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Development of heteroatom radical based synthetic strategies Wickenden, Jason 2013

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Development of Heteroatom Radical Based Synthetic Strategies  by Jason Wickenden  B.Sc, The University of Western Ontario, 2006  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF  DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Chemistry) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver)  December 2013  ? Jason Wickenden, 2013    ii  Abstract  This thesis presents investigations of carbo- and heterocycle formation using radical relay cyclization reactions initiated by alkoxy radicals, cyclic imine formation using substoichiometric stannane and photodeoxygenation reactions involving benzotriazole-borane complexes.  Chapter 1 describes our investigations and development of radical relay cyclization reactions initiated by alkoxy radicals that provided carbo- and heterocyclic compounds.   Pairing N-alkoxyphthalimides as alkoxy radical precursors with the slow addition of radical initiator provided a wide range of carbocycles.  Incorporation of functionality into the linear backbone provided substituted heterocyclic compounds in excellent yield.  Chapter 2 describes the cyclization of aminyl radicals onto silyl enol ethers.  The rate acceleration imparted by the silyl enol ether allowed for high yielding pyrrolidine formation.  Investigations focused on an unexpected cyclic imine product that was observed in our previous studies.  We sought to both optimize our conditions to provide this imine in the highest possible yield, and investigated the mechanism by which this imine product may be formed.    iii  Chapter 3 describes the development of a photodeoxygenation reaction using benzotriazole-borane complexes.  The coordination of a benzotriazole ligand with commercially available borane-tetrahydrofuran provides the benzotriazole-borane complex as a bench stable white powder.  DFT calculations suggested these benzotriazole-borane complexes could behave a radical chain deoxygenation reaction.  Irradiation of a variety of xanthates provided the deoxygenated products in excellent yield.  Furthermore, our work suggests that the benzotriazole ligand may be catalytic in these deoxygenation reactions.    iv  Preface  Chapter 1 is based on research conducted with Dr. Hai Zhu, Natalie Campbell, Joe. C. T. Leung, and Kayli Johnson, and was published in 2009: Zhu, H.; Wickenden, J. G.; Campbell, N. E.; Leung, J. C. T.; Johnson, K. M.; Sammis, G. M. Org. Lett. 2009, 11, 2019.  I wrote the manuscript in collaboration with my supervisor, Prof. Glenn Sammis.  Optimization studies of the rate of addition of metal hydride (Table 1.2) were performed by both Dr. Hai Zhu and myself.  Investigations into the one-pot addition of metal hydrides (Table 1.2, entries 4 and 6) is exclusively my research.   Linear precursor 1.111 (Table 1.3, entry 3) and the corresponding cyclized product 1.139 were synthesized and characterized by Joe C. T. Leung.  Linear precursor 1.116 (Table 1.3, entry 8) was synthesized and characterized by Natalie Campbell.  Chapter 2 is based on research conducted with Dr. Huimin Zhai and was published in 2010: Zhai, H.; Wickenden, J. G.; Sammis, G. M. Synlett, 2010, 3035.  I wrote the manuscript in collaboration with my supervisor, Prof. Glenn Sammis.  Dr. Huimin Zhai synthesized and characterized the compounds depicted in Scheme 2.25, 2.27, 2.30, 2.32, 2.35, 2.36, 2.38, 2,39 and preformed the cyclization experiment in 2.40.  The work outlined in scheme 2.42 was completed by myself and Kayli Johnson.  Each compound was synthesized by both parties, and the spectra were run by myself and Kayli using her account.  v   Chapter 3 is based on unpublished research in the Sammis research group.  DFT calculations found in Table 3.5 were provided to us by our collaborator Dr. Bing Yang.  I carried out all experimental work in this chapter, as well as the synthesis and characterization of all compounds.    vi  Table of Contents  Abstract .................................................................................................................................................... ii Preface ..................................................................................................................................................... iv Table of Contents .................................................................................................................................. vi List of Tables ...........................................................................................................................................xi List of Figures ...................................................................................................................................... xiii List of Schemes ...................................................................................................................................... xv List of Abbreviations and Symbols ................................................................................................. xx Acknowledgements .........................................................................................................................xxiii Dedication ........................................................................................................................................... xxiv Foreword .............................................................................................................................................. xxv Chapter 1: Construction of Carbo- and Heterocycles Using Radical Relay Cyclizations Initiated by Alkoxy Radicals ................................................................................................................ 1 1.1 Introduction ........................................................................................................................................ 1 1.2 Radical Cascade Cyclization Reactions ..................................................................................... 1  1.2.1  Radical Relay Reactions Initiated by sp3 Carbon Radicals .................................... 3  1.2.2  Radical Relay Reactions Initiated by sp2 Carbon Radicals .................................... 5       1.2.2.1  Radical Relay Reactions Initiated by Vinyl Radicals ....................................... 5       1.2.2.2  Radical Relay Reactions Initiated by Aryl Radicals ......................................... 6       1.2.2.3  Radical Relay Reactions Initiated by Additions to Alkynes.......................... 7       1.2.2.4  Radical Relay Reactions Initiated by Nitrogen-Centred Radicals .............. 9 vii   1.2.3 Radical Reactions Involving Alkoxy Radicals ........................................................... 11 1.3  Generation of Alkoxy Radicals................................................................................................... 13 1.4  Alkoxy Radical Inititated Translocation Reactions ........................................................... 18 1.5  Mechanism ........................................................................................................................................ 20 1.6  Results and Discussion ................................................................................................................. 26 1.7  Future Work ..................................................................................................................................... 36 1.8  Conclusion ......................................................................................................................................... 39 1.9  Experimental .................................................................................................................................... 41  1.9.1  General Experimental ....................................................................................................... 41  1.9.2  Synthesis of N-alkoxyphthalimides 1.109, 1.110, 1.112-1.115 ..................... 42  1.9.3  One Pot NMR-Scale Cyclizations  .................................................................................. 54  1.9.4  General Cyclization and Purification Procedure .................................................... 54 Chapter 2 :  Cyclizations of Aminyl Radicals Generated from Substoichiometric Stannane ................................................................................................................................................. 59 2.1 Introduction ..................................................................................................................................... 60  2.1.1 Nitrogen Heterocycle Formation Using the Addition of Alkyl Radicals to Nitrogen-Containing Functional Groups ......................................................................................... 60  2.1.1.1    Aminyl Radical Formation via the Addition of Alkyl Radicals to Nitriles   ....................................................................................................................................................... 60                  2.1.1.2 Carbon-Centred Radical Additions to Imines  ............................................... 61                  2.1.1.3 Carbon-Centred Radical Additions to Azides  ............................................... 65 2.2 Nitrogen Heterocycle Formation Using Nitrogen-Centred Radicals .......................... 69 viii           2.2.1 Indirect Formation of Aminyl Radicals ........................................................................ 70          2.2.2 Direct Methods for the Generation of Aminyl Radicals ......................................... 73 2.3 Aminyl Radical Cyclizations Onto Silyl Enol Ethers .......................................................... 80 2.4 Results and Discussion ................................................................................................................. 85 2.5 Studies Towards a Synthesis of (?)-Lepadiformine A ..................................................... 97 2.6 Future Work ................................................................................................................................... 100 2.7 Conclusion ....................................................................................................................................... 102 2.8 Experimental .................................................................................................................................. 103          2.8.1  General Experimental ...................................................................................................... 103          2.8.2   Synthesis of Silyl Enol Ethers Z-2.140a, 2.140b, 2.145, 2.151 and 2.175 ? 2.179 ........................................................................................................................................................... 104          2.8.3   Cyclization Procedures for Silyl Enol Ethers ......................................................... 114              2.8.3.1 General Cyclization Procedure for Slow Additions  ...................................... 114              2.8.3.2 General Cyclization Procedure for One Portion Additions  ....................... 115              2.8.3.3 Cyclizations of Silyl Enol Ethers Z-2.140a, 2.140b, 2.145 and 2.151  . 115              2.8.3.4 Mechanisitic Investigations (Scheme 2.40)...................................................... 118 Chapter 3 : Boranes as Sources of Hydrogen Atom Transfer Agents ................................ 120 3.1 Metal Hydride Replacements................................................................................................... 121          3.1.1  Improving Purification of Organotin Hydrides ..................................................... 124          3.1.2  Catalytic Organotin Hydrides ....................................................................................... 126          3.1.3  Silicon Hydrides ................................................................................................................. 127          3.1.4  Germanium Hydrides ...................................................................................................... 131 ix  3.2 Boron in Free Radical Processes ............................................................................................ 133          3.2.1  Stabilization Of the Boryl Radical through ?-Conjugation ................................ 133          3.2.2  Coordination of a Lewis Base with Borane ............................................................. 136          3.2.3  Benzotriazole-Borane Complexes ............................................................................... 139 3.3 Mechanistic Investigation ......................................................................................................... 141 3.4 Results and Discussion ............................................................................................................... 142          3.4.1  Basic Reactivity .................................................................................................................. 146          3.4.2  Deoxygenation Reactions Using Sub-stoichiometric 1-Methylbenzotriazole ...   ............................................................................................................................................................. 157 3.5 Future Work ................................................................................................................................... 160 3.6 Conclusion ....................................................................................................................................... 161 3.7 Experimental .................................................................................................................................. 162          3.7.1  General Experimental ...................................................................................................... 162             3.7.1.1  General NMR Method for Deoxygenation ......................................................... 164             3.7.1.2  General Method for ?Scaled? Deoxygenation Reactions ............................... 164           3.7.2  Synthesis of Substrates 3.76a, 3.85, 3.87, 3.89, 3.91, 3.95, 3.97, 3.99, 3.105 and 3.107 ..................................................................................................................................... 164          3.7.3  Barton-McCombie Deoxygenation of Substrates 3.85, 3.87, 3.89, 3.91, 3.95, 3.97, 3.99, 3.105 and 3.107 .............................................................................................................. 174 Bibliography ...................................................................................................................................... 177 Appendix A: Selected Spectra from Chapter 1 ......................................................................... 196 Appendix B: Selected Spectra from Chapter 2 ......................................................................... 219 x  Appendix C: Selected Spectra from Chapter 3 ......................................................................... 242                  xi  List of Tables Table 0.1. Selected rates for radical reactions. ...................................................................... xxvi Table 1.1.  Homolytic bond strengths for selected single bonds to oxygen............................ 13 Table 1.2.  Optimization studies on the rate of addition of the metal hydride. ...................... 27 Table 1.3.  Alkoxy radical initiated cyclization cascades. ......................................................... 28 Table 2.1.  Dependence on the distribution of 2.19-2.21 on the concentration and addition rate of Bu3SnH. ............................................................................................................................. 64 Table 2.2.  SOMO energy values and charge densities of selected aminyl radicals ............... 78 Table 2.3.  Optimization studies for total imine products 2.152 and 2.154. ......................... 91 Table 3.1.  Rate constants for the reaction of some radicals with Bu3SnH and TTMSS. ...... 129 Table 3.2.  Selected rate constants for the reaction of primary alkyl radicals with ............ 131 Table 3.3.  Comparison of the reduction of xanthate 3.8 using different NHC-BH3 complexes...................................................................................................................................................... 136 Table 3.4.  Selected bond dissociation energies of various borane-ligand complexes. ....... 137 Table 3.5.  Calculated bond dissociation energies for borane triazole complexes 3.76b ? 3.78 ............................................................................................................................................ 141 Table 3.6.  Synthesis of xanthates 3.92 ? 3.113. .................................................................... 144 Table 3.7.  Product ratios from reactivity screens of various TAB-BH3 complexes. ............ 147 Table 3.8.  Initiator screen for deoxygenation of 3.92. .......................................................... 148 Table 3.9.  Initiator screen at 30 ?C. ......................................................................................... 150 Table 3.10.  Control study for the radical deoxygenation of xanthate 3.92. ........................ 151 Table 3.11.  Solvent screen using 3.76a and O-benzyl S-methyl carbonodithioate (3.92). 152 xii  Table 3.12.  Polarity reversal catalysis studies using PhSH. .................................................. 153 Table 3.13. Time screen using 3.92. ........................................................................................ 154 Table 3.14.  NMR and ?scaled? TAB borane reduction of benzylic xanthates. ....................... 155 Table 3.15.  Sub-stoichiometric TAB-BH3 in a Barton-McCombie deoxygenation reaction...................................................................................................................................................... 159  xiii  List of Figures Figure 1.1.  Representative reactions of alkoxy radicals. ......................................................... 11 Figure 1.2.  Selected examples of alkoxy radical precursors. .................................................. 14 Figure 1.3.  Substrates used in alkoxy radical initiated cascade studies. ............................... 22 Figure 1.4.  Chair- and boat-like transition states for 5-exo cyclizations................................ 34 Figure 1.5.  Comparison of chair-like transition states for the 5-exo cyclization step. .......... 35 Figure 1.6.  A representation of a typical acetogenin. .............................................................. 37 Figure 1.7.  Trans-1.163 and cis-1.164. .................................................................................... 37 Figure 2.1.  N-hydroxypyridinethione ester 2.83 and N-hydroxypyridinethione carbamate 2.84. .............................................................................................................................................. 75 Figure 2.2.  Selected polyhydroxylated alkaloids. .................................................................... 81 Figure 2.3.  Aminyl radical cyclization for the synthesis of 2-hyrdoxymethyl pyrrolidine 2.117. ........................................................................................................................................... 81 Figure 2.4.  Representations of lepadiformine A (2.169). ....................................................... 97 Figure 3.1.  Propagation steps of a metal hydride reduction. ................................................ 121 Figure 3.2.  Morphine (3.17), prostaglandin F2? (3.18) and silphiperfolene (3.19). .......... 124 Figure 3.3.  Alternative organotin hydride compounds. ........................................................ 125 Figure 3.4.  Alkanethiol additives for polarity reversal catalysis. ......................................... 128 Figure 3.5.  Calculated B-H BDE?s of selected NHC-BH3 complexes. ..................................... 133 Figure 3.6.  ?Minimalist? NHC-BH3?s diMe-Imd-BH3 3.64 and diMe-Tri-BH3 3.65. ............. 135 Figure 3.7.  Thermal dissociation of 3.69. ............................................................................... 139 Figure 3.8.  N-heteroaryl boranes 3.72-3.74. ......................................................................... 139 xiv  Figure 3.9.  Borane triazole complexes 3.76a ? 3.78. ............................................................ 141 Figure 3.10.  Possible TAB-BH3 complexes. ............................................................................ 161                     xv  List of Schemes Scheme 1.1.  Synthesis of (?)-?9(12)-capnellene (1.4). ................................................................ 1 Scheme 1.2.  Radical relay cyclization cascade. .......................................................................... 2 Scheme 1.3.  A total synthesis of (+)?ipomeamarone (1.14) by Sugimura et al. ..................... 3 Scheme 1.4.  Synthesis of bicyclic ketone 1.20 using a 1,5?HAT reaction. .............................. 4 Scheme 1.5.  Synthesis of spiroacetal 1.25 using a 1,5?HAT initiated by a vinyl radical. ....... 6 Scheme 1.6.  Diastereoselective synthesis of a ?-amino acid 1.30. .......................................... 7 Scheme 1.7.  Synthesis of bicyclic lactams starting from alkyne precursors. .......................... 8 Scheme 1.8.  Diastereoselective synthesis of substituted cyclopentanones. ........................... 9 Scheme 1.9.  Synthesis of tetrahydrofuran 1.50 from azide 1.43. .......................................... 10 Scheme 1.10.  Intramolecluar hydrogen transfer reaction. ..................................................... 12 Scheme 1.11.  Barton?s synthesis of aldosterone acetate (1.64). ............................................ 12 Scheme 1.12.  Synthesis of lactone 1.78 from arenesulfenate 1.73. ...................................... 15 Scheme 1.13.  Tin-mediated alkoxy radical generation and subsequent 5-exo-trig cyclization. ................................................................................................................................... 15 Scheme 1.14.  Formation of spiroacetal 1.87 initiated by PIDA/I2. ........................................ 17 Scheme 1.15.  Epoxide fragmentation and radical relay cyclization reaction. ....................... 18 Scheme 1.16.  Radical relay cyclization initiated by a 1,5-HAT reaction. ............................... 19 Scheme 1.17.  Synthesis of cyclopentane 1.102 via radical epoxide fragmentation. ............ 19 Scheme 1.18.  Mechanism of a radical relay cyclization using N-alkoxyphthalimide precursors. ................................................................................................................................... 21 Scheme 1.19.  Synthesis of radical cyclization precursor 1.109. ............................................ 22 xvi  Scheme 1.20.  Synthesis of radical cyclization precursor 1.110. ............................................ 23 Scheme 1.21.  Synthesis of N-alkoxyphthalimide carbamate 1.112. ...................................... 23 Scheme 1.22.  Synthesis of N-alkoxyphthalimide ether 1.114. ............................................... 24 Scheme 1.23.  Synthesis of N-alkoxyphthalimide ether 1.113. ............................................... 25 Scheme 1.24.  Synthesis of N-alkoxyphthalimide ether 1.115. ............................................... 25 Scheme 1.25.  Synthesis of tosylhydrazone 1.117. .................................................................. 26 Scheme 1.26.  Proposed 1,6-hydrogen abstraction. ................................................................. 31 Scheme 1.27.  Mechanism for the formation of mono-substituted tetrahydrofuran 1.145. . 32 Scheme 1.28.  General strategy for the synthesis of acetogenin analogs. ............................... 39 Scheme 2.1.  Synthesis of tricyclic imine 2.7 from bromide 2.1. ............................................ 61 Scheme 2.2.  Synthesis of 2.10 and 2.11 by intramolecular radical addition. ....................... 62 Scheme 2.3.  5-Exo cyclization of bromide 2.15 to form indole 2.16. .................................... 63 Scheme 2.4.  Cyclization of aryl bromide 2.15. ......................................................................... 63 Scheme 2.5.  Alternative mechanism for the formation of pyrrolidine 2.26.......................... 65 Scheme 2.6.  Cyclization of an aryl radical onto an azide. ........................................................ 66 Scheme 2.7.  Synthesis of N-tosylpyrrolidine 2.36 from azide 2.33. ...................................... 66 Scheme 2.8.  Reduction products resulting from the treatment of bromide 2.37 with Bu3SnH. ......................................................................................................................................... 67 Scheme 2.9.  Radical cyclization of bromide 2.40 using TTMSS. ............................................ 67 Scheme 2.10.  Synthesis of spiro-N-tosylpyrrolidine 2.48. ..................................................... 68 Scheme 2.11.  A total synthesis of (?)?aspidospermidine (2.54). .......................................... 69 xvii  Scheme 2.12.  Synthesis of pyrrolidines 2.59a and 2.59b using a tandem radical cyclization........................................................................................................................................................ 70 Scheme 2.13.  Tandem radical cyclization to form indolizidine 2.65. .................................... 72 Scheme 2.14.  Attempted synthesis of pyrrolizidine 2.68 from imine 2.66 via a 5-endo cyclization. ................................................................................................................................... 73 Scheme 2.15.  Application of the HLF reaction in a total synthesis of kobusine (2.72). ........ 74 Scheme 2.16.  Synthesis of 2.74 and 2.75 from the decomposition of tetrazene 2.73. ........ 74 Scheme 2.17.  Electrochemcial oxidation of lithiated amide 2.76. ......................................... 75 Scheme 2.18.  Electrochemical oxidation of N-methoxyamine 2.79. ...................................... 75 Scheme 2.19.  Synthesis of pyrrolizidine 2.90. ......................................................................... 76 Scheme 2.20.  Synthesis of tricyclic pyrrolizidine 2.95. .......................................................... 77 Scheme 2.21.  Proposed mechanism for the formation of stannylaminyl radical 2.99. ......... 77 Scheme 2.22.  Stannylaminyl radical mediated ring expansion of 2.101 to lactam 2.106. .. 79 Scheme 2.23.  Stannylaminyl radical cyclization onto a hydrazone. ....................................... 80 Scheme 2.24. Nitrogen-centred radical cyclization to form pyrrolidine 2.122. .................... 82 Scheme 2.25.  Synthesis of silyl protected CYB-3 (2.124) from Z-2.123. .............................. 82 Scheme 2.26.  Cyclization of silyl enol ether 2.129. ................................................................. 83 Scheme 2.27. One pot synthesis of protected 1,4-dideoxy-1,4-imino-L-ribitol (2.129). ...... 83 Scheme 2.28.  Proposed mechanism for the formation of imine 2.127. ................................ 84 Scheme 2.29. Synthesis of cyclization precursor 2.120. .......................................................... 85 Scheme 2.30.  Synthesis of cyclization precursors Z-2.140a and Z-2.140b. ......................... 86 Scheme 2.31.  Synthesis of cyclization precursor 2.145. ......................................................... 87 xviii  Scheme 2.32.  Synthesis of cyclization precursor 2.151. ......................................................... 88 Scheme 2.33.  One portion addition of superstoichiometric tributyltin hydride to azide 2.120. ........................................................................................................................................... 89 Scheme 2.34.  One portion addition of 50 mol% of tributyltin hydride to azide 2.120. ........ 90 Scheme 2.35.  Cyclization of azide 2.155 varying the equivalents of Bu3SnH. ...................... 92 Scheme 2.36.  Cyclization of azide 2.159 varying the equivalents of Bu3SnH. ...................... 93 Scheme 2.37.  Cyclization of secondary azides 2.162a and 2.162b. ...................................... 94 Scheme 2.38.  Synthesis of both trans- and cis-2,5-disubstituted pyrrolidines 2.164 and 2.166. ........................................................................................................................................... 95 Scheme 2.39.  Addition of allyl magnesium bromide (2.167) to cyclic imine 2.163a. ......... 96 Scheme 2.40.  Mechanistic investigation into the proposed radical transfer step. .................. 96 Scheme 2.41.  Proposed route to (?)?lepadiformine A (2.169). ............................................. 98 Scheme 2.42.  Synthesis of test substrate 2.179. ...................................................................... 99 Scheme 2.43.  Cyclization of test substrate 2.179. ................................................................. 100 Scheme 2.44.  Proposed investigations into the role of the protecting group on the hydrogen atom transfer step. ................................................................................................... 101 Scheme 2.45.  Synthesis of alkene 2.191 from azide 2.189 in one step. .............................. 101 Scheme 2.46.  Proposed cyclization of arenesulfenate 2.192. .............................................. 102 Scheme 3.1.  Barton-McCombie deoxygenation of xanthate 3.9. .......................................... 122 Scheme 3.2.  Mechanism of the Barton-McCombie deoxygenation ...................................... 123 Scheme 3.3.  Synthesis of polymer bound alkyltin hydride 3.24. ......................................... 126 Scheme 3.4.  Synthesis of lactone 3.31 from iodide 3.30. ..................................................... 127 xix  Scheme 3.5.  Catalytic cycle for the Bu3SnH-catalyzed reduction of alkyl halides. .............. 127 Scheme 3.6.  Dideoxygenation of 3.39 using Ph2SiH2. ........................................................... 128 Scheme 3.7.  Polarity reversal catalysis with alkylsilanes and alkanethiols. ....................... 128 Scheme 3.8.  Representative reductive processes accomplished using TTMSS instead of Bu3SnH. ....................................................................................................................................... 130 Scheme 3.9.  Synthesis of hydroxymethyl monosaccharide 3.56 using Ph3GeH. ................ 132 Scheme 3.10.  Synthesis of ether 3.63 via NHC-BH3 mediated radical deoxygenation reaction. ...................................................................................................................................... 134 Scheme 3.11.  Hydrophosphorylation of alkyne 3.67. ........................................................... 138 Scheme 3.12.  Synthesis of benzotriazole-borane 3.76a and 3.76b. .................................... 140 Scheme 3.13.  Radical Pathway Test using a Radical Clock. .................................................. 142 Scheme 3.14.  Synthesis of methyltriazole borane complex 3.76a. ...................................... 142 Scheme 3.15.  Synthesis of alcohol 3.83. ................................................................................. 143 Scheme 3.16.  Possible equilibrium between free and coordinated borane. ....................... 149 Scheme 3.17.  Working Hypothesis of the Mechanism of Radical Deoxygenation using TAB-BH3 (3.76a). ............................................................................................................................... 158 Scheme 3.18.  Attempted deoxygenation of adamantyl xanthate 3.132. ............................. 160 Scheme 3.19.  Equilibrium of 3.76a with 3.85 and 3.115. .................................................... 160 xx  List of Abbreviations and Symbols ?    