13339. HPLC Chiralcel OD-H (80 hexanes:20 is opropanol @ 0.8 ml/min): 95%ee; 20 min (minor) and 26 min (major).

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78 The X-ray intensities were measured using Bruker-APEX2 area-detector CCD diffractometer (CuKa, = 1.54178 ). Indexing was performed using APEX2. Frames were integrated with SAINT V7.51A software package. Absorption correction was performed by multi-scan method implemented in SADABS. The structure was solved using SHELXS-97 and refined using SHELXL-97 contained in SHELXTL v6.10 and WinGX v1.70.01 programs packages.The X-ray Crystal data and refinement conditions are shown in Table 6.1. Table 6.1 Crystal data and structure refinement for 56b Empirical formula C15 H15 N O4 Formula weight 273.28 Temperature 296(2) K Wavelength 1.54178 Crystal system Orthorhombic Space group P2(1)2(1)2(1) Unit cell dimensions a = 5.8676(2) = 90. b = 8.9556(3) = 90. c = 27.5262(8) = 90. Volume 1446.44(8) 3 Z 4 Density (calculated) 1.255 Mg/m3 Absorption coefficient 0.760 mm-1 F(000) 576 Crystal size 0.35 x 0.20 x 0.08 mm3 Theta range for data coll ection 3.21 to 67.78. Index ranges -6<=h<=6, -9<=k<=10, -33<=l<=31 Reflections collected 9269 Independent reflections 1501 [R(int) = 0.0274] Completeness to theta = 67.78 96.3 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.9417 and 0.7769 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 1501 / 0 / 182 Goodness-of-fit on F2 1.084 Final R indices [I>2sigma(I)] R1 = 0.0392, wR2 = 0.1048 R indices (all data) R1 = 0.0520, wR2 = 0.1103 Absolute structure parameter 10(10) Largest diff. peak and hole 0.102 and -0.144 e.-3

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79 N O O O O t -Bu 2,5-dioxopyrrolidin-1-yl 2 -(4-tert-butylphenyl)cy clopropanecarboxylate ( 56c ) was obtained using the general proce dure in 80% yield (62.8 mg). [ ]20 D = -269 (c = 0.59, CHCl3). 1H NMR (400 MHz, CDC13): 7.34 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 2.83 (bs, 4H), 2.74-2.70 (m, 1H), 2.15-2.11 (m, 1H), 1.80-1.75 (m, 1H), 1.62-1.57 (m, 1H), 1.31 (s, 9H). 13C NMR (100 MHz, CDC13): 169.0, 168.7, 150.1, 135.3, 126.0, 125.5, 34.43, 31.26, 27.97, 25.53, 20.84, 18.25. IR (neat, cm-1): 2980 (C-H), 1800 (C=O), 1771 (C=O), 1733 (C=O). HRMS (ESI): Calcd. for C18H21NO4 ([M+Na]+) m/z 338.13628, Found 338.13648. HPLC: Chiralcel OD-H (95 hexanes:5 isopropanol @ 0.8 ml/min): 97%ee; 45 min (minor) and 50 min (major). N O O O O MeO 2,5-dioxopyrrolidin-1-yl 2-(4-methoxyphenyl)cycl opropanecarboxylate ( 56d ) was obtained using the general proce dure in 71% yield (51.8 mg). [ ]20 D = -300 (c = 0.59, CHCl3). 1H NMR (400 MHz, CDC13): 7.07 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 3.79 (s, 3H), 2.81 (bs, 4H), 2.73-2.68 (m, 1H), 2.08-2.04 (m, 1H), 1.77-1.72 (m, 1H), 1.57-1.52 (m, 1H). 13C NMR (100 MHz, CDC13): 169.1, 168.8, 158.7, 130.2, 127.6, 114.0, 55.29, 27.81, 25.54, 20.66, 18.08. IR (neat, cm-1): 1804 (C=O), 1775 (C=O), 1732 (C=O). HRMS (ESI): Calcd. for C15H19N2O5 ([M+NH4]+) m/z 307.12885,

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80 Found 307.12795. HPLC: Chiralcel OD-H (80 he xanes:20 isopropanol @ 0.8 ml/min): 95%ee; 27 min (minor) and 36 min (major). N O O O O Cl 2,5-dioxopyrrolidin-1-yl 2-(4-chlor ophenyl)cyclopropanecarboxylate ( 56e ) was obtained using the general proce dure in 66% yield (48.9 mg). [ ]20 D = -279 (c = 0.40, CHCl3). 1H NMR (400 MHz, CDC13): 7.25 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.0 Hz, 2H), 2.81 (bs, 4H), 2.71-2.66 (m, 1H), 2.11-2.07 (m, 1H), 1.79-1.74 (m, 1H), 1.56-1.51 (m, 1H). 13C NMR (100 MHz, CDC13): 169.0, 169.4, 136.8, 132.8, 128.7, 127.7, 27.47, 25.54, 20.85, 18.22. IR (neat, cm-1): 2980 (C-H), 2890 (C-H), 1802 (C=O), 1773 (C=O), 1730 (C=O). HRMS (ESI): Calcd. for C14H12ClNO4Na ([M+Na]+) m/z 316.03471, Found 316.03380. HPLC: Chiralcel ODH (80 hexanes:20 isopropanol @ 0.8 ml/min): 90%ee; 25 min (minor) and 32 min (major). N O O O O F3C 2,5-dioxopyrrolidin-1-yl 2-(4 -(trifluoromethyl)phenyl) cyclopropanecarboxylate ( 56f ) was obtained using the general proce dure in 77% yield (63.6 mg). [ ]20 D = -226 (c = 0.78, CHCl3). 1H NMR (400 MHz, CDC13): 7.54 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 2.81 (bs, 4H), 2.78-2.73 (m, 1H ), 2.19-2.15 (m, 1H), 1.84-1.79 (m, 1H), 1.621.57 (m, 1H). 13C NMR (100 MHz, CDC13): 169.0, 168.3, 142.4, 129.5, 126.6, 125.58,

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81 125.54. 27.52, 25.53, 21.07, 18.41. 19F NMR (376 MHz, CDC13): -62.96. IR (neat, cm-1): 2978 (C-H), 2892 (C-H), 1802 (C=O), 1778 (C=O), 1737 (C=O). HRMS (ESI): Calcd. for C15H16F3N2O4 ([M+NH4]+) m/z 345.10567, Found 345.10450. HPLC: Chiralcel OD-H (80 hexanes:20 isopropanol @ 0.8 ml/min): 90%ee; 22 min (minor) and 26 min (major). N O O O O A cO 2,5-dioxopyrrolidin-1-yl 2-(4-acetoxyphenyl)cy clopropanecarboxylate ( 56g ) was obtained using the general proce dure in 71% yield (56.8 mg). [ ]20 D = -224 (c = 0.45, CHCl3). 1H NMR (400 MHz, CDC13): 7.16 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.4 Hz, 2H), 2.83 (bs, 4H), 2.76-2.71 (m, 1H), 2.29 (s, 3H), 2.14-2.08 (m, 1H), 1.80-1.76 (m, 1H), 1.59-1.55 (m, 1H). 13C NMR (100 MHz, CDC13): 169.4, 169.0, 168.6, 149.6, 135.8, 127.5, 121.7, 27.67, 25.55, 21.06, 20.81, 18.26. IR (neat, cm-1): 2963 (C-H), 1768 (C=O), 1735 (C=O). HRMS (ESI): Calcd. for C16H16NO6 ([M+H]+) m/z 318.09721, Found 318.09737. HPLC: Chiralcel OD-H (80 he xanes:20 isopropanol @ 0.8 ml/min): 91%ee; 45 min (minor) and 57 min (major). N O O O O O2N 2,5-dioxopyrrolidin-1-yl 2-(3-nitro phenyl)cyclopropanecarboxylate ( 56h ) was obtained using the general proce dure in 50% yield (38.3 mg). [ ]20 D = -150 (c = 0.19, CHCl3). 1H NMR (400 MHz, CDC13): 8.11-8.09 (m, 1H), 7.97 (s, 1H), 7.51-7.47 (m,

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82 2H), 2.85-2.80 (m, 5H), 2.26-2.21 (m, 1H), 1.90-1.85 (m, 1H), 1.62-1.63 (m, 1H). 13C NMR (100 MHz, CDC13): 168.9, 168.1, 148.4, 140.5, 132.9, 129.6, 122.1, 121.0, 27.13, 25.54, 21.11, 18.33. IR (neat, cm-1): 1808 (C=O), 1775 (C=O), 1731 (C=O), 1528 (NO2), 1350 (NO2). HRMS (ESI): Calcd. for C14H16N3O6 ([M+NH4]+) m/z 322.10336, Found 322.10345. HPLC: Chiralcel AD-H (80 he xanes:20 isopropanol @ 0.8 ml/min): 92%ee; 40 min (minor) and 47 min (major). N O O O O 2,5-dioxopyrrolidin-1-yl 2-(naphthalen-2-yl)cyclopropanecarboxylate ( 56i ) was obtained using the general proce dure in 33% yield (25.6 mg). [ ]20 D = -286 (c = 1.06, CHCl3). 1H NMR (400 MHz, CDC13): 7.81-7.76 (m, 3H), 7.61 (s, 1H), 7.49-7.42 (m, 2H), 7.24-7.22 (m, 1H), 2.94-2.89 (m, 1H), 2.83 (bs, 4H), 2.26-2.22 (m, 1H), 1.88-1.83 (m, 1H), 1.74-1.69 (m, 1H). 13C NMR (100 MHz, CDC13): 169.1, 168.7, 135.6, 133.2, 132.5, 128.4, 127.6, 127.5, 126.4, 125.8, 125.2, 124.4, 28.48, 25.56, 20.82, 18.27. IR (neat, cm-1): 2980 (C-H), 1802 (C=O), 1774 (C=O), 1739 (C=O). HRMS (ESI): Calcd. for C18H19N2O4 ([M+NH4]+) m/z 327.13393, Found 327.13379. HPLC: Chiralcel AD-H (80 hexanes:20 isopropanol @ 0.8 ml/min): 91%ee; trans : 59 min (minor) and 92 min (major).

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83O N O O O O EtO 1-(2,5-dioxopyrrolidin-1-yl) 2-ethy l cyclopropane-1,2-dicarboxylate ( 56j ) was obtained using the general proce dure in 57% yield (36.6 mg). [ ]20 D = -235 (c = 0.08, CHCl3). [ ]20 D = -90 (c = 3.8 mg/mL, CHCl3). 1H NMR (400 MHz, CDC13): 4.17 (q, J = 7.2 Hz, 2H), 2.82 (bs, 4H), 2.45-2.41 (m 1H), 2.37-2.33 (m, 1H), 1.67-1.57 (m, 2H), 1.28 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDC13): 170.5, 168.8, 167.5, 61.53, 25.50, 23.71, 19.05, 16.69, 14.07. IR (neat, cm-1): 2984 (C-H), 1781 (C=O), 1727 (C=O). HRMS (ESI): Calcd. for C11H14NO6 ([M+H]+) m/z 256.08156, Found 256.08129. HPLC: Chiralcel AD-H (80 hexane s:20 isopropanol @ 0.8 ml/min): 89%ee; 13 min (minor) and 16 min (major). O N O O O O N 2,5-dioxopyrrolidin-1-yl 2-(dimethylc arbamoyl)cyclopropanecarboxylate ( 56k ) was obtained using the general proce dure in 52% yield (33.4 mg). [ ]20 D = -101 (c = 0.16, CHCl3). 1H NMR (400 MHz, CDC13): 3.17 (s, 3H), 2.97 (s, 3H), 2.82 (bs, 4H), 2.512.47 (m, 1H), 2.45-2.40 (m, 1H), 1.70-1.65 (m, 1H), 1.56-1.51 9m, 1H). 13C NMR (100 MHz, CDC13): 168.9, 168.6, 168.4, 37.27, 35.96, 25.52, 22.66, 18.77, 16.31. IR (neat, cm-1): 2924 (C-H), 2854 (C-H), 1782 (C=O), 1740 (C=O), 1637 (C=O). HRMS (ESI): Calcd. for C11H18N3O5 ([M+NH4]+) m/z 272.12410, Found 272.12386. HPLC: Chiralcel

