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Construction of carbo- and oxacycles using radical relay cyclizations initiated by alkoxy radicals Zhu, Hai 2013

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CONSTRUCTION OF CARBO- AND OXACYCLES USING RADICAL RELAY CYCLIZATIONS INITIATED BY ALKOXY RADICALS   by Hai Zhu  B.Sc., Simon Fraser University, 2005  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF  DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Chemistry)  THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver)  August 2013  © Hai Zhu, 2013 ii  Abstract      An investigation of a versatile radical relay cyclization methodology for the rapid construction of carbo- and heterocycles from simple linear precursors has been presented in this thesis. This thesis mainly focuses on 1,5-hydrogen atom translocation and subsequent cyclization reactions (radical relay cyclization reactions). In Chapter 1, an up-to-date literature review of this concept (radical relay cyclization) is presented including 1,5-hydrogen translocation reactions initiated by carbon radicals as well as oxygen and nitrogen radicals. In Chapter 2, the formation of cyclopentane and cyclohexane derivatives utilizing radical relay cyclization reactions initiated by alkoxy radicals has been described. The diastereoselectivity of final carbocycles is discussed. In Chapter 3, the formation of 1,2-disubstituted tetrahydrofuran and tetrahydropyran derivatives utilizing radical relay cyclization reactions has been described. With the incorporation of an oxygen atom into the precursors, the diastereoselectivity has been increased dramatically compared to carbon analogs. In Chapter 4, the formation of 2,3,5-trisubstituted tetrahydrofuran derivatives utilizing radical relay cyclization reactions has been described. With the strategic incorporation of an oxygen atom into cyclization precursors, 1,5-hydrogen atom translocation and subsequent cyclization reactions are able to compete over direct cyclization reactions and β- fragmentation reactions through the dative control. Furthermore, the incorporation of an oxygen atom into precursors enables 1,6-hydrogen atom translocation reactions to outcompete 1,5- hydrogen atom translocation reactions. In Chapter 5, the application of this radical relay cyclization methodology for the synthesis of the tetrahydrofuran fragment within (–)- amphidinolide K has been demonstrated. The final fragment in (–)-amphidinolide K can be achieved in 60% yield with a >95:5 ratio of cis to trans isomers.  iii  Preface      Chapter 2 is based on the research work in Prof. Glenn Sammis’ lab by me, collaborated with Jason Wickenden, Natalie Campbell, Joe Leung and Kayli Johnson. Part of research in Chapter 2 was included in the published paper:  Zhu, H; Wickenden, J. G.; Campbell, N. E.; Leung, J. C. T.; Johnson, K. M.; Sammis, G. M. Org. Lett. 2009, 11, 2019-2022. Prof. Glenn Sammis wrote the manuscript. For optimization in Table 2.1, entries 8, 9 and 10 were performed by Jason Wickenden. For the formation of carbocycles in Table 2.2, entries 2 and 3 were finished by Joe Leung and Kayli Johnson. Entry 4 in Table 2.2 was finished by Natalie Campbell and entry 1 in Table 2.3 was finished by Joe Leung. All other experimental and characterization work in Chapter 2 was performed by me.      Chapter 3 is based on the work in Prof. Glenn Sammis’s lab by me, collaborated with Jason Wickenden. Part of research in Chapter 2 was included in the published paper:  Zhu, H; Wickenden, J. G.; Campbell, N. E.; Leung, J. C. T.; Johnson, K. M.; Sammis, G. M. Org. Lett. 2009, 11, 2019-2022. Prof. Glenn Sammis wrote the manuscript. For the formation of oxacycles in Table 3.1, entries 1 and 7 were finished by Jason Wickenden. Entry 3 was originally conducted by Natalie Campbell and repeated by me. All other experimental and characterization work in Chapter 3 was performed by me.      Chapter 4 is based on the research work in Prof. Glenn Sammis’s lab by me, collaborated with Joe Leung. Compounds in Scheme 4.1 were synthesized and characterized by Joe Leung. All other experimental and characterization work in Chapter 4 was performed by me. This work will be submitted as a full paper in the near future.      Chapter 5 is based on the research work in Prof. Glenn Sammis’s lab by Natalie Campbell and me. Scheme 5.5 was included in the published paper: Zhu, H; Wickenden, J. G.; Campbell, iv  N. E.; Leung, J. C. T.; Johnson, K. M.; Sammis, G. M. Org. Lett. 2009, 11, 2019-2022. Prof. Glenn Sammis wrote the manuscript. Compounds in Scheme 5.5 were synthesized and characterized by Natalie Campbell. Compounds in Scheme 5.6 were synthesized and characterized by me.       v  Table of Contents  Abstract .......................................................................................................................................... ii Preface ........................................................................................................................................... iii Table of Contents ...........................................................................................................................v List of Tables .............................................................................................................................. viii List of Figures ............................................................................................................................... ix List of Schemes ...............................................................................................................................x List of Abbreviations and Symbols ............................................................................................xv Acknowledgements ................................................................................................................... xvii Chapter  1: Literature Review of Radical Relay Cyclizations ...................................................1 1.1 Introduction ..................................................................................................................... 1 1.2 Radical transfer initiated by carbon-centered radicals .................................................... 2 1.2.1 Hydrogen transfer initiated by sp 3  carbon-centered radicals ...................................... 3 1.2.2 Hydrogen transfer initiated by sp2 carbon-centered radicals ...................................... 5 1.2.2.1 Hydrogen transfer initiated by vinyl radicals...................................................... 5 1.2.2.2 Hydrogen transfer initiated by aryl radicals...................................................... 19 1.3 Radical transfer initiated by nitrogen-centered radicals ............................................... 24 1.4 Radical transfer initiated by oxygen-centered radicals ................................................. 25 1.4.1 Generation of oxygen-centered radicals and their reactivity .................................... 26 1.5 Summary ....................................................................................................................... 33 Chapter  2: Construction of Carbocycles using Radical Relay Cyclization ...........................34 2.1 Optimization studies and proposed mechanism ............................................................ 34 vi  2.2 Preparatoin of radical relay cyclization precursors ....................................................... 38 2.3 Results and discussion .................................................................................................. 43 2.4 Conclusion .................................................................................................................... 49 2.5 Experimental ................................................................................................................. 51 2.5.1 General methods ....................................................................................................... 51 2.5.2 Instrumentation ......................................................................................................... 51 2.5.3 Synthesis of precursors N-hydroxyphthalimides 2.1 ................................................ 52 2.5.4 General cyclization procedures ................................................................................. 69 Chapter  3: Construction of Oxacycles using Radical Relay Cyclization ...............................76 3.1 Preparatoin of radical relay cyclization precursors ....................................................... 76 3.2 Results and discussion .................................................................................................. 81 3.3 Future work ................................................................................................................... 85 3.4 Conclusion .................................................................................................................... 87 3.5 Experimental ................................................................................................................. 89 3.5.1 General methods ....................................................................................................... 89 3.5.2 Instrumentation ......................................................................................................... 89 3.5.3 Synthesis of precursors N-hydroxyphthalimides 3.1 ................................................ 90 3.5.4 General cyclization procedures ............................................................................... 113 Chapter  4: Diastereoselective Construction of Functionalized Tetrahydrofurans Using a Substrate Substitution Pattern Initiated by Alkoxy Radicals................................................119 4.1 Results and discussion ................................................................................................ 120 4.1.1 Competition of 1,6-HAT and 1,5-HAT .................................................................. 120 4.1.2 Altering the substitution pattern of the radical relay cyclization precursors .......... 123 vii  4.2 Future work ................................................................................................................. 127 4.3 Conclusion .................................................................................................................. 127 4.4 Experimental ............................................................................................................... 129 4.4.1 General methods ..................................................................................................... 129 4.4.2 Instrumentation ....................................................................................................... 129 4.4.3 Synthesis of precursors N-hydroxyphthalimides .................................................... 130 4.4.4 General cyclization procedures ............................................................................... 144 Chapter  5: Application to the Synthesis of the Tetrahydrofuran Fragment in (–)- Amphidinolide K.   .....................................................................................................................151 5.1 Synthesis of the tetrahydrofuran fragment by Meyer and Lee ................................... 151 5.2 Synthesis of the tetrahydrofuran fragment by our methodologies .............................. 153 5.3 Conclusion .................................................................................................................. 155 5.4 Experimental ............................................................................................................... 156 5.4.1 General methods ..................................................................................................... 156 5.4.2 Instrumentation ....................................................................................................... 156 5.4.3 Synthesis of the tetrahydrofuran fragment .............................................................. 157 Bibliography ...............................................................................................................................161 Appendices ..................................................................................................................................169 Appendix A: Selected 1 H NMR and 13 C NMR spectra for Chapter 2 .................................... 169 Appendix B: Selected 1 H NMR and 13 C NMR spectra for Chapter 3 .................................... 193 Appendix C: Selected 1 H NMR and 13 C NMR spectra for Chapter 4 .................................... 219 Appendix D: Selected 1 H NMR and 13 C NMR spectra for Chapter 5 .................................... 239 Appendix E: Selected crude 1 H NMR analysis for the cyclization of substrates 4.23 ........... 245 viii  List of Tables  Table 2.1    Optimization studies on the rate of addition of the metal hydride and on the concentration of the reaction mixture. .......................................................................................... 36 Table 2.2    Radical relay 5-exo carbocyclizations ....................................................................... 44 Table 2.3    Radical relay 6-exo carbocyclizations ....................................................................... 