chemical shift ABCN    1,1'-azobis(cyclohexanecarbonitrile) Ac    acetyl AIBN    azobisisobutyronitrile Ar    aryl BDE    bond dissociation energy Boc2O    di-tert-butyl dicarbonate Bn    benzyl br. s.    broad singlet Bu    butyl Bz    benzoyl ?C    degrees Celsius cm-1    reciprocal centimetres cat.    catalytic CSA    camphorsulfonic acid d    doublet DBU    1,8-diazabicyclo[5.4.0]undec-7-ene dd    doublet of doublets ddd    doublet of doublets of doublets DDQ    2,3-dichloro-5,6-dicyano-1,4-benzoquinone DFT    density functional theory DIB    (diacetoxy)iodobenzene DIAD    diisopropyl azodicarboxylate DIBAL-H   diisobutylaluminum hydride DMAP    4-dimethylaminopyridine DMF    dimethylformamide DMS    dimethylsulfide DMSO    dimethylsulfoxide dr    diastereomeric ratio E    entgegen ee    enantiomeric excess eV    electron volts ESI    electrospray ionization Et    ethyl EWG    electron withdrawing group GE    General Electric h    hour ?H    enthalpy 1,5-HAT   1,5-hydrogen atom transfer HOMO    highest occupied molecular orbital HPLC-MS   high-performance liquid chromatography-mass spectrometry HRMS    high resolution mass spectrometry xxi  h?    light i    iso IR    infrared J    coupling constant k    rate constant kcal    kilocalories LDA    lithium diisopropylamide LRMS    low resolution mass spectrum LTA    lead tetracetate LUMO    lowest unoccupied molecular orbital m    multiplet M    molarity or parent mass Me    methyl MHz    Mega Hertz m-CPBA   meta-chloroperbenzoic acid min    minute mmol    millimole mol    mole NCS    N-chlorosuccinimide nd    not determined nm    nanometer NHC    N-heterocyclic carbene NMR    nuclear magnetic resonance  nOe    nuclear Overhauser effect OTf    trifluoromethanesulfonate p    para PCC    pyridinium chlorochromate PET    photoinduced electron transfer PG    protective group Ph    phenyl Phth    phthalimide PIDA    phenyliodine diacetate PMB    para-methoxybenzyl ppm    parts per million Pr    propyl PTA    lead tetraacetate q    quartet qt    quintet R    undefined portion of a molecule R    rectus r.t.    room temperature s    second or singlet S    sinister SET    single electron transfer xxii  SN2    bimolecular nucleophilic substitution SOMO    singly occupied molecular orbital t    triplet t    tert TAB    benzotriazole TBAF    tert-butylammonium flouride TBS    tert-butyldimethylsilyl TBDPS   tert-butyldiphenylsilyl TES    triethylsilyl THF    tetrahydrofuran TLC    thin layer chromatography TMS    trimethylsilyl TTMSS   tris(trimethylsilyl)silane Trt    trityl Ts    para-toluenesulfonyl T.S.    transition state UV    ultraviolet UV-Vis    ultraviolet-visible V    volt W    watt X    undefined halogen Z    zusammen xxiii  Acknowledgements I would like to thank my supervisor, Prof. Glenn Sammis, for his guidance, tolerance and encouragement over the years.  His commitment to chemical research and education has been inspiring.  I would also like to thank all of my committee members and especially Prof. Greg Dake for his assistance editing this thesis.  I am humbled by the caliber of student I have encountered during my tenure in the Sammis research group, Dr. Maria Zlotorzynska, Dr. Paul Bichler, Montserrat Rueda-Becerril, Claire Chatalova Sazepin, Joe C.T. Leung, Natalie Campbell, Dr. Hai Zhu and Dr. Huimin Zhai.  Maria and Paul have been my closest friends and allies while pursing my graduate career at UBC, and their attempt to laugh at my jokes were noted.   They have both been greatly missed since graduating. My graduate work would not have been possible without the support from the dedicated staff in the Department of Chemistry at UBC.  I wish to thank the NMR lab, the Mass Spectrometry lab, Chem Stores and the main office for all their work over the years.   Finally, I wish to thank my parents Glen and Dianne for their constant support throughout every step of my post-secondary education.  Every time I freaked out you were always there to put me back on track.  Michael and Corey for being ?challenging?; Lee, Sandy and Danielle for perpetually asking if I was done yet, and to my future wife Natasha.  Tash, I don?t know how to express how much your support has meant to me.  After I?m done this defense, I will probably retire, so you should really look at getting a second job.    xxiv  Dedication  Dedicated to my Uncle Gord,  From: Gordon Wickenden  Sent: Wednesday, April 05, 2006 8:40 AM To: Wickenden, Glen Subject: Re: Jason HURRAY! Congratulations to Jason... and to his mom and dad too. After all.... it?s the parents who start things, do the pushing and the nagging and the paying etc. etc.... Be proud! You earned it! (as evidenced by the grey hairs!).  Wow! A Wickenden with a PHD, the only other Wickenden I have ever heard of with such distinction was William Elgin Wickenden (an engineer) who has his name all over engineering faculties in the US... and many awards named after him... now we have a second contender in the works.......   The only downer in all this?... he will be so far from home...   Give him our congrats eh?....   You are here celebrating with me in spirit Uncle Gord.  You would have been surprised how that conversation on top of the Ottawa Art Gallery changed my perspective on higher education.     xxv  Foreword  A natural product is a secondary metabolite that is isolated from a plant or animal.  Many natural products have biological activity, primarily cytotoxicity, and are used by organisms against competing plants or animals.  The powerful cytotoxicity of many of these molecules makes them promising lead compounds for the pharmaceutical industry.  For example, taxol is a highly cytotoxic molecule isolated from the Pacific Yew tree has been found to be a powerful pharmaceutical for the treatment of a variety of cancers.  When a natural product has overall desirable properties, but has undesired side effects, chemical modifications can be made to obtain a useful pharmaceutical agent. Thus, natural products are vital to the pharmaceutical industry; over half of all modern anticancer medicines are based natural products.      The pharmaceutical importance of natural products creates a premium on the ability to access these compounds quickly, whether it requires the direct access to the compound or the synthesis of a more potent analog.  Fundamental to this pursuit is the development of new chemical techniques for synthesizing the necessary chemical bonds.  The refinement of development of these techniques, or synthetic methodologies, enables more options for a molecular synthesis and, thus, allows for greater artistry and efficiency in their construction. This dissertation discusses work that has been accomplished towards the development of new synthetic methods.  All of the synthetic methods that will be described employ a radical, which is a reactive chemical species possessing an unpaired electron.  Radicals are prone to a variety of different reactions, such as hydrogen abstractions, xxvi  cyclizations, and fragmentations, and their synthetic utility hinges upon the relative reaction rates of these different pathways.  While many of the key reaction rates are included throughout the following three chapters, a table of the rates that are not explicitly referenced in this dissertation has been included in Table 0.1.  Table 0.1. Selected rates for radical reactions. Entry Intramolecular Reactions Rate Constant (M-1s-1)a Reference 1  kc(25) ? 2 x 103 k-c(25) ? 1 x 108 1 2  kc(25) ? 1 k-c(25) ? 5 x 103 1 3  k(25) = 2.5 x 105  2 4  k(80)cis = 5.5 x 105 3 5  k(80)trans = 2.0 x 105 3 6  k(25) = 5 x 107 4 7  k(80) = 2.5 x 105 5 8  k(25) = 3.9 x 103 2b,c xxvii  9  k(25) = 5.1 x 103 3 10  k(25) = 8.8 x 102 3 11  k(25) = 6.0 x 108 6 12  kc(50) = 5 x 104 k-c(25) = 1.7 x 104 7 13  k(25) = 2.7 x 107 8 14  k(25) = 1.0 x 102 9 a Reaction temperature (?C) as subscript.  In chapter 1, a brief overview of radical relay cyclization chemistry is discussed, focusing on the application of this methodology towards the synthesis of naturally occurring products.  The optimization of this reaction, and investigation into the substrate scope is then discussed.  I envision the future direction of this methodology to involve the synthesis of a variety of acetogenins, a class of naturally occurring and biologically active compounds.  In chapter 2, a brief overview of the application of aminyl radical cyclizations towards the synthesis of small nitrogen-containing molecules is discussed.  During our optimization studies of a previous reaction, an unexpected cyclic imine product was discovered.  The chapter describes the optimization of the reaction to provide the cyclic imine as the major product, and the scope of this transformation is expanded.   A section is xxviii  dedicated for the work done to apply this newly optimized method towards a target-oriented synthesis of (?)-lepadiformine A. In chapter 3, methodology studies on the use of a boron containing compound as a replacement for organotin hydrides is discussed.  Organotin hydrides are used almost exclusively as a reagent in radical reactions.  There is interest to find a suitable replacement for organotin hydrides in radical reactions as they are toxic and disposal is difficult.  This chapter begins with a brief description of the research into finding suitable replacements for organotin hydrides.  This chapter also describes the research and optimization into this new reagent, and the scope of this reaction is also studied.  As part of the future direction of this project, further optimization studies are suggested.              xxix          Chapter 1 : Construction of Carbo- and Heterocycles Using Radical Relay Cyclizations Initiated by Alkoxy Radicals            1  1.1 Introduction The discovery of the triphenylmethyl radical in 1900 by Moses Gomberg10 marked the beginning of the field of free radical chemistry.  Radicals are typically highly chemically reactive and for years little progress was made towards the development of selective methodologies.  It was not until the late 1960?s that the scope of these reactive intermediates began to be appreciably investigated, and the resulting research efforts have provided many powerful radical based methodologies.11  These free radical reactions are an attractive alternative to many ionic methodologies for carbon-carbon bond formation because radicals generally are reactive towards different functional groups than anionic species, have predictable reactivity, and generally require mild conditions for their generation.12  Furthermore, the addition of a radical to an alkene acceptor will form a ?-bond and another radical intermediate, which can further react if another acceptor is nearby.15  Radicals can, therefore, form multiple carbon-carbon bonds in a single reaction, called a cascade reaction.   1.2 Radical Cascade Cyclization Reactions Radical cascade cyclization reactions are important synthetic transformations, which have been used to form complex molecular structures.13,14,15  While many radical cascade reactions have been reported, the most common type  are intramolecular cascade reactions.   Scheme 1.1.  Synthesis of (?)-?9(12)-capnellene (1.4). 2  Curran and co-workers employed a radical cascade cyclization in their classic synthesis of (?)-?9(12)-capnellene (Scheme 1.1, 1.4).16  Intramolecular radical cascade cyclizations are often promoted by the strategic incorporation of radical acceptors in the substrate.  These radical cascade substrates can be modified to allow for different radical acceptors, ring sizes and various functional groups.  Radical cyclization cascade reactions have proven to be important methods in the assembly of complex cyclic molecular structures from linear precursors.  In the absence of any nearby reactive radical acceptors, the radical intermediate can be relayed across the backbone of the substrate (Scheme 1.2, 1.5).  This radical relay typically involves breaking an un-activated carbon-hydrogen ?-bond, which is located five or six atoms away, to effect a hydrogen atom transfer (HAT) reaction  X XHHXHXHX1.5 1.6 1.71.81.9X = O, N, CH2 Scheme 1.2.  Radical relay cyclization cascade. Once the radical intermediate has been ?relayed? across the backbone of a substrate, the newly formed carbon radical (1.7) may then undergo a radical cyclization to afford cyclopentane 1.9.   3  1.2.1 Radical Relay Reactions Initiated by sp3 Hybridized Carbon Radicals Radical translocation reactions initiated from sp3 hybridized carbon radicals have received limited synthetic interest.  While a radical translocation reaction from one sp3 hybridized carbon to another sp3 hybridized carbon atom would be synthetically useful, the rate constant for this transposition is on the order of 102 s-1 and, therefore, is prohibitively slow.  The rate of sp3-sp3 radical translocation increases if the radicals are not equal in stability, for example when the hydrogen atom to be transferred is either allylic, benzylic or ? to a heteroatom, this transformation can be synthetically useful.17,18  Representative examples are outlined in the following paragraphs.    OOHgOAcNaBH4 OOH1,5 - HAT OOCNOOCNstepsOOO1.10 1.11 1.121.131.14 Scheme 1.3.  A total synthesis of (+)?ipomeamarone (1.14) by Sugimura et al. An early example of a radical relay reaction initiated by a sp3 hybridized radical was demonstrated in the context of a total synthesis of (+)-ipomeamarone (Scheme 1.3, 1.14) by 4  Sugimura and co-workers.17  Reduction of the organomercury compound 1.10 with sodium borohydride produced alkyl radical 1.11.  Intramolecular transfer of the hydrogen atom ? to the oxygen afforded ketal radical 1.12, which then reacted with acrylonitrilie to afford nitrile 1.13 in 59% yield.  Nitrile 1.13 was transformed into (+)-ipomeamarone 1.14 in five additional steps.  An elegant radical relay cyclization involving a cyclopropane ring opening and subsequent radical transposition was developed by Rawal and co-workers (Scheme 1.4).18  Treatment of ketone 1.15 with tributyltin radical provided carbon radical 1.16, which further fragmented to provide primary radical 1.17.  A subsequent 1,5-HAT afforded carbon radical 1.18, which then underwent a 5-exo-trig cyclization to afford carbon radical 1.19.  A subsequent fragmentation of the tributylstannyl radical provided the desired bicyclic ketone (1.20).     Scheme 1.4.  Synthesis of bicyclic ketone 1.20 using a 1,5?HAT reaction.  5  1.2.2 Radical Relay Cyclization Reactions Initiated by sp2 Hybridized Carbon Radicals  Most examples of radical relay cyclizations are initiated at sp2 hybridized carbon atoms.  This approach may be further broken into three initiation techniques, which will be briefly reviewed in the following sub-sections. 1.2.2.1 Radical Relay Cyclization Reactions Initiated by Vinyl Radicals   In the late 1980?s, studies by both Curran19 and Parsons20 demonstrated that vinyl halides could be employed to initiate radical relay cyclization reactions.  An elegant example of a radical relay reaction initiated by a vinyl radical was demonstrated by Simpkins and co-workers in the synthesis of spiroacetals (Scheme 1.5).21  Treatment of vinyl iodide 1.21 with tributylstannyl radical provided vinyl radical 1.22, which then undergoes intramolecular 1,5-HAT to form radical 1.23.  Cyclization and intermolecular HAT from tributyltin hydride afforded spiroacetal 1.25 in good yield. 6   Scheme 1.5.  Synthesis of spiroacetal 1.25 using a 1,5?HAT initiated by a vinyl radical. 1.2.2.2 Radical Relay Reactions Initiated by Aryl Radicals  Radical relay cascade reactions involving 1,5-HAT reactions by an aryl radical represents the largest subset of radical translocation reactions.  Work by Curran and co-workers demonstrated that aryl halides are effective precursors for remote functionalization in natural product synthesis.22  Snieckus and co-workers employed this methodology in the diastereoselective synthesis of several ?-amino acids (Scheme 1.6).23  Treatment of aryl bromide 1.26 with tributylstannyl radical provided aryl radical 1.27.  Subsequent 1,5-HAT afforded radical 1.28, which then reacted with acrylonitrile to provide nitrile 1.29.  Treatment of nitrile 1.30 with aqueous acid provided the desired ?-amino acid in good yield. 7   Scheme 1.6.  Diastereoselective synthesis of a ?-amino acid 1.30. 1.2.2.3 Radical Relay Reactions Initiated by Additions to Alkynes  A third method for the formation of sp2 hybridized carbon radicals to initiate relay cyclizations is the addition of a radical to an alkyne.  Bosche and co-workers employed this strategy via an intermolecular addition to an alkyne in the synthesis of the bicyclic lactam (Scheme 1.7, 1.35).24  Treatment of alkyne 1.31 with tributylstannyl radicals afforded vinyl radical 1.32.  A 1,6-HAT reaction afforded a captodatively stabilized radical (1.33), which then underwent a 7-endo-trig cyclization to afford carbon radical 1.34.  Radical scission of the carbon-tin bond afforded the desired product 1.35 in moderate yield, as well as some vinyl stannane 1.36. 8    Scheme 1.7.  Synthesis of bicyclic lactams starting from alkyne precursors. Crich and co-workers strategically employed a radical relay cyclization in diastereoselective synthesis of substituted cyclopentane derivatives (Scheme 1.8).25 Acetal 1.37, containing a camphor derivative as a chiral auxillary, was treated with tributylstannyl radical to afford primary radical 1.38.  A subsequent 5-exo-dig cyclization afforded sp2 hybridized radical 1.39, which next participated in a 1,5-HAT reaction to afford datively stabilized radical 1.40.  The desired acetal 1.42 was isolated in good yield following a 5-exo-trig cyclization, and regeneration of the tributylstannyl radical. 9   Scheme 1.8.  Diastereoselective synthesis of substituted cyclopentanones. 1.2.2.4 Radical Relay Reactions Initiated by Nitrogen-Centred Radicals  Nitrogen-centred radicals26 have been widely used as initiators in radical translocation reactions.  The Hofmann-L?ffler-Freytag reaction has been widely used for the construction of nitrogen containing heterocyclic compounds, and is an example of a remote functionalization via a 1,5-HAT.27 Radical relay cyclization reactions initiated by aminyl radicals have not been as widely studied.  Kim and co-workers have reported a radical relay cyclization reaction initiated by a tin-bound aminyl radical will readily participated in both HAT and cyclization reactions.28 Treatment of the azide (Scheme 1.9, 1.43) with tributylstannyl radical provided radical 1.44, which evolves nitrogen gas to afford the tributylstannylaminyl radical 1.45.  A radical translocation and subsequent 5-exo-trig cyclization provided primary radical 1.47, which eliminated the tributylstannyl radical to 10  afford tetrahydrofuran 1.48.  The nitrogen-tin bond is cleaved during the workup of the reaction, affording the primary amine 1.49, which was further derivatized to tosylate 1.50 for purification purposes.  Reactions of the tributylstannylaminyl radical are further discussed in chapter 2.   Scheme 1.9.  Synthesis of tetrahydrofuran 1.50 from azide 1.43. 11  1.2.3 Radical Reactions Involving Alkoxy Radicals  Figure 1.1.  Representative reactions of alkoxy radicals. Alkoxy radicals have been observed to undergo several important intramolecular reactions, including cyclizations,29 ?-fragmentations30 and 1,5-hydrogen atom translocations31 (Figure 1.1).  The following sections will focus on the generation and use of alkoxy radicals in hydrogen atom transfer reactions.   The regioselective transposition of a hydrogen from a non-activated carbon atom to an alkoxy radical is a valuable tool for the functionalization and alkylation of bonds that are unreactive under ionic conditions.  1,5?HAT?s occur preferentially via a cyclic chair-like transition state (Scheme 1.10, 1.59)32 and, therefore, 1,5?HAT reactions typically dominate over 1,4- and 1,6?HAT?s.33  1,6-HAT reactions only occur if the resulting carbon radical is datively stabilized by a nearby heteroatom.34 12   Scheme 1.10.  Intramolecluar hydrogen transfer reaction. The Barton reaction marked the inception of radical translocation reactions initiated by alkoxy radicals towards the synthesis of a naturally occurring product (Scheme 1.11).35,36   The key step in this total synthesis was built on the novel reaction of a nitrile ester, which underwent homolytic cleavage under photochemical conditions to provide alkoxy radical 1.62.  Radical translocation, followed by the direct functionalization of that newly formed carbon radical (1.63) and tautomerization provided oxime 1.64, which was further hydrolyzed to the desired aldosterone acetate.  Since the seminal work by Barton, numerous advances have been made in oxygen-centered radical processes.37   Scheme 1.11.  Barton?s synthesis of aldosterone acetate (1.64).  13  1.3 Generation of Alkoxy Radicals  The generation of alkoxy radicals has been extensively studied.38 The direct formation of an alkoxy radical from an alcohol is challenging due to the prohibitively strong oxygen-hydrogen bond (Table 1.1, entry 6). 39,40  This constraint may be overcome via the installation of a weaker oxygen-heteroatom bond, such as those found in oxygen-nitrogen, oxygen-oxygen, oxygen-sulfur and oxygen-chlorine bonds (Table 1.1). The oxygen-heteroatom precursors are typically formed using nucleophilic displacement reactions. Table 1.1.  Homolytic bond strengths for selected single bonds to oxygen. entry bond homolytic bond dissociation energy (kcal/mol) 1 HO-OH 51 2 (H3C)3CO-NO 41 3 HO-Cl 60 4 H3CO-SCH3 63 5 H3CO-CH3 83 6 HO-H 120  14   Figure 1.2.  Selected examples of alkoxy radical precursors. Homolysis of an oxygen-heteroatom bond may be readily accomplished under both thermal and photochemical conditions.  Selected examples of alkoxy radical precursors have been provided in Figure 1.2.  Photolysis can be an attractive option as the conditions to homolytically cleave the oxygen-heteroatom bond are generally mild reactions and proceed using ambient light.  However, in some cases this photosensitivity makes the radical precursors unstable, and necessitates their installation immediately prior to irradiation.     Tsunoi and co-workers utilized photolabile benzenesulfenates as alkoxy radical precursors in remote functionalization (Scheme 1.12).41  Photolysis of the sulfenate ester bond in 1.73 afforded an alkoxy radical (1.74), which, following a 1,5-HAT, provided carbon radical 1.75.  At elevated pressure, a reaction with carbon monoxide produced acyl radical 1.76, which reacted with the sulfenyl radical to afford thioester 1.77.  Subsequent nucleophilic acyl substitution reaction afforded lactone 1.78 is modest yield.  15   Scheme 1.12.  Synthesis of lactone 1.78 from arenesulfenate 1.73.  In addition to photolysis, homolysis of an oxygen-nitrogen bond may also be achieved under thermal conditions.  N-Alkoxyphtalimides have been investigated by Kim and co-workers as an excellent method of achieving alkoxy radical cyclization reactions.42 Heating a solution of N-alkoxyphthalimide (Scheme 1.13, 1.79) and tributylstannyl radical results in homolytic cleavage of the nitrogen-oxygen bond, affording an alkoxy radical (1.80).  Oxygen-centered radical 1.80 then undergoes a reductive radical cyclization to afford a substituted tetrahydrofuran (1.82) in excellent yield.  Scheme 1.13.  Tin-mediated alkoxy radical generation and subsequent 5-exo-trig cyclization. 16  N-Alkoxyphtalimides differ from the previously discussed alkoxy radical precursors (Figure 1.2) in that they are stable to ambient and UV irradiation (? > 300 nm).43  Furthermore, N-alkoxyphthalimides are bench stable and are tolerant to a variety of reaction conditions.   Generation of an alkoxy radical directly from an alcohol may also be accomplished using strong oxidants, such as PIDA/I244 or PTA.45 For example, Su?rez and co-workers have formed spiroacetals using PIDA and I2 protocol (Scheme 1.14).46  Treatment of monosaccharide 1.83 with PIDA and I2 leads to the in situ formation of a hypoiodite (1.84).  Homolysis of the oxygen-iodine bond provided an alkoxy radical 1.85, which, following a 1,5-HAT reaction, afforded carbon radical 1.86.  This alkyl radical (1.86) is likely first oxidized to an oxacarbenium ion and then undergoes a cyclization to form spiroacetal 1.87 in good yield.  17   Scheme 1.14.  Formation of spiroacetal 1.87 initiated by PIDA/I2.  All the examples of alkoxy radical generation provided thus far have occurred via the homoloysis of a weak oxygen-heteroatom bond.  The formation of an alkoxy radical by homolysis of a carbon-oxygen bond is difficult, but may occur in strained systems such as epoxides.  This method was first reported by Barton over three decades ago,47 and has proven to be an excellent indirect method for the formation of alkoxy radicals.  Rawal and co-workers have investigated synthetic applications of these epoxide fragmentation reactions, in the context of radical relay cyclization reactions.48  For example, treating epoxide (Scheme 1.15, 1.88) with the phenylsulfinyl radical produces carbon radical 1.89, which fragments the epoxide ring to afford alkoxy radical 1.90.  The ensuing radical translocation reaction afforded carbon radical 1.91, which next cyclized to afford carbon radical 1.92.  A subsequent elimination of the phenylsulfinyl radical afforded alkene 1.93.  18   Scheme 1.15.  Epoxide fragmentation and radical relay cyclization reaction.  1.4 Alkoxy Radical Initiated Translocation Reactions While carbon-centered radical translocation reactions have been utilized in synthesis, linear radical cascade reactions initiated by alkoxy radicals have not been thoroughly investigated.  An early example of this methodology reported by ?ekovi? and co-workers involved the photodecomposition of a nitrite 1.94 (Scheme 1.16).49  While this reaction served as proof of concept, it unfortunately suffered several limitations, such as low yields of cyclized product 1.95, which was partially a result of the amount of linear product 1.96 produced (14%). 19  ONOHONOHOON1.94 1.96 (14%)1.95 (32%)hv Scheme 1.16.  Radical relay cyclization initiated by a 1,5-HAT reaction. Linear radical cascade reactions can also be initiated when a carbon radical is placed ? to an epoxide.  This methodology is effective for the synthesis of carbocycles and generally provides high yields and diastereoselectivities.  There are, however, two limitations to this type of methodology: (1) the one example of a linear substrate (Scheme 1.17, 1.97)48a provided the resulting cyclopentane (1.102) in low yield and diastereoselectivity, and (2) there is no flexibility in the cyclization step as the alkene generated during the course of the reaction (1.98 to 1.99) always serves as the cyclization acceptor (1.100 to 1.101).   Scheme 1.17.  Synthesis of cyclopentane 1.102 via radical epoxide fragmentation.  20  1.5 Mechanism A significant challenge of a radical relay cyclization initiated by alkoxy radicals is that it is difficult to control the selectivity of the radical intermediates.  This is most pronounced with the radical relay cyclization methodology developed by ?ekovi? and co-workers.49  In these systems, the yield of the cyclized products were low due to the challenge of controlling the amount of reactive radical species in solution.  We hypothesized that we could favour the formation of cyclized product in reactions similar to those performed by ?ekovi? if we kept the concentration of radical trapping agents low.  We proposed to do this in two ways: (1) employ an alkoxy radical precursor which would be completely unreactive following homolysis of the oxygen-heteroatom bond and (2) keep the concentration of tributyltin hydride low in solution via slow addition using a syringe pump. N-Alkoxyphtalimides (Scheme 1.18, 1.103) are a promising class of alkoxy radical precursors as they are bench stable compounds that react readily with metal hydrides.  The product (1.81) of the reaction between the tributyltin radical and an N-alkoxyphthalimide (1.103) would be completely unreactive to any further radical reactions.  By limiting the amount of reactive species in solution we sought to maximize the amount of desired cyclized product. 21   Scheme 1.18.  Mechanism of a radical relay cyclization using N-alkoxyphthalimide precursors. The reaction of the tributyltin radical with an N-alkoxyphthalimide (1.103) leads to the formation of alkoxy radical 1.104 and by-product 1.81, which will not further react with any of the key radical intermediates.  The oxygen-centred radical 1.104 can then undergo a 1,5-HAT reaction forming secondary radical 1.105.  If the concentration of tributyltin hydride is kept low, the rate of the intermolecular hydrogen atom transfer with tributyltin hydride should be significantly slower than the rate of cyclization, thus favoring the formation of 1.107.  A HAT reaction between primary radical 1.107 and tributyltin hydride should provide the desired cyclized product 1.108 and regenerate the tributyltin radical. We were interested in first optimizing the reaction conditions to favour the cyclized product (Scheme 1.18, 1.108) and minimize the amount of linear alcohol 1.106 formed.  We tested our hypothesis using linear precursor (Figure 1.3, 1.109).  With optimized conditions 22  in hand, we then investigated the scope of the reaction by including oxygen and nitrogen functionality and by varying the substitution within the linear precursor. Our planned studies required the synthesis of the compounds depicted in Figure 1.3.  Figure 1.3.  Substrates used in alkoxy radical initiated cascade studies. 1.6 Results and Discussion  Scheme 1.19.  Synthesis of radical cyclization precursor 1.109. 23   Scheme 1.20.  Synthesis of radical cyclization precursor 1.110. A Mitsunobu reaction50 between alcohol 1.118 and N-hydroxyphthalimide (1.119) afforded N-alkoxyphthalimide 1.109.  Homologated N-alkoxyphthalimide (Scheme 1.20, 1.110) was synthesized using the same protocol outlined for N-alkoxyphthalimide 1.109.  Scheme 1.21.  Synthesis of N-alkoxyphthalimide carbamate 1.112. Synthesis of N-alkoxyphthalimide 1.112 (Scheme 1.21) began with the protection of 1.123 to provide carbamate 1.124 in quantitative yield.  Carbamate 1.124 was treated with TBDPSCl to afford silyl ether 1.125.  Conjugate addition of silyl ether 1.125 to acrolein 24  under acidic conditions afforded aldehyde 1.126 in good yield.  A Wittig reaction and subsequent removal of the silyl ether afforded alcohol 1.127.  The N-alkoxyphthalimide was then installed by treating alcohol 1.127 with N-hydroxyphthalimide (1.119) using a Mitsunobu reaction.   Scheme 1.22.  Synthesis of N-alkoxyphthalimide ether 1.114. Synthesis of N-alkoxyphthalimide ether 1.114 began with known tosylate 1.12851 (Scheme 1.22). Nucleophilic substitution of the tosylate afforded TBS ether 1.129 in modest yield.  Subsequent removal of the TBS ether afforded alcohol 1.130, which was treated with N-hydroxyphthalimide 1.119 using a Mitsunobu reaction to afford N-alkoxyphthalimide 1.114. 25   Scheme 1.23.  Synthesis of N-alkoxyphthalimide ether 1.113. Synthesis of N-alkoxyphthalimide ether 1.113 (Scheme 1.23) began with a substitution reaction between known tosylate 1.128 and the pent-4-en-1-olate ion.  The resulting TBS ether 1.131 was deprotected with TBAF to afford alcohol 1.132.  The N-alkoxyphthalimide functionality was installed using a Mitsunobu reaction between alcohol 1.132 and N-hydroxyphthalimide 1.119.   Scheme 1.24.  Synthesis of N-alkoxyphthalimide ether 1.115. Synthesis of N-alkoxyphthalimide ether 1.115 (Scheme 1.24) was accomplished in two steps from commercially available 1,5-pentanediol 1.133.  SN2 displacement of the bromide functional group found in 1.134 with the mono-anion of diol 1.133 afforded allyl alcohol 1.135.  Installation of the N-alkoxyphthalimide group was achieved in good yield via a Mitsunobu reaction. 26   Scheme 1.25.  Synthesis of tosylhydrazone 1.117. The synthesis of tosylhydrazone 1.117 (Scheme 1.25) began with a substitution reaction, providing TBS ether 1.129.  The resulting TBS ether 1.129 was treated with TBAF to remove the protecting group affording alcohol 1.130.  A Mitsunobu reaction between N-hydroxyphthalimide 1.119 and alcohol 1.130 afforded N-alkoxyphthalimide 1.114.  Oxidative cleavage of the alkene functional group in 1.114 provided the aldehyde, which was then converted to tosylhydrazone 1.117.  Compounds 1.111 and 1.116 were prepared by Joe C. T. Leung and Natalie Campbell, respectively, using methods similar to those described above.    We first investigated the formation of cyclopentane derivatives using a radical relay cyclization reaction by optimizing the concentration of N-alkoxyphthalimide 1.109 and the rate of addition of stannyl and silyl hydrides (Table 1.2).  27  Table 1.2.  Optimization studies on the rate of addition of the metal hydride.  entry(a) metal Hydride addition reaction Time (h) cyclization/linear (1.136/1.137)(b) 1 Bu3SnH One portion 1 77:23 2 Bu3SnH 1 mL/h 2 92:8 3 Bu3SnH 0.5 mL/h 3 95:5 4 Ph3SnH One portion 1 67:33 5 Ph3SnH 0.5 mL/h 3 80:20 6 (TMS)3SiH One portion 1 90:10 (a) Reactions were carried out on a 0.17 mmol scale.  (b) Conversions determined by NMR spectroscopic analyses of crude reaction mixtures.  Addition of tributyltin hydride in one portion (Table 1.2, entry 1) provided a similar product distribution of cyclized 1.136 to linear 1.137 as had been previously reported on a similar substrate.49  As the rate of tributyltin hydride addition is decreased, the ratio of cyclized product 1.136 to linear alcohol 1.137 achieved was 95:5 (entries 2 and 3).  Slow addition of triphenyltin hydride produced the cyclized product (entries 4 and 5) but the effect of slow addition was not as pronounced as seen with tributyltin hydride (entry 3 versus entry 5).  The radical cascade reaction can be achieved under tin-free conditions using tris(trimethylsilyl)silane (entry 6).  Since the rate of intermolecular hydrogen atom transfer from the silyl hydride is slower compared to the stannyl hydride60a, slow addition was not required to achieve excellent selectivity for the cyclized product 1.136.  28   With the basic reactivity and optimized conditions for the desired cyclized product established, we next sought to investigate the scope of this transformation (Table 1.3) Table 1.3.  Alkoxy radical initiated cyclization cascades(a). entry substrate(b) product(c) yield(%)(d) d.r.(e)  1      79  75:25 2    24 50:50 3    64 65:35 4   63 56:44 5   62 90:10 6   <5 nd 7   41 60:40 29  8   64 86:14 9   55 --- (a) All cyclization reactions were carried out using our optimized conditions (see general cyclization procedure) (b) Reactions were carried out on a >0.25 mmol scale. (c) The relative stereochemistry was determined by nOe experiments. (d) Isolated yields of the mixture of diastereomers after flash column chromatography. (e) The diastereomeric ratio was determined by 1H NMR spectroscopy. (e) Reactions were monitored by 1H NMR spectroscopy and complete conversion of the starting material was observed.   Simple cyclopentane derivatives were formed in good yields as a 75:25 mixtures of cis to trans isomers (entry 1).  Attempts to cyclize homologated N-alkoxyphthalimides to form cyclohexane derivatives provided the desired cyclized product in very low yields and in poor diastereoselectivities (entry 2). Analysis of the crude reaction mixture by 1H NMR spectroscopy revealed a 79:21 mixture of cyclized product 1.138 to linear alcohol. Linear alcohol (Scheme 1.20, 1.121) is presumably formed by trapping the less reactive carbon radical with tributyltin hydride prior to cyclization, and is most likely not the result of trapping the highly reactive alkoxy radical.  As the experimental rate constant for a 5-exo-trig cyclization (105 s-1)52 is several orders of magnitude larger than a 6-exo-trig cyclization (103 s-1),53 this observation agrees with the kinetic data for these two ring closures.  Incorporation of a geminally disubstituted alkene 1.111 resulted in a 6-endo cyclization, presumably due to the stabilization of the resulting radical species upon cyclization.  Attempts to synthesize carbocycles containing more than six carbons provided the linear alcohol as the major product.   For our radical cascade methodology to be widely applicable, it would be desirable to perform cyclizations that would produce heterocyclic compounds.  Nitrogen-containing 30  substrate 1.112 (Table 1.3, entry 4) readily cyclized to form pyrrolidine 1.140 as a 56:44 mixture of cis:trans diastereomers in a 63% yield.  Uncyclized aminoalcohol 1.127 (Scheme 1.21) was not observed by 1H NMR analysis of the crude reaction mixture.  Similar to the carbon analogue, homologated piperidine derivatives were investigated by Joe C. T. Leung, however they were found to form cyclic products in poor yields and diastereoselectivities.  Oxygen-containing heterocycles were also accessed using the radical relay cyclization methodology.  Ether 1.114 (Table 1.3, entry 5) cyclized smoothly to afford 2,3-cis-tetrahydrofuran 1.141 in a 62% yield and as a 90:10 mixture of cis:trans diastereomers.  Attempts to cyclize ether 1.115 (entry 6) to a 3,4-substituted tetrahydrofuran provided the linear alcohol 1.135 (Scheme 1.24) as the only product.  Failure of this reaction to produce any cyclized product is most likely the result of a preferential 1,6-HAT over a 1,5-HAT.  It has previously been observed that alkoxy radicals preferentially abstract hydrogen atoms ? to oxygen atoms.54,55  This hydrogen abstraction is favoured over the 1,5-HAT as the resulting radical can be datively stabilized by the adjacent oxygen atom. 31   Scheme 1.26.  Proposed 1,6-hydrogen abstraction. Treatment of N-alkoxyphthalimide 1.115 with tributyltin radical generates alkoxy radical 1.146.  Dative stabilization by the oxygen atom is sufficient to bias a 1,6-HAT over a 1,5-HAT, providing carbon centered radical 1.147.  The resulting radical can either undergo a 4-exo cyclization to form oxetane 1.148 or an intermolecular HAT reaction between a stannyl hydride. However, 4-exo cyclizations of carbon radicals are slow (kc = 1 s-1) and reversible (k-c = 103 s-1)56b and as a result only the linear product 1.135 is observed.   Cyclization of ether 1.113 (Table 1.3, entry 7) provided tetrahydropyran 1.143 with a slightly better yield (41%) when compared with the carbon analog (<30%), although the diastereoselectivity was still modest.  Cyclization of racemic substrate 1.116, containing an existing stereocentre afforded the trisubstituted tetrahydrofuran 1.144 in a 64% yield and 86:14 ration of the cis isomer to all other isomers.  32   Substituted tetrahydrofurans are common structural motifs in many bioactive polyketide natural products.57  These natural products have a variety of substitution patterns, which we were interested in accessing using our radical relay cyclization methodology.  N-Tosylhydrazones have previously been shown to be excellent radical acceptors for the formation of large heterocyclic compounds,58 yet to the best of our knowledge had never been utilized in a radical relay cyclization reaction.  Incorporation of an N-tosylhydrazone functional group into cyclization substrate would be advantageous as it allows access to tetrahydrofuran containing fragments that possess substitution patterns that differ from the cyclized products listed (Table 1.3, entries 5 and 8).    Scheme 1.27.  Mechanism for the formation of mono-substituted tetrahydrofuran 1.145. The radical relay cyclization reaction began with the treatment of N-tosylhydrazone 1.117 (Scheme 1.27) with the slow addition of tributyltin hydride and AIBN, generating alkoxy radical 1.149.  Subsequent 1,5-HAT produced carbon radical 1.150, which rapidly cyclized to form aminyl radical 1.151.  Elimination of a tosyl radical produced diazine 33  1.152, which further eliminated nitrogen gas to afford a mono-substituted tetrahydrofuran (1.145).  One drawback of our radical relay cyclization methodology is the scarcity of methods to effect this cyclization under organotin-free conditions.  The ideal radical relay substrate would be one that could be carried through several synthetic transformations, and then produce the prerequisite alkoxy radical under relatively mild conditions.  It is also desirable to carefully control the concentration of radical initiator in solution, to maximize the yield of cyclized product.  While N-alkoxyphthalimides satisfy these requirements, alkoxy radical generation requires the slow addition of a stoichiometric amount of tributyltin hydride.  Organotin compounds, such as tributyltin hydride, are toxic and create disposal problems.59  While methods to accomplish this transformation were investigated using tris(trimethylsilyl)silane,60 the cost of this reagent makes any large scale application an expensive endeavor.  Thus, the utility of our radical relay cyclization methodology would be greatly improved if a less toxic alkoxy radical generating methodology were developed.  Our group?s contribution to this research goal will be outlined and elaborated in chapter 3.   Computational studies performed by Beckwith52b,c and Houk61 have demonstrated that the diastereoselectivity of 5-exo radical cyclizations can be predicted by the analysis of both chair-like and boat-like transition states (Figure 1.4).  According to calculations, the two lowest energy transition states (1.153 and 1.155) should provide cis-1.154 as the major diastereomer.  Indeed, cis-1.154 was the major diastereomer observed in our systems.  The major diastereomers were determined using nOe spectroscopy, and/or were derivatized to, and compared with the spectra known compounds.  Cis-1.154 may be produced by either chair-like transition state 1.153 or boat-like transition state 1.155.  34  Trans-1.157 was observed to be the minor diastereomer, and may be produced by either chair-like transition state 1.156 or boat-like transition state 1.158.  Of the two chair-like transition states (1.153 and 1.156), 1.153 would be the lower energy transition state as there is less of a steric interaction between the alkyl group (R) with either of the geminal hydrogen atoms attached to the alkene.  Similarly, comparing the two boat-like transition states (1.155 and 1.158), 1.155 would be the lower energy transition state due to the minimized steric interaction between the alkyl group (R) with either of the terminal hydrogen atoms on the alkene.   Figure 1.4.  Chair- and boat-like transition states for 5-exo cyclizations.  The incorporation of an oxygen atom provided an improvement in the observed diastereoselectivities (Table 1.3, entries 1 and 5).  According to calculations by Beckwith52a and Houk,61 the two lowest energy transition states should be the chair-like transitions states outlined in Figure 1.5.  The transition state that leads to cis-1.154 should be lower in energy than the transition state that provides trans-1.157.  Positioning the alkyl group (R) in the pseudo-equatorial position (1.153) will minimize the 1,3-diaxial-type interactions.  35  When an oxygen atom is incorporated into the framework, the bond lengths in both chair-like transition states (1.159 and 1.161) are shortened.  This tightening of the bond lengths in the transition states does not significantly alter the 1,3-diaxial-type interactions in 1.159, but should result in a greater steric interaction in 1.161.  As transition state 1.159 will have a lower relative energy when compared to transition state 1.161, it should favour the formation of cis-1.160 over trans-1.162.  Figure 1.5.  Comparison of chair-like transition states for the 5-exo cyclization step.  36   The incorporation of a BOC-protected amine into the linear radical precursor provided the pyrrolidine product (Table 1.3, 1.140) in good yield, but poor diastereoselectivity.  The lowered selectivity of this cyclization may be a result of the protecting group.  The lone pair on the nitrogen will be delocalized, which would provide more planar character in the transition state, resulting in poor diastereoselectivity. 1.7 Future Work Annonaceous acetogenins are a structurally diverse class of naturally occurring polyketides that are isolated from a number of tropical and subtropical plants of the Annonaceae family.62  In the past 15 years, these compounds have become an attractive area of phytochemical and pharmacological studies owing to the wide range of biological activities ascribed to them.63,64,65,66,67 The discovery of uvaricin,68 the first of the annonaceous acetogenins as an in vivo active antileukemic (P-388) agent, has invigorated interest in these compounds as possible chemotherapeutic treatments for cancer.  The annonaceous acetogenins are now one of the most rapidly growing classes of new natural products and offer exciting anthelminitic, antitumor, antimalarial, antimicrobial, antiprotozoal and pesticidal activities and promise of becoming new chemotypes for antitumor agents. The acetogenins are a series of C-35/ C-37 natural products that are derived from C-32/ C-34 fatty acids.  They typically present several unique structural characteristics (Figure 1.6).  Most common skeletons are characterized by unbranched aliphatic chains (I and III) bearing a methyl and a 4-methyl butenolide moiety (I and IV).   37   Figure 1.6.  A representation of a typical acetogenin. Acetogenins contain between one and three 2,5-disubstituted tetrahydrofuran (THF) ring(s) in the middle region of the molecule (II),  They often contain several oxygenated functionalities along the aliphatic chains (I ? III) which may be comprised of hydroxyls, acetoxyls, ketones and epoxides, as well as multiple bonds.  Varying the position, substitution and stereochemistry of these substituents allows for a range of potentially bioactive compounds. The acetogenins display a broad range of bioactivities including cytotoxicity towards various cancer cell lines.69,70,71,72   Recent reports have also indicated that the acetogenins have the potential to inhibit cancer cells that are multidrug resistant (MDR),73 allowing new treatment strategies to be developed.  Although the acetogenins occur naturally, they are often isolated as complex mixtures of stereoisomers that share similar structures.  It would be advantageous to have a concise route that would provide both material for pharmacological investigations.  To wit, radical relay cyclization methodology has not been employed during the synthesis of this class of natural products.    Figure 1.7.  Trans-1.163 and cis-1.164.  Studies have illustrated that the acetogenins are toxic towards some cancer cell lines.  However, most acetogenins that have been submitted for biological analysis contain a trans- 38  furan ring orientation (Figure 1.7, 1.163).  Of the approximately 400 acetogenins known, a mere 16 of them contain examples of a THF core matching that in cis-1.164.74  Isolation of these compounds is extremely difficult, for example, 24 mg of cis-annonacin was recovered from 2.2 kg of dried seeds from the Annona muricata tree.75 Two of the known compounds, cis-uvariamicin I and cis-reticulatacin have never been isolated as pure compounds.76 Biological studies on the cis-THF acetogenins are, therefore, sparse and difficult to accomplish.  A concise and modular synthesis of the cis-THF compounds would greatly aide in a thorough biological evaluation of these uncommon compounds. Hydrazones were previously demonstrated to be excellent radical acceptors for the formation of large carbocycles.77  We had previously demonstrated that hydrazones were a suitable class of radical acceptors in a radical relay cyclization reaction.  An extension of the work outlined earlier in this chapter would furnish cis-THF ring with substitution that could permit the installation of both aliphatic chains (Figure 1.6, I and III).  Following a radical relay cyclization reaction, alcohol 1.166 (Scheme 1.28) could be easily transformed into alkene 1.167.  The catalytic installation of an aliphatic fragment (Figure 1.6, III) via a Grubb?s cross metathesis reaction, and subsequent reduction should afford butenolide 1.168.  A simple deprotection/ oxidation protocol will afford aldehyde 1.169 which would allow for the installation of the final aliphatic portion of the molecule (Figure 1.6, I).  Our methodology should allow for the control of both the position of substituents and the stereocentre within the THF ring.   39   Scheme 1.28.  General strategy for the synthesis of acetogenin analogs. 1.8 Conclusion  We have successfully developed a general strategy for the synthesis of carba- and heterocyclic compounds using our improved radical relay cyclization methodology.  Prior to our contribution to this field, there were only sparse reports of relay cyclizations, and those reported provided the cyclized product in low yields or diasteroselectivity.  We have demonstrated the synthetic utility of N-alkoxyphthalimides as bench stable alkoxy radical precursors.   To minimize the amount of linear product arising from a hydrogen atom transfer reaction, we optimized the rate of addition of our metal hydride source.  While we found 40  that several metal hydride sources were amenable with our relay cyclizations, we selected tributyltin hydride due to both cost and availability reasons.  The rate of addition of tributyltin hydride to solution which maximized the amount of cyclized products was found to occur at an addition rate of 0.5 mL/h. Having established the optimal rate of addition that provided the maximum amount of cyclized product, we then incorporated various functional groups into the linear chain radical precursors.  We were particularly interested in oxygen and nitrogen containing linear radical relay precursors as they would provide small, heterocyclic compounds that we hoped to use towards a total synthesis of (  ?)-amphidinolide K.  While nitrogen containing radical precursors did cyclize in modest yield, the diastereoselectivity was low due to the stabilization of the resulting radical following a 1,5-HAT.  Relay cyclizations of tetrahydrofuran derivatives afforded good yields and diastereoselectivites.  Attempts at 6-exo cyclizations on several substrates failed to provide the desired six membered rings. We believe that our contributions in expanding the utility and scope of these relay reactions will provide a novel disconnection strategy for natural products, such as amphidinolide K and certain members of the acetogenin class of natural products.           41   1.9 Experimental 1.9.1 General Experimental All reactions were performed under a nitrogen atmosphere in flame-dried glassware.  Tetrahydrofuran and diethyl ether were distilled from sodium benzophenone ketyl.  Dichloromethane was distilled form calcium hydride.  Thin layer chromatography was performed on Whatman Partisil K6F UV254 pre-coated TLC plates.  Chromatographic separations were effected over Silicycle F60 silica gel (230-400 mesh).  The silica gel was basified with triethylamine prior to packing and then sequentially flushed with the solvent system of choice.  All chemicals were purchased from commercial sources and used as received.  A KD-Scientific KDS100 syringe pump was used for all slow additions.  Melting points were performed using a Mel-Temp II apparatus (Lab devices USA) and are uncorrected.  Infrared spectra were obtained using a Thermo Nicolet 4700 FT-IR spectrometer.  Proton nuclear magnetic resonance spectra were recorded in deuterochloroform or d6-benzene using a Bruker AV-300 or AV-400 spectrometer.  Carbon nuclear magnetic resonance spectra were recorded in deuterochloroform or d6-benzene using a Bruker AV-300 or AV-400 spectrometer.  Chemical shifts are reported in parts per million and are referenced to the centerline of deuterochloroform (7.27 ppm 1H NMR; 77.0 ppm 13C NMR) or d6-benzene (7.16 ppm 1H NMR; 128.1 ppm 13C NMR).  Low resolution mass spectra and high resolution mass spectra were recorded on either a Bruker Esquire-LC spectrometer (for LRMS) or a Waters/Micromass LCT spectrometer (for HRMS).  42   1.9.2 Synthesis of N-alkoxyphtalimides 1.109, 1.110 and 1.112-1.115   2-(Non-8-enyloxy)isoindoline-1,3-dione (1.109):  To a stirring solution of non-8-en-1-ol (2.36 mL, 14.1 mmol) in dry THF (75 mL) at 0?C was sequentially added to triphenylphosphine (4.79 g, 18.3 mmol) and N-hydroxyphthalimide (2.98 g, 18.3 mmol).  This solution was stirred for 10 minutes then diisopropyl azodicarboxylate (3.60 mL, 18.3 mmol) was added at a rate or 0.81 mL/h via syringe pump.  The resulting pale yellow solution was allowed to warm to ambient temperature and stirred overnight.  The mixture was then diluted with H2O (25 mL) and extracted with Et2O (3 x 20 mL).  The combined organic extracts were dried over Na2SO4 and concentrated by rotary evaporation to afford yellow oil.  Triphenylphosphine oxide was precipitated from the crude oil with hexanes (10 mL).  The resulting white precipitate was washed with hexanes (9 x 10 mL) and then the combined organics were concentrated using rotary evaporation.  Purification using flash column chromatography (5:1 petroleum ether/Et2O) yielded phthalimide 1.109 as a white crystalline solid (3.24 g, 80%).  M.p. = 28-32 ?C; IR (film): 2927, 2855, 1790, 1735, 1467, 1372, 1187, 1127, 1016 cm-1; 1H NMR (400 MHz, CDCl3): ? 7.83 ? 7.85 (m, 2 H), 7.74 ? 7.76 (m, 2 H), 5.76 ? 5.86 (m, 1 H), 4.92 ? 5.02 (m, 2 H), 4.20 (t, J = 8 Hz, 2 H), 2.05 (q, J = 8 Hz, 2 H), 1.79 (qt, J = 8 Hz, 2 H), 1.45 ? 1.51 (m, 2 H), 1.33 ? 1.41 (m, 6 H); 13C NMR (100 MHz, CDCl3): ? 163.6, 139.1, 134.4, 129.0, 123.4, 114.2, 78.6, 33.7, 29.1, 28.9, 28.8, 28.1, 25.59.1, 43  28.9, 28.8, 28.1, 25.5; HRMS-ESI (m/z) calcd. for C17H21NO3Na [M+Na]+ 310.1419, found 310.1427.  2-(Dec-9-en-1-yloxy)isoindoline-1,3-dione (1.110): To a stirred solution of dec-9-en-1-ol (1.121) (1.70 g, 10.9 mmol) in dry THF (120 mL) was sequentially added triphenylphosphine (4.32 g, 16.3 mmol) and N-hydroxyphthalimide (2.78 g, 16.3 mmol) at 0 ?C. The solution was stirred until the solids had dissolved. DIAD (4.10 mL, 19.6 mmol) was then added dropwise via syringe pump (0.8 mL/h). The resulting yellow solution was stirred overnight at ambient temperature, and was then quenched with H2O (50 mL). The aqueous layer was extracted with EtOAc (3 x 50 mL), and the combined organic extracts were washed with NaHCO3 (4 x 50 mL), brine (50 mL) and were dried over Na2SO4. The organics were concentrated using rotary evaporation and purified by flash column chromatography (10:1 hexanes/EtOAc) to provide N-alkoxyphthalimide 1.110 as a white crystalline solid (3.25 g, 86%). 1H NMR (300 MHz, CDCl3): ? 7.72 - 7.79 (m, 2 H), 7.65 - 7.72 (m, 2 H), 5.73 (ddt, J = 17, 10, 7, 7 Hz, 1 H), 4.79 ? 4.98 (m, 2 H), 4.13 (t, J = 7 Hz, 2 H), 1.97 (q, J = 7 Hz, 1 H), 1.65 - 1.77 (m, 2 H), 1.37 - 1.48 (m, 2 H), 1.14 - 1.36 (m, 9 H); 13C NMR (75 MHz, CDCl3): ? 163.47, 138.98, 134.28, 128.84, 123.29, 114.02, 78.42, 33.63, 29.16, 29.10, 28.87, 28.73, 28.00, 25.38. HRESIMS (m/z): calcd. for C18H23NO3Na [M+Na]+ 324.1576, found 324.1580.  44   4-tert-Butoxycarbonylaminobutan-1-ol (1.124)78: To a stirring solution of 4-aminobutan-1-ol (3.0 mL, 32 mmol) in dry CH2Cl2 (18 mL) was added triethylamine (5.4 mL, 39 mmol).  To this stirring solution was added Boc2O (7.47 mL, 32.3 mmol) in dry CH2Cl2 (29 mL) via addition funnel.  The solution was then stirred for 10 hours.  The solution was concentrated by rotary evaporation to afford carbamate 1.124 as a yellow oil (6.1 g, 100%).  IR (film): 3346, 2976, 2935, 2870, 1693, 1531, 1479, 1454, 1392, 1366, 1279, 1252, 1171, 1058, 1040 cm-1; 1H NMR (400 MHz, CDCl3): ? 4.77 (br. s., 1 H), 3.62 (t, J = 6 Hz, 2 H), 3.11 (d, J = 6 Hz, 2 H), 2.58 (br. s., 1 H), 1.45 ? 1.45 (m, 4 H), 1.41 (s, 9 H); 13C NMR (100 MHz, CDCl3): ? 156.2, 79.1, 62.1, 40.2, 29.6, 28.3, 26.5.  tert-Butyl 4-(tert-butyldiphenylsilyloxy)butylcarbamate (1.125):  To a stirring solution of carbamate 1.124 (1.90 g, 10.0 mmol) in dry DMF (12 mL) was sequentially added imidazole (0.89 g, 13 mmol) and tert-butylchlorodiphenylsilane (2.57 mL, 10.0 mmol).  The resulting solution was stirred for 14 hours, at which point the reaction was poured into a separatory funnel containing H2O (50 mL) and extracted with Et2O (1 x 50 mL, 2 x 10 mL).  The combined organic extracts were washed with H2O (10 mL) and brine (10 mL), dried over Na2SO4, concentrated by rotary evaporation and purified using flash column chromatography with a gradient system (15:1 to 9:1 hexanes/EtOAc) to yield silyl ether 1.125 as a colourless oil (3.9 g, 90 %).  IR (film): 3350, 2931, 2858, 1701, 1510, 1473, 1428, 1390, 1365, 1251, 1173, 1111, 1040 cm-1; 1H NMR (400 MHz, CDCl3): ? 7.67 ? 7.70 (m, 4 H), 45  7.40 ? 7.44 (m, 6 H), 4.62 (br. s., 1 H), 3.70 (m, 2 H), 1.80 (br. s., 2 H), 1.59 ? 1.61 (m, 4 H), 1.46 (s, 9 H), 1.08 (s, 9 H); 13C NMR (100 MHz, CDCl3): ? 155.9, 135.5, 133.9, 129.5, 127.6, 78.9, 63.5, 40.4, 29.8, 28.4, 26.9, 26.5, 19.2; HRMS-ESI (m/z) calcd. for C25H37NO3SiNa [M+Na]+ 450.2440, found 450.2438.  tert-Butyl 4-(tert-butyldiphenylsilyloxy)butyl(3-oxopropyl)carbamate (1.126):  To a stirring solution of silyl ether 1.125 (3.0915 g, 7.22 mmol) in dry CH2Cl2 (30 mL) at 0 ?C was sequentially added acrolein (4.82 mL, 72.2 mmol) and camphorsulfonic acid (0.3345 g, 1.440 mmol).  The solution was stirred for 15 min at 0 ?C, allowed to warm to ambient temperature, and then stirred for an additional 30 minutes.  The reaction was poured into a separatory funnel containing saturated NaHCO3 (50 mL) and vigorously shaken to quench the reaction.  The organic layer was separated, dried over Na2SO4, and concentrated by rotary evaporation to afford a bright pink liquid.  The liquid was poured into Et2O (50 mL), washed with H2O (15 mL) and brine (15 mL) which eliminated the pinkish hue.  The combined organics were dried over Na2SO4, concentrated by rotary evaporation and purified using flash column chromatography (9:1 hexanes/EtOAc) to yield aldehyde 1.126 as a colourless oil (2.62 g, 75%).  IR (film): 2932, 2858, 1724, 1694, 1473, 1427, 1417, 1390, 1280, 1171, 1141, 1111 cm-1; 1H NMR (400 MHz, CDCl3): ? 9.79 (s, 1 H), 7.66 ? 7.67 (m, 4 H), 7.36 ? 7.43 (m, 6 H), 3.68 (t, J = 6 Hz, 2 H), 3.49 (t, J = 7 Hz, 2 H), 3.19 (br. s., 2 H), 2.68 (t, J = 6 Hz, 2 H), 1.58 ? 1.60 (m, 4 H), 1.44 (s, 9 H), 1.06 (s, 9 H); 13C NMR (100 MHz, CDCl3): ? 202.0, 46  135.5, 133.9, 129.5, 127.9, 79.7, 63.5, 47.5, 43.5, 41.0, 29.8, 28.4, 26.8, 25.1, 19.2, 15.2; HRMS-ESI (m/z): calcd. for C28H41NO4SiNa [M+Na]+ 506.2703, found 506.2693.  tert-Butyl but-3-enyl(4-hydroxybutyl)carbamate (1.127):  To a stirring solution of methyltriphenylphosphonium bromide (9.61 g, 26.9 mmol) in dry THF (68 mL) at ?78 ?C was added butyllithium (16.8 mL, 1.6 M in hexanes, 27 mmol) dropwise over 20 minutes.  The solution was allowed to warm to ambient temperature, and then aldehyde 1.126 (2.60 g, 5.38 mmol) in dry THF (60 mL) was added via addition funnel dropwise over 10 minutes.  The reaction was stirred at ambient temperature for 12 hours, after which the solution was quenched with the addition of H2O (100 mL).  The solution was then poured into a separatory funnel and extracted with Et2O (3 x 30 mL).  The combined organic extracts were dried over Na2SO4 and concentrated using rotary evaporation to provide a colourless oil, which was used without further purification. To a solution of the crude colourless oil in THF (34 mL) was added a 1.0 M solution of TBAF in THF (17.80 mL, 17.80 mmol) and the solution was stirred for 12 hours.  The solvent was removed using rotary evaporation, dissolved in Et2O (50 mL) and washed with a saturated solution of NH4Cl (10 mL) and brine (10 mL).  The combined aqueous washes were extracted with a solution of saturated NH4Cl (10 mL).  The combined aqueous washes were extracted with Et2O (10 mL) and all the organic extracts were combined, dried over Na2SO4 and concentrated using rotary evaporation.  The product was purified using flash column chromatography (1:1 hexanes/EtOAc) to yield alcohol 1.127 as a colourless oil (644 47  mg, 49% over 2 steps).  IR (film): 3431, 2976, 2933, 2868, 1693, 1479, 1454, 1420, 1391, 1366, 1305, 1253, 1227, 1167, 1069 cm-1; 1H NMR (400 MHz, CDCl3): ? 5.70 ? 5.78 (m, 1 H), 4.99 ? 5.07 (m, 2 H), 3.64 (t, J = 6 Hz, 2 H), 3.18 ? 3.23 (m, 4 H), 2.23 ? 2.29 (m, 2 H), 1.54 ? 1.60 (m, 4 H), 1.44 (s, 9 H); 13C NMR (100 MHz, CDCl3): ? 155.7, 135.5, 116.4, 79.3, 62.4, 46.9, 46.8, 33.2, 29.6, 28.4, 24.8; HRMS-ESI (m/z): calcd. for C13H25NO3Na [M+Na]+ 266.1732, found 266.1727.  tert-Butyl but-3-enyl(4-(1,3-dioxoisoindolin-2-yloxy)butyl)carbamate (1.112):  To a stirring solution of alcohol 1.127 (0.6421 g, 2.640 mmol) in dry THF (9 mL) was sequentially added triphenylphosphine (0.9000g, 3.430 mmol) and N-hydroxyphthalimide (0.5595 g, 3.430 mmol).  To this stirring solution was added DIAD (0.68 mL, 3.4 mmol) via syringe pump (0.81 mL/h) and the solution was left to stir for 12 hours.  The reaction was quenched with H2O (10 mL) and extracted with Et2O (3 x 10 mL).  The combined organic extracts were dried over Na2SO4, and concentrated using rotary evaporation to afford a yellow oil.  Triphenylphosphine oxide was precipitated from the crude oil with hexanes (10 mL) and the resulting white precipitate was washed with hexanes (9 x 10 mL) and concentrated using rotary evaporation.  Purification using flash column chromatography with a gradient solvent system (5:1 to 3:1 hexanes/EtOAc) yielded phthalimide 1.112 as a colourless oil (0.82 g, 80%).  IR (film): 2974, 1733, 1688, 1468, 1417, 1365, 1172, 1082 cm-1; 1H NMR (400 MHz, CDCl3): ? 7.73 ? 7.82 (m, 4 H), 5.72 ? 5.80 (m, 1 H), 4.99 ? 5.08 (m, 2 H), 4.19 ? 4.23 (m, 2 H), 3.24 ? 3.27 (m, 4 H). 2.27 ? 2.29 (m, 2 H), 1.75 ? 1.77 (m, 4 H), 1.44 (s, 9 48  H); 13C NMR (100 MHz, CDCl3): ? 163.5, 155.5, 135.5, 134.4, 128.9, 123.4, 116.4, 79.2, 78.0, 46.6, 46.5, 33.3, 28.4, 25.5, 24.4; HRMS-ESI (m/z) calcd. for C21H28N2O5Na [M+Na]+ 411.1896, found 411.1892.  (4-(But-3-enyloxy)butoxy)(tert-butyl)dimethylsilane (1.129):  To a stirring solution of 3-buten-1-ol (0.26 mL, 3.1 mmol) in dry DMF (8.0 mL) was added NaH (60% dispersion in mineral oil, 0.1863 g, 4.660 mmol).  The solution was stirred for 1 hour, after which it was added via addition funnel to a solution of known tosylate 1.128 (1.0366 g, 2.8901 mmol)51 in dry DMF (1.0 mL).  The solution was heated to 75 ?C for 1 hour, allowed to cool to ambient temperature and stirred for an additional 12 hours.  The reaction was quenched via the dropwise addition of H2O (5 mL) and washed with saturated NaHCO3 (10 mL).  The aqueous layer was then extracted with Et2O (3 x 15 mL) and the combined organic extracts were dried over Na2SO4, concentrated by rotary evaporation and purified using flash column chromatography (50:1 hexanes/Et2O) to yield silyl ether 1.129 as a colourless oil (33 mg, 44%).  IR (film): 2930, 2857, 1472, 1361, 1255, 1100 cm-1; 1H NMR (400 MHz, CDCl3): ? 5.80 ? 5.87 (m, 1 H), 5.03 ? 5.12 (m, 2 H), 3.64 (t, J = 4 Hz, 2 H), 3.43 ? 3.49 (m, 4 H), 2.32 ? 2.37 (m, 2 H), 1.57 ? 1.67 (m, 4 H), 0.90 (s, 9 H), 0.05 (s, 6 H); 13C NMR (100 MHz, CDCl3): ? 135.4, 116.2, 70.8, 70.1, 63.0, 34.2, 29.5, 26.2, 26.0, 18.4, -5.3; HRMS-ESI (m/z): calcd. for C14H30O2SiNa [M+Na]+ 281.1913, found 281.1916.   49   4-(But-3-enyloxy)butan-1-ol (1.130):79 To a stirring solution of silyl ether 1.129 (1.4280 g, 5.5220 mmol) in THF (35 mL) was added TBAF (18.2 mL, 1.0 M in THF, 18.2 mmol) and the solution was allowed to stir for 12 hours.  The reaction was then diluted with H2O (25 mL) and extracted with Et2O (3 x 20 mL).  The combined organic extracts were washed with H2O (20 mL) and brine (20 mL), dried over Na2SO4 and concentrated by rotary evaporation.  The product was purified using flash column chromatography (7:1 Et2O/hexanes) to yield alcohol 1.130 as a colourless oil (801 mg, 92%).  IR (film): 3383, 2863, 1642, 1361, 1115 cm-1; 1H NMR (400 MHz, CDCl3): ? 5.77 ? 5.87 (m, 1 H), 5.04 ? 5.13 (m, 2H), 3.65 (t, J = 6 Hz, 2 H), 3.47 ? 3.52 (m, 4 H), 2.33 ? 2.38 (m, 3 H), 1.66 ? 1.71 (m, 4 H); 13C NMR (100 MHz, CDCl3): ? 135.1, 116.5, 70.9, 70.3, 62.7, 34.1, 30.4, 26.9.  2-(4-(But-3-enyloxy)butoxy)isoindoline-1,3-dione (1.114):  To a stirring solution of alcohol 1.130 (732 mg, 5.07 mmol) in dry THF (20 mL) was sequentially added triphenylphosphine (1.73 g, 6.59 mmol) and N-hydroxyphthalimide (1.08 g, 6.59 mmol).  The solution was stirred for 10 minutes at which point DIAD (1.30 mL, 6.59 mmol) was added via syringe pump (0.81 mL/h).  The reaction mixture was then stirred for 10 hours, after which it was diluted with H2O (50 mL) and extracted with Et2O (3x 20 mL).  The combined organic extracts were dried over Na2SO4 and concentrated by rotary evaporation 50  to afford a yellow oil.  Triphenylphosphine oxide was precipitated from the crude oil with hexanes (10 mL).  The resulting white precipitate was washed with hexanes (9 x 10 mL) and the combined organics were concentrated using rotary evaporation.  Purification using flash column chromatography with a gradient solvent system (20:1 ? 3:1 hexanes/EtOAc) yielded phthalimide 1.114 as a colourless oil (1.13 g, 77%).  IR (film): 2943, 2861, 1789, 1732, 1641, 1467, 1373, 1187, 1114, 1082, 1017 cm-1; 1H NMR (400 MHz, CDCl3): ? 7.83 ? 7.85 (m, 2 H), 7.73 ? 7.77 (m, 2 H), 5.79 ? 5.85 (m, 1 H), 5.01 ? 5.10 (m, 2 H), 4.24 (t, J = 6 Hz, 2 H), 3.46 ? 3.53 (m, 4 H), 2.30 ? 2.35 (m, 2 H), 1.78 ? 1.89 (m, 4 H); 13C NMR (100 MHz, CDCl3): ? 163.6, 135.3, 134.4, 129.0, 123.5, 116.2, 78.3, 70.1, 34.2, 25.8, 25.1; HRMS-ESI (m/z): calcd. for C16H19NO4Na [M+Na]+ 312.1212, found 312.1208.  5-(allyloxy)pentan-1-ol (1.135):80  To stirring solution of 1.133 (2.02 mL, 19.0 mmol) in dry THF (80 mL) was added NaH (1.1520 g, 60% dispersion in mineral oil, 28.80 mmol) in small portions.  The solution was stirred for 1h at room temperature, at which point a solution of 3-bromoprop-1-ene (1.79 mL, 21.1 mmol) in dry THF (25 mL) was added slowly via addition funnel.  