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84 AD-H (80 hexanes:20 isopropanol @ 0.8 ml/min): 96%ee; 19 min (minor) and 36 min (major). O N O O O O 2,5-dioxopyrrolidin-1-yl 2-acetylcyclopropanecarboxylate ( 56l ) was obtained using the general procedure in 55% yield (31.1 mg). [ ]20 D = -231 (c = 0.25, CHCl3). 1H NMR (400 MHz, CDC13): 2.81 (bs, 4H), 2.65-2.60 (m, 1H), 2.45-2.41 (m, 1H), 2.35 (s, 3H), 1.60-1.56 (m, 2H). 13C NMR (100 MHz, CDC13): 203.9, 168.8, 167.6, 30.99, 30.37, 25.51, 20.63, 18.30. IR (neat, cm-1): 2924 (C-H), 1780 (C=O), 1735 (C=O), 1704 (C=O). HRMS (ESI): Calcd. for C10H11NO5Na ([M+Na]+) m/z 248.05294, Found 248.05239. HPLC: Chiralcel AD-H (80 hexanes:20 is opropanol @ 0.8 ml/min): 91%ee; 22 min (minor) and 39 min (major). N-hexyl-2-phenylcyclopropanecarboxamide ( 57a ) was obtained in 92% yield (29.1 mg). [ ]20 D = -242 (c = 0.49, CHCl3). 1H NMR (400 MHz, CDC13): 7.25-7.22 (m, 2H), 7.17-7.15 (m, 1H), 7.06-7.04 (m, 2H), 5.65 (bs, 1H), 3.26-3.22 (m, 2H), 2.45-2.43 (m, 1H), 1.58-1.51 (m, 2H), 1.47-1.45 (m, 2H), 1.26 (bs, 6H), 1.21-1.18 (m, 1H), 0.85 (m, 3H). 13C NMR (100 MHz, CDC13): 171.6, 140.9, 128.4, 126.1, 125.9, 39.86, 31.44, 29.64, 26.81, 26.57, 24.85, 22.51, 15.80, 13.97. IR (neat, cm-1): 3295 (N-H), 2956 (C-H), 2925 (C-H), 2857 (C-H), 1634 (C=O ). HRMS (ESI): Calcd. for C16H24NO

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85 ([M+H]+) m/z 246.1858, Found 246.1860. HPLC Ch iralcel AD-H (80 hexanes:20 isopropanol @ 0.8 ml/min): 90%ee; 6 min (minor) and 8 min (major). N-(4-methoxyphenyl)-2-phe nylcyclopropanecarboxamide ( 57b ) was obtained in 62% yield (27.4 mg). [ ]20 D = -252 (c = 0.54, CHCl3). 1H NMR (400 MHz, CDC13): 7.39 (d, J = 8.0 Hz, 2H), 7.34 (bs, 1H), 7.29-7.24 (m, 2H), 7.20-7.19 (m, 1H), 7.09 (d, J = 7.6 Hz, 2H), 6.82 (d, J = 7.6 Hz, 2H), 3.76 (s, 3H), 2. 55-2.54 (m, 1H), 1.70-1.68 (m, 2H), 1.32-1.30 (m, 1H). 13C NMR (100 MHz, CDC13): 170.2, 156.5, 140.8, 131.3, 128.7, 126.5, 126.2, 121.8, 114.3, 55.69, 27.74, 25.90, 16.46. IR (neat, cm-1): 3274 (N-H), 2980 (C-H), 1643 (C=O). HRMS (ESI): Calcd. for C17H18NO2 ([M+H]+) m/z 268.1337, Found 268.1337. HPLC Chiralcel AD-H (90 hexanes: 10 isopropanol @ 1.0 ml/min): 89%ee; 16 min (major) and 28 min (minor). 2-phenylcyclopropanecarboxamide ( 57c ) was obtained in 93% yield (29.6 mg). [ ]20 D = -290 (c = 0.14, CHCl3). 1H NMR (400 MHz, CDC13): 7.25-7.22 (m, 2H), 7.19-7.16 (m, 1H), 7.08-7.05 (m, 2H), 5.82-5.71 (bd, 2H), 2.49-2.45 (m, 1H), 1.68-1.61 (m, 1H), 1.60-1.56 (m, 1H), 1.27-1.23 (m, 1H). 13C NMR (100 MHz, CDC13): 174.1, 140.5, 128.4, 126.3, 126.0, 25.83, 25.66, 16.29. IR (neat, cm-1): 3382 (N-H), 3201 (N-H), 2922

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86 (C-H), 1647 (C=O). HRMS (ESI): Calcd. for C10H12NO ([M+H]+) m/z 162.09134, Found 162.09066. HPLC Chiralcel OD-H (80 he xanes:20 isopropanol @ 0.8 ml/min): 94%ee; 8 min (major) and 10 min (minor). (2-phenylcyclopropyl)(pyrrolidin-1-yl)methanone ( 57d ) was obtained in 91% yield (32.4 mg). [ ]20 D = -376 (c = 0.30, CHCl3). 1H NMR (400 MHz, CDC13): 7.27-7.23 (m, 2H), 7.18-7.14 (m, 1H), 7.11-7.09 (m, 2H), 3.61-3.53 (m, 2H), 3.48 (t, J = 6.8 Hz, 2H), 2.52-2.47 (m, 1H), 1.97 -1.81 (m, 5H), 1.65-1.61 (m, 1H), 1.25-1.21 (m, 1H). 13C NMR (100 MHz, CDC13): 170.4, 141.2, 128.3, 126.1 (2 Ar), 46.58, 46.01, 25.99, 25.39, 24.58, 24.40, 16.26. IR (neat, cm-1): 2979 (C-H), 2873 (C-H), 1607 (C=O). HRMS (ESI): Calcd. for C14H18NO ([M+H]+) m/z 216.13829, Found 216.13775. HPLC Chiralcel OD-H (80 hexanes:20 isopropanol @ 0.8 ml/min): 92%ee; 7 min (minor) and 8 min (major). morpholino(2-phenylcyclopropyl)methanone ( 57e ) was obtained in 95% yield (40.9 mg). [ ]20 D = -178 (c = 0.48, CHCl3). 1H NMR (400 MHz, CDC13): 7.28-7.25 (m, 2H), 7.20-7.16 (m, 1H), 7.10-7.08 (m, 2H), 3.66-3.61 (m, 8H), 2.50-2.45 (m, 1H), 1.93-1.89 (m, 1H), 1.69-1.63 (m, 1H), 1.30-1.24 (m, 1H). 13C NMR (100 MHz, CDC13): 170.6,

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87 140.7, 128.4, 126.3, 125.9, 66.78 (2 C), 45.95, 42.53, 25.52, 22.91, 16.15. IR (neat, cm1): 2980 (C-H), 2890 (C-H), 1632 (C=O). HRMS (ESI): Calcd. for C14H18NO2 ([M+H]+) m/z 232.13321, Found 232.13339. HPLC Chiralcel OD-H (80 hexanes:20 isopropanol @ 0.8 ml/min): 92%ee; 11 min (minor) and 17 min (major). (2S)-methyl 3-phenyl-2-(2-phenylcyclopropanecarboxamido)propanoate ( 57f ) was obtained in 66% yield (17.3 mg). [ ]20 D = -46 (c = 0.34, CHCl3). 1H NMR (400 MHz, CDC13): 7.29-7.17 (m, 6H), 7.08-7.06 (m, 4H), 6.10 (d, J = 7.6 Hz, 1H), 4.94-4.89 (m, 1H), 3.71 (s, 3H), 3.18-3.06 (m, 2H), 2.48-2.43 (m, 1H), 1.60-1.57 (m, 2H), 1.26-1.22 (m, 1H). 13C NMR (100 MHz, CDC13): 172.1, 171.4, 140.5, 135.7, 129.2, 128.5, 128.4, 127.1, 126.3, 126.1, 53.28, 52.30, 37.99, 26.38, 25.41, 15.82. IR (neat, cm-1): 3312 (N-H), 3033 (C-H), 2950 (C-H), 1741 (C=O ), 1639 (C=O). HRMS (ESI): Calcd. for C20H22NO3 ({M+H]+) m/z 324.1599, Found 324.1597. N-((S)-1-hydroxy-3-phenylpropan-2-yl )-2-phenylcyclopropanecarboxamide ( 57g ) was obtained in 93% yield (20.8 mg). [ ]20 D = -161 (c = 0.40, CHCl3). 1H NMR (400 MHz, CDC13): 7.29-7.16 (m, 8H), 7.05-7.03 (m, 2H), 6.00 (d, J = 28.8 Hz, 1H), 4.19-

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88 4.17 (m, 1H), 3.68-3.66 (m, 1H), 3.59-3.55 (m, 1H), 2.91 (bs, 1H), 2.86 (d, J = 7.2 Hz, 2H), 2.45-2.40 (m, 1H), 1.60-1.53 (m, 2H), 1.24-1.18 (m, 1H). 13C NMR (100 MHz, CDC13): 172.5, 140.5, 137.5, 129.2, 128.6, 128.4, 126.6, 126.2, 126.0, 64.01, 53.14, 37.07, 26.63, 25.16, 15.94. IR (neat, cm-1): 3284 (O-H, N-H), 2954 (C-H), 1633 (C=O). HRMS (ESI): Calcd. for C19H22NO2 ([M+H]+) m/z 296.1650, Found 296.1645. N-((R)-1-hydroxy-3-methylbutan-2-yl) -2-phenylcyclopropanecarboxamide ( 57h ) was obtained in 54% yield (11.2 mg). [ ]20 D = -156 (c = 0.22, CHCl3). 1H NMR (400 MHz, CDC13): 7.27-7.23 (m, 2H), 7.19-7.17 (m, 1H), 7.07-7.05 (m, 2H), 5.87 (d, J = 7.2 Hz, 1H), 3.74-3.72 (m, 1H), 3.65-3.64 (m, 2H), 2.78 (bs, 1H), 2.47-2.44 (m ,1H), 1.63-1.60 (m, 2H), 1.24-1.21 (m, 1H), 0.945 (m, 6H). 13C NMR (100 MHz, CDC13): 172.9, 140.7, 128.4, 126.2, 125.9, 64.21, 57.56, 29.13, 26.78, 25.21, 19.43, 18.75, 16.17. IR (neat, cm-1): 3287 (O-H, N-H), 2924 (C-H), 1637 (C=O). HRMS (ESI): Calcd. for C15H22NO2 ({M+H]+) m/z 248.1650, Found 248.1657. O OH OH H2N OH HO O OH OH NH HO HO O THF:H2O:Et3N (1:1:0.05) RT,1h + 2equiv N O O O O N-(2-phenylcyclopropanecarboxamido)-D-glucosamine ( 57i ) was obtained in 47 % yield (20.4 mg) as a mixture of anomers ( : = 1.6:1) as determined by HPLC. The product was purified by preparatory HPLC us ing a Dionex Summit HPLC equipped with the Supelcosil PLC-8 column (250 mm x 21.2 mm, 12 micron part icle size, C8) utilizing

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89 a gradient solvent system of acetonitrile in water (5% MeCN:H2O – 30% MeCN:H2O) with a flow rate of 20 ml/min. [ ]20 D = -51 (c = 0.78, DMSO). 1H NMR (400 MHz, DMSO) (anomeric mixture : = 2:1): 8.02 (d, J = 8.4 Hz, 1H, anomer), 7.95 (d, J = 8.0 Hz, 1H, anomer), 7.29-7.25 (m, 2H, anomeric mixture), 7.18-7.14 (m, 1H, anomeric mixture), 7.10-7.09 (m, 2H, anomeric mixture), 6.52 (d, J = 6.4 Hz, 1H, anomer), 6.41 (d, J = 4.4 Hz, 1H, anomer), 4.94-4.92 (m, 1H, mixture of anomers), 4.88 (d, J = 5.6 Hz, 1H, anomer), 4.85 (d, J = 5.6 Hz, 1H, anomer), 4.65 (d, J = 5.6 Hz, 1H, anomer), 4.50 (t, J = 5.6 Hz, 1H, anomer), 4.45-4.40 (m, 1H), 3.69-3.56 (m, 2H, anomeric mixture), 3.53-3.30 (m, 3H, anomeric mixture), 3.27 (m, 1H, anomer), 3.11 (m, 1H, anomer), 3.05 (m, 1H, anomeric mixture), 2.26-2.18 (m, 1H, anomeric mixture), 2.13-2.09 (m, 1H, anomer), 1.89-1.85 (m, 1H, anomer), 1.36-1.30 (m, 1H, anomeric mixture), 1.20-1.10 (m 1H, anomeric mixture). 13C NMR (100 MHz, DMSO) ( anomer): 171.1, 141.3, 128.3 (2), 125.8, 125.7 (2), 90.58, 72.05, 71.22, 70.50, 61.14, 54.47, 25.32, 23.83, 15.59. 13C NMR (100 MHz, DMSO) ( anomer): 171.13, 141.3, 128.3 (2), 125.8, 125.7 (2), 95.49, 76.77, 74.45, 70.88, 61.14, 57.39, 26.11, 23.83, 15.59. IR (neat, cm-1): 3285 (O-H, N-H), 1637 (C=O), 1613 (C=O), 1563 (C=C). HRMS (ESI): Calcd. for C16H22NO6 ([M+H]+) m/z 324.1447, Found 324.1469.