48 Table 3.1    Radical relay 5-exo oxacyclizations .......................................................................... 81 Table 3.2    Radical relay 6-exo oxacyclizations .......................................................................... 84 Table 4.1    Competition study among relay cyclization, direct cyclization and fragmentation ..................................................................................................................................................... 125   ix  List of Figures  Figure 1.1    Representative examples of oxygen-centered radical precursors ............................. 27 Figure 2.1    Cyclization precursors used in the carbocycle formation ......................................... 38 Figure 3.1    Cyclization precursors used in the oxacycle formation ............................................ 76 Figure 4.1    Radical relay cyclization challenges ...................................................................... 119 Figure 4.2    Stabilization of an alpha carbon radical ................................................................. 120    x  List of Schemes  Scheme 1.1    Radical cyclization cascade ...................................................................................... 1 Scheme 1.2    Radical relay cascade ............................................................................................... 2 Scheme 1.3    Formation of key intermediate 1.12 via 1,5-HAT in the total synthesis of (+)-ipomeamarone and (–)-ngaione ................................................................................................ 3 Scheme 1.4    Synthesis of tetrahydrofuran derivative 1.18 using a alkyl radical-initiated relay cyclization ....................................................................................................................................... 4 Scheme 1.5    Synthesis of 1.20 by a radical relay cyclization initiated by vinyl radical 1.21 ....... 5 Scheme 1.6    Competition between a 1,5-HAT and a 6-exo cyclization ....................................... 6 Scheme 1.7    Substituent effect on the rate of 1,5-HAT vs. direct reduction ................................ 7 Scheme 1.8    Synthesis of (6S,7S)-dihydroxyheliotridane via 1,5-HAT ....................................... 8 Scheme 1.9    Synthesis of spiroketals via 1,5-HAT ...................................................................... 8 Scheme 1.10  Synthesis of spironucleoside 1.43 and 1.44 via 1,5-HAT followed by 5-endo-trig cyclization ....................................................................................................................................... 9 Scheme 1.11  Synthesis of spiro- and fused-cyclic ketones via 1,5-HAT followed by 5-endo-trig cyclization ..................................................................................................................................... 10 Scheme 1.12  Formation of tetrahydrofuran derivatives 1.58 and 1.61 via 1,5-HAT from a hydroxyl group .............................................................................................................................. 11 Scheme 1.13  Synthesis of lactone 1.63 via a radical relay cyclization using an alkyne precursor ....................................................................................................................................................... 12 Scheme 1.14  Competition between 1,5-HAT and intermolecular halogen trapping ................... 12 xi  Scheme 1.15  Synthesis of teterahydrofuran derivative 1.74 using a radical realy cyclization initiated by addition of thiophenyl radical to an alkyne ............................................................... 13 Scheme 1.16  A comparison between the formation of vinyl radicals from alkynes and from vinyl bromides in radical relay cyclizations........................................................................................... 14 Scheme 1.17  Synthesis of enone 1.85 via 1,5-HAT induced by thiophenol ............................... 14 Scheme 1.18  Thiophenol vs. dimethyl phosphonate for the 1,5-HAT followed by cyclizations 15 Scheme 1.19  Synthesis of lactam 1.96 via relay cyclization by addition of tributyltin radical to alkyne 1.92 .................................................................................................................................... 15 Scheme 1.20  Synthesis of tetrahydrofuran derivative 1.98 via 1,5-HAT and subsequent cyclization initiated by nitrate radical ........................................................................................... 16 Scheme 1.21  Synthesis of bicyclic ketone 1.104 and 1.105 via radical relay cyclization initiated by an acyloxy radical .................................................................................................................... 17 Scheme 1.22  Generation of vinyl radical 1.112 via intramolecular addition followed by 1,5-HAT and subsequent 5-endo cyclization ............................................................................................... 18 Scheme 1.23  Diastereoselective synthesis of cyclopentane derivatives via 1,5-HAT followed by 5-exo cyclization ........................................................................................................................... 18 Scheme 1.24  Generation of vinyl radical 1.121 from an allene followed by 1,5-HAT and subsequent 5-exo cyclization ........................................................................................................ 19 Scheme 1.25  Synthesis of benzoindolizidinones 1.125 and 1.126 using a relay cyclization initiated by aryl radicals ................................................................................................................ 20 Scheme 1.26  Synthesis of triquinane core 1.132 of crinipellin A from aryl radical 1.133 followed by 1,5-HAT and 5-exo cyclization................................................................................. 21 Scheme 1.27  Synthesis of tricyclic compound 1.138 via radical relay cyclization ..................... 21 xii  Scheme 1.28  Effect of rotamers on the formation of 1.144 via radical relay cyclization ........... 22 Scheme 1.29  Competition between  1,5-HAT and direct 5-exo cyclization ................................ 23 Scheme 1.30  Synthesis of oxindole 1.155 via radical relay cyclization ...................................... 23 Scheme 1.31  Synthesis of phenanthridine 1.161 via radical relay cyclization ............................ 24 Scheme 1.32  Generation of aminyl radical 1.187 followed by 1,5-HAT and subsequent cyclization ..................................................................................................................................... 25 Scheme 1.33  Three examples of the reactivity of oxygen-centered radicals ............................... 26 Scheme 1.34  Generation of alkoxy radical 1.190 by photochemical conditions ......................... 27 Scheme 1.35  Generation of alkoxy radical 1.196 by N-alkoxyphthalimide 1.194, followed by 5- exo cyclization .............................................................................................................................. 28 Scheme 1.36  Synthesis of carveol through the ring opening of epoxide 1.199 ........................... 29 Scheme 1.37  First example of a radical relay cyclization initiated by an alkoxy radical ............ 29 Scheme 1.38  Generation of alkoxy radical 1.210 through fragmentation, followed by radical relay cyclization ............................................................................................................................ 30 Scheme 1.39  Generation of alkoxy radical 1.218 through fragmentation, followed by radical relay cyclization ............................................................................................................................ 31 Scheme 1.40  Generation of alkoxy radical 1.223 through fragmentation, followed by radical relay cyclization ............................................................................................................................ 31 Scheme 1.41  Generation of alkoxy radical 1.228 through fragmentation, followed by radical relay cyclization ............................................................................................................................ 32  Scheme 1.42  Generation of alkoxy radical 1.233 through fragmentation, followed by radical relay cyclization ............................................................................................................................ 33 xiii  Scheme 2.1     Radical relay cyclization for construction of carbocycles using N- alkoxyphthalimides as precursors ................................................................................................. 35 Scheme 2.2    Synthesis of N-alkoxyphthalimides 2.1a, 2.1h, 2.1i and 2.1l ................................ 39 Scheme 2.3    Synthesis of N-alkoxyphthalimide 2.1d using the Scholloser modification .......... 39 Scheme 2.4   Synthesis of N-alkoxyphthalimide Z-2.1e ............................................................... 40 Scheme 2.5    Synthesis of N-alkoxyphthalimide E-2.1e ............................................................. 41 Scheme 2.6    Synthesis of N-alkoxyphthalimides 2.1f and 2.1g.................................................. 41 Scheme 2.7    Synthesis of N-alkoxyphthalimide 2.1j .................................................................. 42 Scheme 2.8    S Synthesis of N-alkoxyphthalimide 2.1k .............................................................. 42 Scheme 2.9   Chair-like and boat-like transition states of 5-exo cyclizations .............................. 46 Scheme 2.10  Chair-like transition states for the 5-exo cyclizations ............................................ 47 Scheme 2.11  Formation of benzyl radical intermediates during the cyclization of substrates 2.1d and 2.1l .......................................................................................................................................... 49 Scheme 3.1   Synthesis of N-alkoxyphthalimide 3.1b .................................................................. 77 Scheme 3.2    Synthesis of N-alkoxyphthalimide 3.1c ................................................................. 77 Scheme 3.3    Synthesis of N-alkoxyphthalimides E-enriched 3.1d ............................................. 78 Scheme 3.4    Synthesis of N-alkoxyphthalimide Z-enriched 3.1e ............................................... 79 Scheme 3.5    Synthesis of N-alkoxyphthalimide 3.1h ................................................................. 80 Scheme 3.6    Synthesis of N-alkoxyphthalimides 3.1g and 3.1i ................................................. 80 Scheme 3.7    Chair-like transition states for 5-exo cyclizations of oxygen-containing substrates ....................................................................................................................................................... 83 Scheme 3.8    Synthesis of nitrogen-containing ring systems via radical relay cyclization ......... 86 Scheme 3.9    Chemoselective synthesis of piperidine derivatives............................................... 87 xiv  Scheme 4.1    Competition between 5-exo cyclization and 1,5-HAT ......................................... 120 Scheme 4.2    Two possible radical realy cyclization pathways ................................................. 121 Scheme 4.3    Radical relay cyclization initiated by 1,6-HAT ................................................... 121 Scheme 4.4    Competition between 1,6-HAT and 1,5-HAT ...................................................... 122  Scheme 4.5    Reaction of oxygen-transposed substrate 4.22 .................................................... 123 Scheme 4.6    Competing radical pathways initiated by alkoxy radicals .................................... 124 Scheme 4.7    Synthesis of enantioenriched tetrahydrofurans 4.25 ............................................ 124  Scheme 5.1    Synthesis of tetrahydrofuran core fragment within (+)-amphidinolide K by Meyer ..................................................................................................................................................... 151 Scheme 5.2    Retrosynthetic analysis of (–)-amphidinolide K by Lee ...................................... 152 Scheme 5.3    Synthesis of tetrahydronfuran 5.5 by Lee and co-workers ................................... 152 Scheme 5.4    Retrosynthetic analysis of (–)-amphidinolide K by Sammis's group ................... 153 Scheme 5.5    Synthesis of the tetrahydrofuran fragment within (–)-amphidinolide K using radical relay radical cyclization .................................................................................................. 153 Scheme 5.6    Synthesis of the tetrahydrofuran core within (–)-amphidinolike K ..................... 