The solution was stirred for a further 3 h, at which time the reaction was cooled to 0?C and quenched with H2O (50 mL).  The crude mixture was partitioned, and the aqueous layer was extracted with Et2O (3 x 25 mL), and the combined organics were dried over Na2SO4.  Purification using flash column chromatography (1:1 EtOAc/hexanes) isolated 1.135 as a colourless oil (0.644 g, 23 %). 1H NMR (400 MHz, CDCl3): ? 5.86 ? 5.99 (m, 1 H), 5.27 (dd, J = 17, 2 Hz, 1 H), 5.18 (d, J = 10 Hz, 1 H), 3.97 (d, J = 6 Hz, 2 H), 3.66 (t, J = 51  6 Hz, 2 H), 1.54 ? 1.69 (m, 4 H), 1.24 ? 1.53 (m, 3 H); 13C NMR (100 MHz, CDCl3): ? 135.0, 116.8, 71.8, 70.3, 62.9, 32.5, 29.4, 22.4.  2-((5-(but-3-en-1-yloxy)pentyl)oxy)isoindoline-1,3-dione (1.115):  To a solution of alcohol 1.135 (130 mg, 0.820 mmol) in THF (20 mL) was sequentially added triphenylphosphine (322 mg, 1.23 mmol) then N-hydroxyphthalimide (200 mg, 1.23 mmol). The solution was stirred until all solids were dissolved, at which point DIAD (0.29 mL, 297 mg, 1.47 mmol) was added via syringe pump (rate = 0.81 mL/h). The resulting yellow solution was stirred for 12 hours at ambient temperature, and was then quenched with H2O (10 mL).The aqueous layer was extracted with EtOAc (3 x 20 mL), and the combined organic layers were washed with NaHCO3(3 x 20 mL), brine (20 mL) and were dried over Na2SO4. The organics were concentrated using rotary evaporation and purified by flash column chromatography (4:1 EtOAc/hexanes) to provide N-alkoxyphthalimide 1.115 as a colorless oil (186 mg, 69%). IR (neat): 2943, 2856, 1795, 1726, 1473, 1378, 1191, 1117, 982, 886, 704 cm-1; 1H NMR (400 MHz, CDCl3): ? 7.83 (dd, J = 3, 5 Hz, 2 H), 7.74 (dd, J = 3, 6 Hz, 2 H), 5.82 (tdd, J = 7, 10, 17 Hz, 1 H), 5.08 (dd, J = 2, 17 Hz, 1 H), 5.03 (d, J = 10 Hz, 1 H), 4.21 (t, J = 7 Hz, 2 H), 3.51 - 3.42 (m, 4 H), 2.33 (q, J = 7 Hz, 2 H), 1.82 (quin, J = 7 Hz, 2 H), 1.72 - 1.51 (m, 4 H); 13C NMR (100 MHz, CDCl3): ? 163.6, 135.3, 134.4, 128.9, 123.4, 116.2, 78.4, 70.6, 70.1, 34.2, 29.3, 27.9, 22.24; HRMS-ESI (m/z) calcd. for C17H21NNaO4  [M+H]+ 304.1549, found 304.1544. 52   tert-Butyldimethyl(4-pent-4-enyloxy)butoxy)silane (1.131):  To a stirring solution of 4-penten-1-ol (1.12 mL, 11.0 mmol) in dry DMF (27.5 mL) was added NaH (0.66 g, 60% dispersion in mineral oil, 17 mmol).  The solution was stirred for 1 hour, after which it was added via addition funnel to a solution of known tosylate 1.12851 (3.97 g, 11.1 mmol) in dry DMF (22 mL).  The solution was heated to 75 ?C for 1 hour, allowed to cool to ambient temperature and stirred for an additional 24 hours.  The reaction was quenched with the dropwise addition of H2O (3 mL) and extracted with Et2O (4 x 15 mL).  The combined organic extracts were dried over Na2SO4, concentrated by rotary evaporation and purified by flash column chromatography (20:1 hexanes/Et2O) to yield silyl ether 1.131 as a colourless oil (1.4 g, 48%).  IR (film): 3076, 2937, 2860, 1640, 1446, 1367, 1114, 1059 cm-1; 1H NMR (400 MHz, CDCl3): ? 5.76 ? 5.88 (m, 1 H), 4.95 ? 5.06 (m, 2 H), 3.64 (t, J = 6 Hz, 2 H), 3.40 ? 3.44 (m, 4 H), 2.10 (q, J = 7 Hz, 2 H), 1.56 ? 1.72 (m, 6 H), 0.90 (s, 9 H), 0.05 (s, 6 H); 138.4, 114.6, 70.7, 70.1, 63.0, 30.4, 29.0, 26.2, 26.0, 18.3, -5.3; HRMS-ESI (m/z): calcd. for C15H32O2SiNa [M+Na]+ 295.2069, found 295.2071.  4-(Pent-4-enyloxy)butan-1-ol (1.132):  To a solution of silyl ether 1.131 (1.44 g, 5.30 mmol) in dry THF (33 mL) was added TBAF (15.8 mL, 1.0 M in THF, 16 mmol) and the resulting solution was stirred for 5 hours.  The reaction was then diluted with H2O (40 mL) and extracted with Et2O (3 x 20 mL).  The combined organic extracts were dried over Na2SO4, concentrated by rotary evaporation, and purified by flash column chromatography 53  (7:1 Et2O/hexanes) to yield alcohol 1.132 as a colourless oil (0.80 g, 96%).  IR (film): 3385, 2936, 2860, 1641, 1446, 1367, 1116, 1059 cm-1; 1H NMR (400 MHz, CDCl3): ? 5.77 ? 5.87 (m, 1 H), 4.96 ? 5.05 (m, 2 H), 3.65 (t, J = 6 Hz, 2 H), 3.44 ? 3.48 (m, 4 H), 2.42 ? 2.48 (m, 1 H), 2.09 ? 2.15 (m, 2 H), 1.65 ? 1.72 (m, 6 H); 13C NMR (100 MHz, CDCl3): ? 138.1, 114.8, 70.9, 70.3, 62.8, 30.4, 30.2, 28.8, 26.9; HRMS-ESI (m/z): calcd. for C9H18O2Na [M+Na]+ 181.1204, found 181.1206.  2-(4-(Pent-4-enyloxy)butoxy)isoindoline-1,3-dione (1.113):  To a solution of alcohol 1.132 (0.80 g, 5.1 mmol) in dry THF (17 mL) was sequentially added triphenylphosphine (1.72 g, 6.61 mmol) and N-hydroxyphthalimide (1.07 g, 6.61 mmol).  The solution was stirred until the solids were dissolved, at which point DIAD (1.29 mL, 6.61 mmol) was added via syringe pump (0.81 mL/h).  The solution was stirred for 48 hours, and then diluted with H2O (20 mL) and extracted with Et2O (3 x 15 mL).  The combined organic extracts were dried over Na2SO4, concentrated using rotary evaporation, and purified by flash column chromatography (4:1 hexanes/EtOAc) to yield phthalimide 1.113 as a colourless oil (1.1 g, 71%).  IR (film): 3075, 2941, 2857, 1789, 1735, 1640, 1467, 1373, 1187, 1123, 1082 cm-1; 1H NMR (400 MHz, CDCl3): ? 7.74 ? 7.86 (m, 4 H), 5.77 ? 5.87 (m, 1 H), 4.95 ? 5.04 (m, 2 H), 4.25 (t, J = 7 Hz, 2 H), 3.42 ? 3.51 (m, 4H), 2.10 (q, J = 7 Hz, 2 H), 1.78 ? 1.92 (m, 4 H), 1.63 ? 1.69 (m, 2 H); 13C NMR (100 MHz, CDCl3): ? 163.6, 138.3, 134.4, 129.0, 123.5, 114.6, 78.3, 70.2, 70.1, 30.3, 28.9, 25.9, 25.1; HRMS-ESI (m/z): calcd. for C17H21NO4Na [M+Na]+ 326.1368, found 326.1364. 54  1.9.3 One Pot NMR-Scale Cyclizations  To a solution of 1.115 (5.8 mg, 0.020 mmol), AIBN (3.3 mg, 0.020 mmol) and 1,3,5-trimethoxybenzene (1.1 mg, 0.0070 mmol, 0.33 equiv.) in d6-benzene (1 mL) was added either Bu3SnH (7.6 mg, 0.026 mmol), Ph3SnH (9.1 mg, 0.026 mmol) or (TMS)3SiH (6.5 mg, 0.026 mmol).  The reaction mixtures were analyzed using 1H NMR spectroscopy, and were then heated to 90 ?C in NMR tubes fitted with J. Young valves.  After 12 hours, the resulting solutions were analyzed again using 1H NMR spectroscopy.  The NMR yield was determined to be >95% for each reaction, based on using 1,3,5-trimethoxybenzene as an internal standard. 1.9.4 General Cyclization and Purification Procedure To a 0.02 M solution of cyclization precursor 1.109-1.117 (1.0 equiv.) in degassed benzene at reflux was added a 0.2 M solution of Bu3SnH (1.2 equiv.) and AIBN (0.15 equiv.) in degassed benzene by syringe pump (0.5 mL/h).  Following the addition, the reaction was maintained at reflux for an additional 1 hour.  The resulting solution was allowed to cool to ambient temperature, concentrated using rotary evaporation and purified by flash column chromatography to afford a mixture of cyclized products (1.136-1.145) and linear alcohols as a colourless oil.  The product mixture was then dissolved in CH2Cl2 (0.3 M) and cooled to 0 ?C.  m-CPBA (3 equiv.) was then added in one portion and the resulting solution was allowed to warm to ambient temperature and stirred for 12 hours.  The reaction was quenched using a 2 M solution of Na2S2O3 (10 mL), washed with saturated aqueous Na2CO3 (3 x 5 mL), H2O (5 mL), dried over Na2SO4 and concentrated by rotary evaporation.  The cyclized products were purified by flash column chromatography.  The relative 55  stereochemistry was determined using nOe experiments and the major diastereomer is shown.  3-(2-Methylcylcopentyl)propanol (1.136): Phthalimide 1.109 (550 mg, 1.30 mmol) was subjected to the general cyclization procedure.  Purification by flash column chromatography (4:1 hexanes/EtOAc) afforded cyclopentane 1.136 as a colourless oil (262 mg, 79%, cis:trans = 75:25).  IR (neat) 3405, 2951, 2927, 1646, 1057 cm-1; 1H NMR (300 MHz, CDCl3): ? 3.68 (t, J = 7 Hz, 2 H), 1.96 ? 2.09 (m, 0.8 H), 1.70 ? 1.84 (m, 2.8 H), 1.51 ? 1.65 (m, 4 H), 1.38 ? 1.49 m, 1 H), 1.17 ? 1.37 (m, 4 H), 0.99 (d, J = 7 Hz, 0.7 H, trans), 0.81 (d, J = 7 Hz, 2 H, cis); 13C NMR (75 MHz, CDCl3): ? 63.6, 47.6, 43.3, 40.8, 36.1, 34.9, 33.7, 32.5, 32.2, 32.0, 31.0, 30.0, 26.8, 23.6, 22.6, 19.6, 14.9; HRMS-ESI (m/z): calcd. for C10H20O [M+H]+: calcd. 143.1436, found 143.1434.    3-(2-methylcyclohexyl)propan-1-ol (1.138): Phthalimide 1.110 (301 mg, 1.00 mmol) was subjected to the general cyclization procedure.  Purification by flash column chromatography (5:1 hexanes/EtOAc) afforded cyclohexane 1.138 as a colourless oil (422 mg, 27%, cis:trans = 50:50).  IR (neat) 3332, 2923, 2853, 1446, 1057 cm-1; 1H NMR (300 MHz, CDCl3): ? 3.61-3.67 (m, 4 H), 1.10 ? 1.80 (m, 28 H), 0.90 (d, J = 8 Hz, 3 H, trans), 0.84 (d, J = 8 Hz, 3 H, cis); 13C NMR (100 MHz, CDCl3): ? 63.6, 63.4, 43.7, 43.3, 39.8, 39.0, 36.9, 35.9, 56  34.6, 33.5, 32.6, 31.8, 30.7, 29.5, 28.5, 27.7, 26.6, 25.1, 24.9, 22.5, 22.0, 20.27, 14.8, 13.8; HRMS-ESI was attempted, however 1.138 would not ionize.  tert-Butyl 2-(3-hydroxypropyl)-3-methylpyrrolidine-1-carboxylate (1.140):  Phthalimide 1.112 (0.1803 g, 0.4604 mmol) was subjected to the general cyclization procedure.  Purification by flash column chromatography (7:1 Et2O/hexanes) afforded pyrrolidine 1.140 as a colourless oil (71.1 mg, 63%, cis:trans = 56:44, the dr was determined using the mesylated product of 1.140).  IR (film): 3434, 2961, 2975, 1693, 1477, 1455, 1407, 1366, 1255, 1175, 1118, 1068 cm-1; 1H NMR (400 MHz, CDCl3): ? 4.26 (br. s., trans 1 H), 3.94 ? 3.96 (m, trans 3 H), 3.66 ? 3.71 (m, 3 H), 3.49 (br. s., 1 H), 3.24 ? 3.36 (m, 2 H), 3.15 ? 3.16 (m, trans 2 H), 2.73 ? 2.79 (m, trans 1 H), 2.21 ? 2.35 (m, 1 H), 1.75 ? 1.86 (m, trans 3 H), 1.52 ? 1.64 (m, 5 H), 1.47 (s, 9 H), 1.03 (d, J = 7 Hz, 3 H); 13C NMR (100 MHz, CDCl3): ? 155.5, 79.3, 62.9, 62.7, 58.8, 45.7, 45.2, 37.9, 36.5, 31.3, 30.6, 30.5, 30.2, 28.7, 26.7, 26.2, 25.7, 19.5, 19.1, 14.2; HRMS-ESI (m/z): calcd. for C13H25NO3Na [M+Na]+ 266.1732, found 266.1730.  3-(3-Methyl-tetrahydrofuran-2-yl)propan-1-ol (1.141):  Phthalimide 1.114 (1.00 g, 3.46 mmol) was subjected to the general cyclization procedure.  Purification by flash column chromatography (7:1 Et2O/hexanes) afforded furan 1.141 as a colourless oil (308 mg, 62%, cis:trans = 90:10).  IR (film): 3387, 2942, 2874, 1702, 1453, 1379, 1059 cm-1; 1H NMR (400 57  MHz, CDCl3): ? 3.89 ? 3.95 (m, 1 H), 3.81 ? 3.85 (m, 0.24 H), 3.60 ? 3.79 (m, 4 H), 3.28 ? 3.33 (m, trans 1 H), 2.93 ? 2.96 (m, trans 1 H), 2.77 ? 2.80 (m, 1 H), 2.19 ? 2.29 (m, 1 H), 2.05 ? 2.14 (m, 1 H), 1.66 ? 1.74 (m, 3 H), 1.55 ? 1.64 (m, 2 H), 1.42 ? 1.52 (m, 1.4 H), 1.03 (d, J = 7 Hz, 0.33 H), 0.93 (d, J = 7 Hz, 3 H).  13C NMR (100 MHz, CDCl3): ? 81.9, 66.1, 63.0, 35.7, 33.8, 30.6, 27.9, 14.3; HRMS-ESI (m/z): calcd. for C8H16O2Na [M+Na]+ 167.1048, found 167.1053.  3-(3-Methyl-tetrahydro-2H-pyran-2-yl)propan-1-ol (1.143):  Phthalimide 1.113 (303 mg, 0.998 mmol) was subjected to the general cyclization procedure.  Purification by flash column chromatography (10:1 Et2O/hexanes) afforded pyran 1.143 as a colourless oil (64.7 mg, 41%, cis:trans = 60:40).  IR (film): 3380, 2929, 2851, 1461, 1379, 1098, 1069, 1035 cm-1; 1H NMR (400 MHz, CDCl3): ? 3.91 ? 4.02 (m, 1.34 H), 3.87 (ddd, J = 12, 6, 4 Hz, 0.25 H), 3.57 ? 3.70 (m, 3.18 H), 3.33 ? 3.57 (m, 2.40 H), 2.87 ? 2.97 (m, 0.94 H), 2.68 (br. s., 2.25 H), 1.58 ? 1.87 (m, 9.31 H), 1.37 ? 1.58 (m, 5.03 H), 1.23 ? 1.34 (m, 1.14 H), 1.15 (m, 1.15 H), 0.95 (d, J = 7 Hz, 3 H); 13C (100 MHz, CDCl3): ? 83.7, 80.5, 79.9, 68.6, 68.5, 68.4, 63.0, 62.9, 62.9, 36.1, 35.0, 33.7, 32.7, 31.8, 30.8, 30.8, 30.3, 30.2, 30.0, 29.6, 28.8, 26.6, 26.5, 25.7, 20.9, 18.1, 11.9; HRMS-ESI (m/z): calcd. for C9H18O2Na [M+Na]+ 181.1204, found 181.1205.  3-(tetrahydrofuran-2-yl)propan-1-ol (1.145):81  Phthalimide 1.123 (131 mg, 0.280 mmol) was subjected to the general cyclization procedure.  Purification by flash column 58  chromatography (7:1 Et2O/hexanes) provided furan 1.145 as a colourless oil (19.5 mg, 55%).  1H NMR (400 MHz, CDCl3): ? 1.41 ? 1.52 (m, 1 H), 1.64 ? 1.73 (m, 4 H), 1.83 ? 1.93 (m, 2 H), 1.95 ? 2.03 (m, 1 H), 3.37 ? 3.44 (m, 1 H), 3.61 ? 3.71 (m, 2 H), 3.71 ? 3.78 (m, 1 H), 3.81 ? 3.86 (m, 1 H), 3.85 ? 3.94 (m, 1 H); 13C (100 MHz, CDCl3): ? 79.4, 67.8, 63.0, 32.7, 31.5, 30.0, 25.68.                   59            Chapter 2 :  Cyclizations of Aminyl Radicals Generated from Substoichiometric Stannane           60  2.1 Introduction Nitrogen-containing heterocycles are important structural motifs of many pharmaceuticals and bioactive natural products.  Numerous radical based methods have been developed for the synthesis of these structural components, the majority of which utilize carbon radicals.  Although aminyl radical cyclizations are slower and reversible when compared with the corresponding carbon and alkoxy analogs,82 nitrogen-centred radical cyclizations83 have been utilized for the formation of nitrogen containing heterocycles, such as pyrrolidines and imines.  This chapter will provide an overview of the methods for the formation nitrogen containing heterocyclic compounds via carbon- and nitrogen-centred radicals, and will outline some of the synthetic challenges associated with these reactive species.  We will also describe our investigations into cyclic imine formation using sub-stoichiometric organotin radical. 2.1.1 Nitrogen Heterocycle Formation Using the Addition of Alkyl Radicals to Nitrogen-Containing Functional Groups While ionic methods have been the prevailing method for the formation of nitrogen-containing heterocycle formation, alkyl and aminyl radicals present attractive alternatives.  The following sections will provide a brief overview of radical methods for the formation of nitrogen-containing heterocycles that involve the addition of carbon-centered radicals to nitrogen-containing functional groups. 2.1.1.1 Aminyl Radical Formation via the Addition of Alkyl Radicals to Nitriles Indirect formation of a nitrogen-centred radical by a radical addition to a nitrile was first reported by Ogibin and coworkers in the mid 1970?s.84  These initial investigations were an excellent proof of concept, and provided cyclic ketones in modest yields.    61   Scheme 2.1.  Synthesis of tricyclic imine 2.7 from bromide 2.1. An example of indirectly forming a nitrogen-centred radical that further cyclized was reported by Bowman and co-workers (Scheme 2.1).85  Treatment of bromide 2.1 with the tributyltin radical afforded aryl radical 2.2, which immediately cyclized onto a nitrile to form iminyl radical 2.3.  A subsequent 5-exo-trig cyclization generated a primary carbon radical, which then cyclized to form aziridine 2.5.  Fragmentation of 2.5 provided carbon radical 2.6, which was quenched with tributyltin hydride to afford imine 2.7.   2.1.1.2 Carbon-Centred Radical Additions to Imines Nitrogen-centred radical formation by radical addition to an imine is an attractive method for the formation of carbon-nitrogen bonds.  However, pyrrolidine formation using this method often results in mixtures of 5-exo and 6-endo products.86a  This regioselectivity 62  issue can be somewhat attenuated by tethering a radical precursor that may bias the desired carbon-carbon bond forming reaction.  An early example was demonstrated by Takano and co-workers in the key step of a synthesis of a member of the cryptostyline alkaloid family of natural products (Scheme 2.2).86a  Scheme 2.2.  Synthesis of 2.10 and 2.11 by intramolecular radical addition. Treatment of aryl bromide 2.8 with the tributyltin radical provided aryl radical 2.9.  Cyclization of this aryl radical provided the tetrahydroisoquinoline 2.10, arising from a 6-endo cyclization, as the major product. Indole 2.11 was formed via a 5-exo cyclization as the minor product. Further investigation by Takano found that the 5-exo cyclization could be promoted over the 6-endo by increasing the sterics about the imine acceptor.86b To wit, cyclization of imine 2.12, derived from acetophenone, resulted in the formation of dihydroindole 2.13 (Scheme 2.3).  Piperidine 2.14, arising from a 6-endo cyclization, was not observed.  63   Scheme 2.3.  5-Exo cyclization of bromide 2.15 to form indole 2.16. The regioselectivity of an aryl radical cyclization onto an imine typically favours the 6-endo mode of cyclization, which is opposite to the trend observed when an aryl radical is cyclized onto an alkene.87    Scheme 2.4.  Cyclization of aryl bromide 2.15. Warkentin and Thomaszewski have proposed that this intriguing preference for the 6-endo cyclization is due to both kinetic and thermodynamic effects (Scheme 2.4).89a The geometry about the imine functional group is estimated to have a C-N=C bond angle of 119?, which is more suited for the endo mode of cyclization than an alkene with C-C=C angle of approximately 125?.88  The smaller bond angle presents an adequate overlap between the SOMO of the radical centre and the ?*-orbital of the imine to promote the endo mode of attack, favouring 2.16 as the major product.  In addition to orbital alignment, the formation of a carbon-carbon bond is slightly favoured thermodynamically as compared with a carbon?nitrogen bond by approximately 10 kcal/mol.89a  During their investigations into the preference for 6-endo product over the 5-exo product, Warkentin and Thomaszewski found that the product distribution was shaped by 64  both the concentration, and the rate of addition of tributyltin hydride (Table 2.1).  Cyclization of imine 2.18 in dilute conditions provided a mixture of products, but with a preference for the 6-endo product (entry 1, 2.19).  Concentrating the reaction mixture had little effect on the ratio of 2.19:2.20, but overall produced more reduced bromide 2.21 (entries 2 and 3).  The slow addition via syringe pump of a solution of tributyltin hydride and AIBN over 18 hours provided a strong preference for the 6-endo product (entry 4).   Table 2.1.  Dependence on the distribution of 2.19-2.21 on the concentration and addition rate of Bu3SnH.  entry concentration Bu3SnH  (mol/L)a ratio 2.19 : 2.20 ratio 2.19 : 2.21 ratio 2.20 : 2.21 1 0.666 4.2 : 1 0.49 : 1 0.12 : 1 2 0.333 4.1 : 1 0.96 : 1 0.24 : 1 3 0.167 4.2 : 1 2 : 1 0.50 : 1 4b 0.19 16 : 1 - - a Except for entry 4, Bu3SnH in 9.8 fold excess added with 6 mol% AIBN.  Reagents were added in one portion. b Bu3SnH in 1.4 fold excess added with 35 mol% AIBN via syringe pump over 18h.  The effect of concentration on the product distribution was unexpected, and Warkentin and Thomaszewski have hypothesized that other factors that are dependent on tributyltin hydride concentration may be at work.  For example, the hydrogen transfer step that follows cyclization may be slow due to the datively stabilized radical.  A concentrated 65  solution of tributyltin hydride would increase the probability of hydrogen transfer, thus producing more of the 5-exo product 2.20.  A dilute solution of tributyltin radical may permit a radical-radical coupling of the 5-exo product, thus decreasing the amount of 5-exo product relative to that of the 6-endo product.  An alternative mechanism has also been proposed, which would favour the formation of the pyrrolidine 2.20 at elevated concentrations of the tributyltin radical (Scheme 2.5).89a,90  Nucleophilic addition of the tributyltin radical to imine 2.22 may afford radical 2.23.  Hydrogen transfer would provide bromide 2.24 and regenerate the tributyltin radical, which may then abstract the bromine to afford aryl radical 2.25.  An intramolecular radical coupling reaction following the loss of the tributyltin radical from 2.25 provides pyrrolidine 2.26.    Scheme 2.5.  Alternative mechanism for the formation of pyrrolidine 2.26. 2.1.1.3 Carbon-Centred Radical Additions to Azides The addition of a carbon radical to an azide functional group is a rapid method for the formation of heterocyclic compounds.  However, a limited number of reports of this transformation have been reported.  The first definitive evidence of a carbon radical 66  cyclizing onto an azide was reported by Spagnolo and co-workers in 1978 (Scheme 2.6).91  In this seminal publication, it was reported that the reduction of the diazonium salt in a cooled solution of sodium iodide and acetone afforded aryl radical 2.28, which following cyclization and loss of nitrogen gas, provided carbazoyl radical 2.30.  Reduction to the carbazole 2.32 occurs concomitantly with the dimerization of the carbazoyl radical 2.30.   Scheme 2.6.  Cyclization of an aryl radical onto an azide.  Scheme 2.7.  Synthesis of N-tosylpyrrolidine 2.36 from azide 2.33.  Kim and co-workers were the first to report the cyclization of an alkyl carbon radical onto an azide (Scheme 2.7).92  Treatment of an iodide 2.33 with the tributyltin radical provides pyrrolidine 2.35, which was transformed into tosylate 2.36 for ease of purification.  67  While an excellent proof of concept, reaction provided a mixture of products.  The tributyltin radical did not effect clean cyclizations of carbon radicals generated from less reactive precursors, such as bromides and thiocarbonates as the stannyl radical can also attack the azide in a competing reaction.93 For example, treatment of bromide 2.37 with the tributyltin radical provided a mixture of two products (Scheme 2.8).  The major product was azide 2.38, which resulted from the reduction of the bromide with tributyltin hydride.  However, the competing reduction of the azide, followed by tosylation, afforded amine 2.39 as the minor product.    Scheme 2.8.  Reduction products resulting from the treatment of bromide 2.37 with Bu3SnH.  Scheme 2.9.  Radical cyclization of bromide 2.40 using TTMSS.  Selectivity can be improved when tris(trimethylsilyl)silane is used in place of tributyltin hydride.  Azides are inert towards the silyl radical and, therefore, permit selective carbon radical formation.  For example, radical cyclization of bromide 2.40 and subsequent tosylation provided pyrrolidine 2.41 in good yield. 68      Scheme 2.10.  Synthesis of spiro-N-tosylpyrrolidine 2.48.  Kilburn and Santagostino utilized azides radical cyclization acceptors in the synthesis of spiro-N-tosylpyrrolidine derivative 2.48 (Scheme 2.10).94  Treatment of iodide 2.42 with the tris(trimethylsilyl) radical primary alkyl radical 2.43. A 5-exo-trig cyclization afforded radical 2.44, which then ?-fragmented to provide tertiary radical 2.45.  Subsequent carbon radical cyclization onto the azide gave radical 2.46, which, following the loss of nitrogen gas 69  and regeneration of the silyl radical, provided the spiro-pyrrolidine 2.47.  This product was further derivatized to tosylate 2.48 for ease of purification.   Scheme 2.11.  A total synthesis of (?)?aspidospermidine (2.54).  Murphy and co-workers have demonstrated the synthetic utility of this methodology in their approach to the pentacyclic core structure of (?)-aspidospermidine (Scheme 2.11).95  Treatment of iodide with silyl radical provided aryl radical 2.50, which cyclized to form radical 2.51.  Cyclization of radical 2.51 onto the azide, and subsequent loss of nitrogen gas, afforded the desired tetracyclic intermediate 2.53 in good yield.    2.2 Nitrogen Heterocycle Formation Using Nitrogen-Centred Radicals As previously described, aminyl radicals are an important tool for the construction of nitrogen containing heterocyclic compounds.  Aminyl radicals may be generated directly from a radical precursor, or indirectly through a tandem or cascade reaction that produces an aminyl radical, which can subsequently cyclize to form the desired heterocycle.  70  2.2.1 Indirect Formation of Aminyl Radicals  As outlined earlier in this chapter, aminyl radicals may be produced by a radical addition to an imine.  The selectivity for carbon-carbon bond formation can be exploited to form aminyl radicals, which further cyclizes onto a radical acceptor.  Several approaches have been developed that apply this strategy to tandem radical cyclizations.  Scheme 2.12.  Synthesis of pyrrolidines 2.59a and 2.59b using a tandem radical cyclization.  Bowman and co-workers have studied a tandem, one-pot procedure that provides bicyclic pyrrolidines.96  Exposure of imines 2.55a or b (Scheme 2.12) to tributyltin radical provided carbon radicals 2.56a or b.  5-Exo-trig cyclization provided aminyl radicals 2.57a or b, which undergoes an additional 5-exo-trig cyclization to provide radicals 2.58a or b.  Pyrrolidines 2.59a or b is produced following a hydrogen transfer reaction with tributyltin hydride.  Cyclization of terminal alkene 2.55a provided the bicyclic pyrrolidine 2.59a in 71  32% yield, while the phenyl-substituted analog provided the final cyclized product in significantly higher yield (62%).  These results motivated Bowman and co-workers to assess the potential to form indolizidines and pyrrolizidines employing their newly developed tandem radical cyclization protocol.  Treatment of selenide 2.60 (Scheme 2.13) with tributyltin hydride and AIBN provided alkyl radical 2.61, which has two modes of cyclization.  6-Endo cyclization produced aminyl radical 2.62, which underwent a subsequent 5-exo cyclization and hydrogen transfer to produce the desired indolizidine 2.65 as an equimolar mixture of both diastereomers.  Products arising from an initial 5-exo cyclization were not isolated, but 2.66 instead underwent a radical polymerization reaction.    72   Scheme 2.13.  Tandem radical cyclization to form indolizidine 2.65. 73   Scheme 2.14.  Attempted synthesis of pyrrolizidine 2.68 from imine 2.66 via a 5-endo cyclization. Attempts to form pyrrolizidines using an analgous approach failed as it would have required an unfavourable 5-endo cyclization (Scheme 2.14).97  Treatment of selenide 2.66 with the tributyltin radical provided alkyl radical 2.67.  As a subsequent 5-endo cyclization is prohibitively slow, the alkyl radical 2.67 is quenched with tributyltin hydride, forming amine 2.69 after treatment with sodium borohydride. 2.2.2 Direct Methods for the Generation of Aminyl Radicals There are several commonly employed methods for the formation of aminyl radicals which usually rely on homolytic scission of a weak nitrogen-heteroatom bond, under either thermal or photochemical conditions. Cleavage of a nitrogen-halogen bond is the traditional method for the formation of aminyl radicals.  The thermal or photochemical decomposition of a nitrogen-chlorine bond, and subsequent cyclization, under strongly acidic conditions is known as the Hoffmann-L?ffler-Freytag (HLF) reaction.  Shibanuma and co-workers have recently employed the HLF reaction as the key step in a total synthesis of the diterpene alkaloid kobusine (Scheme 74  2.15).98  Treatment of amine 2.70 with NCS provided 2.71 in excellent yield.  Exposure of of the N-chloro precursor 2.71 with trifluoroacetic acid and UV light provided the desired kobusine (2.72) in modest yield.  Scheme 2.15.  Application of the HLF reaction in a total synthesis of kobusine (2.72). While the HLF reaction has been elegantly employed in natural product synthesis, the reaction requires strongly acidic conditions to effectively carry out the hydrogen atom transfer step.  These strongly acidic conditions may reduce its synthetic appeal if multiple functional groups are present.  Scheme 2.16.  Synthesis of 2.74 and 2.75 from the decomposition of tetrazene 2.73.  Early studies into the formation of aminyl radicals employed the thermal extrusion of nitrogen gas from tetrazenes.  Heating tetrazene 2.73 provided pyrrolidine 2.74 as the major product, resulting from a 5-exo cyclization (Scheme 2.16).99  The generation of aminyl radicals employing electrochemical methods has been investigated by Suginome and co-workers.100 Electrolysis of the lithiated amide generated from the parent amine at low temperatures provided aminyl radical 2.77, which cyclized to afford pyrrolidine 2.78 as the exclusive diastereomer.101  The high degree of 75  stereoselectivity observed in this reaction was hypothesized to arise from steric constraints present at the platinum anode during electrolysis.    Scheme 2.17.  Electrochemcial oxidation of lithiated amide 2.76.  Scheme 2.18.  Electrochemical oxidation of N-methoxyamine 2.79.  It was later reported that N-methoxy derivatives cleanly cyclized without the initial lithiation step.  Electrolysis of N-methoxyamine 2.79 initially provides aminium radical 2.80, which cyclized to provide the N-methoxypyrrolidine radical 2.81.  Further oxidation and subsequent nucleophilic attack by solvent, provided ketone 2.82 as the exclusive diastereomer.  Figure 2.1.  N-hydroxypyridinethione ester 2.83 and N-hydroxypyridinethione carbamate 2.84. 76   N-Hydroxypyridinethione esters were first employed by Barton and co-workers as a carbon radical precursor102 (Figure 2.1).  These esters decompose under either thermal or photochemical conditions to produce carbon-centred radicals.  Newcomb and co-workers103 broadened the scope of this new class of radical precursors to include carbamates, which cleanly produce aminyl radicals under thermal or photochemical conditions.  For example, irradiation of carbamate 2.85 produced aminyl radical 2.86 (Scheme 2.19).104  5-Exo cyclization of the resulting aminyl radical (2.86) provided pyrrolidine radical 2.87, which underwent a subsequent cyclization to afford pyrrolizidine radical 2.88. Finally, trapping of the carbon radical with pyridinethiol radical 2.89 afforded the final product, pyrrolizidine 2.90, in excellent yield.  Scheme 2.19.  Synthesis of pyrrolizidine 2.90.  Bowman and co-workers demonstrated the application of arenesulfenamides towards the synthesis of many nitrogen containing heterocyclic compounds.105  This method has proven particularly useful when a polycyclic system is the desired final product.  For 77  example, treatment of arylsulfenamide 2.91 (Scheme 2.20) with the tributyltin radical produced aminyl radical 2.92.  Cyclohexyl radical 2.94 was provided following sequential 5-exo cyclizations, which formed the desired tricyclic pyrrolizidine.   Scheme 2.20.  Synthesis of tricyclic pyrrolizidine 2.95. Direct formation of aminyl radicals can also occur by treating an organic azide with tributyltin radical.106  Azides react with stannyl radicals to produce tin-bound aminyl radicals (Scheme 2.21, 2.99) following the loss of molecular nitrogen.107  Scheme 2.21.  Proposed mechanism for the formation of stannylaminyl radical 2.99. 78  Recent computational studies by Kim and co-workers demonstrated that the tributylstannylaminyl radicals generated from azides are more nucleophilic than aminyl radicals (Table 2.2).108    Table 2.2.  SOMO energy values and charge densities of selected aminyl radicals.a entry  aminyl radical SOMO energyb charge density 1   -9.65 -0.358 2   -9.87 -0.154 3   -10.41 -0.120 a Calculations were performed using the PM3-UHF method. bIonization potential in eV. That the difference in reactivity is suggested to be the result of two factors: (1) tin-bound aminyl radicals have a higher SOMO when compared to tin free aminyl radicals and (2) a higher electron density located around the nitrogen atom, which may be manifested by a more reactive radical species.  Kim exploited the nucleophilic nature of these stannylaminyl radicals in the synthesis of lactams (Scheme 2.22).109  Stannylaminyl radical 2.102 was produced upon treatment of azide 2.101 with the tributyltin radical.  Radical addition to the ketone afforded alkoxy radical 2.103, which provided radical 2.104 following ?-scission of the carbon-carbon bond.  The final ring expanded lactam was provided in excellent yield following the hydrolysis of the nitrogen-tin bond. 79   Scheme 2.22.  Stannylaminyl radical mediated ring expansion of 2.101 to lactam 2.106.  Expanding the scope of these nucleophilic radical cyclization reactions, Kim and co-workers reported the cyclization of stannylaminyl radical onto a hydrazine, which produced an imine as the final product (Scheme 2.23).110 Hydrazone radical 2.107 is produced upon the cyclization of stannylaminyl radical 2.108 onto the hydrazone functional group.  Imine 2.113 was provided in good yield following the expulsion of nitrogen, styrene and the tributyltin radical.    80   Scheme 2.23.  Stannylaminyl radical cyclization onto a hydrazone. 2.3 Aminyl Radical Cyclizations onto Silyl Enol Ethers  The application of heteroatom-centered radicals towards natural product synthesis is an active area of research within our group.  Polyhydroxylated alkaloids represent a large class of bioactive natural products, and include compounds such as pyrrolidines, piperidines, pyrrolizidines and indolizidines.111  While this class of naturally occurring compounds presents auspicious therapeutic potential, the full medicinal potential is largely limited by availability.111c    81   Figure 2.2.  Selected polyhydroxylated alkaloids. Many polyhydroxylated alkaloids possess a 2-hydroxymethyl pyrrolidine core (Figure 2.2, 2.114 and 2.115).  