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90 Figure 6.1. Carbon Assignments for the and -Anomer of 57i 2-(2-(2-(2-phenylcyclopropanecarboxamid o)acetamido)acetamido)propanoic acid2 ( 57j ) was obtained in 60% yiel d (30.8 mg). The cyclopropyl peptide was purified by preparatory HPLC using a Dionex Summit HP LC equipped with the Waters Radial Compression column (300 mm x 25 mm, 15 mi cron particle size, 300 Angstrom pore size, C4) utilizing a gradient solvent sy stem of acetonitrile and water (5% MeCN/H20 – 50%MeCN/H20) with a flow rate of 20 ml/min. [ ]20 D = -185 (c = 0.19, IPA). 1H NMR (400 MHz, D2O): 7.24-7.20 (m, 2H), 7.157.12 (m, 1H), 7.09-7.08 (m, 2H), 4.24 (t, J = 7.6 Hz, 1H), 3.84-3.82 (m, 4H), 2.36-2.31 (m, 1H), 1.88-1.83 (m, 1H), 1.42-1.37 (m, 1H), 1.32-1.25 (m, 4 H). 13C NMR (100 MHz, D2O): 179.4, 178.9, 175.1, 173.7, 143.1, 131.4, 129.3, 128.8, 51.55, 45.67, 44.86, 28.26, 27.69, 18.95, 18.32. IR (neat, cm-1): 3303 (O-H, N-H), 2979 (C-H), 1651 (C=O), 1635 (C=O). HRMS (ESI): Calcd. for C17H22N3O5 ([M+H]+) m/z 348.1559, Found 348.1550.

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91 6.4. Supporting Information for Chapter 4 N NHN HN NH NH HN HN O O O O Porphyrin 7 (P7). An oven-dried Schlenk tube equipped with a st irring bar was degassed on vacuum line and purged with nitrogen. Th e tube was then charged with 5,15-Bis(2,6dibromophenyl)-10,20-bis[3,5-di( tert -butyl)phenyl]porphyrin1 ( 0.2 mmol, 1 eq), isobutylamide (3.2 mmol, 16 eq), Pd(OAc)2 (0.08 mmol, 40%), Xantphos (0.16 mmol, 80%), Cs2CO3 (3.2 mmol, 16 eq). The tube wa s capped with a Teflon screw cap, evacuated and backfilled with nitrogen. After the Teflon screw cap was replaced with a rubber septum, solvent (4-5 mL) was adde d via syringe. The tube was purged with nitrogen (1-2 min) and the septum was th en replaced with the Teflon screw cap and sealed. The reaction mixture was heated in an oil bath at 100 oC with stirring for 72 hours. The resulting reaction mixture was con centrated and the solid residue was purified by flash chromatography (hexanes : ethyl acetate, 7: 3) to af ford the compound as a purple solid (65 75%, in general). 1H NMR (400 MHz, CDC13): 8.97 (d, J = 4.4 Hz, 4H), 8.85 (d, J = 4.8 Hz, 4H), 8.48 (d, J = 7.6 Hz, 4H), 8.00 (s, 4H), 7.90-7.85 (m, 4H), 6.46 (s, 4H), 1.52 (s, 36H), 1.20 (m, 4H), 0.31 (d, J = 7.4 Hz, 24H), -2.53 (s, 2H). 13C NMR (125 MHz, CDC13): 174.7, 149.4, 139.7, 138.8, 133.5, 130.5, 130.1, 123.1, 121.8, 117.8, 108.0, 35.8, 35.0, 31.6, 18.5. UV–vis (CHCl3), max, nm (log ): 425(5.48), 519(4.19), 555(3.84), 595(3.70), 650(3.60). HRMS (ESI): Calcd. for C76H91N8O4 ([M+H]+) m/z 1179.71578, Found 1179.71870.

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92N N N N NH NH HN HN O O O O Co [Co(P7)] Porphyrin Complex Porphyrin 7 (0.054 mmol) and anhydrous CoCl2 (0.43 mmol) were placed in an oven-dried, re-seala ble Schlenk tube. The tube was capped with a Teflon screw-cap, evacuated, and backfilled with nitrogen. The screw cap was replaced with a rubber septum, 2,6-lutidine (0.25 mmol ) and dry THF (3-4 mL) were added via syringe. The tube was purged with nitrogen for 1-2 minutes, and then the septum was replaced with the Teflon screw cap. The tube was sealed, and its contents were heated in an oil bath at 80 oC with stirring overnight. The result ing mixture was cooled to room temperature, taken up in ethyl acetate, and tr ansferred to a separato ry funnel. The mixture was washed with water 3 times and concentrat ed. The solid residue was purified by flash chromatography (hexanes: ethyl acetate, 6: 4) to afford the compound as a purple solid (55.3 mg, 83% ). UV–vis (CHCl3), max, nm (log ): 415(5.23), 530(4.19). HRMS (ESI): Calcd. for C76H88N8O4Co ([M]+) m/z 1235.62550, Found 1235.62638. An oven dried Schlenk tube, that was previously evacuated and backfilled with nitrogen gas, was charged with azide (if so lid, 0.2 mmol), cataly st (0.004 mmol), and 4 MS (100 mg). The Schlenk tube was then ev acuated and back filled with nitrogen. The Teflon screw cap was replaced with a rubber septum and 0.2 ml portion of solvent was added followed by styrene (1.0 mmol), another po rtion of solvent, then azide (if liquid, 0.2 mmol), and the remaining solvent (total 1 mL). The Schlenk tube was then purged with nitrogen for 1 minute and the rubber septum was replaced with a Teflon screw cap.

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93 The Schlenk tube was then placed in an oil bath for the desired time and temperature. Following completion of the reaction, the reaction mixture was purified by flash chromatography. The fractions containing produ ct were collected and concentrated by rotary evaporation to afford the compound. N S O O 2-Phenyl-1-tosylaziridine ( 65aa ) was obtained using the gene ral procedure as colorless oil in 94% yield (51.4 mg). [ ]20 D = -71 (c = 0.35, CHCl3). 1H NMR (400 MHz, CDC13): 7.87 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 7.31-7.27 (m, 3H), 7.20 (m, 2H), 3.78 (dd, J = 7.2, 4.4 Hz, 1H), 2.98 (d, J = 7.2 Hz, 1H), 2.43 (s, 3H), 2.38 (d, J = 4.4 Hz, 1H). 13C NMR (125 MHz, CDC13): 144.5, 134.97, 134.91, 129.6, 128.4, 128.2, 127.8, 126.4, 40.94, 35.84, 21.55. IR (neat, cm-1): 2923, 2854, 1595, 1495, 1458, 1385, 1319, 1307, 1290, 1232, 1188, 1155, 1134, 1117, 1093, 1082, 907, 815, 799, 780, 754, 711, 696, 687, 662, 634. HRMS (ESI): Calcd. for C15H16NO2S ([M+H]+) m/z 274.08963, Found 274.08987. HPLC: Whelk-01 (98 hexanes:02 isopropanol @ 1.0 ml/min): 86%ee; 52 min (minor) and 62 min (major). N S O O OMe 1-(4-Methoxyphenylsulfonyl)-2-phenylaziridine ( 65ba ) was obtained using the general procedure as white solid in 88% yield (51.0 mg). [ ]20 D = -150 (c = 0.04, CHCl3). 1H NMR (400 MHz, CDC13): 7.92 (d, J = 8.8 Hz, 2H), 7.28 (m, 3H), 7.21 (m, 2H), 6.99 (d, J = 8.8 Hz, 2H), 3.74 (dd, J = 7.2, 4.0 Hz, 1H), 3.87 (s, 3H), 2.96 (d, J = 7.2 Hz, 1H),

PAGE 111

94 2.38 (d, J = 4.0 Hz, 1H). 13C NMR (125 MHz, CDC13): 163.6, 135.0, 130.0, 129.3, 128.4, 128.2, 126.4, 114.2, 55.6, 40.9, 35.8. IR (neat, cm-1): 2958, 2924, 2854, 1592, 1576, 1498, 1458, 1442, 1322, 1301, 1259, 1192, 1150, 1116, 1093, 1017, 908, 836, 805, 779, 755, 721, 691, 667, 629. HRMS (ESI): Calcd. for C15H16NO3S ([M+H]+) m/z 290.08454, Found 290.08488. HPLC: Whelk-01 (98 hexanes:02 isopropanol @ 1.0 ml/min): 88%ee; 98 min (minor) and 113 min (major). N S O O N H O N-(4-(2-Phenylaziridin-1-ylsulfonyl)phenyl)acetamide ( 65ca ) was obtained using the general procedure as tan solid in 98% yield (62.2 mg). 1H NMR (400 MHz, CDC13): 7.90 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.61 (bs, 1H), 7.27 (m, 3H), 7.20 (m, 2H), 3.76 (dd, J = 7.2, 4.4 Hz, 1H), 2.97 (d, J = 7.2 Hz, 1H), 2.39 (d, J = 4.4 Hz, 1H), 2.19 (s, 3H). 13C NMR (125 MHz, CDC13): 168.8, 142.9, 134.7, 132.0, 129.1, 128.5, 128.4, 126.4, 119.2, 41.1, 36.0, 24.6. IR (neat, cm-1): 3264, 2969, 2924, 1676, 1606, 1587, 1540, 1496, 1400, 1369, 1323, 1265, 1158, 1093, 908, 838, 823, 805, 779, 760, 728, 719, 697, 682, 668, 638, 623. HRMS (ESI): Calcd. for C16H17N2O3S ([M+H]+) m/z 317.09544, Found 317.09508. N S O O CN 4-(2-Phenylaziridin-1-ylsulfonyl)benzonitrile ( 65da ) was obtained using the general procedure as a white solid in 89% yield (50.8 mg). [ ]20 D = -227 (c = 0.25, CHCl3). 1H

PAGE 112

95 NMR (400 MHz, CDC13): 8.10 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 8.0 Hz, 2H), 7.30 (m, 3H), 7.21 (m, 2H), 3.88 (dd, J = 7.2, 4.8 Hz, 1H), 3.08 (d, J = 7.2 Hz, 1H), 2.48 (d, J = 4.8 Hz, 1H). 13C NMR (100 MHz, CDC13): 206.9, 142.0, 133.5, 128.3, 128.1, 126.1, 117.0, 116.7, 41.4, 36.2. IR (neat, cm-1): 2233, 1458, 1403, 1333, 1291, 1242, 1187, 1162, 119, 1094, 1020, 973, 909, 844, 797, 758, 749, 724, 699, 682, 644, 624. HRMS (ESI): Calcd. for C15H13N2O2S ([M+H]+) m/z 285.06922, Found 285.07029. HPLC: Whelk-01 (98 hexanes:02 isopropanol @ 1.0 ml/min): 87%ee; 71 min (minor) and 86 min (major). N S O O NO2 1-(4-Nitrophenylsulfonyl)-2-phenylaziridine ( 65ea ) was obtained using the general procedure as a white solid in 97% yield (58.9 mg). [ ]20 D = -286 (c = 0.42, CHCl3). 1H NMR (400 MHz, CDC13): 8.37 (d, J = 8.8 Hz, 2H), 8.19 (d, J = 8.8 Hz, 2H), 7.31 (m, 3H), 7.22 (m, 2H), 3.90 (dd, J = 7.2, 4.4 Hz, 1H), 3.11 (d, J = 7.6 Hz, 1H), 2.50 (d, J = 4.4 Hz, 1H). 13C NMR (125 MHz, CDC13): 150.6, 143.9, 134.1, 129.1, 128.7, 128.1, 126.4, 124.3, 41.8, 36.5. IR (neat, cm-1): 3110, 2923, 1607, 1527, 1461, 1348, 1307, 1292, 1192, 1157, 1093, 977, 908, 866, 858, 811, 774, 759, 745, 707, 691, 680, 619. HRMS (ESI): Calcd. for C14H13N2O4S ([M+H]+) m/z 305.05905, Found 305.05901. HPLC: Whelk-01 (98 hexanes:02 is opropanol @ 1.0 ml/min): 88%ee; trans : 47 min (minor) and 58 min (major).