155         xv  List of Abbreviations and Symbols  δ chemical shift Ac acetyl AIBN azoisobutyronitrile Ar aryl Bn benzyl Boc t-butoxycarbonyl Bu butyl t Bu tert-butyl Bz benzoyl °C degrees Celsius CAN cerium(IV)ammonium nitrate cm -1  reciprocal centimeters m-CPBA meta-chloroperoxybenzoic acid d doublet DBU 1,8-diazabicyclo[5,4,0]undec-7-ene dd doublet of doublets DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DIAD diisopropyl azodicarboxylate DIPEA diisopropylethylamine DLP dilauroyl peroxide DMAP 4-dimethylaminopyridine DMF dimethylformamide DMSO dimethylsulfoxide DPMS diphenylmethylsilyl dr diastereomeric ratio E entgegen ee enatiomeric excess ESI electrospray ionization Et ethyl h hour 1,5-HAT 1,5-hydrogen atom translocation Hex hexane HPLC-MS high-performance liquid chromatography-mass spectrometry HRMS high resolution mass spectrum hv light i iso Imid imidazole IR infrared j coupling constant LRMS low resolution mass spectrum m multiplet xvi  M molarity or parent mass Me methyl MHz Mega Hertz min minute mmol millimole mL milliliter NOE nuclear Overhauser effect NMR nuclear magnetic resonance NMM N-Methylmorpholine OTf trifluoromethanesulfonate p para PG protection group Ph phenyl Phth phthalimide PMB 4-methoxyphenyl ppm parts per million Pr Propyl Py pyridine q quartet qt quintet R alkyl s second S sinister SN2 bimolecular nucleophilic substitution t triplet t tert TBAF tetra-n-butyl ammonium fluoride TBS tert-butyldimethylsilyl TBDPS tert-butyldiphenylsilyl THF tetrahydrofuran TIPS triisopropylsilyl Tr trityl Ts para-toluenesulfonyl UV ultraviolet W watt Z zusammen xvii  Acknowledgements       First and foremost, I would like to express my deepest appreciation to my supervisor Prof. Glenn Sammis for his understanding, patience and his valuable suggestion on my project since the beginning of my program here. It has been a great privilege to work under such a knowledgeable and supportive supervisor who truly cares about the success of his students.      I would also like to thank my committee members: Prof. Martin Tanner, Prof. Jennifer Love and Prof. Stephen Withers for their advice. A special thank goes to Prof. Martin Tanner for his time in reviewing my thesis. I thank Dr. Peter Wilson for broadening my vision of organic chemistry and providing tremendous training during my undergraduate study.      I would like to thank all group members in Prof. Sammis’ lab: Jay Wickenden, Joe Leung, Natalie Campbell, Montserrat Rueda-Becerril and Claire Chatalova Sazepin for their friendship and discussion on my project.      In addition, I would like to thank the enthusiastic staff from stores and facilities in the chemistry department at UBC. All work presented here couldn’t have been done without their support and services. I would like to extend my sincere gratitude to UBC, NSERC, MERCK FROSST for their valuable financial support.      Many thanks go foremost to my father for his continuous support throughout my study. His encouragement is much appreciated when the times got tough. I wouldn’t come this far without him. A million heartfelt thanks go to my lovely wife and my lifelong friend, Hong Jiang, for her time and selfless support, and to my sons, Tianbo Zhu and Felix Zhu for their infinite patience and understanding. 1  Chapter  1: Literature Review of Radical Relay Cyclizations 1.1 Introduction      The discovery of the triphenyl methyl radical by Moses Gomberg in 1900 1 marked the inception of the field of organic radical chemistry. Despite this early discovery, radical reactions were not commonly utilized in natural product synthesis until the 1960’s because the reaction selectivity of these reactive intermediates was difficult to control. Intensive efforts over the past half-century have resulted in numerous synthetically powerful radical-based methodologies. These methodologies are particularly useful as they often display orthogonal group tolerance 2  compared to ionic-based methodologies. Free radical reactions are now commonly utilized in numerous types of transformations, especially for the formation of new carbon-carbon bonds.      A powerful synthetic application of free-radicals is the formation of several carbon-carbon bonds in a single step through a radical cascade reaction. The most common type of radical cascade reactions are intramolecular cascade cyclizations, where a series of radical acceptors are placed strategically in a substrate to enable a series of new carbon-carbon bond-forming reactions (Scheme 1.1). 3 These cascades can be modified to allow for different radical acceptors, ring sizes and functional groups. Furthermore, complex molecular architectures can be synthesized in one synthetic step.  Scheme 1.1. Radical cyclization cascade.  2       Although not as commonly utilized as cascade cyclizations, intramolecular radical relay (or radical translocation) cascades are equally powerful methods for the rapid assembly of complex molecular architectures. These cascade reactions usually begin with the formation of a highly reactive radical species (X = alkyl, vinyl, aryl, O or N) that can abstract a proton in δ position. This 1,5-hydrogen atom translocation (1,5-HAT) occurs through a 6-membered chair-like transition state 1.5 (Scheme 1.2) 4  and, therefore, generally is faster than 1,4- and 1,6- translocation reactions. 5  Once the radical has been “translocated” across the backbone, an intramolecular radical cyclization cascade takes place. Radical relay cyclizations have become valuable methods in organic synthesis, as they offer possibilities for the introduction of functional groups on the non-activated carbon atom or formation of a new carbon-carbon bond.  Scheme 1.2. Radical relay cascade. 1.2 Radical transfer initiated by carbon-centered radicals      This section will focus on different types of carbon-centered radical generation as well as their reactivity in relay cyclizations.   3  1.2.1 Hydrogen transfer initiated by sp 3  carbon-centered radicals      Intramolecular 1,5-hydrogen atom translocation by sp 3  carbon-centered radicals (alkyl radicals) has not been utilized extensively in organic synthesis. In most cases, these transformations are energetically unfavorable since the radical center transfers from one sp 3  carbon to a new sp 3 carbon. However, relocation of the radical center from one sp 3  carbon to another sp 3  carbon and subsequent functionalization can be synthetically useful if the 1,5- hydrogen atom translocation of a C-H bond results in a more stabilized sp 3 radical, such as allylic or benzylic radicals or radicals alpha to heteroatoms.      One of the early examples of 1,5-hydrogen atom translocation initiated by a sp 3  radical was demonstrated in the first total synthesis of (+)-ipomeamarone and (–)-ngaione by Sugimura and co-workers. 6  Treatment of 1.9 with NaBH4 generated alkyl radical 1.10 (Scheme 1.3). 6 Intramolecular abstraction of a proton alpha to an oxygen atom (1,5-HAT) afforded ketal radical 1.11, which added to the acceptor acrylonitrile to give 1.12.  Scheme 1.3. Formation of key intermediate 1.12 via 1,5-HAT in the total synthesis of (+)-ipomeamarone and (–)-ngaione. 4       Another successful example of 1,5-hydrogen atom translocation initiated by sp 3  carbon radicals was demonstrated by Rawal in the synthesis of bicyclic ketone 1.18 (Scheme 1.4). 7 Addition of tributyltin radical to the oxygen atom of the ketone and the subsequent opening of the cyclopropane ring (fragmentation) resulted in the formation of primary alkyl radical 1.15. A subsequent 1,5-hydrogen atom translocation, followed by 5-exo cyclization formed tetrahydrofuran derivative 1.18. This radical relay cyclization provided higher yields for oxygen- containing product 1.18b. This difference was postulated to result from two effects: (1) the decreased carbon-oxygen bond length and (2) the decreased carbon-oxygen-carbon bond angle resulting from the two lone-pair electrons.  Scheme 1.4. Synthesis of tetrahydrofuran derivative 1.18 using an alkyl radical-initiated relay cyclization.  5  1.2.2 Hydrogen transfer initiated by sp2 carbon-centered radicals 1.2.2.1 Hydrogen transfer initiated by vinyl radicals      An early example of vinyl radical translocation followed by cyclization to form new carbon-carbon bonds was reported by Heiba and Dessau in 1967. 8  In the late 1980’s, the synthetic utility of 1,5-HAT by vinyl radicals was investigated in detail by Parson’s group9 and shortly after, by Curran’s group.10 In this section, the work from these groups as well as other groups on radical relay cyclizations initiated by vinyl radicals will be discussed. A.  Vinyl radicals produced from vinyl halides  Scheme 1.5. Synthesis of 1.20 by a radical relay cyclization initiated by vinyl radical 1.21.      Parson and co-workers utilized vinyl radicals to initiate radical relay cyclizations for the synthesis of pyrrolizidine ring systems (Scheme 1.5). 8  Irradiation of a solution of vinyl iodide 1.19 and tributyltin hydride resulted in vinyl radical 1.21, which underwent 1,5-hydrogen atom translocation, followed by 5-exo cyclization to form the tricyclic ring system 1.20. 6       In a subsequent study, Parson and co-workers investigated the relative rates of an initial 1,5-hydrogen atom translocation and a competing 6-exo-trig cyclization (Scheme 1.6). 11 Treatment of cyclization precursor 1.24 with tributyltin hydride and AIBN afforded cyclization product 1.28 in 78% yield. The product resulting from an initial 6-exo-trig cyclization product 1.26 was only formed in 17% yield. A similar strategy was utilized by the same authors to synthesize spirocyclic and fused bicyclic compounds. 12   Scheme 1.6. Competition between a 1,5-HAT and a 6-exo cyclization.      Curran et al. subsequently studied the effect different radical stabilizing groups had on 1,5- HAT compared to direct quenching of the vinyl radical by tributyltin hydride. Cyclization of 1.29 (A) resulted in 87% yield of cyclization product 1.31 along with traces of the direct reduction product 1.30, while cyclization of 1.29 (B) resulted in 67% yield of the final cyclization product, without formation of the direct reduction product (Scheme 1.7). 10,13 Cyclization of substrates containing a radical stabilizing group (A, B or E) to weaken the C-H bond provided higher yield of the radical relay cyclization products. Reduction product 1.30 was 7  obtained directly from the vinyl radical 1.32, which was confirmed by introducing deuterated tributyltin hydride into the reactions.  Scheme 1.7. Substituent effect on the rate of 1,5-HAT vs. direct reduction.      Robertson’s group reported the synthesis of (6S,7S)-dihydroxyheliotridane using a radical relay cyclization methodology. Treatment of bromoalkene 1.35 resulted in the formation of vinyl radical 1.37, which underwent a 1,5-HAT (Scheme 1.8). 14 The resulting datively stabilized radical then underwent 5-exo cyclization followed by hydrogen-quenching to afford 1.36 in 64% yield. 8   Scheme 1.8. Synthesis of (6S,7S)-dihydroxyheliotridane via 1,5-HAT.      A similar radical relay strategy was employed by Simpkin and co-workers to synthesize spiroketals (Scheme 1.9). 15 While the size of tetrahydrofuran and tetrahydropyran rings affected the final yields of spiroketals, there was no correlation between the ring size and the yield.  Scheme 1.9. Synthesis of spiroketals via 1,5-HAT.      Both Chatglialoglu 16  and Miyasaka 17 reported the generation of C-1' radicals initiated by vinyl radicals. Treatment of dibromoalkene 1.42 with 1,1,1,2,2,2-hexabutyldistannane resulted in the formation of spironucleosides 1.43 and 1.44 via a 1,5-hydrogen atom translocation followed by an unexpected 5-endo-trig cyclization (Scheme 1.10). This method afforded a 2:1 ratio of 1.43 to 1.44. 9   Scheme 1.10. Synthesis of spironucleoside 1.43 and 1.44 via 1,5-HAT followed by 5-endo- trig cyclization.      Sha and co-workers demonstrated that a radical relay methodology could be utilized to synthesize spiro- or fused-cyclic ketones using α, β-unsaturated esters or nitriles as radical acceptors. Vinyl iodides were smoothly transformed into the final cyclization products. The yields for the spiro-cyclic ketones are generally higher than those for the analogous fused-cyclic ketones (Scheme 1.11). 18  10   Scheme 1.11. Synthesis of spiro- and fused-cyclic ketones via 1,5-HAT followed by 5-endo-trig cyclization.      Vinyl radicals are sufficiently high-energy intermediates that they are not limited to the abstraction of carbon-hydrogen bonds. Ihara and co-workers observed the formation of tetrahydrofuran derivatives via the hydrogen transfer from a hydroxyl group to the vinyl radical (Scheme 1.12). 19 A subsequent 5-exo-trig cyclization provided a tetrahydrofuran ring in moderate yield. 11   Scheme 1.12. Formation of tetrahydrofuran derivatives 1.58 and 1.61 via 1,5-HAT from a hydroxyl group.  B.  Vinyl radicals produced by addition of carbon or heteroatom radicals to alkynes and allenes      To expand the generality and the scope of radical relay cyclizations, efforts have focused on utilizing alternative routes to the key vinyl radical. Early work by Heiba and co-workers investigated using alkynes as vinyl radical precursors in radical relay cyclizations (Scheme 1.13). 20 Treatment of terminal alkyne 1.62 with carbon tetrachloride and benzoyl peroxide resulted in the formation of a trichloromethyl radical, which added to alkyne 1.62 to afford vinyl radical 1.64. A subsequent 1,5-HAT, 5-exo cyclization, and elimination produced lactone 1.63.  12   Scheme 1.13. Synthesis of lactone 1.63 via a radical relay cyclization using an alkyne precursor.       