Previous work in our group had established that silyl enol ethers could be excellent acceptors in alkoxy radical cyclizations.112  We hypothesized that we could also rapidly access nitrogen-containing heterocyclic compounds that possess a 2-hydroxypyrroline core (Figure 2.3, 2.117) using aminyl radical cyclizations on to silyl enol ether.    Figure 2.3.  Aminyl radical cyclization for the synthesis of 2-hyrdoxymethyl pyrrolidine 2.117.  We were interested in using azides as our aminyl radical precursors because they are bench stable, readily synthesized and can provide access to substituted pyrrolidines.  Indeed, treatment of azide 2.120 with the tributyltin radical (Scheme 2.24) cyclized to form pyrrolidine 2.122 in good yield.113  While cyclizations of tin-bound aminyl radicals on to simple alkenes are typically not high-yielding,114 cyclization onto silyl enol ethers provide 82  higher yields of substituted pyrrolidines, presumably because of the dative stabilization of the radical intermediate favours product formation.  Our approach to unprotected pyrrolidines was successfully applied in the synthesis a silyl protected alkaloid, CYB-3 (Scheme 2.25, 2.124).113  Scheme 2.24. Nitrogen-centred radical cyclization to form pyrrolidine 2.122.      Scheme 2.25.  Synthesis of silyl protected CYB-3 (2.124) from Z-2.123. With a successful synthesis of the protected analog of CYB-3 (2.124) in hand, our group next investigated the synthesis of an unnatural polyhydroxylated alkaloid, 1,4-dideoxy-1,4-imino-L-ribitol.115 1,4-Dideoxy-1,4-imino-L-ribitol possesses a particularly challenging substitution pattern that could lead to more steric interactions during the transition state, ultimately lowering the diastereoselectivity of the cyclized pyrrolidines (Scheme 2.26, 2.126). 83   Scheme 2.26.  Cyclization of silyl enol ether 2.129. Cyclization of silyl enol ether 2.125 provided a mixture of pyrrolidine 2.126, imine 2.127 and amine 2.128.  1H NMR analysis of the crude reaction mixture found the ratio of products 2.126 : 2.127 : 2.128 to be 2:1:1.  Both pyrrolidine 2.126 and imine 2.127 were produced a single diastereomers after cyclization.  However imine 2.127 proved too unstable to isolate.  Imine 2.127 could, however, be reduced to the desired pyrrolidine (Scheme 2.27, 2.129) if the crude reaction mixture was treated with a reducing agent.  Exposure of silyl enol ether 2.125 to our cyclization conditions afforded a crude mixture of compounds (Scheme 2.26, 2.126-2.128).  This mixture of compounds was then treated with DIBAL-H, followed by HCl to provide pyrrolidine salt 2.129 with an improved yield.  Scheme 2.27. One pot synthesis of protected 1,4-dideoxy-1,4-imino-L-ribitol (2.129).   84  OTBSOTBSOTBSN3Bu3SnOTBSOTBSOTBSNBu3SnNOTBSOTBSTBSOSnBu3cyclizationhydrogen transferNOTBSOTBSTBSOSnBu3NOTBSOTBSTBSON2NOTBSOTBSTBSOSnBu32.1252.1302.1312.1322.1332.12723452345 Scheme 2.28.  Proposed mechanism for the formation of imine 2.127. We hypothesized the formation of imine 2.127 occurs through the mechanism outlined in Scheme 2.28. Treatment of azide 2.125 with tributyltin radical resulted in the formation of tin-bound aminyl radical 2.130, which rapidly cyclized to afford pyrrolidine radical 2.131.  Subsequent radical trapping would afford tin-bound pyrrolidine 2.132, which would provide pyrrolidine 2.126 (Scheme 2.26) following protonolysis of the nitrogen-tin bond.   The carbon radical 2.133 is hypothesized to form through an intermolecular hydrogen atom transfer116,117 between radical 2.131 and tin-bound pyrrolidine 2.132.  A radical fragmentation reaction involving pyrrolidine 2.13383b results in the formation of imine 2.127, and regeneration of the tributyltin radical.  This mechanism 85  suggests that cyclic imine 2.127 may be formed using a substoichiometric amount of tributyltin hydride.   While the goal of a synthesis of a protected 1,4-dideoxy-1,4-imino-L-ribitol (Scheme 2.27, 2.129) was achieved, we were intrigued by this by-product, and its mechanism of formation.  We hypothesized that this method may also serve as a useful way to make cyclic imine products form simple linear precursors.  Thus, we undertook investigations to elucidate the mechanism of imine formation in this reaction, and optimize it. 2.4 Results and Discussion  Scheme 2.29. Synthesis of cyclization precursor 2.120.  Cyclization precursor 2.120 (Scheme 2.29) was synthesized as previously described.112 Swern oxidation of tosylate 2.134 provided aldehyde 2.135.118  Treatment of aldehyde 2.135 with TBSOTf and H?nig?s base afforded silyl enol ether 2.136 in good yield and diastereoselectivity.  An SN2 reaction between tosylate 2.136 and sodium azide provided azide 2.120109 in excellent yield.  86  HO OHRTsO HR ORN3OTBSTsOR OTBS2.137a R = Me2.137b R = Ph1. TsCl, Et3NDMAP, CH2Cl22. (COCl)2, DMSO, Et3NCH2Cl2, - 78 ?CTBSOTf, DIPEACH2Cl2, 0 ?CNaN3DMF, 50 ?C2.139a (81% yield, 92:8 Z/E)2.139b (81% yield, >95:5 Z/E)Z-2.140a (84% yield, 92:8 Z/E)Z-2.140b (81% yield, >95:5 Z/E)2.138a R = Me (57% yield over 2 steps)2.138b R = Ph (35% yield over 2 steps) Scheme 2.30.  Synthesis of cyclization precursors Z-2.140a and Z-2.140b.  Cyclization precursor Z-2.140a was synthesized and characterized by Dr. Huimin Zhai, and compound Z-2140b was synthesized using a route optimized by Dr. Huimin Zhai.  Characterization of this compound had previously been reported.119 Treatment of diols 2.137a or b with TsCl, Et3N and DMAP afforded the mono-tosylate.  Swern oxidation of the crude reaction mixture provided aldehydes 2.138a or b in modest yield.  Treatment of a cooled solution of aldehydes 2.138a or b with TBSOTf and H?nig?s base afforded the Z-silyl enol ethers 2.139a or b as the major diastereomer.  A SN2 reaction between Z-silyl enol ethers (2.139a,b) and sodium azide afforded the azides Z-2.140a and Z-2.140b. 87   Scheme 2.31.  Synthesis of cyclization precursor 2.145.  The synthesis of cyclization precursor 2.145 (Scheme 2.31) was accomplished as a team, following a route optimized by Dr. Huimin Zhai.   Dr. Zhai completed the synthesis (2.144 to 2.145) and characterization of this compound was accomplished by Dr. Huimin Zhai.  A Swern oxidation of silyl ether 2.141, followed by the addition of phenylmagnesium bromide, afforded alcohol 2.142.  Alcohol 2.142 was next transformed into the phosphonate ester, which was then displaced to afford azide 2.143.  Removal of the silyl group using TsOH afforded alcohol 2.144, which was transformed into cyclization precursor 2.145 following a Swern oxidation and silyl enol ether formation. 88   Scheme 2.32.  Synthesis of cyclization precursor 2.151.  Synthesis of cyclization precursor 2.151 (Scheme 2.32) was accomplished by Dr. Huimin Zhai and the characterization of this compound was accomplished by Dr. Huimin Zhai.  Ring opening of ?-lactone 2.146 was accomplished with N,O-dimethylhydroxylamine hydrochloride and trimethylaluminum afforded alcohol 2.147.  Alcohol 2.147 was transformed into iodide 2.148 using an Appel-type reaction, and the amide was reduced to aldehyde 2.149 with DIBAL-H.  Silyl enol ether formation, followed by SN2 displacement with NaN3 afforded azide 2.151.  We were also interested in the selective formation of cyclic imines using a simple, unbiased cyclization precursor (Scheme 2.33, 2.120).  We hypothesized that the cyclic imine product was being formed following a radical transfer reaction, and subsequent radical fragmentation of the tin-nitrogen bond.  If our hypothesis was correct, the formation of cyclic imine should regenerate the tributyltin radical in the final step (Scheme 2.28).  To test whether our cyclization reaction was catalytic in the tributyltin radical, we used our group?s optimized conditions for the formation of pyrrolidines.113,119 The addition of tributyltin 89  hydride in one portion to azide 2.120 exclusively formed pyrrolidine 2.153, with no detectable amount of starting material (2.120) or cyclic imine 2.152.  Scheme 2.33.  One portion addition of superstoichiometric tributyltin hydride to azide 2.120.1 Using a NMR scale reaction, we next investigated the result of a one portion addition of 50 mol% tributyltin hydride (Scheme 2.34).  Along with the expected pyrrolidine 2.153 and starting material 2.120 were two cyclic imine products (2.152 and 2.154).  Imine 2.152 was the expected product according to our proposed mechanism in Scheme 2.6.  Imine 2.154 is also likely formed by an intermolecular radical translocation reaction at C2 followed by a radical fragmentation reaction.  While a large amount of unreacted azide 2.120 remained, the mass balance of all cyclized products (2.152, 2.153 and 2.154) was greater than the percentage of tributyltin hydride added to the reaction (Table 2.3, entry 1). This supports our hypothesis that tributyltin radical is regenerated in the reaction mechanism.                                                   1 This reaction was carried out by the author and Dr. Huimin Zhai. 90   Scheme 2.34.  One portion addition of 50 mol% of tributyltin hydride to azide 2.120.  We next sought to optimize the reaction conditions to maximize the yield of cyclic imines (2.152 and 2.154) compared to pyrrolidine 2.153.  Lowering the amount of tributyltin hydride to 30 mol% lead to an increase in the amount of cyclic imine (2.152 and 2.154) compared to pyrrolidine 2.153 and unreacted starting material 2.120 (Table 2.3, entry 1).  Unreacted starting material was not observed when the addition rate of tributyltin hydride addition was slowed from 0.4 mL/h to 0.2 mL/h (entries 2 and 3).  Addition rates slower than 0.2 mL/h were not investigated as the addition times were prohibitively long.  Increasing the concentration of the solution resulted in an increase in the amount of pyrrolidine 2.153 relative to imine products (2.152 and 2.154).      91  Table 2.3.  Optimization studies for total imine products 2.152 and 2.154.   entrya addition rate (mL/h) metal hydride R3SnH (mol%) product ratiob (2.152 + 2.154) : 2.153 : 2.120 1 1 portion Bu3SnH 30 1.3 : 1.4 : 1 2 0.4 Bu3SnH 30 1.5 : 1 : 0 3 0.2 Bu3SnH 30 1.9 : 1 : 0 4 0.2 Bu3SnH 15 2.5 : 1 : 0 5 0.2 Bu3SnH 10 1.3 : 1 : 2.3 6 0.2 Ph3SnH 40 1.8 : 1 : 0 7 0.2 Ph3SnH 20 1.8 : 1 : 0 a Reactions were carried out on a 0.31 mmol scale and were 0.03M in benzene. b Product ratios were determined by 1H NMR spectroscopic analysis of the crude reaction mixtures.   Reducing the amount of tributyltin hydride from 30 mol% to 15 mol% using the new, slower addition procedure (entry 4) resulted in an increase in the total imine products (2.152 and 2.154) compared to pyrrolidine 2.153.  Further reducing the amount of tributyltin hydride from 15 mol% to 10 mol% resulted in poor conversion to cyclic products, with the product mixture containing unreacted starting material 2.120 in an equal amount to total cyclic products (entry 5).  Unfortunately, using 15 mol% of tributyltin hydride produced variable results over many experimental trials.  Thus, we opted to use 30 mol% of tributyltin hydride, as these conditions proved to be the most reproducible and reliable.   Altering the stannyl radical source to triphenyltin hydride did not significantly 92  alter the product distribution (entries 6 and 7), and employing dichloroindium hydride afforded poor yields of imine products (2.152 and 2.154).120  Cyclization with 15 mol% tributyltin hydride favoured the formation of cyclic imine 2.152 over imine 2.154 in a 2.1:1 ratio.  For our methodology to be synthetically useful, it must be selective for the formation of one of the cyclic imines over the other.  Our initial investigations (Scheme 2.27) presented a possible solution as cyclization of azide 2.125 selectively formed only one imine regioisomer.  We hypothesized that this was caused by increasing the steric bulk at C3, which slowed the rate of hydrogen abstraction from C2.  To test this hypothesis we examined substrates with varying steric bulk at C3 (Schemes 2.35 and 2.36).  Scheme 2.35.  Cyclization of azide 2.155 varying the equivalents of Bu3SnH.2                                                  2 This reaction was both perfomed and characterized by Dr. Huimin Zhai. 93   In previous studies focusing on the cyclization of azide 2.156 (Scheme 2.35), using excess tributyltin hydride exclusively formed pyrrolidine 2.156 in good yield.119  Lowering the amount of tributyltin hydride and increasing the steric bulk at C3 resulted in the formation of the expected imine products 2.157 and 2.158 in good yield, favouring imine 2.157 over imine 2.158 in a 3.3:1 ratio.  Scheme 2.36.  Cyclization of azide 2.159 varying the equivalents of Bu3SnH.3  We next cyclized azide 2.159 (Scheme 2.36) to investigate the effect of incorporating a phenyl group at C3.  As expected, the one pot addition of tributyltin hydride and AIBN to azide 2.159 resulted in the formation of pyrrolidine 2.160 in good yield.119  Gratifyingly, the slow addition of 30 mol% tributyltin hydride to azide 2.159 resulted in the exclusive formation of imine 2.161 in good yield.  The observed increase in selectivity when cyclizing azide 2.159 using 30 mol% tributyltin hydride supports our hypothesis that the steric bulk at C3 will inhibit the radical transfer reaction to C2.  Imine 2.161 was derivatized to                                                  3 These reactions were performed by Dr. Huimin Zhai.  The characterization of these compounds was accomplished by Dr. Huimin Zhai.   94  pyrrolidine 2.160 and the major diastereomer was determined by comparison this compound.   Scheme 2.37.  Cyclization of secondary azides 2.162a and 2.162b. Encouraged by the increase in selectivities seen in our investigations into steric effects at C3, we hypothesized that an increase in selectivity for one of the imine products may be achieved if we could stabilize the radical at C5 (Scheme 2.28, 2.133). Cyclization of alkyl substituted azide 2.162a (Scheme 2.37) afforded cyclic imine 2.163a in good yield, with the remainder of mass balance corresponding to the undesired cyclic imine (24%) and the corresponding pyrrolidine (8%).  While the methyl substituted azide 2.162a did provide modest selectivity for one imine (2.163a), phenyl substitution exclusively provided one imine product (2.163b) in good yield.  The selectivity for imine 2.163b is presumed to arise from the enhanced stability of the benzylic radical located at C5.  Changing the geometry of the silyl enol ether provided no change to the reported product distributions.  Pairing this newly optimized methodology with our group?s complimentary work on the cyclization of stannylaminyl radicals onto silyl enol ethers enables access to different diastereomers from the same common precursor (Scheme 2.38). Treatment of a refluxing solution of azide 2.145 with a superstoichiometric amount of tributyltin radical afforded pyrrolidine 2.164 in good yield and with excellent selectivity for the trans-diastereomer.  Alternatively, the slow addition (0.2 mL/h) of 30 mol% of tributyltin hydride to a refluxing 95  solution of azide 2.145 afforded imine 2.163b, which was then reduced to the cis-2,5-pyrrolidine 2.166121 in good yield and excellent diastereoselectivity.  Scheme 2.38.  Synthesis of both trans- and cis-2,5-disubstituted pyrrolidines 2.164 and 2.166.4  Synthesis of highly substituted quaternary centres can also be accomplished via addition of a carbon nucleophile to cyclic imines.  Treatment of imine 2.163a (Scheme 2.39) with allyl magnesium bromide 2.167 resulted in the formation of pyrrolidine 2.168 in excellent yield as a 92:8 mixture of cis/trans diastereomers.122                                                  4 These reactions were performed by Dr. Huimin Zhai.   96   Scheme 2.39.  Addition of allyl magnesium bromide (2.167) to cyclic imine 2.163a.5    Scheme 2.40.  Mechanistic investigation into the proposed radical transfer step.6 We hypothesized that the radical translocation step found in our proposed mechanism (Scheme 2.28, 2.131 to 2.133) occurs through an intermolecular pathway.  To test this hypothesis, we designed an experiment in which a tin-bound pyrrolidine (Scheme 2.40, 2.169) could act as a hydrogen transfer agent. Gratifyingly, cyclization of azide 2.120 in the presence of both imine 2.163b and tin-bound pyrrolidine 2.169 led to the complete conversion of the tin-bound pyrrolidine (2.169) to imine 2.168.  As expected, cyclic products 2.152, 2.153 and 2.154 were also formed during this experiment.  This result, in addition with our experiments into the steric bulk at C3, provides further evidence that this radical translocation event is occurring in an intermolecular manner.                                                  5 This reaction was performed by Dr. Huimin Zhai.   6 This reaction was performed by Dr. Huimin Zhai. 97  2.5 Studies Towards a Synthesis of (?)-Lepadiformine A With the potential for the synthesis of cyclic imines using substoichiometric tributyltin hydride established, we began preliminary investigations that would demonstrate the potential of our methodology in natural product synthesis. The marine alkaloid lepadiformine was first isolated from the ascidian Clavelina lepadiformis by Baird and co-workers.123  We were interested in achieving a total synthesis of lepadiformine A (Figure 2.4) as it possesses an intriguing tricyclic core and some interesting biological activity, such as moderate in vitro cytotoxicity against several tumor cell lines, various cardiovascular effects and antiarrythmia properties.123a,c,124   Figure 2.4.  Representations of lepadiformine A (2.169). We envisioned that our recently reported method for the formation of imines under substoichiometric stannane to be directly applicable to a synthetic strategy (Scheme 2.41).  (?)-Lepadiformine A (2.169) would be provided following hydrogenation of alkene 2.170, which would be the product of a hetero-Diels-Alder reaction from the key imine intermediate 2.172.  We hypothesized that treating azide 2.173 with our optimized conditions would produce imine 2.172 in situ, which we anticipated would provide the hetero-Diels-Alder product125 (2.171).    98   Scheme 2.41.  Proposed route to (?)?lepadiformine A (2.169). The synthesis of test substrate 2.179 (Scheme 2.42) began with an SN2 involving pent-4-en-1-ylmagnesium bromide and known epoxide 2.174.126 Mesylation of alcohol 2.175 formed silyl ether 2.176 in excellent yield.  A reaction between silyl ether 2.176 and sodium azide provided azide 2.177 in excellent yield.  Deprotection and a Swern oxidation provided aldehyde 2.178, which was subsequently transformed into silyl enol ether 2.179.  99   Scheme 2.42.  Synthesis of test substrate 2.179. Cyclization of a tin-bound aminyl radical onto a silyl enol ether can provide several products, including pyrrolidines and imines.  As more than one imine product had been previously observed in similar cyclizations, we first investigated a test substrate to determine whether the desired imine (Scheme 2.43, 2.182) would be the major product using our optimized cyclization conditions.  Gratifyingly, it was found that stannylaminyl radical 2.179 cyclized to provide a mixture of 2.182, 2.183 and 2.184 in a ratio of 0.41:1:0.12, as well as reduced azide 2.185 (0.41).  While the optimized conditions previously described did provide imine 2.182 as the major isolated product, time limitations prevented further optimization of this reaction.  100   Scheme 2.43.  Cyclization of test substrate 2.179. 2.6 Future Work We envision the future direction of this project to involve further optimization of our tin-bound aminyl radical cyclization methodology to favour the formation of imine 2.182 (Scheme 2.42).  Imine 2.183 accounted for 19% of the reacted starting material 2.179, which we hypothesize to be the product of an intermolecular radical transfer reaction.  We could potentially increase the yield of imine 2.182 over imine 2.183 by adjusting the steric bulk of the protecting group used in azide 2.179.  For example, incorporation of a sterically encumbered protecting group, such as the tert-butyldiphenylsilyl, should favour the 101  formation of intermediate 2.187 (Scheme 2.44), which involves the hydrogen atom transfer from the least sterically hindered hydrogen.    Scheme 2.44.  Proposed investigations into the role of the protecting group on the hydrogen atom transfer step.  After forming imine 2.182, we will then optimize a route that would provide alkene 2.191 (Scheme 2.45) in one step from azide 2.189.  We expect the hetero-Diels-Alder reaction to proceed readily, as a similar cycloaddition involving an imine as the dienophile has previously been reported.125    Scheme 2.45.  Synthesis of alkene 2.191 from azide 2.189 in one step. An alternative strategy to form the desired imine precursor could employ an iminyl radical cyclization, as these species are known to cyclize at a much faster rate than aminyl radicals.127 However, this cyclization may be in competition with several hydrogen atom 102  transfer reactions.  We hypothesize using electron rich silyl enol ethers as radical acceptors may accelerate the rate of 5-exo cyclization (Scheme 2.45, 2.190) to outcompete the rate of the undesired hydrogen atom transfer reactions (2.188 and 2.189).  We hope to further extend these preliminary investigations towards a total synthesis of (?)-lepadiformine A.   Scheme 2.46.  Proposed cyclization of arenesulfenate 2.192. 2.7 Conclusion In summary, our work represents the first report of cyclic imine formation from a tin-bound aminyl radical cyclization onto a ?-system.  During the course of studies into the cyclization of tin-bound aminyl radicals onto silyl enol ethers, an unexpected imine product was observed.  We hypothesized that this product had arisen from an intermolecular radical transfer reaction.  Using a simple, linear precursor, we successfully optimized our reaction 103  conditions to favour the formation of cyclic imine products over all other possible products.  However, the selectivity of imine formation remained problematic in this linear substrate. Selective imine formation was accomplished using two different methods.  The first method was to slow the rate of intermolecular hydrogen atom transfer by increasing the steric bulk at C3.  Installation of a methyl group at C3 provided one imine over the other with modest selectivity.  However, installation of a phenyl group at C3 provided only one imine product.  The second strategy we investigated to selectively form one imine over the other involved stabilizing the radical at C5 that results from the initial cyclization reaction.  Installation of a methyl group at C5 provided modest selectivity for one imine product.  Once again, supplanting the methyl group with a phenyl group provided only one imine product.  The synthetic potential of our new method was demonstrated by synthesizing both diastereomers of 2,5-disubstituted pyrrolidines from a common linear precursor.  Finally, we undertook preliminary mechanistic investigations to elucidate the nature of this intriguing transformation. The results of these studies supported our hypothesis that the mechanism proceeds through an intermolecular hydrogen transfer step.  We anticipate that this method for the radical synthesis of imines from simple linear precursors will be amenable to synthesis of bioactive alkaloid natural products, such as (?)-lepadiformine A (2.169). 2.8 Experimental 2.8.1 General Experimental All reactions were performed under a nitrogen atmosphere in flame-dried glassware. Tetrahydrofuran, diethyl ether, dichloromethane and benzene were purified by MBRAUN MB-SPS solvent purification system. Thin layer chromatography (TLC) was performed on 104  Whatman Partisil K6F UV254 pre-coated TLC plates. Chromatographic separations were effected over Fluka 60 silica gel. Triethylamine washed silica gel has been stirred with triethylamine prior to packing. All chemicals were purchased from commercial sources and used as received.  Triethylamine washed silica gel has been stirred with triethylamine prior to packing. All chemicals were purchased from commercial sources and used as received.  A KD-Scientific KDS100 syringe pump was used for all slow additions. Infrared (IR) spectra were obtained using a Thermo Nicolet 4700 FT-IR spectrometer. Proton nuclear magnetic resonance (1H NMR) spectra were recorded in deuterochloroform using a Bruker AV-300 or AV-400 spectrometer. Carbon nuclear magnetic resonance (13C NMR) spectra were recorded in deuterochloroform using a Bruker AV-300 or AV-400 spectrometer. Chemical shifts are reported in parts per million (ppm) and are referenced to the centerline of deuterochloroform (7.27 ppm 1H NMR; 77.0 ppm 13C NMR). Low resolution mass spectra (LRMS) and high resolution mass spectra (HRMS) were recorded on either a Bruker Esquire-LC spectrometer (for LRMS) or a Waters/Micromass LCT spectrometer (for HRMS).  The geometry of silyl enol ethers was assigned based on the magnitude of the J coupling in the 1H NMR. 2.8.2 Synthesis of compounds Z-2.140a, 2.140b, 2.145 , 2.151 and 2.175 ? 2.179.  (Z)-(5-Azido-3-methyl-pent-1-enyloxy)-tert-butyl-dimethyl-silane) (Z-2.140a): To a solution of tosylate113 (1.22 g, 3.17 mmol) in DMF (10 mL) was added sodium azide (450 mg, 6.34 mmol). The mixture was heated to 50 ?C for 10 h, then allowed to warm to ambient temperature and diluted with EtOAc (30 mL). The mixture was washed with water (2x15 105  mL), brine (15 mL), dried over Na2SO4, filtered and concentrated by rotary evaporation to provide a yellow oil. Purification by flash chromatography (hexanes) gave 681 mg (84%) of azide Z-2.140a (Z/E = 90:10) as a clear oil. IR (neat) 2930, 2859, 2096, 1655, 1257 cm-1; 1H NMR (400 MHz, CDCl3) ? 6.26 (d, J = 12 Hz, trans 1 H), 6.18 (d, J = 6 Hz, cis 1 H), 4.78 (d, J = 12, 9 Hz, trans 1 H), 4.21 (dd, J = 9, 6 Hz, cis 1 H), 3.34-3.18 (m, 2 H), 2.84-2.71. (m, 1 H), 1.69-1.58 (m, 1 H), 1.54-1.43 (m, 1 H), 1.00 (d, J = 7 Hz, 3 H), 0.93 (s, 9 H), 0.13 (s, 6 H); 13C NMR (100 MHz, CDCl3) ? 138.5, 114.9, 50.0, 36.3, 26.3, 25.7, 25.6, 21.2, 18.2, ?5.4, ?5.5; HRMS-ESI (m/z) [M+Na]+ calcd. for C12H25N3ONaSi: 278.1665. Found: 278.1658.  (Z)-Toluene-4-sulfonic acid 5-(tert-butyl-dimethyl-silanyloxy)-3-phenyl-pent-4-enyl ester (2.139b): To a solution of aldehyde 2.138b113 (846 mg, 2.55 mmol) and diisopropylethylamine (498 mg, 3.83 mmol) in CH2Cl2 (25 mL) at 0 ?C was added tert-butyldimethylsilyl trifluoromethanesulfonate (877 mg, 3.32 mmol) dropwise over 5 min. The resulting solution was stirred for 3 h, then quenched with saturated NaHCO3 (10 mL) and extracted with CH2Cl2 (2 x 10 mL). The organic extracts were dried over Na2SO4, filtered, and the solvent was removed by rotary evaporation to provide a colourless oil. Purification by flash chromatography (5% EtOAc in hexanes) afforded 918 mg (81%) of silyl enol ether 2.139b (Z/E > 95:5) as a clear oil.  IR (neat) 2926, 1732, 1454, 1360 cm-1; 1H NMR (400 MHz, CDCl3) ? 7.76 (d, J = 8 Hz, 2 H), 7.32 (d, J = 8 Hz, 2 H), 7.26-7.08 (m, 5 H), 6.20 (d, J = 6 Hz, 1 H), 4.53 (dd, J = 10, 6 Hz, 1 H), 4.08-3.96 (m, 2 H), 3.89 (q, J = 8 Hz, 1 H), 2.45 (s, 3 H), 2.07-1.97 (m, 2 H), 0.90 (s, 9 H), 0.12 (s, 3 H), 0.08 (s, 3 H); 13C NMR (100 MHz, CDCl3) ? 106  144.5, 144.3, 139.1, 133.4, 129.7, 128.4, 127.9, 127.2, 126.1, 69.2, 36.3, 35.5, 25.6, 21.6, 18.1, ?5.4, ?5.5; HRMSESI (m/z) [M+Na]+ calcd. for C24H34O4NaSSi: 469.1845. Found: 469.1850.  (Z)-(5-Azido-3-phenyl-pent-1-enyloxy)-tert-butyl-dimethyl-silane (Z-2.140b): To a solution of tosylate 2.139b (291 mg, 0.651 mmol) in DMF (10 mL) was added sodium azide (92 mg, 1.3 mmol). The mixture was heated at 50 ?C for 10 h, then allowed to warm to ambient temperature and diluted with EtOAc (30 mL). The reaction solution was washed with water (2 x 15 mL), brine (15 mL), dried over Na2SO4, filtrated and concentrated by rotary evaporation to provide a yellow oil. Purification by flash chromatography (hexanes) afforded 1.7x102 mg (82%) of azide Z-2.140b (Z/E = 96:4) as a clear oil.  IR (neat) 2931, 2858, 2100, 1656, 1256 cm-1; 1H NMR (400 MHz, CDCl3) ? 7.36-7.18 (m, 5 H), 6.27 (dd, J = 6, 1 Hz, 1 H), 4.60 (dd, J = 10, 6 Hz, 1 H), 3.96 (q, J = 9 Hz, 1 H), 3.26 (t, J = 7 Hz, 1 H), 2.00-1.87 (m, 2 H), 0.94 (s, 9 H), 0.15 (s, 3 H), 0.11 (s, 3 H); 13C NMR (100 MHz, CDCl3) ? 144.8, 139.1, 128.5, 127.2, 126.1, 112.7, 49.8, 37.5, 35.6, 25.6, 18.2, ?5.4; HRMS-ESI (m/z) [M+Na]+ calcd. for C17H27N3ONaSi: 340.1821. Found: 340.1812.  (Z)-(5-Azido-hex-1-enyloxy)-tert-butyl-dimethyl-silane (2.151): To a solution of iodide 2.150113 (986 mg, 2.92 mmol) in DMF (10 mL) was added sodium azide (412 mg, 5.80 mmol). The mixture was heated at 50 ?C for 10 h, then diluted with EtOAc (40 mL). The mixture was washed with water (2 x 15 mL), brine (15 mL), dried over Na2SO4, filtrated and 107  concentrated by rotary evaporation to provide a yellow oil. Purification by flash chromatography (hexanes) gave 658 mg (89%) of azide 2.151 (Z/E > 95:5) as a clear oil.  IR (neat) 2930, 2100, 1656, 1256 cm-1; 1H NMR (400 MHz, CDCl3) ? 6.21 (dt, J = 6, 1 Hz, 1 H), 4.43 (q, J = 6 Hz, 1 H), 3.45 (sextet, J = 7 Hz, 1 H), 2.27-2.10 (m, 2 H), 1.69-1.41 (m, 2 H), 1.26 (d, J = 6 Hz, 3 H), 0.94 (s, 9 H), 0.14 (s, 6 H); 13C NMR (100 MHz, CDCl3) ? 139.4, 108.8, 57.5, 36.0, 25.6, 20.3, 19.3, 18.3, ?5.4; HRMS-ESI (m/z) [M+Na]+ calcd. for C12H25N3ONaSi: 278.1665. Found: 278.1666.  5-(tert-Butyl-dimethyl-silanyloxy)-1-phenyl-pentan-1-ol (2.142): To a solution of oxalyl chloride (2.74 g, 21.6 mmol) in CH2Cl2 (70 mL) at ?78 ?C was added a solution of dimethylsulfoxide (2.34 g, 30.2 mmol) in CH2Cl2 (10 mL) dropwise over 10 min. After stirring for an additional 10 min at ?78 ?C, a solution of 5-(tert-butyldimethylsilyloxy)-1-pentanol (2.141) (90%, remainder 1,5-bis(tert-butyldimethylsilyoxy)pentane, 4.32 g, 15.0 mmol) in CH2Cl2 (25 mL) was added dropwise over 10 min. The mixture was stirred for 45 min at ? 78 ?C, and then triethylamine (4.37 g, 43.2 mmol) was added. After the mixture was stirred for 40 min at ? 78 ?C, it was allowed to warm to room temperature and stirred for 1 hour. The mixture was quenched with 10% of aqueous NaHCO3 and then extracted with CH2Cl2 (2 ? 30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated using a rotary evaporation to afford 3.07 g of crude aldehyde as yellow oil. The oil was then dissolved in THF (60 mL) and cooled to 0 ?C. A 3.0 M solution of phenylmagnesium bromide in THF (9.5 mL) was added, via syringe pump, over 1 h. The mixture was allowed to warm to 108  ambient temperature and stirred for an additional 12 h. The mixture cooled to 0 ?C and then quenched with saturated aqueous NH4Cl (30 mL). The resulting mixture was extracted with dichloromethane (2 ? 30 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over MgSO4 and concentrated using a rotary evaporator to afford a yellow oil. Purification by flash chromatography (2% EtOAc in hexanes) gave 3.0 g (67 % yield over 2 steps) of alcohol 2.142 as a colorless oil.  IR (neat) 3384, 2930, 2857, 1255, 1030 cm-1; 1H NMR (400 MHz, CDCl3) ? 7.38-7.31 (m, 4 H), 7.30-7.24 (m, 1 H), 4.66 (t, J = 6 Hz, 2 H), 3.60 (t, J = 6 Hz, 2 H), 2.22 (br. s., 1 H), 1.86-1.67 (m, 2 H), 1.59-1.28 (m, 4 H), 0.89 (s, 9 H), 0.04 (s, 6 H); 13C NMR (100 MHz, CDCl3) ? 144.8, 128.4, 127.4, 125.9, 74.5, 63.0, 38.8, 32.5, 25.9, 22.1, 18.3, ?5.3; HRMS-ESI (m/z) [M+Na]+ calcd. for C17H30N3O2NaSi: 317.1913. Found: 317.1918.  (5-Azido-5-phenyl-pentyloxy)-tert-butyl-dimethyl-silane (2.143): To a solution of alcohol 2.142 (2.94 g, 10.0 mmol) in dry CH2Cl2 (30 mL) at 0?C was added DMAP (1.34 g, 11.0 mmol, followed by a solution of ClP(O)(OPh)2 (2.1 mL, 11 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred allowed to warm to ambient temperature and stirred for 12 h. The reaction was then was poured into EtOAc (80 mL) and washed with saturated aqueous NH4Cl (2 x 30 mL), water (30 mL), and brine (30 mL). The organics were then dried concentrated using a rotary evaporator to afford a yellow oil. To the resulting oil was added DMF (30 mL) and sodium azide (1.42 g, 20.0 mmol). The mixture was heated to 50 ?C for 10 h, then diluted with EtOAc (40 mL). The mixture was washed with water (2 x 20 mL), brine 109  (20 mL). The organics were then dried over Na2SO4, filtrated and concentrated by rotary evaporation to provide a yellow oil. Purification by flash chromatography (hexanes) gave 2.29 g (72%) of azide 2.143 as a clear oil. IR (neat) 2930, 2096, 1254 cm-1; 1H NMR (400 MHz, CDCl3) ? 7.48 - 7.29 (m, 5 H), 4.46 (t, J = 7Hz, 2 H), 3.63 (t, J = 6 Hz, 2 H), 1.98-1.76 (m, 2 H), 1.62?1.30 (m, 4 H), 0.92 (s, 9 H), 0.07 (s, 6 H); 13C NMR (100 MHz, CDCl3) ? 139.8, 128.7, 128.1, 126.9, 66.4, 62.8, 36.0, 32.4, 25.9, 22.6, 18.3, ?5.3; HRMS-ESI (m/z) [M+Na]+ calcd. for C17H29N3ONaSi: 342.1978. Found: 342.1982.  