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96 N S O O O2N 1-(2-Nitrophenylsulfonyl)-2-phenylaziridine ( 65fa ) was obtained using the general procedure as tan oil in 96% yield (58.5 mg). [ ]20 D = -49 (c = 0.40, CHCl3). 1H NMR (400 MHz, CDC13): 8.23 (d, J = 6.4 Hz, 1H), 7.74 (m, 3H), 7.32 (m, 5H), 3.76 (m, 1H), 3.24 (d, J = 7.6 Hz, 1H), 2.63 (d, J = 4.4 Hz, 1H). 13C NMR (125 MHz, CDC13): 148.5, 134.6, 134.4, 132.1, 131.9, 131.2, 128.59, 128.56, 126.5, 124.3, 42.8, 38.0. IR (neat, cm1): 3094, 2921, 1540, 1461, 1365, 1331, 1192, 1163, 1126, 1066, 1017, 979, 908, 851, 774, 750, 745, 697, 654, 631. HRMS (ESI): Calcd. for C14H13N2O4S ([M+H]+) m/z 305.05905, Found 305.05928. HPLC: Whelk-01 (98 hexanes:02 isopropanol @ 1.0 ml/min): 70%ee; 72 min (minor) and 100 min (major). N S O O 1-(Naphthalen-1-ylsulfonyl)-2-phenylaziridine ( 65ga ) was obtained using the general procedure as white solid in 97% yield (60.0 mg). 1H NMR (400 MHz, CDC13): 9.00 (d, J = 8.4 Hz, 1H), 8.27 (d, J = 7.2 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.25 (m, 3H), 7.20 (m, 2H), 3.76 (m, 1H), 3.09 (d, J = 7.2 Hz, 1H), 2.38 (d, J = 4.4 Hz, 1H). 13C NMR (125 MHz, CDC13): 135.17, 135.14, 134.1, 133.3, 129.4, 129.0, 128.6, 128.4, 128.27, 128.22, 127.0, 126.4, 125.7, 123.9, 41.1, 36.7. IR (neat, cm-1): 3060, 1594, 1507, 1459, 1384, 1319, 1191, 1161, 1132, 1110, 1083, 1027, 976, 906, 831, 803, 768, 708,

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97 694, 672, 627, 601. HRMS (ESI): Calcd. for C18H16NO2S ([M+H]+) m/z 310.08963, Found 310.08908. N S O O NO2 1-(4-Nitrophenylsulfonyl)-2p -tolylaziridine ( 65eb ) was obtained using the general procedure as tan solid in 89% yield (56.5 mg). [ ]20 D = -167 (c = 0.37, CHCl3). 1H NMR (400 MHz, CDC13): 8.36 (d, J = 8.8 Hz, 2H), 8.17 (d, J = 8.8 Hz, 2H), 7.10 (m, 4H), 3.86 (dd, J = 7.2, 4.8 Hz, 1H), 3.10 (d, J = 7.2 Hz, 1H), 2.50 (d, J = 4.8 Hz, 1H), 2.31 (s, 3H). 13C NMR (125 MHz, CDC13): 150.6, 144.0, 138.6, 131.0, 129.4, 129.1, 126.3, 124.3, 41.9, 36.4, 21.1. IR (neat, cm-1): 3109, 2958, 1606, 1524, 1347, 1322, 1307, 1290, 1157, 1190, 1092, 977, 912, 866, 855, 817, 794, 752, 746, 729, 697, 679, 668, 611. HRMS (ESI): Calcd. for C15H15N2O4S ([M+H]+) m/z 319.07470, Found 319.07413. HPLC: Whelk-01 (98 hexanes:02 isopropanol @ 1.0 ml/min): 81%ee; 47 min (minor) and 59 min (major). N S O O NO2 1-(4-Nitrophenylsulfonyl)-2m -tolylaziridine ( 65ec ) was obtained using the general procedure as tan solid in 89% yield (57.0 mg). [ ]20 D = -269 (c = 0.30, CHCl3). 1H NMR (400 MHz, CDC13): 8.37 (d, J = 8.8 Hz, 2H), 8.18 (d, J = 8.4 Hz, 2H), 7.20 (t, J = 8.0 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 7.01 (m, 2H), 3.86 (dd, J = 7.2, 4.8 Hz, 1H), 3.09 (d, J = 7.2 Hz, 1H), 2.50 (d, J = 4.8 Hz, 1H), 2.31 (s, 3H). 13C NMR (125 MHz, CDC13):

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98 150.6, 143.9, 138.5, 134.0, 129.5, 129.1, 128.6, 127.0, 124.3, 123.5, 41.9, 36.5, 21.3. IR (neat, cm-1): 3107, 2924, 1607, 1525, 1489, 1457, 1348, 1324, 1307, 1292, 1215, 1156, 1112, 1092, 979, 930, 900, 866, 854, 807, 783, 751, 711, 688, 669, 620. HRMS (ESI): Calcd. for C15H15N2O4S ([M+H]+) m/z 319.07470, Found 319.07410. HPLC: Whelk-01 (98 hexanes:02 isopropanol @ 1.0 ml/min): 80%ee; 42 min (minor) and 54 min (major). N S O O NO2 1-(4-Nitrophenylsulfonyl)-2o -tolylaziridine ( 65ed ) was obtained using the general procedure as tan solid in 88% yield (56.2 mg). [ ]20 D = -238 (c = 0.31, CHCl3). 1H NMR (400 MHz, CDC13): 8.40 (d, J = 8.4 Hz, 2H), 8.22 (d, J = 8.4 Hz, 2H), 7.23-7.11 (m, 3H), 7.06 (d, J = 7.6 Hz, 1H), 3.01 (m, 1H), 3.10 (d, J = 7.2 Hz, 1H), 2.43 (d, J = 4.8 Hz, 1H), 2.41 (s, 3H). 13C NMR (125 MHz, CDC13): 150.6, 143.9, 136.7, 132.3, 130.1, 129.2, 128.4, 126.2, 125.5, 124.3, 40.2, 35.8, 19.0. IR (neat, cm-1): 2980, 1607, 1524, 1349, 1328, 1306, 1243, 1203, 1158, 1092, 1012, 976, 907, 867, 829, 766, 744, 742, 698, 680, 668, 621. HRMS (ESI): Calcd. for C15H15N2O4S ([M+H]+) m/z 319.07470, Found 319.07415. HPLC: Chiralcel OD-H (80 hexane s:20 isopropanol @ 0.8 ml/min): 85%ee; 60 min (minor) and 78 min (major). N S O O NO2 2-(4tert -Butylphenyl)-1-(4-nitroph enylsulfonyl)aziridine ( 65ee ) was obtained using the general procedure as tan oi l in 98% yield (71.0 mg). [ ]20 D = -86 (c = 0.44, CHCl3). 1H NMR (400 MHz, CDC13): 8.37 (d, J = 8.4 Hz, 2H), 8.19 (d, J = 8.4 Hz, 2H), 7.34

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99 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 3.89 (m, 1H), 3.09 (d, J = 7.2 Hz, 1H), 2.51 (d, J = 4.8 Hz, 1H), 1.28 (s, 9H). 13C NMR (125 MHz, CDC13): 151.9, 150.6, 144.0, 131.0, 129.1, 126.1, 125.6, 124.3, 41.9, 36.7, 34.6, 31.2. IR (neat, cm-1): 3060, 2964, 1594, 1533, 1507, 1459, 1320, 1191, 1161, 1133, 1110, 1086, 1027, 977, 907, 832, 804, 770, 744, 696, 673, 628, 604. HRMS (ESI): Calcd. for C18H21N2O4S ([M+H]+) m/z 361.12165, Found 361.12077. HPLC: Whelk-01 (98 hexanes:02 isopropanol @ 1.0 ml/min): 88%ee; 47 min (minor) and 58 min (major). N S O O NO2 Cl 2-(4-Chlorophenyl)-1-(4-nitrophenylsulfonyl)aziridine ( 65ef ) was obtained using the general procedure as white solid in 94% yield (63.5 mg). [ ]20 D = -83 (c = 0.43, CHCl3). 1H NMR (400 MHz, CDC13): 8.37 (d, J = 8.8 Hz, 2H), 8.17 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 3.87 (dd, J = 7.2, 4.8 Hz, 1H), 3.10 (d, J = 7.2 Hz, 1H), 2.54 (d, J = 4.8 Hz, 1H). 13C NMR (125 MHz, CDC13): 150.6, 143.6, 134.6, 132.7, 129.1, 128.9, 127.7, 124.3, 40.9, 36.7. IR (neat, cm-1): 3109, 2958, 2925, 1607, 1523, 1494, 1345, 1323, 1306, 1156, 1091, 1016, 980, 911, 867, 834, 803, 753, 743, 724, 694, 680, 658, 630, 604. HRMS (ESI): Calcd. for C14H12N2O4SCl ([M+H]+) m/z 339.02008, Found 339.02007. HPLC: Whelk-01 (98 hexanes:02 isopropanol @ 1.0 ml/min): 82%ee; 50 min (minor) and 62 min (major). N S O O NO2 Br

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100 2-(4-Bromophenyl)-1-(4-nitrophenylsulfonyl)aziridine ( 65eg ) was obtained using the general procedure as white solid in 96% yield (73.5 mg). [ ]20 D = -143 (c = 0.57, CHCl3). 1H NMR (400 MHz, CDC13): 8.38 (d, J = 8.8 Hz, 2H), 8.18 (d, J = 8.8 Hz, 2H), 7.20 (m, 2H), 7.00 (t, J = 8.4 Hz, 2H), 3.87 (m, 1H), 3.09 (d, J = 7.2 Hz, 1H), 2.45 (d, J = 4.4 Hz, 1H). 13C NMR (125 MHz, CDC13): 150.6, 143.6, 133.2, 131.8, 129.1, 128.0, 124.3, 122.7, 41.1, 36.6. IR (neat, cm-1): 2979, 2924, 1607, 1532, 1491, 1336, 1348, 1319, 1161, 1091, 1009, 981, 906, 854, 802, 769, 753, 739, 722, 688, 668, 625, 617. HRMS (ESI): Calcd. for C14H12N2O4SBr ([M+H]+) m/z 382.96957, Found 382.96952. HPLC: Whelk-01 (98 hexanes:02 isopropanol @ 1.0 ml/min): 86%ee; 53 min (minor) and 66 min (major). N S O O NO2 F 2-(4-Fluorophenyl)-1-(4-nitrophenylsulfonyl)aziridine ( 65eh ) was obtained using the general procedure as white solid in 95% yield (61.5 mg). [ ]20 D = -255 (c = 0.47, CHCl3). 1H NMR (400 MHz, CDC13): 8.38 (d, J = 8.8 Hz, 2H), 8.18 (d, J = 8.8 Hz, 2H), 7.19 (m, 2H), 7.00 (m, 2H), 3.88 (dd, J = 7.2, 4.4 Hz, 1H), 3.09 (d, J = 7.2 Hz, 1H), 2.47 (d, J = 4.4 Hz, 1H). 13C NMR (125 MHz, CDC13): 164.1, 162.1, 144.0, 130.2, 129.4, 128.5, 124.6, 116.1, 115.9, 41.4, 36.9. IR (neat, cm-1): 3109, 1611, 1523, 1512, 1455, 1348, 1323, 1308, 1292, 1231, 1187, 1157, 1120, 1092, 981, 911, 868, 836, 817, 796, 754, 746, 734, 715, 695, 680, 611. HRMS (ESI): Calcd. for C14H12N2O4FS ([M+H]+) m/z 323.04963, Found 323.04920. HPLC: Whelk-01 (98 hexanes:02 isopropanol @ 1.0 ml/min): 88%ee; 48 min (minor) and 57 min (major).