The same strategy for generation of vinyl radicals was employed by Heiba and co-workers towards the synthesis of cyclopentane derivatives (Scheme 1.14). 8 Treatment of terminal alkyne 1.67 with carbon tetrachloride afforded vinylcyclopentane 1.68 in 20% yield. However, when bromotrichloromethane was used in the reaction, the only product obtained was addition product 1.71. The results demonstrated that intermolecular trapping of vinyl radical 1.69 is faster than the hydrogen atom translocation.  Scheme 1.14. Competition between 1,5-HAT and intermolecular halogen trapping. 13   Scheme 1.15. Synthesis of teterahydrofuran derivative 1.74 using a radical relay cyclization initiated by addition of a thiophenyl radical to an alkyne.      Another efficient way to generate vinyl radicals is through the intermolecular addition of sulfur radicals to terminal alkynes, as demonstrated by Burke and Jung (Scheme 1.15). 21 The thiophenyl radical was first generated from thiophenol and AIBN. Addition of the sulfur radical to intermediate 1.72 afforded vinyl radical 1.75. A subsequent relay cyclization afforded tetrahydrofuran derivative 1.74 (trans/cis = 2:1), in 78% yield along with direct reduction product 1.73 in 14% yield.      Generation of vinyl radicals using sulfur radicals was also investigated by Renaud and co- workers (Scheme 1.16). 22  To outcompete direct reduction of the vinyl radical intermediate, radical stabilizing groups, such as silyl ethers, were introduced into substrates to weaken the C-H bond. Treatment of 1.78 with thiophenol and AIBN in tert-BuOH exclusively provided the radical relay cascade reaction product without formation of the direct reduction product. A comparative study of radical relay cyclization initiated by vinyl radicals using tributyltin hydride and AIBN was also reported. The cyclization reactions afforded only moderate yields of cyclization products along with direct reduction products. 14   Scheme 1.16. A comparison between the formation of vinyl radicals from alkynes and from vinyl bromides in radical relay cyclizations.      Radical relay cyclizations initiated by sulfur radicals are an alternative method in the construction of polysubstituted tetrahydrofuran derivatives. Alkyne 1.84 was smoothly transformed into 1,5-hydrogen atom translocation and cyclization product 1.85 (Scheme 1.17). 23 Subsequent oxidation with CrO3/H2SO4 followed by treatment with DBU afforded enone 1.86.  This methodology was further employed to synthesize polysubstituted 1-azabicyclic alkane derivatives, 24 as well as natural product (–)-erythrodiene.25  Scheme 1.17. Synthesis of enone 1.85 via 1,5-HAT induced by thiophenol.      When sulfur radicals were utilized to initiate radical relay cyclizations of substrates without radical stabilizing groups near the site of translocation, typically low product yields were obtained (Scheme 1.18). 26  This substrate limitation could be overcome with the use of dimethyl 15  phosphonate as the radical initiator. Treatment of 1.87 with five equivalent dimethyl phosphonate and dilauroyl peroxide in cyclohexane exclusively afforded cyclization product 1.91 in excellent yield.  Scheme 1.18. Thiophenol vs. dimethyl phosphonate for the 1,5-HAT followed by cyclization.   Scheme 1.19. Synthesis of lactam 1.96 via relay cyclization by addition of tributyltin radical to alkyne 1.92.       Heterobicyclic ring systems can also be obtained by treating terminal alkynes with tributyltin hydride (Scheme 1.19). 27 Addition of a catalytic amount of tributyltin radical onto alkyne 1.92 16  resulted in the generation of vinyl radical 1.93, which underwent relay cyclization to afford fused bicyclic β-lactam 1.96. The 6-endo cyclization is preferred over the 5-exo cyclization.  Scheme 1.20. Synthesis of tetrahydrofuran derivative 1.98 via 1,5-HAT and subsequent cyclization initiated by nitrate radical.      Vinyl radicals can also be generated by adding oxygen-centered radicals to alkynes in the presence of inorganic salts. Wille and co-workers demonstrated the formation of tetrahydrofuran derivatives and pyrrolidine derivatives by a tandem oxidative, self-termination cyclization reaction. Ether 1.97 was treated with lithium nitrate, which induced the nitrate radical to generate vinyl radical 1.99 (Scheme 1.20). 28 Radical 1.99 then underwent 1,5-hydrogen atom translocation, followed by 5-exo cyclization to give radical 1.101. Homolytic cleavage of the weak oxygen-nitrogen bond led to the formation of tetrahydrofuran derivative 1.98 in 85% yield, with concomitant release of nitrogen dioxide. Fused pyrrolidine derivatives could also be synthesized using the similar methodology with inorganic salt ceric ammonium nitrate as the radical initiator. 29  17   Scheme 1.21. Synthesis of bicyclic ketone 1.104 and 1.105 via radical relay cyclization initiated by an acyloxy radical.      Wille and co-workers applied this methodology to a cyclic ring system containing an internal alkyne (Scheme 1.21). 30  2-Thioxopyridin-1(2H)-yl 4-methoxybenzoate was employed to generate acyloxy radical 1.103, which added to 1.102 to provide vinyl radical 1.106. Vinyl radical 1.106 then underwent radical relay cyclizations to afford cyclic products 1.104 and 1.105 in total 89% yield.      An alternative method to generate vinyl radicals is through intramolecular additions of carbon radicals to alkynes. Clive and co-workers reported a general pathway to synthesize cyclopentane, 31 tetrahydrofuran and piperidine derivatives. 32 The strategy began with the generation of an alkyl radical followed by 5-exo-digonal ring closure to afford vinyl radicals 1.112 (Scheme 1.22). A subsequent 1,5-hydrogen atom translocation formed a silicon-centered radical, which, then cyclized back onto the alkene through a 5-endo-trigonal pathway to provide bicyclic rings 1.110. This methodology was further utilized by Clive for the total synthesis of methyl epi-jasmonate 33 and (+)-juruenolide C. 32  18   Scheme 1.22. Generation of vinyl radical 1.112 via intramolecular addition followed by 1,5- HAT and subsequent 5-endo cyclization.      Radical relay cyclizations can be highly diastereoselective when a chiral auxiliary is incorporated into the molecule. Reaction of acetal 1.115 with tributyltin hydride and AIBN provided the final cyclopentane derivatives with good yield and excellent diastereoselectivity (Scheme 1.23). 34   Scheme 1.23. Diastereoselective synthesis of cyclopentane derivatives via 1,5-HAT followed by 5-exo cyclization.      Reiβig and co-workers examined allenes as precursors for vinyl radical generation (Scheme 1.24). 35 Addition of samarium iodide to ketone 1.118 resulted in the formation of ketyl radical 1.120. The intermolecular addition of 1.120 to methoxyallene occurred at the terminal carbon to 19  afford vinyl radical 1.121. The subsequent regioselective hydrogen translocation followed by 5- exo cyclization afforded ring closure product 1.119 in moderate yield.  Scheme 1.24. Generation of vinyl radical 1.121 from an allene followed by 1,5-HAT and subsequent 5-exo cyclization.  1.2.2.2 Hydrogen transfer initiated by aryl radicals      Radical relay cyclizations initiated by aryl radicals were investigated and developed by Curran’s group who focused on radical translocation and subsequent cyclization reactions.36 In an early work, It was reported that treatment of o-bromobenzamide 1.124 with tributyltin hydride (2 equiv) and AIBN (5 mol %) in refluxing benzene afforded aryl radical 1.127 (Scheme 1.25). 37 A subsequent 1,5-hydrogen atom translocation and 6-exo cyclization provided a 1:1 ratio of final benzoindolidinones 1.125 and 1.126 in 67% yield. This methodology was later applied to the synthesis of more elaborate molecules by Ikeda, 38,39,40  Staliński41 and Fujitani.42 20   Scheme 1.25. Synthesis of benzoindolizidinones 1.125 and 1.126 using a relay cyclization initiated by aryl radicals.      Curran and Schwartz sought to construct more elaborate cyclic systems using a tandem radical cyclization initiated by aryl radicals. 43 In the synthesis of crinipellin A, construction of the triquinane core started with substrate 1.131, which contains several strategically placed radical acceptors (Scheme 1.26). Treatment of silyl ether 1.131 with tributyltin hydride and AIBN provided aryl radical 1.133, which underwent 1,5-hydrogen atom translocation to afford α-alkoxy radical 1.134. A sequence radical cyclization cascade followed by hydrogen quenching of radical 1.136 provided triquinane core 1.132 in 65% yield.  21   Scheme 1.26. Synthesis of triquinane core 1.132 of crinipellin A from aryl radical 1.133 followed by 1,5-HAT and 5-exo cyclization.  Scheme 1.27. Synthesis of tricyclic compound 1.138 via radical relay cyclization.      Further studies by Curran and co-workers demonstrated that a relay cyclization could be initiated from o-iodoanilide 1.137 (Scheme 1.27). 44 Treatment of o-iodoanilide 1.137 with tributyltin hydride and AIBN resulted in the formation of aryl radical 1.139, which then 22  underwent 1,5-hydrogen atom translocation to afford radical 1.140. A sequence radical cyclization cascade followed by hydrogen quenching of radical 1.142 afforded tricyclic ring 1.132 in 75% yield.      This concept was further explored by Curran in the formation of α-amidoyl radicals starting from unsymmetric o-iodobenzamide derivatives (Scheme 1.28). 45 The outcome depended on the ratio of two rotamers 1.143 and 1.145.  α-Amidoyl radical 1.146, derived from rotamer 1.145, provided single cyclization product 1.144 in 42% yield, while the reaction of rotamer 1.143 led to a mixture of unidentified products.    Scheme 1.28. Effect of rotamers on the formation of 1.144 via radical relay cyclization.       Jones and co-workers studied the competition reaction between a 1,5-hydrogen atom translocation and a direct 5-exo cyclization (Scheme 1.29). 46  Treatment of 1.147 with tributyltin hydride and AIBN in refluxing toluene led to 1,5-hydrogen atom translocation and subsequent cyclization product 1.149 in 92% yield. Direct 5-exo cyclization product 1.148 was not formed. 23    Scheme 1.29. Competition between 1,5-HAT and direct 5-exo cyclization.      Beckwith and Storey investigated substrates, in which there were no alkenes as acceptors after the initial 1,5-hydrogen atom translocation step (Scheme 1.30). 47 Treatment of N-methyl amide 1.153 with tributyltin hydride and AIBN in refluxing benzene gave direct reduction product 1.154 as the major product. However, when the reaction was performed at a high temperature, the radical relay cyclization product was predominant, providing 1.155 in 81% isolated yield.  Scheme 1.30. Synthesis of oxindole 1.155 via radical relay cyclization. 24       Spagnolo and co-workers investigated the reactivity of iminyl radicals generated from an aryl radical translocation (Scheme 1.31). 48 Cyclization of 1.159 under standard radical reaction conditions provided cyclization product 1.161 in 45% yield and 15% of reduction product 1.160 from iminyl radical 1.164.   Scheme 1.31. Synthesis of phenanthridine 1.161 via radical relay cyclization. 1.3 Radical transfer initiated by nitrogen-centered radicals      Nitrogen-centered radicals 49 have been widely studied as initiators for radical relay cyclizations. In a representative example, Kim and co-workers used azides as precursors to generate tributylstannyl aminyl radicals (Scheme 1.32). 50  Azide 1.166 was treated with tributyltin hydride and AIBN to give tributyltin substituted aminyl radical 1.168, which then underwent 1,5-hydrogen atom translocation followed by 5-exo cyclization to afford tetrahydrofuran derivative 1.167. 25   Scheme 1.32. Generation of aminyl radical 1.168 followed by 1,5-HAT and subsequent cyclization. 1.4 Radical transfer initiated by oxygen-centered radicals      The chemistry of oxygen-centered radicals has been studied extensively. 51 Oxygen-centered radicals are a highly reactive species and undergo a series of intramolecular reactions including direct cyclization, 52 β-fragmentation53 and 1,5-hydrogen atom translocation reactions (Scheme 1.33). 54  This section will focus on 1,5-hydrogen atom translocation and subsequent cyclization reactions initiated by alkoxy radicals. 26   Scheme 1.33. Three examples of the reactivity of oxygen-centered radicals. 1.4.1 Generation of oxygen-centered radicals and their reactivity      Oxygen-centered radicals can be generated by cleavage of weak oxygen-heteroatom bonds, such as oxygen-chlorine bonds, 55  oxygen-sulfur bonds, 56  or oxygen-nitrogen bonds. 57  These precursors are facile to prepare through a simple substitution or acylation. Representative examples of oxygen-centered radical precursors are illustrated in Figure 1.1. These precursors can be transformed into alkoxy radicals by either standard thermal conditions with initiators or using photochemical conditions. 27   Figure 1.1. Representative examples of oxygen-centered radical precursors.  Scheme 1.34. Generation of alkoxy radical 1.190 by photochemical conditions.       Homolytic cleavage of an oxygen-nitrogen bond can be utilized to generate an oxygen- centered radical under photochemical conditions. In an early example of the generation of oxygen-centered radicals, photolysis of 1.189 led to oxygen-centered radical 1.190, which underwent 1,5-HAT to afford carbon-centered radical 1.191 (Scheme 1.34).  