5-Azido-5-phenyl-pentan-1-ol (2.144): To a solution of silyl ether 2.143 (2.10 g, 6.58 mmol) in methanol (25 mL) at ambient temperature was added p-toluenesulfonic acid monohydrate (380 mg, 2.01 mmol) and the solution was stirred for 3 hours. The solvent was removed using a rotary evaporator and the residue was purified by flash chromatography (4:1 hexanes/EtOAc) to provide 981 mg (73%) of alcohol 2.144 as a colorless oil. IR (neat) 3422, 2931, 2859, 2097, 1656, 1259 cm-1; 1H NMR (400 MHz, CDCl3) ? 7.42-7.28 (m, 5 H), 4.43 (t, J = 7 Hz, 2 H), 3.58 (t, J = 6 Hz, 2 H), 2.35 (s, 1 H), 1.92-1.70 (m, 2 H), 1.61-1.40 (m, 3 H), 1.40-1.29 (m, 1 H); 13C NMR (100 MHz, CDCl3) ? 139.5, 128.6, 128.1, 126.7, 66.2, 62.1, 35.8, 32.0, 22.4; HRMS-ESI (m/z) [M+Na]+ calcd. for C11H15N3ONa: 228.1113. Found: 228.1115.  110   (E)-(5-Azido-5-phenyl-pent-1-enyloxy)-tert-butyl-dimethyl-silane (2.145): To a solution of oxalyl chloride (913 mg, 7.21 mmol) in dry CH2Cl2 (70 mL) at ? 78 ?C was added a solution of dimethylsulfoxide (780 mg, 10.0 mmol) in CH2Cl2 (10 mL) dropwise over 10 minutes. After 10 minutes, a solution of alcohol 2.144 (1.01 g, 4.98 mmol) in CH2Cl2 (6 mL) was added dropwise over 5 minutes. The mixture was allowed to stir for 45 min. at ? 78 ?C, and then triethylamine (1.09 g, 10.8 mmol) was added. After the mixture was stirred for 40 min at ?78 ?C, it was warmed to room temperature for 1 h. The mixture was quenched with 10% of aqueous NaHCO3 and then extracted with CH2Cl2 (2 ? 30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated using a rotary evaporation to afford 801 mg (80%) of crude aldehyde as yellow oil. The oil was then dissolved in CH2Cl2 (60 mL), and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.46 g, 9.78 mmol) and tert-butyldimethylsilyl chloride (1.18 g, 7.82 mmol) were added. The resulting solution was stirred for 12 hours, then quenched with saturated NaHCO3 (10 mL) and extracted with CH2Cl2 (2 x 10 mL). The organic extracts were dried over Na2SO4, filtered, and the solvent was removed by rotary evaporation to provide a yellow oil. Purification by flash chromatography (1% EtOAc in hexanes) gave 1.08 g (87%) of silyl enol ether 2.145 (E/Z = 69:31) as a colorless oil. IR (neat) 2930, 2096, 1663, 1256, 1179 cm-1; 1H NMR (400 MHz, CDCl3) ? 7.51-7.28 (m, 5 H), 6.26 (d, J = 12 Hz, trans 1 H), 6.23 (d, J = 8 Hz, cis 1 H), 4.96 (dt, J = 12, 8 Hz, 1 H), 4.44 (q, J = 6 Hz, 1 H), 2.19-2.09 (m, 1 H), 1.99-1.70 (m, 3 H), 0.94 (s, 9 H), 0.92 (s, 9 H), 0.15 (s, 6 H), 0.13 (s, 6 H); 13C NMR (100 MHz, CDCl3) ? 141.3, 139.9, 139.7, 111  139.6, 128.8, 128.7, 128.2, 128.1, 126.9, 109.5, 108.6, 26.3, 25.70, 25.65, 25.6, 24.0, 20.5, 18.3, 18.2, ?3.0, ?5.2, ?5.4, ? 5.7; HRMS-ESI (m/z): [M+H-N2]+ calcd. for C17H28NOSi: 290.1940. Found: 290.1943.  1-(tert-Butyldiphenylsilyloxy)undec-10-en-5-ol (2.175):  To a stirring solution of epoxide 2.174 (1.13g, 3.20 mmol) in anhydrous Et2O (4 mL) was added a solution of freshly prepared Grignard reagent (0.40 mL, 3.4 mmol) in THF (4 mL).  The reaction was stirred for 12 hours at room temperature, at which point the reaction was quenched via the dropwise addition of sat. NH4Cl (5 mL).  The organic layer was washed with brine (3 x 10 mL), and then dried over Na2SO4.  The crude mixture was purified using flash column chromatography (7:1 to 5:1 hexanes/EtOAc) affording 2.175 as a colourless oil (1.11 g, 82%).  IR (film): 3346, 3071, 2931, 2857, 2360, 2311, 1427, 1111 cm-1; 1H NMR (400 MHz, CDCl3) ? 7.68 (dd, J = 2, 8 Hz, 4 H), 7.46 ? 7.36 (m, 6 H), 5.90 ? 5.75 (m, 1 H), 5.07 ? 4.91 (m, 2 H), 3.73 ? 3.64 (m, 2 H), 3.58 (s, 1 H), 2.08 (q, J = 7 Hz, 2 H), 1.68 ? 1.51 (m, 4 H), 1.49 ? 1.38 (m, 1 H), 1.32 ? 1.27 (m, 1 H), 1.06 (s, 9 H); 13C NMR (100 MHz, CDCl3) ? 138.9, 135.6, 134.1, 129.6, 114.1, 71.8, 63.8, 37.2, 37.1, 33.7, 32.5, 29.0, 26.9, 25.1, 21.9, 19.2; HRMS-ESI (m/z) [M+Na]+ calcd. For C27H40O2NaSi: 447.2695. Found: 447.2693.  1-((tert-Butyldiphenylsilyl)oxy)undec-10-en-5-yl methanesulfonate (2.176):  To a solution of alcohol 2.175 (0.67 g, 1.6 mmol) in DCM (9 mL) at 0 oC was added mesyl chloride 112  (0.13 mL, 1.7 mmol) then triethylamine (0.24 mL, 1.7 mmol).  The reaction was stirred for 1.5 hours at 0 oC then allowed to warm to ambient temperature overnight.  The crude reaction mixture was diluted with H20 (10 mL) and partitioned and the aqueous layer was extracted with EtOAc (3 x 10 mL).  The combined organic extracts were then washed with brine (20 mL), dried over Na2SO4, and the solvent was removed using rotary evaporation to yield 2.176 as a colourless oil (0.75 g, 96%) that did not require further purification.  IR (film): 3071, 3049, 2931, 2858, 2359, 1640, 1472, 1427, 1358, 1174, 1111 cm-1; 1H NMR (400 MHz, CDCl3) ? 7.67 (dd, J = 2, 8 Hz, 4 H), 7.50 ? 7.32 (m, 6 H), 5.90 ? 5.71 (m, 1 H), 5.10 ? 4.88 (m, 2 H), 4.77 ? 4.63 (m, 1 H), 3.68 (t, J = 6 Hz, 2 H), 2.97 (s, 3 H), 2.18 ? 2.01 (m, 2 H), 1.76 ? 1.57 (m, 6 H), 1.54 ? 1.35 (m, 6 H), 1.06 (s, 9 H); 13C NMR (100 MHz, CDCl3) ? 138.5, 135.5, 133.9, 129.6, 127.6, 114.7, 84.0, 63.5, 38.7, 34.3, 34.1, 33.5, 32.2, 28.6, 26.9, 24.3, 21.4, 19.2; HRMS-ESI (m/z) [M+Na]+ calcd. For C27H42O4NaSi: 525.2471. Found: 525.2482.  ((5-Azidoundec-10-en-1-yl)oxy)(tert-butyl)diphenylsilane (2.177):  To a solution of mesylate 2.176 (0.73 g, 1.5 mmol) in DMF (12 mL) was added sodium azide (0.19 g, 2.9 mmol).  The resulting solution was heated to 50 oC for 12 hours, and then allowed to cool to ambient temperature.  The crude reaction mixture was then diluted with Et2O (30 mL) and washed with H20 (2 x 15 mL) followed by brine (15 mL) and dried over Na2SO4.  The crude oil was then purified using flash column chromatography (5:1 hexanes/EtOAc) to yield 2.177 as a colourless oil (0.54 g, 83%).  IR (film): 3071, 2932, 2858, 2097, 1472, 1162, 1274, 1112 cm-1; 1H NMR (400 MHz, CDCl3) ? 7.68 (dd, J = 2, 8 Hz, 4 H), 7.49 ? 7.33 (m, 6 H), 5.90 ? 113  5.73 (m, 1 H), 5.09 ? 4.90 (m, 2 H), 3.68 (t, J = 6 Hz, 2 H), 3.25 ? 3.18 (m, 1 H), 2.15 ? 2.01 (m, 2 H), 1.64 ? 1.56 (m, 2 H), 1.54 ? 1.47 (m, 6 H), 1.47 ? 1.35 (m, 4 H), 1.07 (s, 9 H); 13C NMR (100 MHz, CDCl3) ? 138.6, 135.6, 134.0, 129.5, 127.6, 114.6, 63.6, 63.0, 34.2, 34.1, 33.6, 32.3, 28.7, 26.9, 25.5, 22.5, 19.2; HRMS-ESI (m/z) [M+Na]+ calcd. For C27H39N3ONaSi: 472.2760. Found: 472.2751.  5-Azidoundec-10-enal (2.178):  To a solution of azide 2.177 (0.49 g, 1.1 mmol) in THF (7 mL) was added TBAF (1.41 mL, 1.41 mmol).  After 1.5 hours the reaction mixture was diluted with H2O and extracted with Et2O (3 x 10 mL).  The combined organic extracts were washed with brine (15 mL), dried over Na2SO4 and the solvent was removed using rotary evaporation.  This crude reaction mixture was used in the next step without further purification.  To a solution of oxalyl chloride (0.13 mL, 1.5 mmol) in DCM (2 mL) at ? 78 oC was added a solution of DMSO (0.21 mL, 3.0 mmol) in DCM (2 mL).  After 45 minutes had expired while stirring at ? 78 oC, a solution of alcohol ## (0.16 g, 0.75 mmol) in DCM (2 mL) was added.  The solution was then allowed to warm to ambient temperature, and stirred overnight (12 hours).  The resulting reaction mixture was diluted with H2O (10 mL) and extracted with DCM (3 x 10 mL).  The combined organic extracts were washed with H2O (10 mL), brine (10 mL) and dried over Na2SO4.  The solvent was removed using rotary evaporation then purified using flash column chromatography (5:1 hexanes/EtOAc), providing 2.178 as a yellow oil (0.13 g, 82 %).  IR (film): 3077, 2936, 2859, 2721, 2097, 114  1726, 1640 cm-1; 1H NMR (400 MHz, CDCl3) ? 9.79 (t, J = 1 Hz, 1 H), 5.89 ? 5.73 (m, 1 H), 5.06 ? 4.93 (m, 2 H), 3.33 ? 3.20 (m, 1 H), 2.49 (td, J = 2, 7 Hz, 2 H), 2.16 ? 2.01 (m, 2 H), 1.87 ? 1.63 (m, 2 H), 1.59 ? 1.50 (m, 4 H), 1.49 ? 1.34 (m, 4 H);  13C NMR (100 MHz, CDCl3) ? 201.8, 138.5, 114.6, 62.7, 43.5, 34.1, 33.7, 33.5, 28.6, 25.5, 18.7; HRMS-ESI (m/z) [M+Na]+ calcd. For C11H19N3ONa: 232.1426. Found: 232.1423.  ((5-Azidoundeca-1,10-dien-1-yl)oxy)(tert-butyl)dimethylsilane (2.179):  To a solution of aldehyde 2.178 (53 mg, 0.25 mmol) in DCM (1.3 mL) was added DBU (0.11 mL, 0.76 mmol) and TBSCl (77 mg, 0.51 mmol).  After stirring for 12 hours, the solvent was removed using rotary evaporation and the crude reaction mixture  was then purified by flash column chromatography (24:1 hexanes/EtOAc) to yield a 2:1 E to Z ratio of silyl enol ethers 2.179 as a colourless oil (69 mg, 85%).  IR (film): 2931, 2858, 2360, 2097, 1662 cm-1; 1H NMR (400 MHz, CDCl3) ? 6.33 ? 6.24 (m, trans, 1 H), 6.24 ? 6.17 (m, cis, 1 H), 5.88 ? 5.74 (m, trans, 3 H/cis, 2 H), 4.49 ? 4.37 (m, cis, 1 H), 3.32 ? 3.21 (m, 1 H), 2.24 ? 1.91 (m, 4 H), 1.61 ? 1.34 (m, 8 H), 0.97 ? 0.90 (m, 9 H), 0.14 (s, 6 H); 13C NMR (100 MHz, CDCl3) ? 141.1, 138.6, 114.6. 109.9, 62.6, 62.2, 35.2, 34.3, 34.2, 33.6, 33.6, 28.7, 28.7, 25.7, 25.6, 25.6, 24.0, 20.4, 18.3, -5.2, -5.4; HRMS-ESI (m/z) [M+Na]+ calcd. For C17H33N3ONa: 346.2291. Found: 346.2281.  2.8.3 Cyclization Procedures for Silyl Enol Ethers 2.8.3.1 General Cyclization Procedure for Slow Additions  A solution of Bu3SnH (0.3 equiv.) and AIBN (0.10 equiv.) was added via syringe pump (0.2 mL/h) over 5 h to a solution of silyl enol ether (1.0 equiv.) and AIBN (0.15 equiv.) in 115  degassed benzene (0.05 M) at 80 ?C and reaction mixture was stirred for another 3 hours. The solution was allowed to cool to room temperature and the solvent was removed by rotary evaporation. Purification by flash chromatography afforded the cyclized products. 2.8.3.2 General Cyclization Procedure for One Portion Additions A solution of Bu3SnH (1.2 equiv.), AIBN (0.15 equiv.), and silyl enol ether in degassed benzene (0.05 M) was heated to 80 ?C and stirred for 12 hours, and the solution was allowed to cool to room temperature and the solvent was removed by rotary evaporation. Purification by flash chromatography afforded the cyclized product. 2.8.3.3 Cyclizations of Silyl Enol Ethers Z-2.140a, 2.140b, 2.145 and 2.151.  2-(tert-Butyl-dimethyl-silanyloxymethyl)-3,4-dihydro-2H-pyrrole (2.152) and 5-(tert Butyldimethyl-silanyloxymethyl)-3,4-dihydro-2H-pyrrole (2.154): Silyl enol ether 2.120 (256 mg, 1.06 mmol) was subjected to the general cyclization procedure for the slow addition of stannane. Purification by flash chromatography (30% EtOAc in hexanes) afforded 109 mg (48%) of imine 2.152 and 2.154128 as a light yellow oil, which will decompose within hours at room temperature. 1H NMR (400 MHz, CDCl3) ? 7.61 (t, J = 1 Hz, 1 H), 4.39 (s, 2 H), 4.23-4.14 (m, 1 H), 3.89-3.81 (m, 2 H), 3.67 (dd, J = 9, 5 Hz, 1 H), 2.64-2.44 (m, 2 H), 1.94-1.79 (m, 2 H), 1.76-1.67 (m, 2 H), 0.92 (s, 9 H), 0.89 (s, 9 H), 0.09 (s, 6 H), 0.06 (s, 3 H), 0.05 (s, 3 H); 13C NMR (100 MHz, CDCl3) ? 167.4, 74.6, 65.8, 63.8, 61.0, 37.1, 34.8, 25.9, 25.8, 23.1, 22.0, 18.3, 18.0, -4.8, -5.1, -5.4. 116   2-(tert-Butyl-dimethyl-silanyloxymethyl)-3-methyl-3,4-dihydro-2H-pyrrole (2.157): Silyl enol ether 2.155 (301 mg, 1.18 mmol) was subjected to the general cyclization procedure for slow additions. Purification by flash chromatography (25% EtOAc in Hexanes) afforded 100 mg of imine 2.157 and 2.158 (10:1) as a light yellow oil, which will decompose at room temperature after a couple of days. 1H NMR (400 MHz, CDCl3) ? 7.54 (s, 1 H), 3.85 (dd, J = 10, 4 Hz, 1 H), 3.70-3.61 (m, 1 H), 3.83 (dd, J = 10, 6 Hz, 1 H), 2.81-2.72 (m, 1 H), 2.20 2.13 (m, 2 H), 1.05 (d, J = 7 Hz, 3 H), 0.88 (s, 9 H), 0.05 (s, 3 H), 0.03 (s, 3 H); 13C NMR (100 MHz, CDCl3) ? 166.8, 81.8, 65.3, 45.6, 31.9, 25.9, 23.4, 20.4, 18.2, -5.4; HRMS-ESI (m/z): [M+Na]+ calcd. for C12H25NOSiNa: 250.1603. Found: 250.1595.  5-(tert-Butyl-dimethyl-silanyloxymethyl)-4-methyl-3,4-dihydro-2H-pyrrole (2.158): Further elution afforded 80 mg of mixture of 2.158 and 2.157 (61:39) as a light yellow oil, which will decompose at room temperature after a couple of days. 1H NMR (400 MHz, CDCl3) ? 7.54 (s, 1 H), 4.39 (s, 2 H), 3.86 (dd, J = 10, 4 Hz, 1 H), 3.84-3.70 (m, 1 H), 3.70-3.61 (m, 1 H), 3.83 (dd, J = 10, 6 Hz, 1 H), 3.06-2.96 (m, 1 H), 2.81-2.72 (m, 1 H), 2.51-2.38 (m 1 H), 2.20-2.13 (m, 2 H), 1.17 (d, J = 7 Hz, 3 H), 1.06 (d, J = 7 Hz, 3 H), 0.92 (s, 9 H), 0.89 (s, 9 H), 117  0.10 (s, 6 H), 0.06 (s, 3 H), 0.04 (s, 3 H); 13C NMR (100 MHz, CDCl3) ? 166.9, 81.8, 65.3, 62.4, 59.0, 45.6, 42.0, 32.0, 31.5, 25.9, 25.7, 23.5, 20.5, 18.3, 17.2, -3.6, -5.4, -5.5.  2-(tert-Butyl-dimethyl-silanyloxymethyl)-3-phenyl-3,4-dihydro-2H-pyrrole (2.161): Silyl enol ether 2.159 (286 mg, 0.901 mmol) was subjected to the general cyclization procedure for the slow addition of stannane. Purification by flash chromatography (20% EtOAc in Hexanes) afforded 172 mg (66%) of imine 2.161, which will decompose at room temperature after a couple of days. 1H NMR (400 MHz, CDCl3) ? 7.68 (s, 1 H), 7.33-7.26 (m, 2 H), 7.23-7.13 (m, 3 H), 3.87 (dd, J = 10, 4 Hz, 1 H), 3.83 (dd, J = 10, 4 Hz, 1 H), 3.37-3.30 (m, 1 H), 3.11 (dq, J = 10, 2 Hz, 1 H), 2.67 (dd, J = 14, 6 Hz, 1 H), 0.88 (s, 9 H), 0.05 (s, 6 H); 13C NMR (100 MHz, CDCl3) ? 166.2, 145.6, 128.6, 127.0, 126.2, 83.4, 64.8, 47.0, 42.8, 25.9, 23.4, 18.2, -5.4, -5.5; HRMS-ESI (m/z): [M+H]+ calcd. for C17H28NOSi: 290.1940. Found: 290.1934.  2-(tert-Butyl-dimethyl-silanyloxymethyl)-5-methyl-3,4-dihydro-2H-pyrrole (2.163a): Further elution (20% Hexanes in EtOAc) afforded 167 mg (51%) of imine 2.163a as a light yellow oil, which will decompose at room temperature after a couple of days. 1H NMR (400 MHz, CDCl3) ? 4.14-4.05 (m, 1 H), 3.83 (dd, J = 10, 4 Hz, 1 H), 3.59 (dd, J = 10, 6 Hz, 1 H), 2.68-2.38 (m, 2 H), 2.01 (s, 3 H), 2.03-1.91 (m, 1 H), 1.82-1.73 (m, 1 H), 0.87 (s, 9 H), 0.05 (s, 3 H), 118  0.03 (s, 3 H); 13C NMR (100 MHz, CDCl3) ? 175.5, 74.3, 66.1, 39.1, 25.9, 25.6, 19.7, 18.2, -5.4; HRMS-ESI (m/z): [M+Na]+ calcd. for C12H25NOSiNa: 250.1603. Found: 250.1596.  2-(tert-Butyl-dimethyl-silanyloxymethyl)-5-phenyl-3,4-dihydro-2H-pyrrole (2.163b): Silyl enol ether 2.163b (269 mg, 0.85 mmol) was subjected to the general cyclization procedure for the slow addition of stannane. Purification by flash chromatography (10% EtOAc in Hexanes) afforded 159 mg (65%) of imine 2.169b as a light yellow oil, which will decompose at room temperature after a couple of days. 1H NMR (400 MHz, CDCl3) ? 7.86-7.82 (m, 2 H), 7.43-7.40 (m 3 H), 4.43- 4.32 (m, 1 H), 3.97 (dd, J = 10, 4 Hz, 1 H), 3.74 (dd, J = 10, 6 Hz, 1 H), 3.08-2.96 (m, 1 H), 2.95-2.86 (m 1 H), 2.18-2.07 (m, 1 H), 2.03-1.92 (m, 1 H), 0.87 (s, 9 H), 0.07 (s, 3 H), 0.02 (s, 3 H); 13C NMR (100 MHz, CDCl3) ? 173.6, 134.7, 130.2, 128.3, 127.7, 74.8, 66.2, 35.2, 25.9, 25.2, 18.2, -5.3, -5.4; HRMS-ESI (m/z) [M+H]+ calcd. for C17H28NOSi: 290.1940. Found: 290.1935.  2.8.3.4 Mechanistic Investigations (Scheme 2.40) To a solution of azide 2.142 (63 mg, 0.20 mmol) and AIBN (2.0 mg, 0.05 equiv.) in degassed benzene (20 mL) at 80 ?C was added a solution of Bu3SnH (18 mg, 0.3 equiv., 0.062 mmol) and AIBN (3.5 mg, 0.1 equiv., 0.021 mmol) using a syringe pump (0.2 mL/h) over 4 h. The reaction mixture was stirred for another 3 h at 80?C. Analysis of an aliquot of the reaction mixture using 1H NMR showed that the ratio of imine 2.171 to pyrrolidine 2.175 was 1:0.15. The solution was allowed to cool to room temperature and azide 2.142 (56 mg, 0.23 mmol) 119  and AIBN (2.0 mg, 0.05 equiv., 0.014 mmol) were added to the reaction mixture. The reaction was heated to 80?C, then a solution of Bu3SnH (20 mg, 0.3 equiv., 0.069 mmol) and AIBN (3.8 mg, 0.1 equiv., 0.023 mmol) was added using a syringe pump (0.2 mL/h) over 4 h. The reaction mixture was stirred for another 3 h at 80?C. The solution was allowed to cool to room temperature and the solvent was removed by rotary evaporation. Crude 1H NMR analysis showed no evidence of remaining pyrrolidine 2.175.                  120            Chapter 3 : Boranes as Sources of Hydrogen Atom Transfer Agents           121  3.1 Metal Hydride Replacements Radical processes are of considerable importance in organic chemistry.  Over the past half century, a detailed picture of the reactivity, selectivity and stability of many types of organic radicals has emerged.  Metal hydrides are a critical component in many of these radical reactions as they facilitate the formation of radicals in a radical chain process and serve as hydrogen atom transfer agents (Figure 3.1).   Figure 3.1.  Propagation steps of a metal hydride reduction. Since organotin hydrides were first reported in 1957,129 they have been ubiquitous in organic free radical chain reactions and their application and use is continually expanding.130  Organotin hydrides are crucial in radical additions to alkenes and alkynes, in reductive carbon-carbon bond formation reactions, and have proved particularly useful in the reduction of alkyl halides, amino groups, nitro groups, thiols, selenides, carboxylates and alcohols.   122  In the early 1970?s Barton and McCombie developed a method to effectively deoxygenate secondary alcohols131 as methods for the deoxygenation of primary and tertiary alcohols had already been established.  During these seminal investigations, it was found that the treatment of a xanthate (3.8) with tributyltin hydride and a radical initiator cleanly provided the dexoycarbohydrate 3.9.131  Scheme 3.1.  Barton-McCombie deoxygenation of xanthate 3.9. The Barton-McCombie deoxygenation proceeds according to the mechanism outlined in Scheme 3.2.   The reaction begins with the rapid and reversible addition of the tributyltin radical to the thiocarbonyl group of xanthate 3.10, providing datively stabilized radical 3.11.  Radical 3.11 then undergoes an irreversible fragmentation reaction to provide alkyl radical 3.12 and S-tributylstannyl dithiocarbonate 3.13.  Hydrogen atom transfer between radical 3.12 and tributyltin hydride provides the reduced alkane 3.16, and regenerates the tributyltin radical.  The main driving force behind this reaction is the conversion of the weaker carbon-sulfur ?-bond into a much stronger carbon-oxygen ?-bond.132  The choice of a methyl group on the sulfide sulfur of xanthate 3.10 is also important as the formation of a methyl radical 3.14 is a difficult process and, therefore, the reaction typically favours the fragmentation reaction to occur on the side of the oxygen.   123   Scheme 3.2.  Mechanism of the Barton-McCombie deoxygenation The requisite xanthate can be easily obtained by treatment of the alcohol with base, carbon disulfide and methyl iodide.  Variations of thiocarbonyl derivatives have also been reported, including thiocarbonyl imidazoles,133 O-arylthiocarbonates134 and thiocarbamates.135  While these alternatives are attractive due to milder conditions and ease of installation, they are more expensive. In addition to their use in Barton-McCombie reactions, organotin hydrides have been utilized in numerous radical cyclization reactions, exemplified in some efficient syntheses of large rings, intricate polycyclic structures and a wide range of heterocyclic compounds (Figure 3.2).  For example, they been utilized in the key steps in many total syntheses,136 such as (?)-morphine (3.17) by Parker,137 prostaglandin F2? (3.18) by Stork,138 and (?)-silphiperfolene (3.19) by Curran.139 124   Figure 3.2.  Morphine (3.17), prostaglandin F2? (3.18) and silphiperfolene (3.19). Despite the utility and prevalence of organotin reagents in synthetic radical chemistry, these tin-based reagents are toxic.140  This leads to a host of problems such as they are difficult to safely dispose of,140 the desired products resulting from organotin methodologies are often contaminated with traces of the tin reagent,141 and the purity of commercially available organotin hydrides varies widely.  Furthermore, medicines and food additives contaminated with tin are unsafe for human consumption.142   These issues have limited the use of tin-hydride reagents on large scale.  While other reagents based on mercury, cobalt, manganese, and samarium are also effective, these metal hydrides can be expensive.  A new technology that has similar synthetic performance to tin-hydrides, yet does not have the same toxicity problems140 would allow for the wider use of radical methodology in both pharmaceutical and food industries.   3.1.1 Improving Purification of Organotin Hydrides A considerable amount of research has investigated the synthesis and application of organotin hydrides that can be readily removed from crude reaction mixtures (Figure 3.3).  Pyridylstannane 3.20, which forms highly polar organotin by-products that can readily be removed by flash column chromatography, affords product yields equivalent to those seen with tributyltin hydride.143  Many organotin hydrides, such as triphenyltin hydride 3.21, are 125  extremely non-polar, and can be readily removed from a column with a non-polar eluent such as hexanes.  Procedures have been developed where the organotin by-products of a crude reaction mixture are reduced to regenerate the tin hydride compound using a mixture of tert-butanol and sodium cyanoborohydride.  In theory, these procedures permit the organotin hydride to be reused.   Figure 3.3.  Alternative organotin hydride compounds. Water-soluble tin hydrides 3.22144 and 3.23145 allow for radical reductions and cyclizations to be carried out ?environmentally friendly? aqueous solutions.  However they do little to address the disposal issues.  More importantly, these water-soluble tin hydrides can be readily removed from the crude reaction mixture during the workup step, thereby minimizing residual tin by-products.  Of all the modified tin-hydride reagents, polymer supported tin hydrides (3.24) are the easiest to remove from a reaction mixture as the polymer beads are insoluble in organic solvents and can simply be removed by filtration.  While these polymer supported tin 126  hydrides have been applied in the reduction of halide and in radical ring closures,146 their preparation can be demanding.146,147  For example, Neumann and co-workers reported the synthesis of one such derivatized polymer bead (Scheme 3.3).148  These poor yielding reactions required harsh conditions, long reaction times and use a stoichiometric amount of tributyltin hydride to provide the polymer bound tributyltin hydride derivative.  Scheme 3.3.  Synthesis of polymer bound alkyltin hydride 3.24. 3.1.2 Catalytic Organotin Hydrides While the use of stoichiometric amounts of tributyltin hydride is prevalent, several processes using catalytic amounts of organotin compounds have been developed.  Corey and co-workers reported in 1975 (Scheme 3.4)149 that irradiation of iodide 3.30 with a catalytic amount of tributyltin chloride and sodium borohydride provided lactone 3.31 in excellent yield.   127   Scheme 3.4.  Synthesis of lactone 3.31 from iodide 3.30. Giese and Stork employed a similar catalytic reaction during their investigations into deoxygenation reactions150 and cyclic acetal formation via carbon radical cyclizations.151 Following the radical reduction of the alkyl halide 3.37 (Scheme 3.5) to the corresponding alkane 3.38, tributyltin hydride 3.35 is regenerated via a reaction with sodium borohydride 3.34.   Scheme 3.5.  Catalytic cycle for the Bu3SnH-catalyzed reduction of alkyl halides. 3.1.3 Silicon Hydrides Silicon represents the largest class of radical chain propagation alternatives.  They are attractive alternatives to organotin hydrides as they are much less toxic.  Triethylsilanes152 and diphenylsilanes153 have been used in radical chain processes, however these reactions, as illustrated in Scheme 3.6.  However, the silicon-hydrogen bond is stronger than the tin-hydrogen bond and, therefore, these reactions often require high temperatures and the large quantities of radical initiator required for these reactions to proceed.154  For example, 128  Ph2SiH2 was used in a dideoxygenation of 1,6-anhydro-D-glucose 3.39, which required a full equivalent of the radical initiator AIBN, and provided the desired product 3.40 in low yield.155    Scheme 3.6.  Dideoxygenation of 3.39 using Ph2SiH2.  Figure 3.4.  Alkanethiol additives for polarity reversal catalysis. A solution to this problem is to include a catalytic amount of an alkanethiol, such as thiophenol (Figure 3.4, 3.42) or tert-dodecanethiol (3.41), with the trialkylsilane in the reaction mixture.  Nucleophilic alkyl radicals (Scheme 3.7, 3.44) abstract hydrogen atoms more readily from alkanethiols (3.46) than from the more electron-rich trialkylsilanes.  The resulting electrophilic sulfinyl radical 3.45 will then abstract a hydrogen atom from the electron-rich trialkylsilane 3.47 more readily than the alkyl radicals 3.44.  This permits a catalytic turnover of the alkanethiol 3.46 and regenerates the silyl radical 3.48 in a process called polarity reversal catalysis.156  Scheme 3.7.  Polarity reversal catalysis with alkylsilanes and alkanethiols. 129   The silicon-hydrogen bond can be dramatically weakened by replacing the alkyl groups with silyl groups, leading to reagents such as tris(trimethylsilyl)silane (TTMSS).157  First reported by Gilman and co-workers in the mid-1960?s,158 TTMSS was further investigated by Chatgilialoglu in radical chain processes as a substitute for tributyltin hydride.159  TTMSS is an attractive alternative to organotin compounds as it produces fewer and less toxic by-products during the course of a radical chain reaction.  The rates of reduction of various radicals are generally slower with TTMSS when compared to tributyltin hydride (Table 3.1).  This often permits radical chain reactions using one pot additions of stoichiometric amounts of TTMSS, instead of using the slow addition and high dilution procedures that accompany many organotin hydrides, as was observed in our radical relay cyclization methodology discussed in Chapter 1.160 Table 3.1.  Rate constants for the reaction of some radicals with Bu3SnH and TTMSS.  entry radical kSnH (M-1s-1) kSiH (M-1s-1) 1  2.4 x 106 3.8 x 105 2  1.5 x 106 1.4 x 105 3  1.9 x 106 2.6 x 105 4  7.8 x 108 3.0 x 108 5  2.0 x 108 1.1 x 108  130   TTMSS serves as a tin-hydride surrogate in numerous radical reactions.  For example, the reductive removal of halogen atoms,161 selenides,161c and xanthates162 have all been reported using TTMSS instead of tributyltin hydride (Scheme 3.8),   NHCO2CH3ONOOINHCO2CH3ONOO(TMS)3SiHPhCH3, 55?C3.49 3.50 (90%)ORORO OC(S)OPhONHNOO(TMS)3SiH, AIBNC6H6, 80?COROROONHNOO3.53 3.54 (94%)OTBSOTBSONHNOOSePh(TMS)3SiH, AIBNC6H6, 80?COTBSOTBSONHNOO3.51 3.52 (87%) Scheme 3.8.  Representative reductive processes accomplished using TTMSS instead of Bu3SnH.  While TTMSS has provided an excellent, non-toxic alternative to the organotin hydrides, they suffer from several drawbacks that have limited their use.  The (TMS)3Si? 131  radicals add to multiple bonds.  To wit, (TMS)3SiH has proven an efficient reagent for the hydrosilylation of alkenes and alkynes.163  3.1.4 Germanium Hydrides Germanium hydrides have also been investigated as possible replacements for organotin  hydrides.  The rate constants have been reported for the reaction of a primary alkyl radical with the Group 14 metal hydrides, 164 and selected examples are provided in Table 3.2. Table 3.2.  Selected rate constants for the reaction of primary alkyl radicals with  Group 14 metal hydrides.164  entry metal hydride rate constant (M-1s-1) 1 Et3SiH 5.2 x 103 2a Ph3SiH 4.6 x 104 3 (TMS)3SiH 1.2 x 106 4 Bu3GeH 3.4 x 105 5 Ph3GeH 3.8 x 106 6b (TMS)3GeH 1.9 x 107 7b Bu3SnH 6.4 x 106 8b Ph3SnH 2.2 x 107 a Rate constant measured at 110?C. b Rate constants measured at 50?C.   132  The relative rates for the reaction with a primary radical increase in the order of R3SiH<R3GeH<R3SnH, which is in good agreement with the thermodynamic data for Group 14 hydrides.  Reactions using Bu3GeH are generally slow, and not synthetically useful.  For example Bu3GeH (entry 4) reacts with a sp3 hybridized carbon radical 3.5 times slower than (TMS)3SiH (entry 3), and 20 times slower than Bu3SnH (entry 7).  Incorporating silyl groups on the germanium increases the reactivity dramatically, making (TMS)3GeH (entry 6) three times more reactive than Bu3SnH (entry 7) and 16 times more reactive than (TMS)3SiH (entry 3).  While germanium hydrides act as reducing agents in radical chain reactions, applications involving germanium hydrides are sparse.    Scheme 3.9.  Synthesis of hydroxymethyl monosaccharide 3.56 using Ph3GeH.  Kahne and co-workers required the preparation of monosaccharide 3.56 for mechanistic studies in a total synthesis of calicheamicin ?1.165  Attempts to replace the secondary iodide failed using ionic methods, due to a competing elimination pathway.  Studies then focused on generating a radical under an atmosphere of carbon monoxide, to provide hydroxymethyl 3.56.  Using tin hydride only provided the direct reduction product, but employing a catalytic amount of Ph3GeH with NaBH3CN provided a small amount of the desired product.  This reaction is effective using less-substituted iodides, providing yields greater than 60%.165  However, the lower reactivity observed with germyl radicals typically limits these types of reactions to iodides. 133   Tris(trimethylsilyl)germane can act as a reducing agent for halides.166  However the rate of a reaction between a primary alkyl radical and (TMS)3GeH is even faster than that of Bu3SnH which limits is use in organic synthesis, along with cost. 3.2     Boron in Free Radical Processes Borane (BH3) is an attractive alternative to Group 14 metal hydrides as they have a high hydrogen content, low toxicity, are readily available and are inexpensive.  However the potential of boron as a replacement for other traditional reagents is limited by the high B-H BDE of borane of 106.6 kcal/mol, which is much stronger when compared to the BDE of popular reagents such as Bu3Sn-H (74 kcal/mol) and (Me3Si)3Si-H (79 kcal/mol).167  In an effort to reduce the boron-hydrogen bond strength into the range of the popular reagents used in radical chain methodology, two general methods have been employed. 3.2.1 Stabilization of the Boryl Radical through ?-Conjugation  N-Heterocyclic carbene borane (NHC-BH3) can be readily formed from the simple addition of an N-heterocyclic carbene (NHC) to borane.  First reported by Bittner and co-workers,168 these compounds form via Lewis acid/base interactions analogous to other Lewis base coordinations (ethers, sulfides, amines and phosphines for example).  In practice, NHC-BH3?s are different from other traditional borane-ligand complexes as they are easily manipulated and are very stable.   Figure 3.5.  Calculated B-H BDE?s of selected NHC-BH3 complexes. 134   The first use of various NHC-BH3?s as a synthetic reagent in a radical chain reduction were reported by Curran and co-workers in 2008169 (Figure 3.5).  DFT calculations indicated that borane complexes 3.57 and 3.58 have BDE?s of 80 and 79 kcal/mol respectively.  These values are in the range of commonly used metal hydride reagents, such as Bu3SnH (74 kcal/mol) and (TMS)3SiH (79 kcal/mol).  This decreased BDE is believed to arise from the delocalization of spin density in the resulting ligated boryl radicals.169 A number of xanthates were investigated, providing modest yields of the deoxygenated products.  Treatment of xanthate 3.59 (Scheme 3.10) with the NHC-BH2? radical, provided stabilized radical 3.60, which fragments to give carbon radical 3.62.169  Subsequent hydrogen atom transfer, and regeneration of the boryl radical, provides ether 3.63 in good yield.   Scheme 3.10.  Synthesis of ether 3.63 via NHC-BH3 mediated radical deoxygenation reaction. 135   While an excellent proof of concept as to the potential of NHC-BH3 complexes in radical chain mechanisms, these reactions suffered from several drawbacks.  Reactions typically require NHC-BH3 3.57 (usually 2.0 equivalents) and large amounts of radical initiator (50-100 mol%).  Furthermore, the rate constant (kH) for a reaction between a secondary alkyl radical and NHC-BH3 3.57 was found to be on the order of 104 M-1s-1, which is lower than the popular hydrogen donor reagents, such as Bu3SnH and TTMSS, but higher than reagents such as Et3SiH that do not propagate chain reactions.167  This may in part be the result of a persistent radical,170 which is thought to be the result of steric shielding of the boryl radical by the relatively large diisopropyl (dipp) substituents.  Further investigations by Curran and co-workers provided a second generation of ?minimalist? NHC-BH3 complexes (Figure 3.6, 3.64 and 3.65).    Figure 3.6.  ?Minimalist? NHC-BH3?s diMe-Imd-BH3 3.64 and diMe-Tri-BH3 3.65. These complexes are better hydrogen atom donors (kH ? 105) than NHC-BH3 3.57, as the boryl radical resulting form NHC-BH3 3.64 and 3.65 are not as persistent,171 translating into improved performance172 (Table 3.3).  136  Table 3.3.  Comparison of the reduction of xanthate 3.8 using different NHC-BH3 complexes.  