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101 N S O O NO2 F3C 1-(4-Nitrophenylsulfonyl)-2-(4-(trifluoromethyl)phenyl)aziridine ( 65ei ) was obtained using the general procedure as a white solid in 96% yield (71.8 mg). [ ]20 D = -157 (c = 0.48, CHCl3). 1H NMR (400 MHz, CDC13): 8.39 (d, J = 8.4 Hz, 2H), 8.19 (d, J = 8.8 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 3.94 (dd, J = 7.2, 4.8 Hz, 1H), 3.14 (d, J = 7.2 Hz, 1H), 2.48 (d, J = 4.4 Hz, 1H). 13C NMR (125 MHz, CDC13): 151.0, 143.8, 138.5, 129.5, 127.1, 126.04, 126.00, 124.7, 41.1, 37.1. IR (neat, cm-1): 3112, 2927, 1621, 1608, 1530, 1348, 1322, 1162, 1116, 1091, 1066, 1017, 982, 909, 849, 756, 713, 696, 630. HRMS (ESI): Calcd. for C15H12N2O4 F3S ([M+H]+) m/z 373.04644, Found 373.04658. HPLC: Whelk-01 (98 hexanes:02 isopropanol @ 1.0 ml/min): 76%ee; 43 min (minor) and 51 min (major). N S O O NO2 2-(Naphthalen-2-yl)-1-(4-nitr ophenylsulfonyl)aziridine ( 65ej ) was obtained using the general procedure as tan solid in 75% yield (53.5 mg). [ ]20 D = -232 (c = 0.40, CHCl3). 1H NMR (400 MHz, CDC13): 8.38 (d, J = 8.4 Hz, 2H), 8.21 (d, J = 8.8 Hz, 2H), 7.81 (m, 3H), 7.74 (s, 1H), 7.50 (m, 2H), 7.27 (m, 1H), 4.07 (m, 1H), 3.20 (d, J = 7.2 Hz, 1H), 2.63 (d, J = 4.4 Hz, 1H). 13C NMR (125 MHz, CDC13): 150.6, 143.9, 133.2, 132.9, 131.4, 129.1, 128.7, 127.75, 127.73, 126.6, 126.5, 126.2, 124.3, 123.2, 42.2, 36.6. IR (neat, cm-1): 3107, 2922, 1604, 1529, 1401, 1346, 1326, 1305, 1156, 1092, 949, 917, 862,

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102 852, 800, 767, 742, 713, 679, 669, 640, 623, 608. HRMS (ESI): Calcd. for C18H15N2O4S ([M+H]+) m/z 355.07470, Found 355.07456. N S O O N H O N-(4-(2p -Tolylaziridin-1-ylsulfonyl)phenyl)acetamide ( 65cb ) was obtained using the general procedure as tan o il in 83% yield (55.1 mg). 1H NMR (400 MHz, CDC13): 7.98 (s, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 8.8 Hz, 2H), 7.08 (s, 4H), 3.71 (dd, J = 6.8, 4.4 Hz, 1H), 2.93 (d, J = 6.8 Hz, 1H), 2.39 (d, J = 4.4 Hz, 1H), 2.29 (s, 3H), 2.16 (s, 3H). 13C NMR (100 MHz, CDC13): 168.9, 148.9, 138.3, 132.0, 131.6, 129.2, 129.1, 126.3, 119.2, 41.2, 35.8, 24.6, 21.2. IR (neat, cm-1): 3346, 3111, 1701, 1590, 1529, 1402, 1370, 1320, 1261, 1155, 1093, 909, 820, 731, 683, 635, 619. HRMS (APCI): Calcd. for C17H19N2O3S ([M+H]+) m/z 331.11109, Found 331.11052. N S O O N H O N-(4-(2-(4tert -Butylphenyl)aziridin-1-yl sulfonyl)phenyl)acetamide ( 65ce ) was obtained using the general procedure as tan oil in 84% yield (62.3 mg). 1H NMR (400 MHz, CDC13): 8.00 (s, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 3.74 (dd, J = 7.2, 4.8 Hz, 1H), 2.94 (d, J = 7.2 Hz, 1H), 2.39 (d, J = 4.8 Hz, 1H), 2.17 (s, 3H), 1.27 (s, 9H). 13C NMR (100 MHz, CDC13): 169.0, 151.5, 143.0, 132.0, 131.6, 129.1, 126.2, 125.5, 119.2, 41.1, 35.9, 34.5, 31.2, 24.5. IR (neat, cm-1): 3334, 2965, 1703, 1591, 1529, 1402, 1365, 1321, 1263, 1156,

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103 1093, 910, 839, 749, 731, 689, 639, 617. HRMS (APCI): Calcd. for C20H25N2O3S ([M+H]+) m/z 373.15804, Found 373.15904. N S O O N H O Cl N-(4-(2-(4-Chlorophenyl)aziridin-1-ylsulfonyl)phenyl)acetamide ( 65cf ) was obtained using the general procedure as tan oil in 93% yield (65.3 mg). 1H NMR (400 MHz, CDC13): 7.98 (s, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 3.68 (dd, J = 7.2, 4.4 Hz, 1H), 2.93 (d, J = 7.2 Hz, 1H), 2.33 (d, J = 4.4 Hz, 1H), 2.16 (s, 3H). 13C NMR (100 MHz, CDC13): 168.9, 143.1, 134.2, 133.3, 131.8, 129.1, 128.7, 127.8, 119.2, 40.3, 36.1, 24.7. IR (neat, cm-1): 3333, 3112, 1701, 1590, 1529, 1494, 1402, 1370, 1322, 1262, 1156, 1092, 1014, 981, 908, 827, 776, 735, 689, 637, 623, 613. HRMS (APCI): Calcd. for C16H16N2O3SCl ([M+H]+) m/z 351.05647, Found 351.05748. 6.5. Supporting Information for Chapter 5 An oven dried Schlenk tube, that was previously evacuated and backfilled with nitrogen gas, was charged with azide (if solid, 0.2 mmol), catal yst (0.004 mmol), and 5 MS (100 mg). The Schlenk tube was then ev acuated and back filled with nitrogen. The Teflon screw cap was replaced with a rubber septum and 0.5 ml of solvent was added followed by azide (if liquid, 0.2 mmol) and th e remaining solvent (total 1mL). The Schlenk tube was then purged with nitrog en for 2 minutes and the rubber septum was replaced with a Teflon screw cap. The Schlenk tube was then placed in an oil bath for the desired time and temperature. Following comp letion of the reaction, the reaction mixture

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104 was concentrated and purified by dry loading the sample on a Teledyne flash chromatography instrument running a gradient solvent system of 100:0 (hexanes: ethyl acetate) to 50:50 (hexanes: ethyl acetate) The fractions containing product were collected and concentrated by rotary evaporation to afford the pure compound. S O O NH 70a was synthesized by the general procedur e from 2,4,6-triisopropylbenzene-1-sulfonyl azide as a tan solid in 96% yield (54.2mg). 1H NMR (400 MHz, CDC13): 7.21 (s, 1H), 6.98 (s, 1H), 4.68 (s, 1H), 3.60 (heptet, J = 6.8 Hz, 1H), 2.97 (heptet, J = 6.8 Hz, 1H), 1.62 (s, 6H), 1.34 (d, J = 6.8 Hz, 6H), 1.26 (d, J = 6.8 Hz, 6H). 13C NMR (100 MHz, CDC13): 155.4, 146.7, 145.2, 130.8, 124.2, 117.7, 59.72, 34.58, 29.81, 29.38, 23.81, 23.51. IR (neat, cm–1): 3244, 2960, 2922, 2865, 1598, 1459, 1382, 1295, 1172, 1151, 1129. HRMS (ESI): Calcd. for C15H23NO2SNa ([M+Na]+) m/z 304.13417, Found 304.13441. S O O NH 70b was synthesized by the general procedur e from 2,5-diisopropyl benzene-1-sulfonyl azide as a tan solid in 94% yield (45.0mg). 1H NMR (400 MHz, CDC13): 7.57(s, 1H), 7.47 (dd, J = 8.0,1.2 Hz, 1H), 7.28 (d, J = 8.0Hz, 1H), 4.61 (s, 1H), 3.00 (heptet, J = 7.2 Hz, 1H), 1.63 (s, 6H), 1.27 (d, J = 7.2 Hz, 6H). 13C NMR (100 MHz, CDC13): 150.5,

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105 143.5, 135.1, 132.1, 122.5, 118.4, 60.62, 33.95, 29.68, 23.71. IR (neat, cm–1): 3240, 2965, 2930, 2899, 2871, 1486, 1463, 1382, 1302, 1277, 1158, 1143, 1122, 1073. HRMS (ESI): Calcd. for C12H18NO2S ([M+H]+) m/z 240.10528, Found 240.10532. S O O NH 70c was synthesized by the general procedur e from 2,4,6-triethylbenzene-1-sulfonyl azide as a tan oil in 90% yield (43.2mg). 1H NMR (400 MHz, CDC13): 7.11 (s, 1H), 6.96 (s, 1H), 4.68 (m, 1H), 4.64 (m, 1H), 2.98 (q, J = 7.6 Hz, 2H), 2.70 (q, J = 7.6 Hz, 2H), 1.57 (d, J = 6.8 Hz, 3H), 1.33 (t, J = 7.6 Hz, 3H), 1.25 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDC13): 150.6, 142.4, 140.1, 131.3, 128.6, 120.2, 52.64, 28.99, 24.62, 21.55, 15.36, 14.57. IR (neat, cm–1): 3251, 2976, 2935, 2875, 1600, 1459, 1374, 1279, 1174, 1146. HRMS (ESI): Calcd. for C12H18NO2S ([M+H]+) m/z 240.10528, Found 240.10416. S O O NH 70d was synthesized by the general procedure from 2,5-diethylbenzene-1-sulfonyl azide as a tan oil in 91% yield (38.6mg). 1H NMR (400 MHz, CDC13): 7.57 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 4.81 (s, 1H), 4.78-4.70 (m, 1H), 2.74 (q, J = 7.6 Hz, 2H), 1.58 (d, J = 6.8 Hz, 3H), 1.26 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDC13): 146.2, 139.3, 135.7, 133.5, 123.8, 120.1, 53.40, 28.77, 21.75, 15.46. IR (neat,

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106 cm–1): 3256, 2932, 1489, 1455, 1417, 1372, 1282, 1211, 1150. HRMS (ESI): Calcd. for C10H14NO2S ([M+H]+) m/z 212.07398, Found 212.07422. S O O NH 70e was synthesized by the general procedur e from 2,4,6-trimethyl benzene-1-sulfonyl azide as a tan solid in 96% yield (38.1mg). 1H NMR (400 MHz, CDC13): 7.04 (s, 1H), 6.94 (s, 1H), 4.87 (s, 1H), 4.42 (d, J = 5.2 Hz, 2H), 2.56 (s, 3H), 2.38 (s, 3H). 13C NMR (100 MHz, CDC13): 144.0, 137.2, 133.9, 131.5, 131.3, 122.2, 45.06, 21.44, 16.78. IR (neat, cm–1): 3236, 2957, 2920, 1594, 1447, 1379, 1281, 1170, 1146. HRMS (ESI): Calcd. for C9H12NO2S ([M+H]+) m/z 198.05833, Found 198.05891. S O O NH 70f was synthesized by the general pro cedure from 2,3,5,6-tetramethylbenzene-1sulfonyl azide as a tan so lid in 91% yield (38.5mg). 1H NMR (400 MHz, CDC13): 7.15 (s, 1H), 4.79 (s, 1H), 4.32 (d, J = 5.2 Hz, 2H), 2.49 (s, 3H), 2. 29 (s, 3H), 2.19 (s, 3H). 13C NMR (125 MHz, DMSO): 140.0, 136.1, 133.1, 132.1, 129.6, 127.5, 43.40, 16.16, 15.34, 14.37, 14.27. IR (neat, cm–1): 3269, 2959, 2929, 2858, 1727, 1490, 1460, 1382, 1268, 1138, 1072, 1038. HRMS (ESI): Calcd. for C10H14NO2S ([M+H]+) m/z 212.07398, Found 212.07460.

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107 S O O NH 70g was synthesized by the general pro cedure from 2,3,4,5,6-pentamethylbenzene-1sulfonyl azide as a tan so lid in 95% yield (42.6mg). 1H NMR (400 MHz, CDC13): 4.89 (s, 1H), 4.33 (d, J = 5.2 Hz, 2H), 2.53 (s, 3H), 2.25 (s, 3H), 2.36 (s, 3H), 2.12 (s, 3H). 13C NMR (125 MHz, DMSO): 137.5, 134.8, 134.5, 133.6, 131.2, 127.9, 42.81, 18.38, 16.35, 13.13. IR (neat, cm–1): 3250, 2957, 2929, 2871, 1728, 1458, 1378, 1272, 1200, 1148, 1072, 1036. HRMS (ESI): Calcd. for C11H16NO2S ([M+H]+) m/z 226.08963, Found 226.08941. S O O NH Br 70h was synthesized by the general procedure from 4-bromo-2-ethylbenzene-1-sulfonyl azide as a tan solid in 93% yield (48.9mg). 1H NMR (400 MHz, CDC13): 7.65-7.59 (m, 2H), 7.53 (s, 1H), 4.96 (s, 1H), 4.78-4.71 (m, 1H), 1.60 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDC13): 143.8, 134.6, 132.5, 127.8, 127.2, 122.5, 52.91, 21.15. IR (neat, cm–1): 3268, 2966, 2924, 2871, 1727, 1572, 1459, 1389, 1320, 1284, 1193, 1165, 1138, 1073. HRMS (ESI): Calcd. for C8H12N2O2SBr ([M+NH4]+) m/z 278.97974, Found 278.97988.