A subsequent recombination of 1.191 with the initially formed NO radical afforded oxime 1.193. 57a 28       In addition to photochemical conditions, generation of alkoxy radicals can be induced under thermal conditions. Kim reported that heating solutions of N-alkoxyphthalimides with tributyltin radical resulted in the generation of alkoxy radicals (Scheme 1.35). 58  Treatment of N- alkoxyphthalimide 1.194 with tributyltin hydride and AIBN resulted in homolytic cleavage of the oxygen-nitrogen bond to yield alkoxy radical 1.196, which then underwent 5-exo cyclization to form tetrahydrofuran derivative 1.197 in 93% yield. Compared to other alkoxy radical precursors, N-alkoxyphthalimides are relatively stable and can be carried through multiple steps.  Scheme 1.35. Generation of alkoxy radical 1.196 by N-alkoxyphthalimide 1.194, followed by 5-exo cyclization.      Alkoxy radicals can also be formed through homolytic cleavage of oxygen-carbon bonds. This usually can be achieved through fragmentation of an epoxide with an α-carbinyl radical. The earliest example of this type of fragmentation was demonstrated by Barton’s group, as shown in Scheme 1.36. 59  Treatment of 1.198 with tributyltin hydride and AIBN afforded carbinyl radical 1.199, which underwent fragmentation to afford alkoxy radical 1.200. The external hydrogen abstraction from tributyltin hydride resulted in the formation of (+)-trans- carveol, which, upon treatment with 3,5-dinitrobenzoyl chloride, was transformed to ester 1.202 in 65% yield. 29   Scheme 1.36. Synthesis of carveol through the ring opening of epoxide 1.199.  Scheme 1.37. First example of a radical relay cyclization initiated by an alkoxy radical.      Radical relay cyclizations initiated by alkoxy radicals were first investigated by Čeković and co-workers (Scheme 1.37). 60  Photolysis of nitrite 1.203 gave alkoxy radical 1.204, which underwent 1,5-hydrogen atom translocation to generate carbon radical 1.205. Alkyl radical 1.205 was then either quenched by a nitroso radical to form nitroso alcohol 1.206 in 14% yield or directly cyclized onto the alkene to afford 5-exo cyclization product 1.208 in 32% yield. 30       Alkoxy radicals generated from the radical fragmentation of epoxides were utilized by Rawal and co-workers to initiate relay cyclizations.  Treatment of substrate 1.209 with tributyltin hydride and AIBN resulted in the formation of a carbon radical (Scheme 1.38). 61 A subsequent fragmentation of the epoxide formed alkoxy radical 1.210,  which then underwent a radical relay cyclization to produce the desired product 1.213 in 69% yield. An unexpected side adduct 1.215 was also detected in approximately 10% yield, which presumably resulted from β-fragmentation reaction of alkoxy radical 1.210.  Scheme 1.38. Generation of alkoxy radical 1.210 through fragmentation, followed by radical relay cyclization.      This method was further explored by Rawal’s group in the formation of bicyclic products containing a carbonyl group on the ring. Treatment of keto-epoxide 1.216 with tributyltin hydride and AIBN afforded bicyclic product 1.217 with single cis-isomer as the major product in 65% yield (Scheme 1.39). 62  31    Scheme 1.39. Generation of alkoxy radical 1.218 through fragmentation, followed by radical relay cyclization.  Scheme 1.40. Generation of alkoxy radical 1.223 through fragmentation, followed by radical relay cyclization.      Different radical initiators to generate alkoxy radicals from the opening of epoxides were investigated by the same group. Addition of diphenyl disulfide and AIBN to 1.221 generated alkoxy radical 1.223, which performed a cascade reaction to afford carbon-centered radical 1.225 (Scheme 1.40). 63 Enol 1.222 was regenerated by removal of the thiyl radical. 32       Relay cyclizations initiated by oxirane carbinyl radicals were also investigated by Murphy and co-workers (Scheme 1.41). 64 Treatment of bromoepoxide 1.226 with tributyltin hydride and AIBN afforded carbinyl radical 1.227, which underwent fragmentation to generate alkoxy radical 1.228. A subsequent relay cyclization provided cyclopentane derivative 1.231 as the major product. The direct 6-exo cyclization product 1.229 was obtained in only 27% yield.  Scheme 1.41. Generation of alkoxy radical 1.228 through fragmentation, followed by radical relay cyclization.      Kim reported an alkoxy radical-initiated relay cyclization starting from alkene 1.232 (Scheme 1.42). 65  Addition of tributyltin radical to the alkene resulted in the radical epoxide opening to afford alkoxy radical 1.233. A subsequent relay cyclization and extrusion of tributyltin radical afforded bicyclic product 1.235 in 82% yield. 33    Scheme 1.42. Generation of alkoxy radical 1.233 through fragmentation, followed by radical relay cyclization. 1.5. Summary      This chapter presented a review of relay cyclizations initiated by carbon-, nitrogen-, and oxygen-centered radicals. Compared to the synthetic utility of 1,5-hydrogen atom translocation and subsequent cyclization initiated by alkenyl, aryl, and nitrogen-centered radicals, the synthetic scope of alkoxy radical-initiated radical relay cyclizations was limited due to the lack of flexibility in the options of radical acceptors and problems controlling side reactions. We sought to develop a general solution for the formation of carbo- and heterocycles starting from simple linear precursors.         34  Chapter  2: Construction of Carbocycles using Radical Relay Cyclizations      Oxygen-centered radicals are highly reactive species and readily undergo 1,5-hydrogen atom translocations, even from non-activated C-H bonds. These processes are exceedingly fast, with a measured rate to be in the order of 10 7  s -1 . 66 As detailed in Chapter 1 of this thesis, there are relatively few examples of oxygen-centered radical-initiated relay cyclizations. The seminal work by Čeković demonstrated the basic concept of radical relay cyclizations, but the yields of the products were low (25-32%). Radical relay cyclization methodologies developed by Rawal, 61,62,63  Murphy 64 and Kim 65 involving the formation of alkoxy radicals from radical epoxide fragmentations were successful in selected cases, but typically provided low yields for simple linear substrates. This chapter will focus on the development of a new, general method for radical relay cyclizations initiated from alkoxy radicals. 2.1 Optimization studies and proposed mechanism      One of the major limitations of relay cyclization methodologies initiated by alkoxy radicals is that it is challenging to control the selectivity of the different radical pathways. This was most evident with the methodology developed by Čeković,60 in which the yields of the desired products were low due to the undesired radical trapping of the 1,5-hydrogen atom translocation products prior to cyclization. In Čeković’s methodology, the most significant limitation was the generation of the alkoxy radical from the nitrite as photolysis results in two radical species, the relative concentration of which is impossible to control. We proposed that the key factor is the control of the concentration of the trapping agents to minimize the undesired trapping of the oxygen- or carbon-centered radicals prior to cyclization. We, therefore, turned our attention to N- alkoxyphthalimides as oxygen-centered radical precursors (Scheme 2.1). 35   Scheme 2.1. Radical relay cyclization for the construction of carbocycles using N- alkoxyphthalimides as precursors.       The addition of tributyltin hydride and AIBN to N-alkoxyphthalimide 2.1 in refluxing benzene should lead to the formation of alkoxy radical 2.3 and stable byproduct 2.2. 58,67,68 Tin- bound phthalimide 2.2 is unreactive under the standard radical conditions. The subsequent 1,5- hydrogen atom translocation by radical 2.3 provides carbon-centered radical 2.4. With the low concentration of metal hydride in the reaction mixture by slow addition of metal hydride during the reaction course, the rate of the hydrogen-quench to produce 2.7 should be slower than the rate of cyclization to form 2.5. Trapping of the desired radical 2.5 with metal hydride should then provide major cyclized product 2.6 with the relatively small amount of direct reduced product linear alcohol 2.7.   36  Table 2.1. Optimization studies on the rate of addition of the metal hydride and on the concentration of N-alkoxyphthalimide 2.1a.  entry (a)  n metal hydride addition rate concentration (M) cyclization/linear (2.6a/2.7a) (b)  1 2 Bu3SnH one portion 0.02 60:40 2 2 Bu3SnH 0.5 mL/h 0.02 64:36 3 2 Bu3SnH 0.5 mL/h 0.005 66:34 4 2 Bu3SnH 0.25 mL/h 0.02 67:33 5 1 Bu3SnH one portion 0.02 63:37 6 1 Bu3SnH 0.5 mL/h 0.02 90:10 7 1 Bu3SnH 0.4 mL/h 0.02 95:5 8 1 Ph3SnH one portion 0.02 67:33 9 1 Ph3SnH 0.4 mL/h 0.02 80:20 10 1 (TMS)3SiH one portion 0.02 90:10 (a) Reactions were carried out on 0.17 mmol scale. (b) Conversions were determined by NMR spectroscopic analysis of crude reaction mixtures.      The formation of cyclohexane derivatives was first investigated utilizing radical relay cyclization by optimizing the concentration of N-alkoxyphthalimide 2.1i and the rate of addition of tributyltin hydride (Table 2.1). Addition of tributyltin hydride in one portion (entry 1) afforded a roughly 60 to 40 ratio of the cyclized product (2.6i) to the linear product (2.7i). Slow addition of tributyltin hydride to N-alkoxyphthalimide 2.1i (0.02 M) in benzene (entry 2) provided a mixture of the cyclized to the linear product as a ratio of up to 64:36. Further decreasing the 37  concentration of N-alkoxyphthalimide 2.1i afforded a slightly higher ratio of the desired cyclized product to the linear alcohol (entry 3). When the concentration of N-alkoxyphthalimide 2.1i was kept at 0.02 M, decreasing the rate of addition of tributyltin hydride did not significantly increase the ratio of the cyclized product to the linear product (entry 4). Next, we focused on the formation of cyclopentane derivatives (entries 5-10). Addition of tributyltin hydride in one portion (entry 5) afforded a roughly 63 to 37 ratio of the cyclized product (2.6a) to the linear product (2.7a). Addition of tributyltin hydride at 0.5 mL/h to a 0.02 M solution of the N- alkoxyphthalimide in benzene afforded a higher ratio of the cyclized to the linear product compared to the cyclohexane analog (entry 6). Decreasing the rate of the addition of tributyltin hydride to 0.4 mL/h provided a mixture of the desired cyclized product (2.6a) to the linear product (2.7a) in a ratio of up to 95:5 (entry 7). Further decreasing the rate of addition of tributyltin hydride did not improve the ratio of cyclized product to linear alcohol. Other metal hydride sources (entries 8-10) were investigated in this radical relay cyclization by Jason Wickenden, a graduate student in the Sammis group. Triphenyltin hydride also provided better conversions to the cyclized product than the linear product with slower addition rates in a similar trend (entries 8-9), although the ratio of the cyclized to linear product was lower than the ratio was achieved with tributyltin hydride (entry 7 vs. entry 9).  The cyclization reaction also worked well when the metal hydride source changed to tris(trimethylsilyl)silane (entry 10).  However, slow addition rates are not necessary to control selectivity for cyclized product 2.6a as the rate of hydrogen translocation from silanes is slower than from metal hydrides. 69       With optimized conditions for the synthesis of carbocycles using this new radical relay cyclization methodology (entry 7, Table 2.1), we were interested in how varying the radical 38  acceptors and substitution pattern affected the yields and diastereoselectivity of cyclization products. All studied precursors are listed in Figure 2.1.  Figure 2.1. Cyclization precursors used in the carbocycle formation. 2.2 Preparation of radical relay cyclization precursors      For the preparation of precursors 2.1a, 2.1h, 2.1i and 2.1l, a Mitsunobu reaction was employed to install the N-alkoxyphthalimide (Scheme 2.2). 39   Scheme 2.2. Synthesis of N-alkoxyphthalimides 2.1a, 2.1h, 2.1i and 2.1l.  Scheme 2.3. Synthesis of N-alkoxyphthalimide 2.1d using the Scholloser modification.      Synthesis of 2.1d (a 74:26 mixture of E/Z diastereoisomers) started with monoprotection of diol 2.12 to afford 2.13 in 65% yield (Scheme 2.3). Oxidation of 2.13 followed by a Scholloser modification 70  of Wittig reaction  and deprotection afforded alcohol 2.14. Mitsunobu incorporation of the phthalimide moiety afforded N-alkoxyphthalimide 2.1d.   40   Scheme 2.4. Synthesis of N-alkoxyphthalimide Z-2.1e.      N-Alkoxyphthalimide Z-2.1e was prepared from commercially available diol 2.15 (Scheme 2.4). Monotosylation of diol 2.15 gave 2.16 in 66% yield. A subsequent Swern oxidation and soft enolization provided 2.18 in 50% yield over two steps. Silyl enol ether 2.18 was then transformed to N-alkoxyphthalimide Z-2.1e in 65% yield as a single diastereoisomer by SN2 displacement using N-hydroxyphthalimide as the nucleophile.      