entry NHC-BH3 equivalents AIBN (mol%) time (h) yield (%) 1 3.57 2 100 16 75 2 3.64 1 10 2 89 3 3.65 1 10 2 88  Reduction of furanose derived xanthate 3.8 using NHC-BH3 3.57 required large amounts of both 3.57 and AIBN, and provided the deoxygenated product 3.9 in good yield (entry 1).  The yield was improved when both 3.64 and 3.65 (entries 2 and 3) were used as the NHC-BH3 ligand, along with fewer equivalents of the NHC-BH3 ligand and catalytic amounts of AIBN.  A disadvantage of radical chain reductions using NHC-BH3 complexes is that it is not easy to recycle the boron derived products following xanthate reduction. 3.2.2 Coordination of a Lewis Base with Borane      Boron-hydrogen bonds can be weakened by the formation of Lewis acid-base complexes.173  Rablan and co-workers have calculated the strengths of boron-hydrogen bonds in many borane-ligand complexes, as shown in Table 3.4.173  137  Table 3.4.  Selected bond dissociation energies of various borane-ligand complexes. entry borane-ligand complex homolytic bond dissocation energy (kcal/mol)a 1  107 2 B HHHH BHH  100 3  103 4  95 5  92 6  103 7  70 a BDE?s were calculated using Pople?s G-2 method at 298K. The boron-hydrogen bonds in both borane and diborane (entries 1 and 2) are too strong to for a radical chain reaction to occur. While a modest decrease in BDE is observed when borane forms a Lewis base complex with an ether (entry 3) or with a sulfide (entry 4), these complexes, they are known to rapidly exchange with other Lewis bases, including 138  alkenes, alkynes and carbonyl functional groups.  These exchanges usually result in the hydroboration of the ?-systems.  In contrast, complexes involving phosphines174 (entry 5) are very stable.175  These compounds are relatively easy to form and are the basis of a section of organophosphorous chemistry.  These phosphine-borane complexes are so stable that it is often difficult to decomplex the two components.  Therefore, this class of phosphine-boranes typically displays chemistry associated with hydrophosphorylation, and not hydroboration.175,176  For example, heating a mixture of phosphine 3.66 (Scheme 3.11) and alkyne 3.67 results in the hydrophophorylated product 3.68, not the hydroborated product.177   Scheme 3.11.  Hydrophosphorylation of alkyne 3.67. Trimethylamine-borane and pyridine-borane (entries 6 and 7) have been used as a radical hydrogen source as the complexation sufficiently lowers the BDE?s.178  Amine-borane complexes are versatile reagents.  At lower temperatures, amine-borane complex 3.60 (Figure 3.7) is favoured and displays reactivity similar to other amine-borane complexes.  At elevated temperatures, these complexes react similarly to free borane (3.71).175  As the amine-borane complex is in equilibrium with free borane, the temperature at which one type of reactivity is observed could be controlled in part by the nature of the amine substituents.   139   Figure 3.7.  Thermal dissociation of 3.69. Pyridine-borane complexes are similar to NHC-borane complexes in that they both have adjacent ?-systems that could help stabilize a boryl radical. Similar to the effect observed in NHC-BH3 ligands by Curran and co-workers, the weakening of the boron-hydrogen bond is hypothesized to arise from the delocalization of the radical to the ligand.   Recent work by Laleve? and co-workers reported the formation of pyridine-borane complexes 3.72-3.74 (Figure 3.8).179  Kinetic information collected during these experiments found the boron-hydrogen BDE?s to be 81-82 kcal/mol, in the range of both NHC-BH3 complexes 3.57 and 3.58 (Figure 3.5).    Figure 3.8.  N-heteroaryl boranes 3.72-3.74. 3.2.3 Benzotriazole-Borane Complexes Nitrogen-containing aromatic compounds, such as pyridine-borane, provide improved stability compared to their amine counterparts, and have been used in several synthetic applications.180  Compared to other N-heterocyclic aromatic compounds, benzotriazole ligands possess unique characteristics that make them particularly attractive Lewis bases. Strong dipole moments and high electron density on the nitrogen make these ligands more nucleophilic and less basic, and form stable gold and rhodium metal-ligand 140  complexes.181  In addition, these complexes have a greater stability towards air, moisture and heat when compared to their pyridine analogs.   Scheme 3.12.  Synthesis of benzotriazole-borane 3.76a and 3.76b. Investigations by Shi and co-workers reported the formation of several benzotriazole-borane complexes (Scheme 3.12).182  These complexes were synthesized by treating the appropriate benzotriazole ligand with a borane-tetrahydrofuran.  Removal of substitution at N3 (R = H) of the benzotriazole ligands resulted in complex mixtures of complexes, most likely arising from multiple binding sites on the ligand.  Benzotriazoles with at N2 did not provide any of the desired TAB-BH3 complexation.  The lack of product formation is hypothesized to be a result of the steric hindrance of the N2 substitution.  TAB-BH3 complexes 3.76a and 3.76b formed readily and in high yield and were selected for further investigations.  It was hypothesized that TAB-BH3 complexes, such as 3.76a and 3.76b, could act as reducing agents.  Indeed, these complexes displayed similar reactivity to well-established reagents used for the reduction of imines.182 During their investigations of these TAB-BH3 complexes (Figure 3.9, 3.76a-3.78), DFT calculations had also indicated that the boron-hydrogen BDE?s were in the range of many traditional reagents used in radical chain reactions (Table 3.5).183   141   Figure 3.9.  Borane triazole complexes 3.76a ? 3.78. Table 3.5.  Calculated bond dissociation energies for borane triazole complexes 3.76b ? 3.78.a entry borane-triazole complex B-H BDE (kcal/mol) B-N BDE (kcal/mol) 1 3.76b 71.1 28.1 2 3.77 67.4 28.5 3 3.78 72.0 26.5 a All values were calculated using the B3LYP/6-31+G(d) basis set. We began a collaboration with the Shi and co-workers to investigate the potential use of the benzotriazole-borane complexes in Barton-McCombie deoxygenation reactions.  3.3   Mechanistic Investigation Previous work in our group by Jackie Luk had provided evidence that the mechanism involved in the deoxygenation of xanthates was radical in nature.  This was accomplished using the ?radical clock? xanthate (Scheme 3.13, 3.79) as a mechanistic probe.  The rate of opening a cyclopropane ring alpha to a carbon radical has been reported to be ~108 s-1,184 which is faster than most known radical reactions.  If the deoxygenation of xanthate 3.79 proceeded through a radical-free pathway, the expected product would have been cyclopropane 3.80.  However, treatment of xanthate 3.79 using previously optimized 142  conditions produced alkene 3.83, which is formed by the radical fragmentation of cyclopropyl radical intermediate 3.81.  These findings suggest that the deoxygenation reaction is proceeding through a radical mechanism.  Scheme 3.13.  Radical Pathway Test using a Radical Clock. 3.4 Results and Discussion  Scheme 3.14.  Synthesis of methyltriazole borane complex 3.76a.  Deprotonation of benzotriazole 3.84 (Scheme 3.14) followed by methylation provided methylbenzotriazole 3.85 in excellent yield.  Mixing a concentrated solution of triazole 3.85 and borane-dimethylsulfide provided the desired methyltriazole borane complex 3.76a in quantitative yield.185  Borane-triazole complexes (3.76b?3.78) were 143  provided in milligram quantities from the Shi research group, and were prepared using a similar method to the one listed in Scheme 3.14.  Scheme 3.15.  Synthesis of alcohol 3.83.  Treatment of carboxylic acid 3.86 (Scheme 3.15) with excess carbonate and methyl iodide provided ester 3.87.  Ester 3.87 was reduced to the corresponding alcohol using lithium aluminum hydride. 144  Table 3.6.  Synthesis of Xanthates 3.92 ? 3.113.  entry alcohol xanthate yield (%) 1   99 2   23 3   32 4   60 5   63  145  6   69 7   80 8   72 10   86 11   55 12   89 146  13   27   A number of xanthates were prepared according to the conditions outlined above.  The procedure to synthesize benzylic xanthates was optimized, and reaction times proved to be critically important.  Benzylic xanthates have been reported to be unstable,186 and decomposed when left at room temperature.  Leaving the reaction mixture to stir for longer than the noted times also provided the desired product in lower yields.  We next synthesized a series of bicyclic primary xanthates (entries 1-13).  Secondary benzylic alcohols were also synthesized (entries 11-12) as well as the triphenylmethyl xanthate 3.113 (entry 13).   3.4.1 Basic Reactivity  We first assessed the radical reactivity of the TAB-BH3 complexes 3.76a-3.78 in the Barton-McCombie deoxygenation of xanthate 3.92 (Table 3.7).  Control studies had been previously studied in our group as part of an undergraduate research project, however the optimized reaction conditions were not providing the desired deoxygenated products reliably.  It was decided to start these investigations again so as to firmly establish the exact nature of this radical reaction.      147   Table 3.7.  Product ratios from reactivity screens of various TAB-BH3 complexes.  entry TAB-BH3 ratio 3.114 : 3.92 1 3.76a 1 : 3.7 2 3.76b 1 : 7 3 3.77 1 : 7.3 4 3.78 --a a No product was observed. Every complex that was investigated did not promote the reaction appreciably, and unreacted starting material accounted for the majority of the mass balance (entries 1-3).  Irradiation of the nitro-substituted TAB ligand 3.78 provided a solid yellow compound in the NMR tube, preventing further crude NMR analysis.  The incompatibility of TAB-BH3 3.78 may be the result of the nitro functional group, which has been reported to undergo radical denitrohydrogenation reactions.187  Methylbenzotriazloe-borane complex 3.76a was chosen to further screen this reaction as it provided the best ratio of product (3.114) to starting material (3.92).   148  Table 3.8.  Initiator screen for deoxygenation of 3.92.  entry radical Initiator 10 hr. half-life (?C) NMR yield (%) 1 AIBN 65 55 2 Lauroyl Peroxide 65 72 3 ABCN 88 78 4 (tBuO)2 125 80 5 tBuOOH 170 83  We next sought to select the appropriate initiator to use with our methylbenzotriazole-borane complex.  A number of commonly employed radical initiators were investigated for use in a TAB-BH3 radical deoxygenation reaction (Table 3.8).  Replacing AIBN with lauroyl peroxide and ABCN (entries 1 and 2) improved the yield from 55% to 72%.  Changing the initiators to tBuOOH and (tBuO)2 provided higher yields. It has been reported that borane-triazole complexes in solution exist in an equilibrium,188 which was confirmed by Dr. Maria Zlotorzynska by an NMR experiment where the reduction of an aldehyde was observed when exposed to the conditions tested in Table 3.8.   A radical initiator that has a longer half-life in solution would allow time for the formation of the reactive bound-state boranes (Scheme 3.16, 3.76a) as the BDE of free borane (3.115) is too high for it to act as a radical hydrogen donor.  149   Scheme 3.16.  Possible equilibrium between free and coordinated borane. During these investigations, varying amounts of benzyl alcohol were observed in the crude NMR spectrum.  The benzyl alcohol is believed to be the product of the reduction of xanthate 3.92 by free borane, which is in equilibrium with TAB-BH3 complex 3.76a (Scheme 3.16).  To suppress the reduction pathway we attempted to lower the temperature at which our reactions were performed.  Indeed, reducing the temperature of our reactions from 60 ?C to 30 ?C provided the deoxygenated product in greater yield, and no detectable benzyl alcohol.    150  Table 3.9.  Initiator screen at 30 ?C.  entrya initiator mol% initiator  yield 3.114 (%) yield 3.92 (%) 1 tBuOOH 15 37 39 2 lauroyl peroxide 15 26 62 3 lauroyl peroxide 7.5 47 47 4 AIBN 15 70 13 5 ABCN 15 70 10 a All experiments were run at a concentration of 0.05M.  All experiments were run on a NMR scale using 1,3,5-trimethoxybenzene as an internal standard.  We next screened the radical initiators at 30 ?C.  Initiation using 15 mol% lauroyl peroxide provided the product in moderate yield. Reducing the amount of lauroyl peroxide in half provided the desired product in poor yield.  Both AIBN and ABCN afforded 3.114 in good yield, with minimal amounts of unreacted xanthate 3.92.  ABCN was selected as the initiator for the subsequent radical deoxygenation reactions.  These results were opposite to what we had initially observed (Table 3.8).  As previously discussed, reducing the temperature of our Barton-McCombie deoxygenation should favour the formation of 3.76a (Scheme 3.16).  As more of this complex would be present in solution at lower temperatures, faster thermal initiators should provide the deoxygenated product in higher yield.  Furthermore, lowering the temperature of the solution successfully suppressed any possible reduction pathways, and the undesired benzyl alcohol product was not observed.  151  Table 3.10.  Control study for the radical deoxygenation of xanthate 3.92.  entry compound(s) presenta equivalents NMR % yield 1 3.85 1 0 2 3.118 0.15 0 3 3.119 1.1 0 4 3.92 1 0 5 3.119 and 3.118 1.1 0.15 0 6 3.92, 3.85, 3.118 and 3.119  70 a Each reaction contained 1.0 equivalent of xanthate 3.92 and 0.33 equivalent of 1,3,5-trimethoxybenzene, which was used as the internal standard.  To ensure the observed reactivity was a result of all the components of our system, we next set up several control reactions (Table 3.10).  Treatment of xanthate 3.92 with one part of our radical system failed to produce any observed product (entries 1-3).  Similarly, a combination of borane (3.119) and ABCN (3.118, entry 5) did not provide any observed product.  However, irradiation of the combination of all the components (entry 6) did provide the deoxygenated product 3.114 in good yield. During the course of our lower temperature optimization studies, we observed the formation of a solid precipitate in the bottom of the NMR tube, which we suspected may be the TAB-BH3 complex (3.76a).  Initially, we attempted to prevent the precipitation by forming the TAB-BH3 complex in situ, via the addition of BH3?DMS just before irradiation.  152  Unfortunately, no improvement in yield was observed.  For our Barton-McCombie deoxygenation reactions to be efficient, we required a solvent that would dissolve the TAB-BH3 complex (3.76a), and thereby permit the radical deoxygenation to occur.  We performed basic solubility tests on several commonly used deuterated solvents to assess their potential use in our system.189  Deoxygentation using acetone as a solvent did not provide any product (Table 3.11, entry 1).  Acetonitrile provided the desired product in good yield (entry 2) and using dichloromethane provided the desired product in excellent yield.  Table 3.11.  Solvent screen using 3.76a and O-benzyl S-methyl carbonodithioate (3.92).  entry solvent NMR % yield (3.114)  1 d6 ? acetone 0 2 d3 - ACN 62 3 CD2Cl2 77    Recent reports by Curran and co-workers had found secondary alkyl radicals react with NHC-BH3 complexes with rate constants on the order of (104).171  The slow hydrogen transfer step in these systems had been overcome via the addition of a catalytic amount of thiol, and resulted in greatly improved yields.190   We next examined whether the addition of a polarity reversal catalyst, such as thiophenol, could further improve the yield of our radical deoxygenation reactions.  The addition of 5 mol% of PhSH to the NMR tube of 153  a reaction resulted in a 10% increase in yield (Table 3.12, entries 1 and 2).  However, increasing the amount of PhSH in solution did not improve the product yield further (entries 3-7).   Table 3.12.  Polarity reversal catalysis studies using PhSH.  entry mol% PhSH NMR % yield 1 0 65 2 5 75 3 10 77 4 15 78 5 20 75 6 25 73 7 30 79   We next sought to assess the time required for our radical deoxygenation reactions to complete (Table 3.13).  After one hour, a small amount of product had been formed (entry 2).   However, allowing the reaction to proceed for 6 hours provided the product in 72% yield.  Further irradiation (>6 h) did not lead to improved yield (entries 3?6).  A possible explanation for the lack of 3.76a in solution is that the TAB-BH3 complex is consumed as the deoxygenation reaction progresses.  The lower concentration of 3.76a would prevent 154  further deoxygenated product from forming. To keep the concentration of 3.76a high in solution, we began to add excess BH3?DMS prior to irradiation. Table 3.13. Time screen using 3.92.   entry time (h) % product % starting material TAB-BH3 complex TAB 1 0 0 100 1 0 2 1 32 58 5.48 1 3 2 56 33 2.13 1 4 3 63 20 1 1.26 5 4 69 13 1 3.69 6 5 72 10 1 10.43   Using our newly optimized reaction conditions, we next tested a range of xanthates for reactivity towards a Barton-McCombie deoxygenation reaction (Table 3.14).  In a typical experiment, the xanthate, TAB-BH3 (1.2 equiv.), ABCN (15 mol%) and BH3?DMS (1.0 equiv.) were added to the reaction vessel and placed in the UV reactor for 6 hours.  For NMR scale reactions, 1,3,5-trimethoxybenzene was added to the crude reaction mixture to serve as an internal standard.  155  Table 3.14.  NMR and ?Scaled? TAB Borane Reduction of Benzylic Xanthates.  entry xanthate product NMR yield (%)a isolated yield (%)b 1   80 27 2   86 48 3  H3COH3COOCH33.121  94 49 4   96 81 5   71 69 156  6   88 60 7   0 ---- 8   22 0 9   87 71 a CD2Cl2 was used as the solvent. b Anhydrous CH2Cl2 was used as the solvent.  Reduction of primary benzylic xanthates (Table 3.14, entries 1 - 7) occurred readily as was indicated using 1H NMR analysis of the crude mixture.  Many reduced xanthates were difficult to isolate (entries 1-3) and, thus, have lower isolated yields.  Attempts to reduce xanthate (entry 7) were did not provide deoxygenated product or starting material using our protocol, which may be due to the presence of the cyano group, a functionality that is known to react with radicals.191 Attempts to deoxygenate a secondary benzylic xanthate resulted in poor yields of deoxygenated product (entry 8).  This xanthate was particularly unstable, and was observed 157  decompose at room temperature, possibly resulting in the lower yield.   Increasing the scale of this reaction did not produce optimized isolated yields.  Gratifyingly, tertiary benzylic xanthate (entry 9) provided the deoxygenated product in good yield. 3.4.2 Deoxygenation Reactions Using Sub-stoichiometric 1-Methylbenzotriazole As outlined in Table 3.13, we had previously monitored the ratio of the desired TAB-BH3 complex to the free TAB ligand present in solution, and had altered our experimental protocol so as to keep the concentration of the TAB-BH3 complex high in solution.  Because of this result, we hypothesized that the TAB may be used in catalytic amounts, as outlined in scheme 3.17. 158   Scheme 3.17.  Working Hypothesis of the Mechanism of Radical Deoxygenation using TAB-BH3 (3.76a). Treatment of the TAB-BH3 complex (3.76a) with an initiator would lead to a hydrogen abstraction, providing boryl radical 3.116.  Treatment of boryl radical 3.116 with xanthate 3.90 provides radical 3.128.  Cleavage of the carbon-oxygen ?-bond, would provide carbon radical 3.129 and complex 3.130. Breaking the boron-nitrogen in 3.130 would liberate the TAB ligand 3.85, which could re-form 3.76a if the concentration of borane (3.115) in solution is kept sufficiently high.  We were intrigued by the possibility of catalytic behavior, and designed experiments that varied the equivalents of both the TAB ligand and free borane in solution (Table 3.15).  159  Table 3.15.  Sub-stoichiometric TAB-BH3 in a Barton-McCombie deoxygenation reaction.  entrya mol% TAB equivalents BH3?DMS NMR yield (%) 1 5 1 47 2 10 1 40 3 20 1 41 4 30 1 57 5 40 1 58 6 50 1 57 7 5 2 49 8 10 2 56 9 20 2 66 10 30 2 70 11 40 2 74 12 50 2 77 a All experiments were run at a concentration of 0.05M.  All experiments were run on a NMR scale using 1,3,5-trimethoxybenzene as an internal standard.    We began our studies using one equivalent of borane in excess.  Deoxygenation reactions did not occur reliably when less than 30 mol% of 3.76a was employed (Table 3.14, entries 1-3).  Altering the equivalents of 3.76a from 30 to 50 mol% did not significantly 160  alter the amount of deoxygenated product (entries 4-6).  Increasing the amount of free borane present in solution provided higher amounts of deoxygenated product when using less than 20 mol% of 3.76a (entries 7-9); increasing the mol% from 20 to 50 mol% provided yields of deoxygenated product equivalent to those seen using a super-stoichiometric of 3.76a. 3.5    Future Work  Scheme 3.18.  Attempted deoxygenation of adamantyl xanthate 3.132.   We envisage an extension of this methodology to increase the scope of our TAB-BH3 Barton-McCombie deoxygenations  While our conditions worked well in the reduction of benzylic xanthates, it provided only modest results when attempting other substrates.  Attempts to deoxygenate adamantyl xanthate 3.132 using our optimized conditions displayed only trace amounts of adamantane (3.133), providing unreacted starting material, and 1-adamantol as the remaining mass balance.  Scheme 3.19.  Equilibrium of 3.76a with 3.85 and 3.115.  The amount of TAB-BH3 complex (Scheme 3.18, 3.76a) present in solution is believed to be temperature dependent.  At higher temperatures, more free borane 3.115 161  and benzotriazole 3.85 would be present in solution, and at lower temperatures the desired precatalyst would be favoured.   However we lacked the equipment to reliably accomplish this task.  Use of a UV chamber that would allow for cooling below room temperature should provide a higher amount of TAB-BH3 complex 3.76a in solution, thereby providing more deoxygenated product.  Figure 3.10.  Possible TAB-BH3 complexes. Another method for increasing the amount of a TAB-BH3 complex in solution would be to increase the boron-nitrogen bond strength.  DFT calculations provided to us by the Shi group had indicated that the electron rich para-methoxy TAB-BH3 3.77 (Figure 3.10), had the highest boron-nitrogen BDE?s of all the ligands investigated.  Increasing the amount, type and location of electron donating groups may help minimize the amount of free borane in solution by strengthening the boron-nitrogen bond.     3.6  Conclusion  In summary, we have demonstrated that TAB-BH3 complexes will participate in a radical chain deoxygenation reaction.  This method readily deoxygenates benzylic xanthates with excellent isolated yields.  Several radical initiators were investigated, and results were 162  unreliable.  It was hypothesized that an equilibrium between coordinated TAB-BH3 and free triazole ligand was preventing boryl radical formation.   We lowered the internal temperature of our UV reactor to approximately 30 ?C which provided better yields of deoxygenated products.  The radical initiators were re-investigated, and ABCN was chosen as the radical initiator.   With the initiator selected, we next began to increase the scope of our reactions.  These studies were problematic as they were low yielding and significant amounts of a solid precipitate were formed in the NMR tube.  It was found that the TAB-BH3 complex was sparingly soluble in deuterated benzene, and solubility tests showed that deuterated dichloromethane provided the deoxygenated product in high yields.  We also found that the addition of 5 mol% PhSH provided a slight improvement in yield.  A variety of benzylic xanthates were exposed to our optimized conditions, provided the desired products in excellent yields.  Furthermore, during the course of these studies, it was found that the active TAB-BH3 complex was consumed after approximately 3 hours.  The addition of excess BH3 kept the concentration of TAB-BH3 high, and helped improve the overall efficacy of the reaction.  These studies also suggested that our radical chain deoxygenation reactions could proceed using a catalytic amount of benzotriazole ligand.  Furthermore, preliminary investigations demonstrated that the reaction could proceed with a substoichiometric amount of benzotriazole.   3.7 Experimental 3.7.1 General Experimental All reactions were performed under a nitrogen atmosphere in flame-dried glassware.  Tetrahydrofuran and diethyl ether were distilled from sodium benzophenone ketyl.  163  Dichloromethane was distilled form calcium hydride.  Thin layer chromatography was performed on Whatman Partisil K6F UV254 pre-coated TLC plates.  Chromatographic separations were effected over Silicycle F60 silica gel (230-400 mesh).  The silica gel was basified with triethylamine prior to packing and then sequentially flushed with the solvent system of choice.  All chemicals were purchased from commercial sources and used as received.  A KD-Scientific KDS100 syringe pump was used for all slow additions.  Melting points were performed using a Mel-Temp II apparatus (Lab devices USA) and are uncorrected.  Infrared spectra were obtained using a Thermo Nicolet 4700 FT-IR spectrometer.  Proton nuclear magnetic resonance spectra were recorded in deuterochloroform or d6-benzene using a Bruker AV-300 or AV-400 spectrometer.  Carbon nuclear magnetic resonance spectra were recorded in deuterochloroform or d6-benzene using a Bruker AV-300 or AV-400 spectrometer.  Chemical shifts are reported in parts per million and are referenced to the centerline of deuterochloroform (7.27 ppm 1H NMR; 77.0 ppm 13C NMR) or d6-benzene (7.16 ppm 1H NMR; 128.1 ppm 13C NMR).  Low resolution mass spectra and high resolution mass spectra were recorded on either a Bruker Esquire-LC spectrometer (for LRMS) or a Waters/Micromass LCT spectrometer (for HRMS).  Photochemical reactions were performed using a Rayonet? Photochemical Reactor (Catalog number RPR-100) affixed with a Rayonet? Motor Assembly Carasol (Catalog number RMA-4) using 250, 300 or 350 nm UV lamps.    164  3.7.1.1 General NMR Method for Deoxygenation Xanthate (0.05 mmol) was dissolved in the noted deuterated solvent (1 mL) in an NMR tube. Substituted benzotriazole borane (0.06 mmol) and radical initiator (0.0075 mmol) is added to this solution. 1,3,5-trimethoxybenzene (0.015 mmol) is added as an internal standard. The NMR tube is then placed in the photoreactor (350 nm UV light) for 18 hours. 3.7.1.2 General Method for ?Scaled? Deoxygentation Reactions  Xanthate (0.35 mmol) was dissolved in dry, degassed CH2Cl2 (7 mL, 0.05 M) in a 10 mL microwave vial.  Benzotriazole-borane complex 3.76a (0.42 mmol), ABCN (0.0525 mmol), and PhSH (0.0175 mmol) were then added.  The vial was sealed and irradiated for 6 hours.     3.7.2 Synthesis of Substrates 3.76a, 3.92, 3.94, 3.96, 3.98, 3.102, 3.104, 3.105, 3.111 and 3.113.   1-methylbenzotriazole borane (3.76a): 1-methylbenzotriazole 3.85 (0.6657 g, 5.000 mmol) was dissolved in dry THF (5 mL) at room temperature. To this solution, BH3-THF (5.5 mL, 1.0 M in THF) was added dropwise by a syringe. The solution was stirred and checked by TLC. After completion (30 minutes), 0.38 g of 3.76a (52%) was obtained by vacuum filtration as a white solid. 1H NMR (400 MHz, CDCl3) ? 8.21 (m, 1H), 7.61-7.71 (m, 3H), 4.39 165  (s, 3H) 2.34-3.01 (br m, 3H) ppm; 13C NMR (400 MHz, CDCl3) ? 139.79, 134.08, 129.32, 127.30, 118.15, 110.06, 35.67 ppm.  O-benzyl S-methyl dithiocarbonate (3.92): A solution of 3.91 (2.07 mL, 20.1 mmol) was prepared in THF (50 mL). The solution was cooled to 0 oC and sodium hydride (0.9599g, 60% dispersion in mineral oil, 24.00 mmol) was added portion wise. The resulting solution was then warmed to room temperature and stirred for one hour. After cooling the solution to 0 oC, carbon disulfide (2.40 mL, 40.0 mmol) was added dropwise and the resulting solution was stirred for one hour at room temperature. Methyl iodide (1.49 mL, 24.0 mmol) was then added to the solution at 0 oC and the solution was re-warmed to room temperature. This solution was stirred overnight (18 hours). The reaction mixture was quenched with ammonium chloride and then extracted with diethyl ether three times. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered, and then concentrated by rotary evaporation to give a yellow oil. Purification by flash chromatography (3:1 hexanes:ethyl acetate) gave 3.96 g of 3.92 (99%) as a yellow oil. IR (neat) 3089-2848, 1197, 1057 cm-1; 1H NMR (400 MHz, CDCl3) ? 7.35-7.44 (m, 5H), 5.56 (s, 2H) 2.59 (s, 3H) ppm; 13C NMR (400 MHz, CDCl3) ? 215.70, 134.71, 128.62, 128.53, 75.13, 19.09 ppm. 166   O-(benzo[d][1,3]dioxol-5-ylmethyl) S-methyl carbonodithioate (3.94):  A solution of 3.93 (2.00 g, 13.2 mmol) was prepared in THF (70 mL). The solution was cooled to 0 oC and sodium hydride (1.5256 g, 60% dispersion in mineral oil, 38.14 mmol) was added portion wise. The resulting solution was then warmed to room temperature and stirred for one hour. After cooling the solution to 0oC, carbon disulfide (3.97 mL, 65.8 mmol) was added dropwise and the resulting solution was stirred for one hour at room temperature. Methyl iodide (3.93 mL, 63.1 mmol) was then added to the solution at 0 oC and the solution was re-warmed to room temperature. This solution was stirred overnight (5 hours). The reaction mixture was quenched with ammonium chloride and then extracted with diethyl ether three times. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered, and then concentrated by rotary evaporation to give a yellow oil. Purification by flash chromatography (50:1 hexanes:ethyl acetate) gave 728 mg of 3.94 (23%) as a yellow oil. 1H NMR (400 MHz, CDCl3) ? 7.35-7.44 (m, 5H), 5.56 (s, 2H) 2.59 (s, 3H) ppm; 13C NMR (400 MHz, CDCl3) ? 215.7, 148.2, 123.0, 122.2, 109.5, 108.4, 101.5, 75.4, 38.4, 19.3 ppm.   167   S-methyl O-3,4,5-trimethoxybenzyl carbonodithioate (3.96):  A solution of 3.95 (2.00 mL, 12.1 mmol) was prepared in THF (30 mL). The solution was cooled to 0oC and sodium hydride (1.2080g, 60% in oil, 30.20 mmol) was added portion wise. The resulting solution was then warmed to room temperature and stirred for one hour. After cooling the solution to 0 oC, carbon disulfide (1.82 mL, 30.2 mmol) was added dropwise and the resulting solution was stirred for one hour at room temperature. Methyl iodide (1.51 mL, 24.2 mmol) was then added to the solution at 0 oC and the solution was re-warmed to room temperature. This solution was stirred for 4 hours, at which point the reaction mixture was cooled to 0 oC and quenched with water (5 mL) and then extracted with EtOAc (3 x 25 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and then concentrated by rotary evaporation to give a yellow oil. Purification by flash chromatography (5:1 hexanes:ethyl acetate) gave 2.51 g of 3.96 (80%) as a yellow solid. 1H NMR (400 MHz, C6D6) ? 6.30 (s, 2H), 5.46 (s, 2H), 3.80 (s, 3H), 3.30 (s, 6H), 2.15 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) ? 153.3, 133.5, 105.9, 105.8, 75.4, 56.1, 56.0, 36.2, 19.1 ppm.   168   S-methyl O-(naphthalen-1-ylmethyl) carbonodithioate (3.104):  A solution of 3.103 (2.00 g, 12.6 mmol) was prepared in THF (63 mL). The solution was cooled to 0 oC and sodium hydride (0.7584g, 60% in oil, 18.96 mmol) was added portion wise. The resulting solution was then warmed to room temperature and stirred for one hour. After cooling the solution to 0 oC, carbon disulfide (2.29 mL, 37.9 mmol) was added dropwise and the resulting solution was stirred for one hour at room temperature. Methyl iodide (2.36 mL, 37.9 mmol) was then added to the solution at 0 oC and the solution was re-warmed to room temperature. This solution was stirred for 4 hours, at which point the reaction mixture was cooled to 0 oC and quenched with water (5 mL) and then extracted with EtOAc (3 x 25 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and then concentrated by rotary evaporation to give a yellow oil. Purification by flash chromatography (50:1 to 30:1 hexanes:ethyl acetate) gave 2.51 g of 3.104 (80%) as a yellow oil. 1H NMR (400 MHz, CDCl3) ? 7.77 (d, J = 12 Hz,  2H), 7.66-7.70 (m, 2H). 7.30-7.39 (m, 3H),  5.86 (s, 2H), 2.33 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) ? 215.4, 133.6, 131.6, 130.2, 129.7, 128.6, 128.6, 126.7, 126.0, 125.0, 123.4, 73.6, 19.0 ppm.   169   O-((6-methoxynaphthalen-2-yl)methyl) S-methyl carbonodithioate (3.105):  A solution of 3.88 (0.50 g, 3.0 mmol) was prepared in THF (15 mL). The solution was cooled to 0 oC and sodium hydride (0.1784g, 60% in oil, 4.460 mmol) was added portion wise. The resulting solution was then warmed to room temperature and stirred for one hour. After cooling the solution to 0 oC, carbon disulfide (0.54 mL, 8.91 mmol) was added dropwise and the resulting solution was stirred for one hour at room temperature. Methyl iodide (0.56 mL, 8.9 mmol) was then added to the solution at 0 oC and the solution was re-warmed to room temperature. This solution was stirred for 4 hours, at which point the reaction mixture was cooled to 0 oC and quenched with water (5 mL) and then extracted with EtOAc (3 x 25 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and then concentrated by rotary evaporation to give a yellow oil. Purification by flash chromatography (24:1 hexanes:ethyl acetate) gave 0.594 g of 3.105 (72%) as a yellow oil. 1H NMR (400 MHz, CDCl3) ? 