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108 S O O NH O2N 70i was synthesized by the general procedure from 2-ethyl-5-nitrobenzene-1-sulfonyl azide as a tan solid in 99% yield (45.2mg). 1H NMR (400 MHz, CDC13): 8.60 (d, J = 1.6 Hz, 1H), 8.49 (dd, J = 8.4, 2.0 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H) 4.91 (s, 1H), 4.87 (m, 1H), 1.69 (d, J = 6.4 Hz, 3H). 13C NMR (100 MHz, CDC13): 148.5, 147.7, 137.5, 128.1, 125.3, 117.4, 53.32, 21.40. IR (neat, cm–1): 3243, 1600, 1529, 1351, 1282, 1162, 1137, 1094, 1049, 1025. HRMS (ESI): Calcd. for C8H12N3O4S ([M+NH4]+) m/z 246.05430, Found 246.05436. S O O NH 70j was synthesized by the general procedur e from 2,5-dicyclohexylbenzene-1-sulfonyl azide as a tan solid in 87% yield (55.4mg). 1H NMR (400 MHz, CDC13): 7.53 (s, 1H), 7.42 (dd, J = 8.0, 1.2 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 4.67 (s, 1H), 2.59-2.46 (m, 1H), 1.85-1.73 (m, 12H), 1.63-1.53 (m, 2H), 1.44-1.21 (m, 6H). 13C NMR (100 MHz, CDC13): 149.8, 143.6, 135.3, 132.3, 122.7, 118.9, 63.47, 44.24, 37.75, 34.21, 26.63, 25.89, 24.78, 22.55. IR (neat, cm–1): 3268, 2928, 2851, 1728, 1447, 1384, 1296, 1268, 1164, 1137, 1072. HRMS (ESI): Calcd. for C18H26NO2S ([M+H]+) m/z 320.16788, Found 320.16886.

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109 S O O NH C4H9 70k was synthesized by the general procedure from 2,5-dibutylbenzene-1-sulfonyl azide as a tan oil. Extensive efforts were made to attempt the separation of the 5-membered from 6-membered ring products. However, we were only able to isolate a small fraction of the pure 5-membered ring products in both of the cases, which allowed for NMR assignments and determination of the 5to 6-membered ring product ratios by integration from 1H NMR spectra of 5and 6-me mbered ring product mixtures. 1H NMR (400 MHz, CDC13): 7.56 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H) 4.66-4.60 (m, 2H), 2.70 (t, J = 7.6 Hz, 2H), 1.95-1.90 (m, 1H), 1.77-1.70 (m, 1H), 1.62 (m, 2H), 1.521.44 (m, 2H), 1.36 (sext, J = 7.2 Hz, 2H), 0.98 (t, J = 7.2 Hz, 3H), 0.95 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz, CDC13): 144.8, 137.9, 135.5, 133.6, 123.7, 120.5, 57.51, 37.69, 35.23, 33.23, 22.19, 13.82, 13.71. IR (neat, cm–1): 3259, 2958, 2931, 2872, 1489, 1465, 1381, 1287, 1152, 1107. HRMS (ESI): Calcd. for C14H22NO2S ([M+H]+) m/z 268.13658, Found 268.13665. S O O NH C3H7 70l was synthesized by the general procedure fr om 2,5-dipropylbenzene-1-sulfonyl azide as a tan oil. Extensive efforts were made to attempt the separation of the 5-membered from 6-membered ring products. However, we were only able to isolate a small fraction of the pure 5-membered ring products in both of the cases, which allowed for NMR

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110 assignments and determination of the 5to 6-membered ring product ratios by integration from 1H NMR spectra of 5and 6-me mbered ring product mixtures. 1H NMR (400 MHz, CDC13): 7.57 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 4.62 (m, 2H), 2.68 (t, J = 7.6 Hz, 2H), 2.05-2.00 (m, 1H), 1.83-1.78 (m, 1H), 1.67 (sext, J = 7.6 Hz, 2H), 1.03 (t, J = 7.2 Hz, 3H), 0.95 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz, CDC13): 144.6, 137.5, 135.7, 133.6, 123.7, 120.6, 58.85, 37.56, 28.72, 24.22, 13.66, 9.88. IR (neat, cm–1): 3272, 2964, 2931, 2872, 1489, 1458, 1379, 1281, 1151, 1094, 1049. HRMS (ESI): Calcd. for C12H18NO2S ([M+H]+) m/z 240.10528, Found 240.10521.

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111 Chapter 7 Spectral Data 6.1. Spectral Data for Chapter 2 Spectra 6.1.1. 1H and 13C NMR for 10a. O H O H H

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112 Spectra 6.1.2. GC/MS Spectra for 10a.

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113 Spectra 6.1.3. 1H and 13C NMR for 10b.

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114 Spectra 6.1.4. GC/MS Spectra for 10b.

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115 Spectra 6.1.5. 1H and 13C NMR for 10c.

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116 Spectra 6.1.6. GC/MS Spectra for 10c.

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117 Spectra 6.1.7. 1H and 13C NMR for 10d. O H O H H i Bu O H O H H i Bu

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118 Spectra 6.1.8. GC/MS Spectra for 10d.

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119 Spectra 6.1.9. 1H and 13C NMR for 10e. O H O H H MeO O H O H H MeO

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120 Spectra 6.1.10. GC/MS Spectra for 10e.

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121 Spectra 6.1.11. 1H and 13C NMR for 10f. O H O H H B r O H O H H B r

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122 Spectra 6.1.12. GC/MS Spectra for 10f.

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123 Spectra 6.1.13. 1H and 13C NMR for 10g. O H O H H O O H O H H O

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124 Spectra 6.1.14. GC/MS Spectra for 10g.

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125 Spectra 6.1.15. 1H and 13C NMR for 10h.

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126 Spectra 6.1.16. GC/MS Spectra for 10h.

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127 Spectra 6.1.17. 1H and 13C NMR for 10i. O O H H O O H H

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128 Spectra 6.1.18. GC/MS Spectra for 10i.

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129 6.2. Spectral Data for Chapter 3 Spectra 6.2.1. 1H and 13C NMR for 56a.

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130 Spectra 6.2.2. HPLC Spectra for 56a.

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131 Spectra 6.2.3. 1H and 13C NMR for 56b.

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132 Spectra 6.2.4. HPLC Spectra for 56b.

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133 Spectra 6.2.5. 1H and 13C NMR for 56c. N O O O O t -Bu N O O O O t -Bu

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134 Spectra 6.2.6. HPLC Spectra for 56c.

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135 Spectra 6.2.7. 1H and 13C NMR for 56d. N O O O O MeO N O O O O MeO

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136 Spectra 6.2.8. HPLC Spectra for 56d.

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137 Spectra 6.2.9. 1H and 13C NMR for 56e.

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138 Spectra 6.2.10. HPLC Spectra for 56e.

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139 Spectra 6.2.11. 1H and 13C NMR for 56f. N O O O O F3C N O O O O F3C

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140 Spectra 6.2.12. HPLC Spectra for 56f.

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141 Spectra 6.2.13. 1H and 13C NMR for 56g.

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142 Spectra 6.2.14. HPLC Spectra for 56g.

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143 Spectra 6.2.15. 1H and 13C NMR for 56h. N O O O O O2N

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144 Spectra 6.2.16. HPLC Spectra for 56h.

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145 Spectra 6.2.17. 1H and 13C NMR for 56i.

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146 Spectra 6.2.18. HPLC Spectra for 56i.

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147 Spectra 6.2.19. 1H and 13C NMR for 56j.

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148 Spectra 6.2.20. HPLC Spectra for 56j.

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149 Spectra 6.2.21. 1H and 13C NMR for 56k.

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150 Spectra 6.2.22. HPLC Spectra for 56k.

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151 Spectra 6.2.23. 1H and 13C NMR for 56l.

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152 Spectra 6.2.24. HPLC Spectra for 56l.

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153 Spectra 6.2.25. 1H and 13C NMR for 57a.

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154 Spectra 6.2.26. HPLC Spectra for 57a.

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155 Spectra 6.2.27. 1H and 13C NMR for 57b.

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156 Spectra 6.2.28. HPLC Spectra for 57b.

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157 Spectra 6.2.29. 1H and 13C NMR for 57c.

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158 Spectra 6.2.30. HPLC Spectra for 57c.

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159 Spectra 6.2.31. 1H and 13C NMR for 57d.

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160 Spectra 6.2.32. HPLC Spectra for 57d.

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161 Spectra 6.2.33. 1H and 13C NMR for 57e.

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162 Spectra 6.2.34. HPLC Spectra for 57e.

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163 Spectra 6.2.35. 1H and 13C NMR for 57f. O N H O OMe O N H O OMe

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164 Spectra 6.2.36. 1H and 13C NMR for 57g.

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165 Spectra 6.2.37. 1H and 13C NMR for 57h. O N H (R) OH

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166 Spectra 6.2.38. 1H and 13C NMR for 57i.

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167 Spectra 6.2.39. 1H and 13C NMR for 57j.

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168 6.3. Spectral Data for Chapter 4 Spectra 6.3.1. 1H NMR for P7

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169 Spectra 6.3.2. 1H and 13C NMR for 65aa.

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170 Spectra 6.3.3. HPLC Specta for 65aa.

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171 Spectra 6.3.4. 1H and 13C NMR for 65ba.

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172 Spectra 6.3.5. HPLC Spectra for 65ba.

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173 Spectra 6.3.6. 1H and 13C NMR for 65ca.

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174 Spectra 6.3.7. 1H and 13C NMR for 65da.

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175 Spectra 6.3.8. HPLC Spectra for 65da.

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176 Spectra 6.3.9. 1H and 13C NMR for 65ea.

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177 Spectra 6.3.10. HPLC Spectra for 65ea.

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178 Spectra 6.3.11. 1H and 13C NMR for 65fa.

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179 Spectra 6.3.12. HPLC Spectra for 65fa.

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180 Spectra 6.3.13. 1H and 13C NMR for 65ga.

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181 Spectra 6.3.14. 1H and 13C NMR for 65eb.

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182 Spectra 6.3.15. HPLC Spectra for 65eb.

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183 Spectra 6.3.16. 1H and 13C NMR for 65ec.

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184 Spectra 6.3.17. HPLC Spectra for 65ec.

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185 Spectra 6.3.18. 1H and 13C NMR for 65ed.

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186 Spectra 6.3.19. HPLC Spectra for 65ed.

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187 Spectra 6.3.20. 1H and 13C NMR for 65ee. N S O O NO2

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188 Spectra 6.3.21. HPLC Spectra for 65ee.

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189 Spectra 6.3.22. 1H and 13C NMR for 65ef.

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190 Spectra 6.3.23. HPLC Spectra for 65ef.

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191 Spectra 6.3.24. 1H and 13C NMR for 65eg.

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192 Spectra 6.3.25. HPLC Spectra for 65eg.

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193 Spectra 6.3.26. 1H and 13C NMR for 65eh. N S O O NO2 F

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194 Spectra 6.3.27. HPLC Spectra for 65eh.

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195 Spectra 6.3.28. 1H and 13C NMR for 65ei.

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196 Spectra 6.3.29. HPLC Spectra for 65ei.

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197 Spectra 6.3.30. 1H and 13C NMR for 65ej.

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198 Spectra 6.3.31. 1H and 13C NMR for 65cb. N S O O N H O N S O O N H O

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199 Spectra 6.3.32. 1H and 13C NMR for 65ce.

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200 Spectra 6.3.33. 1H and 13C NMR for 65cf. N S O O N H O Cl

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201 6.4. Spectral Data for Chapter 5 Spectra 6.4.1. 1H and 13C NMR for 70a.

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202 Spectra 6.4.2. 1H and 13C NMR for 70b.

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203 Spectra 6.4.3. 1H and 13C NMR for 70c.

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204 Spectra 6.4.4. 1H and 13C NMR for 70d.

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205 Spectra 6.4.5. 1H and 13C NMR for 70e.

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206 Spectra 6.4.6. 1H and 13C NMR for 70f.

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207 Spectra 6.4.7. 1H and 13C NMR for 70g. S O O NH

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208 Spectra 6.4.8. 1H and 13C NMR for 70h.

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209 Spectra 6.4.9. 1H and 13C NMR for 70i.

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210 Spectra 6.4.10. 1H and 13C NMR for 70j.

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211 Spectra 6.4.11. 1H NMR for 70ka + 70kb.

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212 Spectra 6.4.12. 1H and 13C NMR for 70ka.

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213 Spectra 6.4.13. 1H NMR for 70la + 70lb.

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214 Spectra 6.4.14. 1H and 13C NMR for 70a.