Synthesis of E-enriched 2.1e began with the same diol 2.15 as Z-enriched 2.1e (Scheme 2.5). Monodisplacement of a hydroxyl group provided alcohol 2.19. Oxidation of alcohol 2.19 resulted in aldehyde 2.20, which was directly treated with TBSCl and DBU to afford E-enriched 2.1e in 61% yield over two steps. 41   Scheme 2.5. Synthesis of N-alkoxyphthalimide E-2.1e.      N-Alkoxyphthalimide 2.1f was prepared from commercially available δ-valerolactone (Scheme 2.6). Treatment of δ-valerolactone with 3-butenylmagnesum bromide in anhydrous Et2O afforded a ketone alcohol, which was subsequently transformed into 2.1f using a Mitsunobu reaction. Ketone 2.1f was readily converted to 2.1g with ethylene glycol in the presence of p-toluenesulfonic acid.  Scheme 2.6. Synthesis of N-alkoxyphthalimides 2.1f and 2.1g. 42   Scheme 2.7. Synthesis of N-alkoxyphthalimides 2.1j.      Synthesis of 2.1j began with Swern oxidation of 2.22 (Scheme 2.7). A subsequent Wittig olefination 71  followed by deprotection afforded alcohol 2.24. Mitsunobu incorporation of the phthalimide moiety afforded N-alkoxyphthalimide 2.1j as a 65:35 mixture of E/Z diastereoisomers.  Scheme 2.8. Synthesis of N-alkoxyphthalimides 2.1k. 43       Synthesis of 2.1k commenced with monotosylation of diol 2.25 to give 2.26 in 70% yield (Scheme 2.8). A subsequent Swern oxidation and soft enolization provided 2.27 in 88% yield over two steps. Silyl enol ether 2.27 was then transformed into N-alkoxyphthalimide 2.1k in 65% yield as a single diastereoisomer by SN2 displacement using N-hydroxyphthalimide as the nucleophile.      Compounds 2.1b, 2.1c were prepared by Joe Leung (graduate student) and Kayli Johnson (former undergraduate student) in the Sammis group. Compound 2.1d with a 65:35 mixture of E/Z isomers was prepared by Kayli Johnson and 2.1l was prepared by Joe Leung. 2.3 Results and discussion      The cyclization precursors were then subjected to the optimized cyclization conditions (Table 2.2). Overall, the yield range of carbocycles was from 52% to 79%, and the diastereoselectivity was as high as 80:20. Cyclopentane derivative 2.6a was isolated in 79% yield as a 75:25 mixture of cis to trans isomers (entry 1). To investigate the effect of the remote alkyl group on the diastereoselectivity, cyclizations of secondary and tertiary N-alkoxyphthalimides were examined. Cyclization of secondary N-alkoxyphthalimide 2.1b produced 2.6b in 66% yield as a mixture of 80:20 cis to trans isomers (entry 2). Cyclization of tertiary N-alkoxyphthalimide 2.1c provided 2.6c in 64% yield as a ratio of 75:25 cis to trans isomers (entry 3). They all proceeded to a comparable ratio of cyclization product 2.6 and reductive linear alcohol 2.7.      44   Table 2.2. Radical relay 5-exo carbocyclizations.    entry substrate (a)  geometry (E/Z) product (b)  yield (c) %  dr (d)  1  -  79 75:25 2  -  66 80:20 3  -  64 75:25 4  65:35  55 (e)  75:25 5  74:26  52 (e)  78:22 6  5:95  62  65:35 7  70:30  65 75:25 8  -  <5 - 9  -  55 56:44 10  -  71 - (a) Reactions were carried out on >0.25 mmol scale. (b) The relative configuration was determined by nOe experiments. (c) Isolated yields of the mixture of diastereomers after flash chromatography. (d) The diastereomeric ratio was determined by 1H NMR spectroscopy of crude reaction mixtures. (e) The isolated yield corresponds to a two-step cyclization/silylation procedure.      1,5-Hydrogen atom translocation and subsequent cyclizations onto 1,2-disubstituted alkenes were then examined. Cyclization of 2.1d (a 65:35 mixture of E to Z isomers) afforded cyclopentane derivative 2.6d in 55% yield as a 75:25 ratio of cis to trans isomers (entry 4). Next 45  the effect E/Z ratio of the starting material on the cyclization diastereoselectivity was examined. Cyclization of precursor 2.1d with a 74:26 ratio of E to Z isomers provided cyclopentane derivative 2.6d in comparable yield with a slight increase in diastereoselectivity (entry 5) compared to entry 4. The yields of the isolated cyclization products (entries 4 and 5) were relatively low since the two step process involved protection of free alcohols to separate the pure cyclization products from the tin adduct.      Silyl enol ethers 72 functioning as different acceptors could be used to broaden the synthetic utility of the radical relay cyclization methodology as the cyclization product provides protected alcohols, which could be used as a handle for further synthetic transformations. Z-Enriched silyl enol ether 2.1e (entry 6) gave cyclopentane derivative 2.6e in 62% yield as a 65:35 mixture of cis to trans diastereoisomers, while E-enriched silyl enol ether 2.1e (entry 7) provided cyclopentane derivative 2.6e in a comparable yield and slightly higher diastereoselectivity (cis/trans = 75:25).      Another synthetically versatile functionality in the cyclized products would be a ketone incorporated in the cyclopentane ring. Radical relay cyclization of ketone 2.1f only provided very low yield of cyclopentanone 2.6f (entry 8). However, the protected ketone 2.1g was smoothly transformed to ketal 2.6g in moderate yield as a 56:44 mixture of cis to trans isomers (entry 9). N-Alkoxyphthalimide 2.1h, with an alkyne as an alternative radical acceptor, was readily cyclized to cyclopentane derivative 2.6h with a slightly higher yield compared to most of the alkene acceptors that were investigated (entry 10). 46   Scheme 2.9. Chair-like and boat-like transition states of 5-exo cyclizations.      Computational and experimental studies by Beckwith 73  and Houk 74  showed that the diastereoselectivity of 5-exo radical cyclizations can be predicted by analysis of both chair- and boat-like transition states through minimum transition state energy. According to this Beckwith- Houk model, the diastereoselectivity of simple cyclization products could be rationalized by the use of four possible transition states: chair-like transition states 2.28 and 2.30 and boat-like transition states 2.31 and 2.32 (Scheme 2.9). Of the two chair-like transition states, 2.28 should have lower energy than 2.30 since there is less steric interaction between R and geminal H. Likewise, boat-like transition state 2.31 should be more stable than 2.32 because of the similar steric minimization. Among the four possible transition states, the radical intermediates should react through the more stable transition states to provide final cis-cyclization product 2.29 as the major diastereomer.      The diastereoselectivity difference for the cyclizations of Z-enriched and E-enriched 1,2- disubsituted alkenes can also be explained through the Beckwith-Houk model. The formation of the major cis-product is based on the 5-exo transition states (Scheme 2.10).  For a Z-enriched alkene, transition state 2.34 has higher energy than transition state 2.36, leading to the preferred cis-product formation. Compared to E-enriched alkenes, the lower diastereoselectivity in the 47  cyclization of Z-enriched alkenes (R 1  = Ph, OTBS) can be explained by an additional significant A 1,3  strain between R 1  and H in both chair-like transition states (2.34 and 2.36). This steric interaction should destabilize the transition state and make it closer in energy to the higher- energy boat-like transition state. While there is no such interaction for E-enriched alkenes, the higher diastereoselectivity is expected through transition state 2.35.  Scheme 2.10. Chair-like transition states for the 5-exo cyclization.                48  Table 2.3. Radical relay 6-membered carbocyclizations.     entry substrate (a)  product (b)  yield (c) (%)  dr (d)   1  65 55:45  2  62 66:34 3  58 - 4  64 65:35 (a) Reactions were carried out on >0.25 mmol scale. (b) The relative configuration was determined by nOe experiments.  (c) Isolated yields of the mixture of diastereomers after flash chromatography. (d) The diastereomeric ratio was determined by 1 H NMR spectroscopy of crude reaction mixtures. (e) The isolated yield corresponds to a two-step cyclization/silylation procedure.      We next examined 1,5-hydrogen atom translocation followed by 6-membered ring formation (Table 2.3). Cyclization of homologated N-alkoxyphthalimide 2.1i (Table 2.1, entry 2) provided only a low yield of the cyclized product cyclohexane. Analysis of the crude reaction mixture by 1 H NMR spectroscopy indicated that a 64:36 ratio of the cyclohexane derivative to 9-decen-1-ol was obtained. Presumably, 9-decen-1-ol results from the hydrogen-quench of the radical (2.4) prior to cyclization (Scheme 2.1). The isolation and characterization of pure cyclohexane derivative 2.6i was done by Jason Wickenden, a graduate student in the Sammis’ group. Cyclization of the 1,2-disubstituted alkenes also provided corresponding products. Precursor 2.1j afforded cyclization product 2.6j in 65% yield as a 55:45 mixture of cis to trans diastereoisomers (entry 1). Cyclization of substrate 2.1k containing silyl enol ether as the acceptor afforded 2.6k in 62% yield with cis-product as the major isomer (entry 2). With a simple alkyne as an acceptor, a 58% product was obtained (entry 3). 49       Compared to 1,2-disubstitued olefin 2.1d (Table 2.2, entries 4 and 5), geminal disubstituted alkene 2.1m exclusively generated 6-endo cyclization product 2.6m (Table 2.3, entry 4) in 64% yield and in a moderate 65:35 ratio of trans to cis isomers. Presumably both substrates formed benzyl radical intermediates, which resulted in 5-exo and 6-endo products respectively (Scheme 2.11).  Scheme 2.11. Formation of benzyl radical intermediates during the cyclization of substrates 2.1d and 2.1m.  2.4  Conclusion      We have successfully developed a general approach for the construction of carbocycles from linear simple precursors, utilizing a versatile radical relay cyclization methodology. All 5-exo and 6-exo cyclizations provided major cis products. The major trans product was obtained in a 6- endo cyclization reaction. While the yields of both 5-exo and 6-exo cyclization products were comparable, the diastereoselectivity of 5-exo cyclizations was considerably higher than 6-exo cyclizations. There was a slight increase in diastereoselectivity for the 5-exo cyclizations of the E-enriched substrates compared to Z-enriched analogs. Prior to our work, the yields of carbocycles starting from simple linear precursors were low due to the competing direct hydrogen quench pathway. The work presented in this chapter supports our hypothesis that with 50  slow addition of tributyltin hydride, the intramolecular radical relay cyclization predominated over other competing radical pathways.      The formation of 7-membered ring systems using radical relay cyclizations was limited due to the difficult control of different radical pathways. After successfully synthesizing 5- and 6- membered ring systems, we proposed that the radical relay cyclization methodology may be extended for the synthesis of cycloheptane derivatives through incorporation of suitable functional groups, such as silyl enol ether or phenyl, into precursors, which can increase the selectivity of the desired cyclization pathway.      In summary, we have demonstrated that alkoxy radical-initiated radical relay cyclizations provide a synthetically versatile method for the formation of both 5- and 6-membered carbocycles. The high yields and diastereoselectivity of 5-exo carbocycles have the potential to provide new and reliable methods for use in natural product synthesis.            51  2.5 Experimental 2.5.1 General methods      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. All other solvents were used without further purification. Thin layer chromatography (TLC) was performed on Whatman Partisil K6F UV254 pre-coated TLC plates. Chromatographic separations were effected over Fluka 60 silica gel. The silica gel was basified by stirring with triethylamine prior to packing and then sequentially flushed with the solvent system of choice. All reagents were purchased from commercial sources and used as received. 2.5.2 Instrumentation      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 (IR) spectra were obtained using a Thermo Nicolet 4700 FTIR spectrometer. Proton nuclear magnetic resonance ( 1 H NMR) spectra were recorded using a Bruker AV-300 or AV-400 spectrometer. Carbon nuclear magnetic resonance ( 13 C NMR) spectra were recorded 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 1 H NMR; 77.0 ppm 13 C NMR) or d6-benzene (7.16 ppm 1 H NMR; 128.1 ppm 13 C NMR). High resolution mass spectra (HRMS) were recorded on a Waters/Micromass LCTspectrometer.    52  2.5.3 Synthesis of precursors N-hydroxyphthalimides 2.1 Synthesis of 2.1a       2-(Non-8-enyloxy)isoindoline-1,3-dione (2.1a): To a stirred solution of non-8-en-1-ol (2.15 g, 15.1 mmol) in dry THF (120 mL) was sequentially added triphenylphosphine (6.01 g, 22.6 mmol) and N-hydroxyphthalimide (3.81 g, 22.6 mmol) at 0 °C.  The solution was stirred until the solids had dissolved; at which point diisopropylazodicarboxylate (5.60 mL, 27.2 mmol) was 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 × 50 mL), and the combined organic extracts were washed with NaHCO3 (3 × 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 2.1a as a white crystalline solid (3.78 g, 87%). m.p. 28 - 32 °C; IR (film): 2927, 2855, 1790, 1735, 1467, 1372, 1187, 1127, 1016 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 7.75 - 7.83 (m, 2 H), 7.68 - 7.75 (m, 2 H), 5.74 (ddt, J = 17.1, 10.3, 6.7, 6.7 Hz, 1 H), 4.83 - 5.01 (m, 2 H), 4.15 (t, 2 H, J = 6.7 Hz), 1.95 - 2.05 (m, 2 H), 1.69 - 1.81 (m, 2 H), 1.40 - 1.51 (m, 2 H), 1.27 - 1.39 (m, 7 H); 13 C NMR (125 MHz, CDCl3): δ 163.7, 139.2, 134.5, 129.1, 123.5, 114.3, 78.7, 33.9, 29.2, 28.9, 28.3, 28.1, 25.6; HRESIMS (m/z): calcd. for C17H21NO3Na [M+Na] +  310.3433, found 310.1419.    