7.81 (s,  1H), 7.75-7.78 (dd, J = 8 Hz, 4 Hz, 2H), 7.48 (d, J = 8 Hz, 1H),  7.15-7.20 (m, 2H), 5.77 (s, 2H), 3.94 (s, 3H), 2.59 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) ? 217.0, 158.2, 129.7, 129.6, 128.6, 128.1, 127.3, 126.7, 119.2, 105.7, 77.3, 75.6, 55.3, 19.1ppm.  170   S-methyl O-4-(trifluoromethyl)benzyl carbonodithioate (3.98):  A solution of 3.97 (1.56 mL, 11.4 mmol) was prepared in THF (57 mL). The solution was cooled to 0oC and sodium hydride (0.6812g, 60% in oil, 17.03 mmol) was added portion wise. The resulting solution was then warmed to room temperature and stirred for one hour. After cooling the solution to 0 oC, carbon disulfide (2.05 mL, 34.05 mmol) was added dropwise and the resulting solution was stirred for one hour at room temperature. Methyl iodide (2.12 mL, 34.1 mmol) was then added to the solution at 0 oC and the solution was re-warmed to room temperature. This solution was stirred for 4 hours, at which point the reaction mixture was cooled to 0 oC and quenched with 10% HCl (5 mL), diluted with water (50 mL), and the aqueous layer was then extracted with EtOAc (3 x 25 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and then concentrated by rotary evaporation to give a yellow oil. Purification by flash chromatography (24:1 hexanes:ethyl acetate) gave 1.81 g of 3.98 (60%) as a yellow oil. 1H NMR (400 MHz, CDCl3) ? 7.66 (d, J = 8 Hz,  2H), 7.53 (d, J = 8 Hz, 2H), 5.71 (s, 2H),  2.61 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) ? 215.5, 138.8, 130.7, 128.3, 125.5, 122.5, 75.6, 19.2 ppm.  171   O-4-cyanobenzyl S-methyl carbonodithioate (3.102):  A solution of 3.101 (1.2764 g, 9.591 mmol) was prepared in THF (48 mL). The solution was cooled to 0 oC and sodium hydride (0.5756 g, 60% in oil, 14.39 mmol) was added portion wise. The resulting solution was then warmed to room temperature and stirred for one hour. After cooling the solution to 0 oC, carbon disulfide (1.74 mL, 28.8 mmol) was added dropwise and the resulting solution was stirred for one hour at room temperature. Methyl iodide (1.79 mL, 28.8 mmol) was then added to the solution at 0 oC and the solution was re-warmed to room temperature. This solution was stirred for 4 hours, at which point the reaction mixture was cooled to 0 oC and quenched with water (5 mL) and further diluted with water (50 mL).  The crude reaction mixture was partitioned using EtOAc (75 mL) and the organic layer was washed with brine (3 x 50 mL). The organic layer was next dried over anhydrous sodium sulfate, filtered, and then concentrated by rotary evaporation to give a clear oil. Purification by flash chromatography (10:1 hexanes:ethyl acetate) gave 1.48 g of 3.102 (69%) as a white solid. 1H NMR (400 MHz, CDCl3) ? 7.68 (d, J = 8 Hz,  2H), 7.50 (d, J = 8 Hz, 2H), 5.69 (s, 2H),  2.60 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) ? 215.5, 140.1, 132.3, 128.4, 118.4, 112.3, 73.1, 19.3 ppm.  172   O-benzhydryl S-methyl carbonodithioate (3.111):  A solution of 3.110 (1.50 g, 8.14 mmol) was prepared in THF (40 mL). The solution was cooled to 0 oC and sodium hydride (0.4814 g, 60% in oil, 12.21 mmol) was added portion wise. The resulting solution was then warmed to room temperature and stirred for one hour. After cooling the solution to 0 oC, carbon disulfide (1.47 mL, 24.4 mmol) was added dropwise and the resulting solution was stirred for one hour at room temperature. Methyl iodide (1.52 mL, 24.4 mmol) was then added to the solution at 0 oC and the solution was re-warmed to room temperature. This solution was stirred for 4 hours, at which point the reaction mixture was cooled to 0 oC and quenched with water (5 mL) and further diluted with water (50 mL).  The crude reaction mixture was partitioned using EtOAc (75 mL) and the organic layer was washed with brine (3 x 50 mL). The organic layer was next dried over anhydrous sodium sulfate, filtered, and then concentrated by rotary evaporation to give a yellow oil. Purification by flash chromatography (5:1 hexanes:ethyl acetate) gave 1.98 g of 3.111 (89%) as a yellow oil. 1H NMR (400 MHz, CDCl3) ? 7.69 (s, 1H), 7.28-7.38 (m, 10H), 2.60 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) ? 215.5, 188.5, 140.2, 128.6, 128.3, 127.5, 53.4, 13.05 ppm.   173   S-methyl O-trityl carbonodithioate (3.113):  A solution of 3.112 (2.00 g, 7.68 mmol) was prepared in THF (48 mL). The solution was cooled to 0 oC and sodium hydride (0.4608 g, 60% in oil, 11.52 mmol) was added portion wise. The resulting solution was then warmed to room temperature and stirred for one hour. After cooling the solution to 0 oC, carbon disulfide (1.39 mL, 23.0 mmol) was added dropwise and the resulting solution was stirred for one hour at room temperature. Methyl iodide (1.43 mL, 23.0 mmol) was then added to the solution at 0 oC and the solution was re-warmed to room temperature. This solution was stirred for 4 hours, at which point the reaction mixture was cooled to 0 oC and quenched with water (5 mL) and further diluted with water (50 mL).  The crude reaction mixture was partitioned using EtOAc (75 mL) and the organic layer was washed with brine (3 x 50 mL). The organic layer was next dried over anhydrous sodium sulfate, filtered, and then concentrated by rotary evaporation to give a cloudy oil. Purification by flash chromatography (50:1 hexanes:ethyl acetate) gave 0.50 g of 3.113 (19%) as a white solid. 1H NMR (400 MHz, CDCl3) ? 7.24-7.32 (m, 15H), 2.28 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) ? 187.2, 143.6, 129.8, 127.9, 127.3, 13.3 ppm.      174  3.7.3 Barton-McCombie Deoxygenation of Substrates 3.114, 3.120-3.124 and 3.127.    Toluene (3.114):  Xanthate 3.92 was deoxygenated using the conditions outlined in the general method for scaled deoxygenation reactions and was isolated by fractional distillation (110 ?C) as a colourless liquid (0.013 g, 27%).  1H NMR (400 MHz, CDCl3) ? 7.14-7.28 (m, 5H), 2.36 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) ? 137.9, 129.0, 128.2, 125.3, 21.4 ppm.  5-methylbenzo[d][1,3]dioxole  (3.120):  Xanthate 3.94 was deoxygenated using the conditions outlined in the general method for scaled deoxygenation reactions and was isolated by fractional distillation (760 mmHg, 36 ?C) as a colourless liquid (0.0328 g, 48%).  1H NMR (400 MHz, CDCl3) ? 6.75 (d, J = 8 Hz, 1H), 6.70 (s, 1H), 6.63 (d, J = 8 Hz, 1H), 5.94 (s, 2H), 2.32, (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) ? 147.4, 145.2, 131.4, 121.4, 109.5, 108.0, 100.6, 21.1 ppm.  175  1,2,3-trimethoxy-5-methylbenzene (3.121):  Xanthate 3.96 was deoxygenated using the conditions outlined in the general method for scaled deoxygenation reactions and was purified using flash column chromatography (10:1?5:1 hexanes:ethyl acetate) isolated 3.121 as a colourless oil (0.0180 g, 49%).  1H NMR (400 MHz, CDCl3) ? 6.40 (s, 2H), 3.85 (s, 6H), 3.83 (s, 3H), 2.32 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) ? 153.0, 133.6, 106.0, 60.9, 56.0, 21.8 ppm.  1-methylnaphthalene (3.122):  Xanthate 3.104 was deoxygenated using the conditions outlined in the general method for scaled deoxygenation reactions and was purified using flash column chromatography (24:1 hexanes:ethyl acetate) isolated 3.122 as a colourless oil (0.0412 g, 81%).  1H NMR (400 MHz, CDCl3) ? 8.05-8.08 (dd, J = 12 Hz, 4 Hz, 1H), 7.90-7.93 (dd, J = 8 Hz, 4 Hz, 1H), 7.77 (d, J = 8 Hz, 1H), 7.53-7.60 (dqt, J = 8 Hz, 2 Hz, 2H), 7.44 (t, J = 8 Hz, 1H), 7.38 (d, J = 8 Hz, 1H), 2.76 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) ? 134.2, 133.5, 132.6, 128.5, 126.5, 126.3, 125.7, 125.5, 124.1, 19.3 ppm.  2-methoxy-6-methylnaphthalene (3.123):  Xanthate 3.105 was deoxygenated using the conditions outlined in the general method for scaled deoxygenation reactions and was purified using flash column chromatography (24:1 hexanes:ethyl acetate) isolated 3.123 as a white solid (0.0421 g, 69%).  1H NMR (400 MHz, CDCl3) ? 7.65-7.68 (m, 2H), 7.56 (s, 1H), 176  7.28-7.31 (dd, J = 8 Hz, 4 Hz, 1H), 7.12-7.15 (m, 2H), 3.39 (s, 3H), 2.49 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) ? 157.0, 128.7, 128.6, 126.7, 126.6, 118.6, 105.7, 55.3, 21.4 ppm.   1-methyl-4-(trifluoromethyl)benzene (3.124):  Xanthate 3.98 was deoxygenated using the conditions outlined in the general method for scaled deoxygenation reactions and was isolated by fractional distillation (0.01 mmHg, 131 ?C) as a colourless liquid (0.0336 g, 60%).  1H NMR (400 MHz, CDCl3) ? 7.52 (d, J = 8 Hz, 2H), 7.29 (d, J = 8 Hz, 2H), 2.43 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) ? 213.1, 142.0, 132.7, 129.3, 127.7, 125.1, 123.1, 125.1, 83.6, 21.4 ppm.  Triphenylmethane (3.127):  Xanthate 3.113 was deoxygenated using the conditions outlined in the general method for scaled deoxygenation reactions and was purified using flash column chromatography (24:1 hexanes:ethyl acetate) isolated 3.127 as a white solid (0.0421 g, 69%).  1H NMR (400 MHz, CDCl3) ? 7.21-7.32 (m, 9H), 7.56 (s, 1H), 7.14 (d, J = 8 Hz, 6H) 5.57 (s, 1H) ppm; 13C NMR (100 MHz, CDCl3) ? 143.9, 129.5, 128.3, 126.3, 56.9 ppm.     177  Bibliography  1. Beckwith, A. L. J.; Ingold, K. U. in Rearrangements in Ground and Exited States; de Mayo, P., Ed.; Academic: New York, 1980. 2. (a) Beckwith, A. L. J.; Easton, C. J.; Lawrence, T.; Saelis, A. K. Aust. J. Chem. 1983, 36, 545. (b) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron Lett. 1985, 26, 373. (c) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985, 41, 3925. 3. Chatgilialoglu, C.; Ingold, K. U.; Scaiano, J. C. J. Am. Chem. Soc. 1981, 103, 7739. 4. Newcomb, M. Tetrahedron 1993, 49, 1151. 5. Yadav, V.; Fallis, A. G. Can. 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Tetrahderon 1997, 53, 17543.                  196             Appendix A:  Selected Spectra from Chapter 1       197     JW 2-115_001000fid.esp7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity10.842.122.102.142.041.002.092.041.331.351.371.471.591.761.781.802.022.042.062.074.194.204.224.924.944.974.985.015.025.775.785.815.825.855.877.277.747.757.767.83CH2 201918 1716 1514 1312 11O10N125346798O21O221.110JW 2-115C_001000fid.esp160 150 140 130 120 110 100 90 80 70 60 50 40 30Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity25.5128.1329.0029.2329.2933.7576.6877.0077.3278.60114.12123.45128.99134.39139.16163.64CH2 201918 1716 1514 1312 11O10N125346798O21O221.110198      jlbook1p013_001fid.esp12 11 10 9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)00.00010.00020.00030.00040.00050.00060.00070.00080.00090.0010Normalized Intensity8.182.002.031.870.903.827.847.837.817.757.74 7.737.725.865.845.805.755.735.01 5.004.954.934.904.214.194.161.501.481.381.361.34ONOOCH21.109jlbook1p013_002000fid220 200 180 160 140 120 100 80 60 40 20 0 -20Chemical Shift (ppm)00.00010.00020.00030.00040.00050.00060.00070.00080.00090.0010Normalized Intensity163.57 139.01134.34128.92123.38114.1478.5077.0033.6729.0628.8628.7328.0625.43CH2 ONOO1.019199      JW 2-101_001000fid.esp7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.00010.00020.00030.00040.00050.00060.00070.00080.00090.0010Normalized Intensity9.001.172.002.010.92M01(s)M05(t)M04(d)M02(m)M06(br. s.) M03(br. s.)1.241.251.411.561.591.602.583.113.123.523.543.603.623.634.777.27OHNHOOCH3CH3CH31.124JW 2-101C_001000fid.esp160 140 120 100 80 60 40 20 0Chemical Shift (ppm)0.00010.00020.00030.00040.00050.00060.00070.00080.00090.0010Normalized Intensity156.15(4)79.09(2)77.3077.0076.6862.08(12)40.23(9)29.62(11)28.33(6,7,3)26.49(10)OHNHOOCH3CH3CH31.124200      JW 2-103_001000fid.esp7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.00010.00020.00030.00040.00050.00060.00070.00080.00090.0010Normalized Intensity9.008.361.801.820.665.663.64M07(m)M02(s)M05(s)M06(br. s.)M04(br. s.)M01(m)M03(m)7.70 7.69 7.687.677.43 7.427.407.387.274.623.703.14 1.61 1.60 1.591.461.101.08ONHOOCH3CH3CH3SiCH3CH3CH31.1251.125JW 2-103C_001000fid.esp160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)0.00010.00020.00030.00040.00050.00060.00070.00080.00090.0010Normalized Intensity155.93(14)135.51(2,6,21,25)133.85(20,1)129.54(23,4)127.59(22,24,3,5)78.94(16)77.3277.0076.6863.48(9)40.40(12)29.79(10)28.41(27,28,17)26.85(19,30,29)26.49(11)19.17(18)ONHOOSiCH3CH3CH3CH3CH3CH3201      JW 2-106_001000fid.esp10 9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)00.00010.00020.00030.00040.00050.00060.00070.00080.00090.0010Normalized Intensity8.494.101.701.731.845.480.79M10(m)M09(m)M07(m)M01(s)M06(t)M04(t)M08(m) M05(br. s.)M03(m)M02(s)9.79 9.799.787.67 7.66 7.667.42 7.40 7.397.377.36 3.70 3.683.673.51 3.493.483.192.69 2.681.601.59 1.581.441.060.90ON OHO OCH3 CH3CH3SiCH3CH3CH31.1261.126JW 2-106CC_001000fid.esp200 180 160 140 120 100 80 60 40 20 0Chemical Shift (ppm)0.00010.00020.00030.00040.00050.00060.00070.00080.00090.0010Normalized Intensity200.95135.50133.90129.53127.5879.7077.32 77.0076.6865.8063.5447.4543.49 41.0229.7928.3626.8425.1119.1715.22ONSiCH3CH3CH3O OCH3CH3CH3OH202      JW 3-05_001000fid.esp7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.00010.00020.00030.00040.00050.00060.00070.00080.00090.0010Normalized Intensity9.002.163.941.971.910.917.275.80 5.78 5.765.745.72 5.075.065.02 5.025.015.014.994.99 3.66 3.643.633.23 3.213.193.182.29 2.272.252.03 1.591.57 1.56 1.541.44OHNO OCH3CH3CH3CH21.1271.127JW 3-05C_001000fid.esp160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)0.00010.00020.00030.00040.00050.00060.00070.00080.00090.0010Normalized Intensity155.69135.47116.4179.2977.0062.3646.8746.7833.19 29.6428.4124.78OHNO OCH3CH3CH3CH2203      JW 3-07_001000fid.esp8 7 6 5 4 3 2 1 0Chemical Shift (ppm)00.00010.00020.00030.00040.00050.00060.00070.00080.00090.0010Normalized Intensity9.004.301.963.951.961.990.923.83M05(m)M01(s)M03(m)M07(m) M06(m)M08(m) M04(m)M02(m)7.82 7.82 7.817.757.747.737.727.275.805.79 5.775.765.73 5.08 5.085.035.015.014.994.984.224.214.19 3.27 3.253.253.242.292.27 1.76 1.751.751.44NO OCH3 CH3CH3CH2ONOO1.1121.112JW 3-07C_001000fid.esp160 140 120 100 80 60 40 20 0Chemical Shift (ppm)0.00010.00020.00030.00040.00050.00060.00070.00080.00090.0010Normalized Intensity163.51155.48 135.53134.37128.92123.40116.3879.19 78.0177.32 77.0076.6846.6346.5133.2728.3925.4824.3721.65NOOON CH2O OCH3 CH3CH3204      JW 2-41-2_001000fid.esp8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.00010.00020.00030.00040.00050.00060.00070.00080.00090.0010Normalized Intensity5.899.072.243.002.102.021.941.900.010.050.860.901.501.521.551.571.681.701.731.752.463.543.563.584.044.064.097.277.337.367.787.81OOSiCH3CH3CH3CH3CH3SOOCH31.1281.128JW 2-41C_001000fid.esp140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)00.00010.00020.00030.00040.00050.00060.00070.00080.00090.0010Normalized Intensity-5.4218.2321.6025.6225.8728.5362.0970.6076.5777.0077.43127.87129.78133.23144.60OO SOOCH3SiCH3CH3CH3CH3CH3205      JW 2-104_001000fid.esp7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.00010.00020.00030.00040.00050.00060.00070.00080.00090.0010Normalized Intensity5.909.074.161.973.981.890.93M05(m)M08(m)M01(s)M07(m)M02(s)M03(m)M04(m)M06(m)0.05(13,12)0.90(16,15,17)1.561.581.581.591.60(4)1.61(5)1.621.632.332.35(9)2.373.433.453.46(8)3.473.493.64(3)3.655.035.05(11)5.075.125.805.815.825.83(10)5.855.855.865.877.27CH2 OOSiCH3CH3CH3CH3CH31.129206      JW 2-66_001000fid.esp7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.00010.00020.00030.00040.00050.00060.00070.00080.00090.0010Normalized Intensity4.363.084.322.000.97CHLOROFORM-d91052, 76, 83, 40.921.661.671.691.701.712.332.342.362.383.473.493.513.653.675.045.075.085.135.775.795.825.835.845.865.877.27CH2 OOH1.1301.130JW 2-66C_001000fid.esp140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)00.00010.00020.00030.00040.00050.00060.00070.00080.00090.0010Normalized Intensity109CHLOROFORM-d27584326.8730.3934.1262.7470.2870.9477.00116.51135.06CH2 OOH207     JW 2-108_001000fid.esp8 7 6 5 4 3 2 1 0Chemical Shift (ppm)00.00010.00020.00030.00040.00050.00060.00070.00080.00090.0010Normalized Intensity4.001.943.941.981.890.911.96M04(m)M07(m)M02(m)M03(m)M06(m)M08(dd)M05(m)M01(m)7.85 7.84 7.837.83 7.767.757.747.275.855.83 5.815.795.10 5.105.06 5.06 5.035.035.014.254.244.223.533.513.483.462.352.34 2.322.30 1.891.88 1.861.811.80 1.80CH2 O ONOO1.1141.114JW 2-108C_001000fid.esp160 140 120 100 80 60 40 20 0Chemical Shift (ppm)00.00010.00020.00030.00040.00050.00060.00070.00080.00090.0010Normalized Intensity163.61135.33134.40128.98123.45116.2278.2677.0070.1134.1825.80 25.10CH2 O ONOO208     JW 2-69_001000fid.esp7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity2.913.891.871.811.871.790.8543, 5268109CHLOROFORM-dM08(d)M06(dd)M03(t)M04(t)M07(m)M02(m)M05(d)M01(m)1.391.401.421.451.471.581.611.631.661.683.433.453.473.643.663.683.963.985.165.205.305.315.865.885.905.915.945.955.975.99OH765432O189CH2101.1351.135JW 2-69C_001000fid.esp128 120 112 104 96 88 80 72 64 56 48 40 32 24 16Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity22.4329.4432.5262.8570.2571.8376.5777.0077.43116.78134.96CH2 1098O1 23456OH7209     JW 2-70_001000fid.esp7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity4.342.081.971.931.940.900.910.864.06M06(d,19)M04(d,17)M07(d,19)M05(t,11)M03(t,15)M08(m,18)M01(m,13,14)M09(m,9,8,7,6) M02(quin,12)1.441.571.661.701.841.851.873.463.473.493.973.984.204.224.245.165.195.265.305.885.895.905.925.935.955.965.977.747.757.767.767.847.84CH2 19 1817O161514131211O10N1 2534679 8O20O211.115O O NOO1.115JW 2-70C_001000fid.esp160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity27.9939.9970.0871.8276.7077.0077.3278.4384.09111.79(8,7)116.73(19)123.48(9,6)128.99(4,3)134.42(18)163.64(5,2)CH2 19 1817O161514131211O10N1 2534679 8O20O21210      KMJ1-05b_006000fid.esp14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1Chemical Shift (ppm)00.000050.000100.000150.00020Normalized Intensity6.099.096.194.001.900.930.080.901.551.571.601.611.672.102.122.142.153.403.413.423.643.654.954.985.015.055.805.815.825.845.865.87CH2OOSiCH3CH3CH3CH3CH31.1311.131KMJ1-05b_005000fid220 200 180 160 140 120 100 80 60 40 20 0 -20Chemical Shift (ppm)00.00010.00020.00030.00040.00050.00060.00070.00080.00090.0010Normalized Intensity-5.2918.3525.9729.5630.3563.0170.1170.7477.00114.61138.39CH2OOSiCH3CH3CH3CH3CH3211      KMJ 1-07a_001000fid.esp14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1Chemical Shift (ppm)00.00010.00020.00030.00040.00050.00060.00070.00080.00090.0010Normalized Intensity6.121.004.111.950.951.651.661.671.681.681.691.711.722.132.152.422.452.473.443.453.473.653.674.964.984.985.015.055.785.815.835.855.87CH2OOH1.1321.132KMJ 1-07b_001000fid220 200 180 160 140 120 100 80 60 40 20 0 -20Chemical Shift (ppm)00.00010.00020.00030.00040.00050.00060.00070.00080.00090.0010Normalized Intensity26.9328.7830.2630.3962.7570.3470.8876.6977.0077.32114.78138.14CH2OOH212     KMJ 1-08c_001000fid.esp14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1Chemical Shift (ppm)00.00010.00020.00030.00040.00050.00060.00070.00080.00090.0010Normalized Intensity2.044.122.011.950.924.011.571.631.651.671.822.112.132.153.423.433.503.514.234.254.264.954.975.005.045.795.815.835.855.877.747.757.767.767.847.847.857.86CH2 OONOO1.1131.113KMJ 1-08c_002000fid.esp220 200 180 160 140 120 100 80 60 40 20 0 -20Chemical Shift (ppm)00.000050.000100.000150.000200.000250.000300.000350.000400.000450.000500.00055Normalized Intensity25.1125.8628.9130.3370.1070.1678.28114.64123.46128.98134.40138.33163.63CH2 OONOO213      Hai 29-2_001000fid8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)00.00010.00020.00030.00040.00050.00060.00070.00080.00090.0010Normalized Intensity2.304.604.440.752.003.703.683.652.011.79 1.78 1.77 1.761.751.611.58 1.571.551.401.311.301.281.241.161.000.830.80OHCH31.1361.136haiIIIP31C(300)_001000fid.esp88 80 72 64 56 48 40 32 24 16 8Chemical Shift (ppm)0.00010.00020.00030.00040.00050.00060.00070.00080.00090.0010Normalized Intensity14.6919.3522.4123.3726.5329.6430.6631.9633.4434.7235.9040.6243.0947.4063.22OHCH3214     JW 3-06_001000fid.esp7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity0.762.993.3035.794.780.790.830.850.910.961.101.191.221.221.251.251.261.281.291.411.451.581.581.591.611.611.641.691.721.731.803.613.613.633.653.663.677.27126354CH311789OH101.138OH OHandCis-1.138 Trans-1.138JW 3-06C_001000fid.esp75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity0.9913.7814.7520.2722.0822.4624.9226.4726.5526.6427.6627.9829.5029.5629.6731.7932.6034.5835.8736.9439.0739.8043.2943.7263.0763.4263.6276.6877.0077.20126354CH311789OH10215     1.140JW 3-12-1_001000fid.esp7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.00010.00020.00030.00040.00050.00060.00070.00080.00090.0010Normalized Intensity2.249.050.280.560.130.180.650.290.111.0181.0361.2641.3091.4411.4631.4691.5871.6041.6181.6251.6371.9682.2803.2523.2723.2803.3373.6683.6763.6823.6913.6983.7053.7123.9574.259NOOCH3CH3CH3OHCH31.140JW 3-12C_002000fid150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)0.00010.00020.00030.00040.00050.00060.00070.00080.00090.0010Normalized Intensity14.18114.45619.10319.54525.74726.25028.68830.45631.34036.49037.67945.17645.69458.82962.68562.73062.85263.18876.88777.20777.51179.26479.355128.788128.910134.274137.565155.166155.455NOOCH3CH3CH3OHCH3216      JW 2-117-1_001000fid.esp7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.00010.00020.00030.00040.00050.00060.00070.00080.00090.0010Normalized Intensity3.006.411.100.940.114.200.920.931.241.421.431.581.591.591.691.711.721.742.082.242.782.792.803.303.613.653.673.683.723.733.743.763.913.933.957.27O OHCH31.1411.141JW 2-117C_001000fid.esp88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)00.00010.00020.00030.00040.00050.00060.00070.00080.00090.0010Normalized Intensity14.2527.8630.5533.7835.7263.0066.1076.6877.0077.3281.85O OHCH3217      JW2-74_001000fid.esp13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1Chemical Shift (ppm)00.00010.00020.00030.00040.00050.00060.00070.00080.00090.0010Normalized Intensity3.005.032.252.401.340.820.830.941.171.461.551.641.671.681.681.691.701.791.801.851.862.682.923.353.373.383.613.623.643.943.963.963.974.004.00OOHCH31.1431.143JW2-74_005000fid.esp220 200 180 160 140 120 100 80 60 40 20 0 -20Chemical Shift (ppm)-0.000500.00050.0010Normalized Intensity11.8718.1220.9326.5428.7930.1931.8332.6734.9836.1562.8763.0368.3868.5779.9080.5483.68OOHCH3218      219             Appendix B:  Selected Spectra from Chapter 2           220    Characterized by Dr. Huimin Zhai  221      Characterized by Dr. Huimin Zhai   222    Characterized by Dr. Huimin Zhai   223    Characterized by Dr. Huimin Zhai  224    Characterized by Dr. Huimin Zhai  225     Characterized by Dr. Huimin Zhai  226     Characterized by Dr. Huimin Zhai   227     JW 4-06-1_002000fid.esp7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.00010.00020.00030.00040.00050.00060.00070.00080.00090.0010Normalized Intensity7.0824.642.013.911.001.167.617.617.274.39 4.394.383.87 3.87 3.863.85 3.843.84 3.833.692.61 2.602.58 2.58 1.90 1.88 1.881.86 1.73 1.551.440.930.920.890.850.13 0.12 0.110.090.060.050.040.001110129N813OTBS14 3425N16OTBS72.152 and 2.1542.152 and 2.154JW 4-06C_002000fid.esp180 160 140 120 100 80 60 40 20 0Chemical Shift (ppm)00.00010.00020.00030.00040.00050.00060.00070.00080.0009Normalized Intensity167.3574.5865.7763.83 61.0537.11 34.7925.88 25.7523.0922.0118.2718.04 -4.78-5.06 -5.35-5.441110129N813OTBS143425N16OTBS7228     Characterized by Dr. Huimin Zhai  229     Characterized by Dr. Huimin Zhai  230     Characterized by Dr. Huimin Zhai  231     Characterized by Dr. Huimin Zhai   232     Characterized by Dr. Huimin Zhai  233     Characterized by Dr. Huimin Zhai  234     Characterized by Dr. Huimin Zhai  235     Characterized by Dr. Huimin Zhai  236     Characterized by Dr. Huimin Zhai  237     Characterization perfomed by Kayli Johnson  KMJ 2-57C_002000FID.ESP13 12 11 10 9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity9.401.308.474.002.000.992.111.980.976.154.09M01(s,29,30,16)M02(m,14)M11(dd,2,6,18,22)M07(m,9)M05(q,26)M10(m,3,4,5,19,20,21)M03(m,12,11,23,24)M09(m,27)M08(m,28b,28a)M04(m,25,10)1.031.061.361.421.441.461.591.602.072.083.673.683.704.944.944.974.995.005.035.045.825.835.867.377.397.407.677.697.69OHOSiCH3CH3CH3HH2.175KMJ 2-57C_003000FID.ESP220 200 180 160 140 120 100 80 60 40 20 0 -20Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityM09(s)M11(s)M13(s)M01(s)M02(s)M03(s)M06(s)M07(s)M08(s)M10(s)M12(s)M14(s)M15(s)M16(s) M04(s)M17(s)19.2121.8725.1126.8728.9637.2463.8071.83114.36127.58129.51134.07135.57138.91CH2OHOSiCH3CH3CH32.175238    Characterization perfomed by Kayli Johnson  KMJ 2-63B_002000FID.ESP10 9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity9.406.335.792.122.792.110.912.000.986.264.18M01(s)M11(m)M05(m)M06(t)M07(m)M10(m)M04(m)M09(m)M02(m)M03(m)M08(m)0.081.061.411.431.561.591.701.711.712.072.082.973.013.673.683.704.704.954.954.974.984.994.995.035.045.785.795.815.847.377.377.397.417.427.437.667.667.687.68CH2OOSiCH3CH3CH3SOOCH32.176KMJ 2-63B_003000FID.ESP140 130 120 110 100 90 80 70 60 50 40 30 20 10Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityM11(s)M13(s)M14(s)M01(s)M02(s)M03(s)M04(s)M05(s)M06(s)M07(s)M08(s)M09(s)M10(s)M12(s)M15(s)M16(s)M17(s)M18(s)19.2221.4224.3126.8728.6034.1334.3138.6763.4883.96114.65127.62129.57133.94135.54138.51CH2OOSiCH3CH3CH3SOOCH32.176239    Characterization perfomed by Kayli Johnson   KMJ 2-64A_002000FID.ESP8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity8.614.075.241.821.930.931.901.820.895.583.74M03(m)M04(m)M01(s)M07(m)M11(m)M06(t)M02(m)M05(m)M10(m)M09(m) M08(m)1.071.451.501.501.511.551.571.582.062.072.082.093.213.223.243.673.683.704.964.984.995.005.005.015.045.055.795.805.815.835.857.387.387.397.417.427.427.677.677.697.697.69CH2OSiCH3CH3CH3NN+N-2.177KMJ 2-64A_003000FID.ESP140 130 120 110 100 90 80 70 60 50 40 30 20 10Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityM04(s)M06(s)M08(s)M09(s)M12(s) M10(s)M11(s)M01(s)M02(s)M03(s)M05(s)M07(s)M14(s)M16(s)M15(s)M17(s)19.2122.4525.5426.8728.6932.2733.5934.1334.1763.0063.59114.55127.59129.53134.00135.55138.63CH2OSiCH3CH3CH3NN+N-2.177240    Characterization perfomed by Kayli Johnson   KMJ 2-70A_002000FID.ESP9 8 7 6 5 4 3 2 1Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity4.294.412.242.162.171.071.011.031.001.01M07(m,15a)M08(m,15b)M02(m)M10(m,2a)M06(m,6)M05(td,13) M01(m)M04(m,3)M09(m,14)M03(m)1.361.371.391.401.411.431.521.541.561.561.571.571.701.721.792.052.102.472.482.492.492.512.513.253.253.263.273.293.304.954.984.984.995.045.045.045.765.775.805.825.845.869.799.79NOHN+N-HH2.178KMJ 2-70A_003000FID.ESP200 180 160 140 120 100 80 60 40 20Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityM01(s)M04(s)M05(s)M06(s)M09(s)M02(s)M07(s)M08(s)M10(s)M11(s)18.6825.4728.6333.5333.7034.1443.4762.68114.62138.52201.76CH2NOHN+N-2.178241    Characterization perfomed by Kayli Johnson    KMJ 2-71B_003000FID.ESP7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.7Normalized Intensity5.949.148.393.440.621.000.312.580.940.310.66M01(s)M02(m)M10(m)M11(m)M05(m)M06(m)M07(m)M09(m)M08(m)M04(m)M03(m)0.020.140.870.920.930.941.421.511.511.521.531.541.551.562.052.062.082.193.263.263.273.283.283.294.434.444.944.954.954.974.984.995.035.045.785.805.826.216.216.266.276.297.27CH2ONN+N-SiCH3CH3CH3CH3CH32.179KMJ 2-71B_002000FID.ESP140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityM02(s)M03(s)M05(s)M09(s)M10(s)M11(s)M12(s)M13(s)M14(s)M15(s)M16(s)M17(s)M18(s)M19(s)M01(s)M04(s)M06(s)M07(s)M08(s)M20(s)M21(s)-5.37-5.2318.3420.3724.0125.5625.6325.7128.6733.5935.2062.2162.55109.86114.57138.62141.08CH2ONN+N-SiCH3CH3CH3CH3CH32.179242                       Appendix C: Selected Spectra from Chapter 3             243     JL01-082-4.esp13 12 11 10 9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.022.032.005.197.357.33 7.327.277.267.257.244.834.824.803.153.133.112.562.542.061.56O SS383.92JL01-082-4.esp220 200 180 160 140 120 100 80 60 40 20 0 -20Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity19.0634.8374.1776.8777.1977.51100.13126.91128.76129.12215.87O SS383.92244     JW Xanthate C.001.esp9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity2.962.001.043.502.221.041.842.252.334.535.867.257.277.347.357.367.667.687.767.793.1043.104JW Xanthate C carbon.001.esp200 180 160 140 120 100 80 60 40 20 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity18.9573.5777.32123.41125.07125.95126.67129.70130.17133.57215.39245     JW Xanthate D.001.esp7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity2.833.331.922.170.972.000.912.593.945.777.157.167.277.757.767.777.787.813.105JW Xanthate D carbon.001.esp200 180 160 140 120 100 80 60 40 20 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity19.1055.3375.5576.7077.32105.70119.24126.74127.28129.55129.74158.17217.073.105246     JW 6-145.001.esp7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity2.691.862.002.722.454.175.956.726.746.766.807.273.943.94JW Xanthate A carbon.001.esp200 180 160 140 120 100 80 60 40 20Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity19.2838.4275.41101.47108.43109.47122.15123.03148.18215.72247     JW Xanthate E.001.esp7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.012.001.991.982.615.717.277.527.547.653.983.98JW Xanthate E carbon.001.esp200 180 160 140 120 100 80 60 40 20 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity19.1773.5777.0077.32122.54125.25125.49128.30130.74138.75215.54248     JW 7-31.001.esp7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.006.873.161.972.102.153.303.805.466.407.163.963.96JW Xanthate B carbon.001.esp150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity19.1336.2356.0356.1160.7875.4376.7077.32105.82105.86133.51153.09153.31249     JW Xanthate F.001.esp7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity2.972.001.961.952.605.697.277.497.517.677.693.1023.102JW Xanthate F carbon.001.esp200 180 160 140 120 100 80 60 40 20 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity 19.3073.1376.6877.0077.32112.26118.39128.40132.37140.08215.53250     JW 8-05 CDCl3.001.esp7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.2112.691.001.542.002.412.607.277.377.387.693.1113.111JW Xanthate G carbon.001.esp200 180 160 140 120 100 80 60 40 20Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity13.0553.3676.6877.0077.32127.46128.28128.62140.20188.52215.45251     JW Xanthate H.001.esp7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.0015.892.287.247.247.267.267.277.297.297.307.323.1133.113JW Xanthate H carbon.001.esp180 160 140 120 100 80 60 40 20Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity13.2876.6877.0077.30127.29127.86129.78143.58187.23252     JW Product 1.001.esp7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.005.002.367.147.167.177.197.247.263.1143.114JW Product 1 carbon.001.esp136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity21.4476.6877.0077.32125.29128.22129.03137.87253     JW Product 2.001.esp7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity2.992.002.935.946.646.666.706.746.767.273.1203.120JW Product 2 carbon.001.esp160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity21.0976.6877.0077.32100.61107.97109.52121.44131.39145.23147.42254     JW Product 3.001.esp9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.002.885.981.982.323.833.856.407.273.1213.121JW Product 3 carbon.001.esp150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity21.8255.9860.8576.7077.32105.93133.55153.00255     JW Product 4.001.esp8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity2.990.980.971.920.970.930.932.767.277.397.427.447.577.577.597.767.913.1223.122JW Product 4 carbon.001.esp128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity19.3376.6877.30124.08125.49126.33126.51128.48132.58133.52256     JW Product 5.001.esp7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.003.091.890.380.920.921.932.493.937.127.277.567.657.673.1233.123JW Product 5 carbon.001.esp150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity21.4455.2576.6877.0077.32105.65118.60126.56126.70128.57128.71157.01257     JW Product 6.001.esp7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.152.002.032.437.277.287.307.517.533.1243.124JW Product 6 carbon.001.esp140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity21.3976.6877.0077.32125.10125.14129.29142.04258     JW Product 7.001.esp7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity1.006.219.855.577.137.157.297.307.323.1273.127JW Product 7 carbon.001.esp140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity56.8476.6877.0077.32126.29128.30129.46143.90

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