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215 References 1) For reviews of carbene tran sfer: (a) Davies, H. M. L. Angew. Chem. Int. Ed 2006 45 6422. (b) Doyle, M. P.; Forbes, D. C. Chem. Rev 1996 98 911. (c) Lebel, H.; Marcoux, J.F.; Molinaro, C.; Charette, A. B. Chem. Rev 2003 103 977. (d) Pellissier, H. Tetrahedron 2008 64 7041. (e) Zhang, Z.; Wang, J. Tetrahedron 2008 64 6577. 2) For reviews of nitrene transfer: (a) Davies, H. M. L.; Long, M. S. Angew. Chem. Int. Ed 2005 44 3518. (b) Davies, H. M. L.; Manning, J. R. Nature 2008 451 417. (c) Halfen, J. A. Curr. Org. Chem 2005 9 657. (d) Muller, P.; Fruit, C. Chem. Rev 2003 103 2905. (e)Katsuki, T. Chem. Lett. 2005 34 ,1304. 3) Selected examples of Ruthenium catalyzed cyclopropanation: (a) Che, C. M.; Huang, J.-S.; Lee, F.-W.; Li, Y.; Lai, T.-S.; Kwa ng, H.-L.; Teng, P-F.; Lee, W.-S.; Lo, W.-C.; Peng, S.-M.; Zhou, Z.-Y. J. Am. Chem. Soc 2001 123 4119. (b) Miller, J. A.; Jin, W.; Nguyen, S. T. Angew. Chem. Int. Ed. Engl 2002 41 2953. (c) Nishiyama, H.; Itoh, Y.; Matsumoto, H.; Park, S.-B.; Itoh, K. J. Am. Chem. Soc 1994 116 2223.

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216 4) Selected examples of Ruthenium catalyzed aziridination/amination: (a) Fantauzzi, S.; Gallo, E.; Caselli, A.; Piangiolino, C.; Ragaini, F.; Cenini, S. Eur. J. Org. Chem. 2007 6053. (b) Kawabata, H.; Omura, K.; Katsuki, T. Tetrahedron Lett 2007 47 1571. (c) Omura, K.; Murakami, M.; Uchida, T.; Irie, R.; Katsuki, T. Chemistry Letters 2003 32 354. (d) Yu, X.-Q.; Huang, J.-S.; Zhou, X.-G.; Che, C.-M. Org. Lett. 2000 2 2233. 5) Selected examples of Rhodium catalyz ed cyclopropanation: (a) Doyle, M. P.; Winchester, W. R.; Hoorn, J. A. A.; Lynch, V.; Simonsen, S. H.; Ghosh, R. J. Am. Chem. Soc. 1993 115 9968. (b) Hu, W.; Timmons, D. J.; Doyle, M. P. Org Lett 2002 4 901. (c) Lou, Y.; Horikawa, M.; kloster, R. A.; Hawrylik, N. A.; Corey, E. J. J. Am. Chem. Soc 2004 126 8916. 6) Selected examples of Rhodium catalyzed azi ridination/amination: (a) Fiori, K. W.; Du Bois, J. J. AM. Chem. Soc. 2007, 129, 562. (b) Guthikonda, K.’ Du Bois, J. J. Am. Chem. Soc 2002 124 13672. (c) Liang, C.; Peillard, F. R.; Fruit, C; Muller, P,; Dodd, R. H.; Dauban, P. Angew. Chem. Int. Ed 2006 45 4641. (d) Reedy, R. P.; Davies, H. M. L. Org. Lett. 2006, 8, 5013. (e) Stokes, B. J.; Dong, H.; Leslie, B. E.; Pumphrey, A. L.; Driver, T. G. J. Am. Chem. Soc 2007 129 7500. (f) Zalatan, D. N.; Du Bois, J. J. Am. Chem. Soc. 2008, 130, 9220. (g) Lebel, H.; Huard, K.; Lectard, S. J. Am. Chem. Soc. 2005, 127, 14198. 7) Selected examples of Copper catalyzed cy clopropanation: (a) Evans, D. A.; Woerpel, K. A.; Hinnman, M. M.; Faul, M. M. J. Am. Chem. Soc 1991 113 726. (b) Fritschi, H.; Leutenegger, U.; Pfaltz, A. Agnew. Chem. Int. Ed. Engl 1986 25 1005. (c) Lo, M. M.-C.; Fu, G. C. J. Am. Chem. Soc 1998 120, 10270.

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217 8) Selected examples of Copper catalyzed aziridination/amination: (a) Dauban, P.; Saniere, L.; Tarrade, A.; Dodd, R. H. J. Am. Chem. Soc. 2001 123 7707. (b) Evans, D. A.; Faul, M. M.; Bilodeau, M. T.; Anderson, B. A.; Barnes, D. M. J. Am. Chem. Soc 1993 115 5328. (c) Fructos, M. R.; Trofimenko, S.; Diaz-Requejo, M. M.; Perez, P. J. J. Am. Chem. Soc 2006 128 11784. (d) Li, Z.; Conser, K. R.; Jacobsen, E. N. J. Am. Chem. Soc 1993 115 5326. (e) Sanders, C. J.; Gillespie, K. M.; Bell, D.; Scott, P. J. Am. Chem. Soc 2000 122 7132. 9) Cyclopropane reviews: (a) Donaldson, W. A. Tetrahedron 2001 57 8589. (b) Pietruszka, J. Chem. Rev 2003 103 1051. (c) Salaun, J. Chem. Rev 1989 89 1247. (d) Wessjohann, L. A.; Brandt, W. Chem. Rev 2003 103 1625. 10) (a) Nakamura, A.; Konishi, A.; Tatsuno, Y.; Otsuka, S. J. Am. Chem. Soc 1978 100 3443. (b) Nakamura, A.; Konishi, A.; Tsujitani, R.; Kudo, M.; Otsuka, S. J. Am. Chem. Soc 1978 100 3449. 11) (a) Fukuda, T.; Katsuki, T. Tetrahedron 1997 53 7201. (b) Ito, Y. N.; Katsuki, T. Bull. Chem. Soc. Jpn 1999 72 603. 12) (a) Niimi, T.; Uchida, T.; Irie, R.; Katsuki, T. Tet. Lett 2000 41 3647. (b) Niimi, T.; Uchida, T.; Irie, R.; Katsuki, T. Adv. Synth. Catal 2001 343 79. 13) Shitama, H.; Katsuki, T. Chem. Eur. J 2007 13 4849. 14) (a) Uchida, T.; Saha, B.; Katsuki, T. Tet. Lett 2001 42 2521. (b) Uchida, T.; Katsuki, T. Synthesis 2006 1715. 15) Yamada, T.; Ikeno, T.; Sekino, H.; Sato, M. Chemistry Letters 1999 719. 16) (a) Ikeno, T.; Sato, M.; Yamada, T. Chemistry Letters 1999 1345. (b) Ikeno, T.; Sato, M.; Sekino, H.; Nishizuka, A.; Yamada, T. Bull. Chem. Soc. Jpn 2001 74 2139.

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218 17) (a) Huang, L.; Chen, Y.; Gao, G.-Y.; Zhang, X. P. J. Org. Chem 2003 68 8179. (b) Penoni, A.; Wanke, R.; Tollari, S.; Gallo, E.; Musella, D.; Ragaini, F.; Demartin, F.; Cenini, S. Eur. J. Inorg. Chem 2003 1452. 18) (a) Caselli, A.; Gallo, E.; Ragaini, F. ; Ricatto, F.; Abbiati, G.; Cenini, S. Inorganica Chimica Acta 2006 359 2924. (b) Chen, Y.; Gao, G.-Y.; Zhang, X. P. Tet. Lett 2005 46 4965. 19) (a) Chen, Y.; Fields, K. B.; Zhang, X. P. J. Am. Chem. Soc 2004 126 14718. (b) Chen, Y.; Zhang, X. P. Synthesis 2006 1696. 20) Chen, Y.; Zhang, X. P. J. Org. Chem 2007 72 5931. 21) Chen, Y.; Ruppel, J. V.; Zhang, X. P. J. Am. Chem. Soc 2007 129 12074. 22) Zhu, S.; Ruppel, J. V.; Lu, H.; Wojtas, L.; Zhang, X. P. J. Am. Chem. Soc 2008 130 5042. 23) Zhu, S.; Perman, J.; Zhang, X. P. Angew. Chem. Int. Ed 2008 DOI:10.1002/anie.200803857. 24) Sharma, V. B.; Jain, S. L.; Sain, B. Catalysis Lett. 2004 94 57. 25) Gao, J.; Woolley, F. R.; Zingaro, R. A. Org. Biomol. Chem 2005 3 2126. 26) Langlotz, B. K.; Wadepohl, H.; Gade, L. H. Angew. Chem. Int. Ed 2008 47 4670. 27) Chen, Y.; Zhang, X. P. J. Org. Chem 2004 69 2431. 28) (a) Ikeno, T.; Iwakura, I.; Yamada, T. J. Am. Chem. Soc 2002, 124 15152. (b) Iwakura, I.; Ikeno, T.; Yamada, T. Org. Lett 2004 6 949. 29) Yamada, Y.; Yamamoto, T.; Okawara, M. Chem. Lett 1975 361.

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219 30) For select examples of in situ variants, see (a) Esteoule, A.; Duran, F.; Retailleau, P.; Dodd, R. H.; Dauban, P. Synthesis 2007 1251. (b) Guthikonda, K.; When, P. M.; Caliando, B. J.; Du Bois, J. Tetrahedron 2006 62 11331. (c) Li, Z.; Ding, X.; He, C. J. Org. Chem 2006 71 5876. (d) Xu, Q.; Appella, D. H. Org. Lett 2008 10 1497. 31) Selected examples of the early use of metallopor phryins in nitrene transfer reactions: (a) Breslow, R.; Gellman, S. H. J. Chem. Soc., Chem. Comm. 1982 24 1400. (b) Breslow, R.; Gellman, S. H. J. Am. Chem. Soc. 1983 105 6728. (c) Groves, J. T.; Nemo, T. E.; Myers, R. S. J. Am. Chem. Soc. 1979 101 1032. (d) Mansuy, D.; Mahy, J. P.; Dureault, A.; Bedi, G.; Battioni, P. J. Chem. Soc., Chem. Commun 1984 1161. 32) Gao, G.-Y.; Harden, J. D.; Zhang, X. P. Org. Lett 2005 7 3191. 33) Gao, G.-Y.; Jones, J. E.; Vyas, R.; Harden, J. D.; Zhang, X. P. J. Org. Chem 2006 71 6655. 34) Jones, J. E.; Ruppel, J. V.; Gao, G.-Y.; Moore, T. M.; Zhang, X. P. J. Org. Chem 2008 73 7260. 35) (a) Cenini, S.; Gallo, E.; Penoni A.; Ragaini, F.; Tollari, S. Chem. Commun 2000 2265. (b) Ragaini, F.; Penoni, A.; Gallo, E.; To llari, S.; Gotti, C. L.; Lapadula, M.; Mangioni, E.; Cenini, S. Chem. Eur. J 2003 9 249. 36) Harden, J. D.; Ruppel, J. V.; Gao, G.-Y.; Zhang, X. P. Chem. Commun 2007 4644. 37) Li, Z.; Quan, R. W.; Jacobsen, E. N. J. Am. Chem. Soc 1995 117 5889. 38) Kirkland, T. A.; Colucci, J.; Geraci, L. S. ; Marx, M. A.; Schneider, M.; Kaelin, D. E.; Martin, S. J. Am. Chem. Soc 2001 123 12432.