53  Synthesis of 2.1d, Table 2.1, entry 5       (E)-9-phenylnon-8-en-1-ol (2.14): To a solution of oxalyl chloride (0.96 mL, 1.46 g, 11.5 mmol) in dry CH2Cl2 (30 mL) at –78 °C was added a solution of dimethyl sulfoxide (1.60 mL, 1.78 g, 23.0 mmol) in CH2Cl2 (10 mL) dropwise over 10 min. The solution was allowed to stir for an additional 10 min. A solution of silyl ether 2.13 (2.50 g, 9.59 mmol) in CH2Cl2 (10 mL) was then added dropwise over 10 min and the resulting solution was allowed to stir for 30 min at –78 °C. Triethylamine (6.50 mL, 4.85 g, 47.9 mmol) was added dropwise over 10 min and the solution was stirred for 30 min at –78 °C. The bath removed and the mixture was stirred for another 2 h. The reaction was quenched with H2O (50 mL) and extracted with CH2Cl2 (3 × 20 mL). The combined organics were washed with H2O (30 mL) and brine (30 mL), dried over Na2SO4, and concentrated by rotary evaporation to yield aldehyde as a yellow oil which was used without further purification.      A phenyllithium solution in dibutyl ether (3.84 mL, 5.76 mmol) was added at room temperature dropwise within 15 min to a stirred suspension of commercially available benzyltriphenylphosphonium bromide (2.24 g, 5.76 mmol) in THF (20 mL). The resulting deep- red solution was cooled to –78 °C, and a solution of the crude aldehyde (1.48 mmol) in dry Et2O (20 mL) was added over 5 min. After 15 min of stirring at –78 °C, the reaction mixture was warmed to –20 °C and treated another portion of phenyllithium solution in dibutyl ether (3.84 mL, 5.76 mmol). After the reaction was stirred for 30 min at – 20 °C, MeOH (1.0 mL) was 54  added dropwise. The resulting suspension was stirred for an additional 2 h at room temperature, then H2O (10 mL) was added and the mixture was extracted with Et2O (3 × 20 mL). The combined organic layers were dried over Na2SO4, and concentrated by rotary evaporation to yield phenyl alkene.      The crude phenyl alkene was dissolved in THF (25 mL) and added TBAF (10 mL, 1.0 M in THF, 10 mmol). The solution was to stir 2 h at ambient temperature. The reaction was quenched with H2O (20 mL) and extracted with Et2O (3 × 20 mL). The combined organic layers 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 (3:1 hexanes/EtOAc) to yield alcohol 2.14 as a colorless oil (305 mg, 30%, two steps). IR (film): 3386, 2965, 2921, 2852, 1639, 1456, 1373, 1260, 1108, 1021, 917, 804 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 5.77– 5.88 (m, 1 H), 5.00–5.15 (m, 2 H), 3.80-3.83 (m, 1 H), 3.46 3.52 (m, 4 H), 2.57 (br. s., 1 H), 2.35 (q, J = 6.7 Hz, 2 H), 1.67 - 1.71 (m, 2 H), 1.56 -1.63 (m, 1 H), 1.45 - 1.53 (m, 1 H), 1.19 (d, J = 6.3 Hz, 3 H; 13 C NMR (100 MHz, CDCl3): δ 135.0, 116.5, 71.2, 70.3, 67.7, 36.8, 34.1, 26.4, 23.4; HRMS-ESI (m/z): calcd. for C9H19O2 [M+H]  + 159.1385, found 159.1381.       2-(9-Phenylnon-8-enyloxy)-2H-isoindoline-1,3-dione (2.1d, Table 2.1, entry 5): To a solution of alcohol 2.14 (640 mg, 2.93 mmol) in dry THF (50 mL) was sequentially added triphenylphosphine (1.15 g, 4.39 mmol) and N-hydroxyphthalimide (1.06 g, 4.39 mmol). The solution was stirred until the solids dissolved, at which point diisopropylazodicarboxylate (1.06 g, 5.27 mmol) was added via syringe pump (0.8 mL/h). The resulting yellow solution was 55  allowed to stir overnight at ambient temperature. The reaction was quenched with H2O (25 mL) and extracted with Et2O (3 × 25 mL). The combined organic extracts were dried over Na2SO4 and concentrated using rotary evaporation to yield a yellow oil. The product was purified by flash column chromatography (4:1 hexanes/EtOAc) to yield N-alkoxyphthalimide 2.1d as a white solid (851 mg, 80%, trans:cis = 74:26). m.p. 89 - 91 °C; IR (film): 3506, 3024, 2926, 2854, 2254, 1789, 1732, 1599, 1494, 1467, 1395, 1372, 1274, 1187, 1128, 1082, 1016 cm –1 ; 1 H NMR (400 MHz, CDCl3): δ 7.79 - 7.88 (m, 2 H), 7.71 - 7.78 (m, 2 H), 7.24 - 7.37 (m, 4 H), 7.14 - 7.24 (m, 1 H), 6.34 - 6.44 (m, 1 H), 6.23 (dt, J = 6.8, 15.8 Hz, 0.74 H), 5.63 - 5.70 (m, 0.26 H), 4.17 - 4.24 (m, 2 H), 2.30 - 2.38 (m, 0.59 H), 2.22 (q, J = 6.8 Hz, 1.50 H), 1.74 - 1.86 (m, 2 H), 1.44 - 1.56 (m, 4 H), 1.34 - 1.43 (m, 4 H); 13 C NMR (100 MHz, CDCl3): δ 163.6, 137.9, 134.4, 133.1, 131.1, 129.7, 128.9, 128.7, 128.4, 128.1, 126.7, 126.4, 125.9, 123.4, 78.5, 32.9, 29.8, 29.2, 29.1, 29.1, 29.0, 28.5, 28.1, 28.1, 25.5, 25.4; HRMS-ESI (m/z): calcd. for C23H25NO3Na [M+Na] +  386.1732, found 386.1732. Synthesis of 2.1e, Table 2.1, entry 6       9-Hydroxynonyl 4-methylbenzenesulfonate (2.16): To a solution of 1,9-nonanediol (2.15) (3.80 g, 23.7 mmol), para-toluenesulfonyl chloride (1.81 g, 9.50 mmol) in dry CH2Cl2 (50 mL) was added pyridine (1.87 g, 23.7 mmol) and the solution was stirred overnight. The solution was then concentrated by rotary evaporation and the oil was dissolved in Et2O (150 mL), washed with 2% aqueous HCl (3 × 40 mL), brine (40 mL), dried over Na2SO4, and concentrated by rotary evaporation. The product was purified by flash column chromatography (3:1 hexane/EtOAc) to yield monotosylate 2.16 as a colorless oil (1.97 g, 66%). IR (film): 3385, 56  2929, 2856, 1598, 1465, 1358, 1189, 1176, 1122, 1097, 1035, 1010 cm –1 ; 1 H NMR (400 MHz, CDCl3): δ 7.76 - 7.82 (m, J = 8.2 Hz, 2 H), 7.32 - 7.37 (m, J = 8.1 Hz, 2 H), 4.02 (t, J = 6.5 Hz, 2 H), 3.63 (t, J = 6.6 Hz, 2 H), 2.45 (s, 3 H), 1.63 (quin, J = 6.9 Hz, 2 H), 1.54 (quin, J = 6.8 Hz, 2 H), 1.47 (s, 1 H), 1.20 - 1.37 (m, 10 H); 13 CNMR (100 MHz, CDCl3): δ 144.6, 133.2, 129.8, 127.8, 70.6, 62.9, 32.7, 29.3, 29.2, 28.8, 28.7, 25.6, 25.2, 21.6; HRMS-ESI (m/z): calcd. for C16H26O4NaS [M+Na] +  337.1450, found 337.1450.       9-Oxononyl 4-methylbenzenesulfonate (2.17): To a solution of oxalyl chloride (0.65 mL, 7.63 mmol) in dry CH2Cl2 (30 mL) at –78 °C was added dimethylsulfoxide (1.08 mL, 15.3 mmol) dropwise over 5 min. The solution was stirred at –78 °C for 30 min, then monotosylate 2.16 (2.00 g, 6.36 mmol) in CH2Cl2 (10 mL) was added dropwise over 10 min. The resulting solution was stirred for 30 min. Triethylamine (4.40 mL, 31.8 mmol) was then added and the solution was stirred for 30 min at –78 °C. The bath removed and the mixture was stirred for another 2 h. The reaction was quenched with H2O (20 mL) and extracted with CH2Cl2 (3 × 20 mL). The combined organics were washed with H2O (20 mL) and brine (20 mL), dried over Na2SO4, and concentrated by rotary evaporation and purified by flash column chromatography (3:1 hexane/EtOAc) to yield aldehyde 2.17 as a colorless oil (1.58 g, 80%). IR (film): 2977, 2856, 1706, 1426, 1412, 1358, 1300, 1188, 1173, 1096 cm –1 ; 1 H NMR (400 MHz, CDCl3): δ 9.75 (t, J = 1.7 Hz, 1 H), 7.75 - 7.81 (m, J = 8.2 Hz, 2 H), 7.31 - 7.38 (m, J = 8.2 Hz, 2 H), 4.01 (t, J = 6.5 Hz, 2 H), 2.45 (s, 3 H), 2.41 (td, J = 1.7, 7.3 Hz, 2 H), 1.56 - 1.66 (m, 4 H), 1.23 - 1.34 (m, 8 H); 13 C NMR (100 MHz, CDCl3): δ 202.8, 144.6, 133.2, 129.8, 127.8, 70.6, 43.8, 29.0, 57  28.9, 28.7, 28.6, 25.2, 21.9, 21.6; HRMS-ESI (m/z): calcd. for C16H24O4NaS [M+Na] + 335.1293, found 335.1284.       (Z)-9-((tert-Butyldimethylsilyl)oxy)non-8-en-1-yl 4-methylbenzenesulfonate (2.18): To a solution of aldehyde 2.17 (800 mg, 2.56 mmol) in CH2Cl2 (14 mL) at 0 °C was added N,N- diisopropylethylamine (662 mg, 5.12 mmol). To this solution was added tert- butyldimethyltrifluoromethanesulfonate (1.01g, 3.84 mmol) dropwise over 5 min, and the yellow solution was allowed to warm to room temperature and stirred overnight. The reaction was quenched by addition of NaHCO3 (10 mL), extracted with CH2Cl2 (2 × 10 mL). The organic layers were washed with brine (10mL), dried over Na2SO4, concentrated using rotary evaporation, and purified by column chromatography (10:1 hexanes/EtOAc) to yield the title product as a colourless oil (450 mg, 50%). IR (film): 2929, 1639, 1186 cm –1 ; 1 H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 8.4 Hz, 2 H), 7.35 (d, J = 8.0 Hz, 2 H), 6.17 (d, J = 6.0 Hz, 1 H), 4.38 - 4.45 (m, 1 H), 4.02 (t, J = 6.6 Hz, 2 H), 2.45 (s, 3 H), 2.01 - 2.08 (m, 2 H), 1.60 - 1.67 (m, 2 H), 1.22 - 1.34 (m, 8 H), 0.92 (s, 9 H), 0.12 (s, 6 H); 13 C NMR (100 MHz, CDCl3): δ 144.6, 138.5, 133.2, 129.8, 127.9, 110.5, 70.7, 29.5, 29.0, 28.8, 28.8, 25.6, 25.3, 23.5, 21.6, 18.3, -5.4; HRMS-ESI (m/z): calcd. for C26H42NO4Si [M+H] +  460.2883, found 460.2888.   58        (Z)-2-((9-((tert-Butyldimethylsilyl)oxy)non-8-en-1-yl)oxy)isoindoline-1,3-dione (2.1e, Table 2.1, entry 6): To a solution of sulfonate 2.18 (437 mg, 1.01 mmol) in DMF (5 mL) was added N-hydroxyphthalimide (248 mg, 1.51 mmol), diisopropylethylamine (0.35 mL, 2.02 mmol). The solution was heated to 90 °C and stirred for 5 h. The reaction mixture was cooled to room temperature and quenched with H2O (20 mL), extracted with Et2O (3 × 20 mL). The combined organics were washed with H2O (20 mL) and brine (20 mL), dried over Na2SO4, and concentrated by rotary evaporation and purified by flash column chromatography (3:1 hexane/EtOAc) to yield N-alkoxyphthalimide 2.1e as a colorless oil (270 mg, 65%). IR (film): 2942, 2866, 1791, 1736,1654, 1466, 1398,1369, 1258, 1187, 1127, 1092 cm –1 ; 1 H NMR (400 MHz, CDCl3): δ 7.82 - 7.87 (m, 2 H), 7.74 - 7.78 (m, 2 H), 6.17 (d, J = 5.8 Hz, 1 H), 4.41 - 4.48 (m, 1 H), 4.20 (t, J = 6.9 Hz, 2 H), 2.04 - 2.12 (m, 2 H), 1.76 - 1.84 (m, 2 H), 1.44 - 1.52 (m, 2 H), 1.35 (br. s., 6 H), 0.93 (s, 9 H), 0.12 (s, 6 H); 13 C NMR (100 MHz, CDCl3): δ 163.7, 138.4, 134.4, 129.0, 123.5, 110.7, 78.7, 29.6, 29.2, 29.1, 28.1, 25.6, 25.5, 23.5, 18.3, -5.4; HRMS-ESI (m/z): calcd. for C23H35NO4Si [M+Na] +  440.2233, found 440.2230. Synthesis of 2.1e, Table 2.1, entry 7       2-((9-Hydroxynonyl)oxy)isoindoline-1,3-dione (2.19): To a solution of 1,9-nonanediol (2.15) (4.10 g, 25.6 mmol) in regular THF (50 mL) was sequentially added triphenylphosphine 59  (2.68 g, 10.2 mmol) and N-hydroxyphthalimide (1.43 g, 8.53 mmol). The solution was stirred until the solids were dissolved, at which point diisopropylazodicarboxylate (2.06 g, 10.2 mmol) was added via syringe pump (0.8 mL/h). The resulting yellow solution was stirred overnight at ambient temperature, and was then quenched with H2O (20 mL). The aqueous layer was extracted with EtOAc (3 × 50 mL), and the combined organic layers were washed with NaHCO3 (3 × 40 mL), brine (30 mL) and dried over Na2SO4. The organic layers were concentrated using rotary evaporation and purified by flash column chromatography (2:1 hexanes/EtOAc) to provide N-alkoxyphthalimide 2.19 (contaminated with 8% DIAD) as a white solid (1.39 g, 53%). IR (film): 3379, 2929, 2853, 1785, 1727, 1464, 1404, 1376, 1187, 1126, 1056, 1015, 975, 875, 710, 699 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 7.75 - 7.83 (m, 2 H), 7.67 - 7.75 (m, 2 H), 4.15 (t, J = 6.7 Hz, 2 H), 3.59 (t, J = 6.7 Hz, 2 H), 2.00 (s, 1 H), 1.69 - 1.79 (m, 2 H), 1.48 - 1.56 (m, 2 H), 1.39 - 1.48 (m, 2 H), 1.23 - 1.36 (m, 8 H); 13 C NMR (100 MHz, CDCl3): δ 163.6, 134.3, 128.8, 123.3, 78.4, 62.7, 32.6, 29.2, 29.1, 29.0, 28.0, 25.5, 25.3; HRMS-ESI (m/z): calcd. for C17H24NO4 [M+H] + 306.1705, found 306.1704.       2-((9-((tert-Butyldimethylsilyl)oxy)non-8-en-1-yl)oxy)isoindoline-1,3-dione (2.1e, Table 2.1, entry 7): To a solution of oxalyl chloride (0.28 mL, 3.33 mmol) in dry CH2Cl2 (20 mL) at – 78 °C was added dimethylsulfoxide (0.47 mL, 15.3 mmol) dropwise over 5 min. The solution was stirred at –78 °C for 30 min, then monophthilimide 2.19 (850 mg, 2.78 mmol) in CH2Cl2 (10 mL) was added dropwise over 10 min. The resulting solution was stirred for 30 min. Triethylamine (4.40 mL, 31.8 mmol) was then added and the solution was stirred for 30 min at – 60  78 °C. The bath removed and the mixture was stirred for another 2 h. The reaction was quenched with H2O (10 mL) and extracted with CH2Cl2 (3 × 20 mL). The combined organics were washed with H2O (20 mL) and brine (20 mL), dried over Na2SO4, and concentrated by rotary evaporation to yield an aldehyde as a white solid which was used without further purification.      To a solution of the crude aldehyde (200 mg, 0.66 mmol) in CH2Cl2 (6.0 mL) at room temperature was added 1,8-diazabicyclo[5.4.0]undec-7-ene (301 mg, 1.97 mmol). To this solution was added tert-butyldimethylchloride (198 mg, 1.32 mmol) dropwise over 5 min, and the yellow solution was stirred overnight. The mixture was concentrated using rotary evaporation, and purified by flash chromatography (10:1 hexanes/EtOAc) to yield the title product as a colourless oil (167 mg, 61% two steps). IR (film): 2942, 2866, 1791, 1736, 1654, 1466, 1398, 1369, 1258, 1187, 1127, 1092 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 7.81 - 7.87 (m, 2 H), 7.72 - 7.78 (m, 2 H), 6.22 (d, J = 12 Hz, 0.7 H, trans), 6.17 (d, J = 6.0 Hz, 0.3 H, cis), 4.97 - 5.02 (m, 0.7 H), 4.41- 4.46 (m, 0.3 H), 4.20 (t, J = 6.8 Hz, 1 H), 2.05 - 2.08 (m, 0.64 H), 1.85 - 1.93 (m, 1.46 H), 1.75 - 1.84 (m, 2 H), 1.43 - 1.53 (m, 2 H), 1.33 (m, 6 H), 0.92 (s, 9 H), 0.13 (s, 6 H); 13 C NMR (100 MHz, CDCl3): δ 163.7, 140.0, 138.4, 134.4, 129.0, 126.6, 123.5, 111.6, 78.6, 30.3, 29.6, 29.1, 28.9, 28.1, 27.2, 25.7, 25.6, 25.5, 23.5, 18.3, 18.3, -5.2, -5.4; HRMS-ESI (m/z): calcd. for C15H36NO3Si [M+H] + 418.2418, found 418.2418. Synthesis of 2.1f       2-(5-Oxonon-8-enyloxy)isoindoline-1,3-dione (2.1f): 3-Butenylmagnisum bromide (50 mL, 25 mmol) was added dropwise (30 min) to a solution of tetrahydro-2H-pyran-2-one (2.26 mL, 25 61  mmol) in anhydrous Et2O (50 mL) at –78 °C under N2. The mixture was stirred at the same temperature for 1 h and NH4Cl (50 mL) was added. The mixture was extracted with Et2O (3 × 50 mL) and the combined organic layers were washed with water and brine and dried over anhydrous Na2SO4, filtered, and concentrated to give the corresponding hydroxyketone.     