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220 39) (a) Martin, S. F.; Austin, R. E.; Oalmann, C. J.; Baker, W. R.; Codon, S. L.; de Lara, E.; Rosenberg, S. H.; Spina, K. P.; Stein, H. H.; Cohen, J.; Kleinert, H. D. J. Med. Chem 1992 35 1710. (b) Pellicciari, R.; Marinozzi, M.; Natalini, B.; Costantino, G.; Luneia, R.; Giorgi, G.; Moroni, F.; Thomsen, C. J. J. Med. Chem 1996 39 2259. (c) Shimamoto, K.; Ohfune, Y. J. Med. Chem 1996 39 407. 40) (a) Barberis, M.; Perez-Prieto, J.; Stiriba, S.-E.; Lahuerta, P. Org. Lett 2001 3 3317. (b) Doyle, M. P.; Austin, R. E.; Bailey, S.; Dwyer, M. P.; Dyatkin, A. B.; Kalinin, A. V.; Kwan, M. M. Y.; Liras, S.; oalmann, C. J.; Pieters, R. J.; Protopopova, M. N.; Raab, C. E.; Roos, G. H. P.; Zhou, Q.-L.; Martin, S. F. J. Am. Chem. Soc 1995 117 5763. (c) Doyle, M. P.; Hu, W.; Weathers, T. M. Chirality 2003 15 369. (d) Doyle, M. P.; Kalinin, A. V. J. Org. Chem 1996 61 2179. (e) Doyle, M. P.; Pieters, R. J. J. Am. Chem. Soc. 1991 113 1423. (f) Saha, B.; Uchida, T.; Katsuki, T. Chemistry Letters 2002 846. 41) (a) Doyle, M. P.; Dorrow, R. L.; Terpstra, J. W.; Rodenhouse, R. A. J. Org. Chem 1985 50 1663. (b) Doyle, M. P.; Loh, K.-L.; De Vries, K. M.; Chinn, M. M. Tetrahedron Lett 1987 28 833. (c) Gross, Z.; Galili, N.; Simkhovish, L. Tetrahedron Lett 1999 40 1571. (d) Haddad, N.; Galili, N. Tetrahedron Lett 1997 8 3367. (e) Jeganathan, A.; Richardson, S. K.; Mani, R. S.; Haley, B. E.; Warr, D. S. J. Org. Chem 1986 51 5362. (f) Muthusamy, S.; Gunanathan, C. Synlett 2003 1599.

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221 42) (a) Brown, D. S.; Elliot, M. C.; Moody, C. J.; Mowlem, T. J.; Marino, J. P.; Padwa, A. P. J. Org. Chem 1994 59 2447. (b) Gois, P. M.P.; Afonso, C. A. M. Eur. J. Org. Chem 2004 3773. (c) Grohmann, M.; Buck, S.; Schaffler, L.; Maas, G. Adv. Synth. Catal. 2006 348 2203. 43) For select examples, see: (a) Garrido, D. M.; Corbett, D. F.; Dwornik, K. A.; Goetz, A. S.; Littleton, T. R.; McKeown, S. C.; Mills, W. Y.; Smalley, T. L. Jr.’ Briscore, C. P.; Peat, A. J. Bioorg. Med. Chem.Lett 2006 16 1840. (b) Graham, D. W.; Ashton, W. T.; Barash, L.; Brown, J. E.; Brown, R. D.; Canning, L. F.; Chen, A.; Springer, J. P.; Rogers, E. F. J. Med. Chem 1987 30 1074. (c) Morain, P.; Lestage, P.; De Nanteuil, G.; Jochemsen, R.; Robin, J.-L.; Guez, D.; Boyer, P.-A. CNS Drug Rev 2002 8 31. (d) Jiang, T.; Kuhen, K. L.; Wolff, K.; Yin, H.; Bieza, K.; Caldwell, J.; Bursulaya, B.; Wu, T. Y.-H.; He, Y. Bioorg. Med. Chem. Lett 2006 16 2105. (e) Sandanayaka, V. P.; Prashad, A. S.; Yang, Y. ; Williamson, T.; Lin, Y. I.; Mansour, T. S. J. Med. Chem 2003 46 2569. 44) N2CHCO2Su has not been previously employed for asymmetric cyclopropanation. For a single report on Ru-catalyzed n on-asymmetric cyclopropanation with N2CHCO2Su see: Werle, T.; Maas, G. Adv. Synth. Catal 2001 343 37. 45) (a) Gnadm F.; Reiser, O. Chem. Rev 2003 103 1603. (b) Cativiela, C.; Diaz-deVillegas, M. D. Tetrahedron: Asymmetry 2000 11 645. (c) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C.; Tanko, J; Hudlicky, T. Chem. Rev 1989 89 165. (d) Danishefsky, S. Acc. Chem. Res 1979 12 66.

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222 46) (a) Hu, X. E. Tetrahedron 2004 60 2701. (b) Pineschi, M. Eur. J. Org. Chem 2006 4979. (c) Singh, G. S.; D’hooghe, M.; De Kimpe, N. Chem. Rev 2007 107 2080. (d) Sweeny, J. B. Chem. Soc. Rev 2002 31 247. (e) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994 33 599. 47) For reviews, see: (a) Cenini, S.; Gallo, E.; Caselli, A.; Ragaini, F.; Fantauzzi, S.; Piangiolino, C. Coord. Chem. Rev. 2006 250 1234. 48) (a ) Kwart, H.; Khan, A. A. J. Am. Chem. Soc 1967 89 1951. (b) Omura, K.; Uchida, T.; Irie, R.; Katsuki, T. Chem. Comm. 2004 2060. (c) Piangiolino, C.; Gallo, E.; Caselli, A.; Fantauzzi, S.; Ragaini, F.; Cenini, S. Eur. J. Org. Chem 2007 743. 49) (a) Johannsen, M.; Jorgensen, A. Chem. Rev 1998 98 1689. (b) Muller, T. E.; Beller, M. Chem. Rev 1998 98 675. (c) Salvatore, R. N.; Yoon, C. H.; Jung, K. W. Tetrahedron 2001 57 7785. 50) For examples of C–H Amination with ArI=NTs, see: (a) Mahy, J.-P.; Bedi, G.; Battioni, P.; Mansuy, D. New J. Chem 1989 13 651. (b) Nageli, I.; Baud, C.; Bernardinelli, G.; Jacquier, Y.; Moran, M.; Muller, P. Helv. Chim. Acta 1997 80 1087. (c) Au, S.-M.; Huang, J.-S.; Che, C.-M.; Yu, W.-Y. J. Org. Chem 2000 65 7858. (d) Yang, J.; Weinberg, R.; Breslow, R. Chem. Commun 2000 531. (e) Yamawaki, M.; Tsutsui, H.; Kitaga ki, S.; Anada, M.; Hashimoto, S. Tetrahedron Lett 2002 43 9561. (f) Liang, J.-L.; Huang, J.-S.; Yu, X.-Q.; Zhu, N.; Che, C.-M. Chem. Eur. J. 2002 8 1563. (g) Cui, Y.; He, C. J. Am. Chem. Soc 2003 125 16202. (h) Li, Z.; Capretto, D. A.; Rahaman, R.; He, C. Angew. Chem., Int. Ed. 2007 46 5184.

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223 51) (a) Simkhovich, L.; Gross, Z. Tetrahedron Lett 2001 42 8089. (b) Albone, D. P.; Aujla, P. S.; Taylor, P. C.; Challenger, S.; Derrick, A. M. J. Org. Chem 1998 63 9569. (c) Albone, D. P.; Challenger, S.; Derric k, A. .; Fillery, S. M.; Irwin, J. L.; Parsons, C. M.; Takada, H.; Taylor, P. C.; Wilson, D. J. Org. Biomol. Chem 2005 3 107. 52) (a) Chanda, B. M.; Vyas, R.; Bedekar, A. V. J. Org. Chem 2001 66 30. (b) Vyas, R.; Gao, G.-Y.; Harden, J. D.; Zhang, X. P. Org. Lett 2004 6 1907. 53) (a) Lebel, H.; Huard, K. Org. Lett 2007 9 639. (b) Lebel, H.; Huard, K.; Lectard, S. J. Am. Chem. Soc 2005 127 14198. (c) Lebel, H.; Leogane, O.; Huard, K.; Lectard, S. Pure Appl. Chem 2006 78 363. 54) For selected examples, see: (a) Elgazwy, A.-S. S. H. Tetrahedron 2003 59 7445. (b) Lee, A. W. M.; Chan, W. H.; Zhang, S.-J.; Zhang, H.-K. Curr. Org. Chem 2007 11 213. (c) Headrick, S. A. Ph.D. Dissertation. University of Tennessee, Knoxville, TN, U.S.A., 2003. (d) Baker, D. C.; Jiang, B. U.S. Patent 6,353,112 B1, 2002. (f) Mao, J.; Baker, D. C. U.S. Patent 6,458,962 B1, 2002. (e) Baker, D. C.; Mayasundari, A.; Mao, J.; Johnson, S. C.; Yan, S. U.S. Patent 6,562,850 B1, 2003. (f) Singh, S. K.; Reddy, P. G.; Rao, K. S.; Lohray, B. B.; Misra, P.; Rajjak, S. A.; Rao, Y. K.; Venkateswarlu, A. Bioorg. Med. Chem. Lett 2004 14 499. (g) Pal, M.; Veeramaneni, V. R.; Kumar, S.; Vangoori, A.; Mullangi, R.; Misra, P.; Rajjak, S. A.; Lohray, V. B.; Casturi, S. R.; Yeleswarapu, K. R. Lett. Drug Design Discovery 2005 2 329.

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224 Peer Review Publications by Author 1) Chen, Y.; Ruppel, J. V.; Zhang, X. P. J. Am. Chem. Soc 2007 129 12074. 2) Ruppel, J. V.; Kamble, R. M.; Zhang, X. P. Org. Lett 2007 9 4889. 3) Harden, J. D.; Ruppel, J. V.; Gao, G.-Y.; Zhang, X. P. Chem. Comm 2007 4644. 4) Gao, G.-Y.; Ruppel, J. V.; Allen, D. B.; Chen, Y.; Zhang, X. P. J. Org. Chem 2007 72 9060. 5) Zhu, S.; Ruppel, J. V.; Lu, H.; Lukasz, W.; Zhang, X. P. J. Am. Chem. Soc 2008 130 5042. 6) Ruppel, J. V.; Jones, J. E.; Huff, C. A.; Kamble, R. M.; Chen, Y.; Zhang, X. P. Org. Lett. 2008 10 1995. 7) Gao, G,-Y.; Ruppel, J. V.; Fields, K. B.; Xu, X.; Chen, Y.; Zhang, X. P. J. Org. Chem 2008 73 4855. 8) Jones, J. E.; Ruppel, J. V.; Gao, G,-Y.; Moore, T. M.; Zhang, X. P. J. Org. Chem 2008 73 7260.

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About the Author Joshua V. Ruppel was born to Stephen and Jean Ann Ruppel on August 19th 1980 in Vincennes, IN. Following his interests and aptitude in science, Joshua was admitted to the Edgewater High School Engineering, Sc ience, and Technology program where he was able to complete his high school educat ion in 1998. Following his graduation from the University of Central Florida in 2003 w ith a bachelor’s degree in chemistry, Joshua joined Dr. X. Peter Zhang at the Univer sity of Tennessee. In 2006, the Zhang group moved to the University of South Florida wh ere Joshua completed a productive graduate career publishing 8 research papers in peer re viewed journals with several more potential manuscripts being prepared.


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ABSTRACT: Metalloporphyrins have been shown to catalyze many fundamental and practically important chemical transformations, some of which represent the first demonstrations of these catalytic processes. The most notable examples include an assortment of atom/group transfer reactions, such as oxene, nitrene, and carbene transfers. Atom/group transfer reactions allow for the direct conversion of abundant and inexpensive alkenes and alkanes into value-added functional molecules. Previous reports from our group have shown that cobalt-porphyrin based carbene and nitrene transfer reactions are some of the most selective and practical catalytic systems developed for cyclopropanation and aziridination. Backed by a family of D-symmetric chiral cobalt porphyrins our group continues the development of stereoselective carbene and nitrene transfer reactions.Metal-catalyzed cyclopropanation of olefins with diazo reagents has attracted great research interest because of its fundamental and practical importance. The resulting cyclopropyl units are recurrent motifs in biologically important molecules and can serve as versatile precursors in organic synthesis. Supported by a family of D-symmetric chiral cobalt porphyrins, we have demonstrated the use of succimidyl diazoacetate as carbene source for a highly diastereo- and enantioselective cyclopropanation process. The resulting cyclopropyl succinimdyl esters are highly reactive and serve as valuable synthons for generating cyclopropylcarboxamides. We have also developed the first cobalt-porphyrin based intramolecular cyclopropanation, which is able to produce the resulting bicyclic lactones in high yields and enantioselectivity. Nitrene transfer reactions are also an attractive route to produce biologically and synthetically important molecules such as amines and aziridines.Although much progress has been made in nitrene transfer reactions utilizing [N-(p-toluenesulfonyl) imino]phenyliodinane (PhI=NTs) the nitrene source suffers from several drawbacks. Consequently, there has been growing interest in developing catalytic nitrene transfer reactions using alternate nitrene sources. To this end, we have utilized arylsulfonyl azides as nitrene source to explore their use in the development of a cobalt-porphyrin catalyzed enantioselective aziridination system. The cobalt catalyzed process can proceed under mild and neutral conditions in low catalyst loading without the need of other reagents, while generating nitrogen gas as the only byproduct. We have also explored the use of arylsulfonyl azides as nitrene source in a cobalt-catalyzed intramolecular C-H amination process.
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