Triphenylphosphine (7.21 g, 27.5 mmol) and N-hydroxyphthalimide (4.48 g, 27.5 mmol) were added to a stirred solution of the crude hydroxyketone in dry THF (150 mL) at 0 °C, followed by the addition of DIAD (5.81 mL, 30.0 mmol) by syringe pump at a rate of 0.81 mL/h. The resulting yellow solution was allowed to stir overnight, then was quenched with H2O (50 mL) and extracted with EtOAc (3 × 100mL). The combined organic layers were washed with NaHCO3 and brine, dried over Na2SO4 and concentrated to give a thick yellow oil. Purification by flash chromatography (4:1 hexanes/EtOAc) yielded the title product as a white crystalline product (4.67 g, 62% yield over two steps.). m.p. 43 - 45 °C; IR (film): 2950, 1789, 1731, 1467, 1373, 1187, 1129, 1082, 982, 877, 702 cm -1 ; 1 H NMR (400 MHz, CDCl3):  7.8 - 7.9 (m, 2H), 7.7 - 7.8 (m, 2H), 5.8 (dddd, J = 17.0, 10.3, 6.6, 6.5 Hz, 1H), 4.9 - 5.1 (m, 2H), 4.2 - 4.3 (t, J = 6.6 Hz, 2H), 2.5 - 2.6 (m, 4H), 2.3 (m, 2H), 1.7 - 1.9 (m, 2H); 13 C NMR (100 MHz, CDCl3):  209.6, 163.5, 137.0, 134.4, 128.8, 123.4, 115.1, 78.0, 41.9, 41.7, 27.7, 27.4, 19.8; HRMS-ESI (m/z): calcd. for C36H35NO5Na [M+Na] + 324.1314, found 324.1311. Synthesis of 2.1g       2-(4-(2-(But-3-enyl)-1,3-dioxolan-2-yl)butoxy)isoindoline-1,3-dione (2.1g): A solution of ketone 2.1f (220 mg, 0.73 mmol), ethylene glycol (0.12 mg, 2.20 mmol) and a catalytic amount 62  of p-TsOH in toluene (13 mL) was heated at reflux under N2 overnight with a Dean and Stark apparatus. Saturated sodium bicarbonate was added, and the mixture was extracted with diethyl ether. The combined ethereal layers were washed with aqueous NaHCO3 (10%) and brine, dried, filtered, and concentrated by rotary evaporation to give a clear oil. Purification by flash chromatography (4:1 hexanes/EtOAc) gave ketal 2.1g as an oil (189 mg, 75%): IR (film): 2923, 2360, 1731, 1639, 1466, 1127, 1017, 982 cm -1 ; 1 H NMR (400 MHz, CDCl3):  7.8 - 7.9 (m, 2H), 7.7 - 7.8 (m, 2H), 5.7 - 5.9 (dddd, J = 17.0, 10.3, 6.5, 6.5 Hz, 1H), 4.9 - 5.1 (m, 2H), 4.2 (t, J = 6.6 Hz, 2H), 3.9 (s, 4H), 2.0 - 2.2 (m, 2H), 1.8 - 1.9 (m, 2H), 1.6 - 1.8 (m, 4H), 1.5 - 1.6 (m, 2H).; 13 C NMR (75 MHz, CDCl3):  163.8, 138.8, 134.6, 129.1, 123.7, 114.4, 111.4, 78.5, 65.2, 37.0, 36.5, 28.5, 28.3, 20.2; HRMS-ESI (m/z): calcd. for C36H35NO5Na [M+Na] +  368.1474, found 368.1470. Synthesis of 2.1h       2-(Non-8-yn-1-yloxy)isoindoline-1,3-dione (2.1h): To a stirred solution of non-8-yn-1-ol (2.09) (1.1 g, 7.8 mmol) in dry THF (60 mL) was sequentially added triphenylphosphine (3.07 g, 11.7 mmol) and N-hydroxyphthalimide (1.91 g, 11.7 mmol) at 0 °C.  The solution was stirred until the solids had dissolved. Diisopropylazodicarboxylate (2.75 mL, 14.1 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 × 50 mL), and the combined organic extracts were washed with NaHCO3 (4 × 50 mL), brine (50 mL) and were dried over Na2SO4. The organic layer was concentrated using rotary evaporation and purified by flash column chromatography (10:1 63  hexanes/EtOAc) to provide N-alkoxyphthalimide 2.1h as a white crystalline solid (3.78 g, 87%, containing 0.17g EtOAc). IR (film): 3282, 2930, 2852, 1795, 1721, 1469, 1365, 1252, 1191, 1121, 982, 873, 708 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 7.79 - 7.85 (m, 2 H), 7.71 - 7.77 (m, 2 H), 4.19 (t, J = 6.7 Hz, 2 H), 2.18 (td, J = 7.0, 2.7 Hz, 2 H), 1.93 (t, J = 2.7 Hz, 1 H), 1.74 - 1.83 (m, 2 H), 1.47 - 1.58 (m, 4 H), 1.36 - 1.46 (m, 4 H); 13 C NMR (125 MHz, CDCl3): δ 163.6, 134.4, 129.0, 123.4, 84.6, 78.5, 68.1, 28.7, 28.5, 28.3, 28.0, 25.4, 18.3; HRESIMS (m/z): calcd. for C17H19NO3Na [M+Na] +  308.1263, found 308.1267. Synthesis of 2.1i       2-(Dec-9-en-1-yloxy)isoindoline-1,3-dione (2.1i): To a stirred solution of dec-9-en-1-ol (2.10) (1.70 g, 10.8 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. Diisopropylazodicarboxylate (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 × 50 mL), and the combined organic extracts were washed with NaHCO3 (4 × 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 2.1i as a white crystalline solid (3.25 g, 86%). m.p. 30 - 33 °C; 1 H NMR (300 MHz, CDCl3): δ 7.72 - 7.79 (m, 2 H), 7.65 - 7.72 (m, 2 H), 5.73 (ddt, J = 17.0, 10.3, 6.7, 6.7 Hz, 1 H), 4.79 – 4.98 (m, 2 H), 4.13 (t, J = 6.7 Hz, 2 H), 1.97 (q, J = 64  6.7 Hz, 1 H), 1.65 - 1.77 (m, 2 H), 1.37 - 1.48 (m, 2 H), 1.14 - 1.36 (m, 9 H); 13 C NMR (75 MHz, CDCl3): δ 163.7, 139.2, 134.5, 129.1, 123.6, 114.3, 78.7, 33.9, 29.4, 29.0, 28.5, 28.3, 28.2, 25.6. HRESIMS (m/z): calcd. for C18H23NO3Na [M+Na] +  324.1576, found 324.1580. Synthesis of 2.1j       2-((10-Phenyldec-9-en-1-yl)oxy)isoindoline-1,3-dione (2.1j): To a solution of oxalyl chloride (0.93 mL, 1.38 g, 10.9 mmol) in dry CH2Cl2 (20 mL) was added dimethylsulfoxide (1.54 mL, 1.70 g, 21.8 mmol) in CH2Cl2 (9 mL) dropwise over 5 min at –78 °C. The mixture was stirred at same temperature for additional 30 min then 10-((tert-butyldimethylsilyl)oxy)decan-1- ol 2.22 (1.5 g, 5.46 mmol) in CH2Cl2 (10 mL) was added dropwise over 5 min and the solution was stirred for additional 30 min. Triethylamine (6.07 mL, 4.41 g, 43.6 mmol) was added slowly. The resulting mixture was warmed to ambient temperature slowly and stirred overnight. The reaction was quenched by addition of H2O (50 mL) and extracted with CH2Cl2 (3 × 40mL). The combined organic layers were washed with brine (30mL), dried over Na2SO4, concentrated by rotary evaporation to give the title compound as a colourless oil which was used for the next step without further purification. 65       To a solution of benzyltriphenylphosphonium bromide (4.73 g, 10.9 mmol) in THF (25 mL) at –78 °C was added nBuli (6.82 mL, 1.6 M in THF, 10.9 mmol). The mixture was allowed to warm to ambient temperature and stirred for 1 h. The reaction was cooled to 0 °C and then aldehyde in THF (5 mL) was added. The resulting mixture was allowed to warm to ambient temperature and was heated to reflux overnight.  The reaction was quenched with saturated aqueous NH4Cl (50 mL) and extracted with Et2O (3 × 25 mL). The combined organics were dried over Na2SO4 and concentrated by rotary evaporation to yield silyl ether 2.23 as a colorless oil (1.52 g, 80% over two steps). 1 H NMR (400 MHz, C6D6): δ 7.29 - 7.36 (m,  3.66 H), 7.08 - 7.22 (m, 1.38 H), 6.36 - 6.43 (m, 0.96), 6.20 - 6.27 (m, 0.55 H), 5.64 - 5.70 (m, 0.47 H), 3.58 - 3.64 (m, 2 H), 2.32 - 2.34 (m, 1 H), 2.18 - 2.24 (m, 1 H), 149 - 1.52 (m, 4 H), 1.25 - 1.35 (m, 8 H), 0.91 (s, 9 H), 0.06 (s, 6 H); 13 C NMR (125 MHz, C6D6): δ 135.3, 131.2, 129.7, 128.7, 128.7, 128.5, 128.1, 126.7, 126.4, 125.9, 63.3, 33.0, 32.9, 31.6, 30.0, 29.5, 29.5, 29.4, 29.4, 29.3, 29.2, 28.6, 26.0, 25.8, 22.7, 18.4, 14.1, -5.3.      To a stirring solution of silyl ether 2.23 (1.5 g, 4.3 mmol) in THF (25 mL) was added TBAF (12.9 mL, 1.0 M in THF, 12.9 mmol), and the solution was stirred overnight at ambient temperature. The reaction was quenched with H2O (20 mL) and extracted with Et2O (3 × 20 mL). The combined organic layers 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 (4:1 then 1:1 hexanes/EtOAc) to yield alcohol 2.24 as a colorless oil (920 mg, 92%). 1 H NMR (400 MHz, CDCl3): δ 7.27 - 7.38 (m, 4 H), 7.16 - 7.25 (m, 1 H), 6.36 - 6.44 (m, 1 H), 6.19 - 6.28 (m, 0.66 H), 5.67 (dt, J = 11.7, 7.3 Hz, 0.32 H), 3.60 - 3.69 (m, 2 H), 2.33 (qd, J = 7.4, 1.7 Hz, 0.67 H), 2.18 - 2.25 (m, 1.67 H), 1.54 - 1.63 (m, 2 H), 1.41 - 1.51 (m, 2 H), 1.32 - 66  1.39 (m, 8 H); 13 C NMR (100 MHz, CDCl3): δ 133.2, 131.1, 129.7, 128.7, 128.4, 126.7, 126.4, 125.9, 63.2, 29.9, 29.4, 29.4, 29.4, 29.3, 29.2, 29.1, 28.6, 25.7, 25.7.      To a solution of alcohol 2.24 (890 mg, 3.83 mmol) in THF (50 mL) was sequentially added triphenylphosphine (1.51 g, 5.74 mmol) and N-hydroxyphthalimide (936 mg, 5.74 mmol). The solution was stirred until the solids were dissolved, at which point diisopropylazodicarboxylate (1.42 mL, 1.39 g, 6.89 mmol) was added via syringe pump (0.80 mL/h). The resulting yellow solution was stirred overnight at ambient temperature, and was then quenched with H2O (30 mL). The aqueous layer was extracted with EtOAc (3 × 30 mL), and the combined organic layers were washed with NaHCO3 (3 × 30 mL), brine (30 mL) and were dried over Na2SO4. The organics were concentrated using rotary evaporation and purified by flash column chromatography (4:1 hexanes/EtOAc) to provide N-alkoxyphthalimide 2.1j as a colorless oil (1.70 g, 90%). IR (film): 2926, 2860, 1795, 1743, 1473, 1369, 1195, 1126, 978, 882, 704 cm -1 ; 1 H NMR (400 MHz, CDCl3) δ 7.81 - 7.87 (m, 2 H), 7.71 - 7.78 (m, 2 H), 7.25 - 7.37 (m, 4 H), 7.16 - 7.22 (m, 1 H), 6.35 - 6.44 (m, 1 H), 6.19 - 6.42 (m, 0.63 H), 5.64 - 5.70 (m, 0.34 H), 4.18 - 4.23 (m, 2 H), 2.29 - 2.37 (m, 0.68 H), 2.16 - 2.26 (m, 1.23 H), 1.75 - 1.84 (m, 2 H), 1.43 - 1.55 (m, 4 H), 1.30 - 1.41 (m, 6H); 13 C NMR (100 MHz, CDCl3): δ 163.8, 134.6, 133.3, 130.0, 129.2, 128.89, 128.6, 128.2, 126.9, 126.6, 126.1, 123.6, 78.8, 33.1, 30.1, 29.5, 29.4, 29.3, 28.8, 28.3, 25.7, 25.7; HRMS-ESI (m/z): calcd. for C24H27NO3Na [M+Na] +  400.1889, found 400.1880.      67  Synthesis of 2.1k       10-((tert-Butyldimethylsilyl)oxy)dec-9-en-1-yl 4-methylbenzenesulfonate (2.27): To a solution of oxalyl chloride (0.62 mL, 0.93 g, 7.31 mmol) in dry CH2Cl2 (35 mL) was added dimethylsulfoxide (1.30 mL, 1.43 g, 14.6 mmol) dropwise over 5 min at –78 °C. The solution was stirred at same temperature for additional 30 min then 10-Hydroxydecyl 4- methylbenzenesulfonate (2.26) (2.00 g, 6.09 mmol) in CH2Cl2 (5 mL) was added dropwise over 5 min. The solution was stirred for additional 90 min. Triethylamine (3.15 mL, 22.4 mmol) was added slowly. The resulting mixture was warmed to ambient temperature slowly and stirred overnight. The reaction was quenched by addition of H2O (100 mL) and extracted with CH2Cl2 (3 × 40 mL). The combined organic layers were washed with brine (30mL), dried over Na2SO4, concentrated by rotary evaporation to give the title compound as a colourless oil which was used for the next step without further purification.      To a solution of the crude aldehyde in CH2Cl2 (30 mL) at 0 °C was added N,N- diisopropylethylamine (2.10 mL, 1.56 g, 12.1 mmol). To this solution was added triisopropyl trifluoromethanesulfonate (2.80 g, 9.13 mmol) dropwise over 5 min, and the solution was stirred overnight at 0 °C. The reaction was quenched by addition of NaHCO3 (10 mL), extracted with CH2Cl2 (2 × 20 mL). The organic layers were washed with brine (20 mL), dried over Na2SO4, concentrated using rotary evaporation, and purified by column chromatography (4:1 hexanes/EtOAc) to yield the title product as a colourless oil (2.59 g, 88% over two steps). IR (film): 2926, 2852, 1708, 1356, 1178, 1195, 947, 817, 665 cm -1 ; 1 H NMR (400 MHz, C6D6): δ 68  7.80 (d, J = 8.2 Hz, 2 H), 7.35 (d, J = 8.5 Hz, 2 H), 6.24 - 6.29 (m, 0.94 H), 4.97 - 5.02 (m, 0.09 H), 4.34 -  4.41 (m, 0.94 H), 4.03 (t, J = 6.4 Hz, 2 H), 2.45 (s, 3 H), 2.0 - 2.11 (m, 2 H), 1.60 - 1.66 (m, 3 H), 1.20 - 1.32 (m, 12 H), 1.09 (s, 18 H); 13 C NMR (100 MHz, C6D6): δ 144.4, 139.1, 135.0, 129.9, 128.0, 110.0, 70.9, 29.7, 29.4, 29.3, 29.1, 29.0, 25.5, 23.7, 17.9, 17.8, 12.5, 12.1; HRMS-ESI (m/z): calcd. for C26H47O4SSi [M+H] +  483.2964, found 483.2957.       2-((10-((tert-Butyldimethylsilyl)oxy)dec-9-en-1-yl)oxy)isoindoline-1,3-dione (2.1k): To a solution of silyl enol ether 2.27 (2.38 g, 4.90 mmol) and N-hydroxyphthalimide (1.20 g, 7.35 mmol) in DMF (15 mL) was added diisopropylethylamine (1.70 mL, 1.29 g, 9.80 mmol). The resulting mixture was then heated to 90 °C and stirred for 5 h. The solution was cooled to room temperature. The reaction was quenched with H2O (10 mL), extracted with Et2O (40 mL). The combined organic layers were washed with H2O (10 mL), NaHCO3 (3 × 20 mL), brine (20 mL) and dried over Na2SO4. The organic layer was filtered and concentrated by rotary evaporation. The product was purified by flash column chromatography (4:1 hexanes/EtOAc) to yield title compound as a colorless oil (1.5 g, 65%). IR (film): 2943, 2856, 1791, 1734, 1647, 1469, 1400, 1365, 1252, 1186, 1134, 1086, 1021, 986, 882, 708 cm –1 ; 1 H NMR (400 MHz, CDCl3): δ 7.83 (dd, J = 5.5, 3.1 Hz, 2 H), 7.71 - 7.77 (m, 2 H), 6.23 - 6.28 (m, 1 H), 4.34 - 4.42 (m, 1 H), 4.19 (t, J = 6.8 Hz, 2 H), 2.05 - 2.13 (m, 2 H), 1.73 - 1.84 (m, 2 H), 1.41 - 1.51 (m, 2 H), 1.26 - 1.36 (m, 8 H), 1.08 (s, 18 H); 13 C NMR (100 MHz, CDCl3): δ 163.8, 139.0, 134.5, 129.2, 123.6, 110.1, 78.8, 29.8, 29.5, 29.4, 29.1, 28.3, 25.7, 23.7, 17.9, 12.5; HRMS-ESI (m/z): calcd. for C27H43NNaO4Si [M+H] +  496.2859, found 96.2850. 69  Synthesis of 2.1l       2-(Non-8-yn-1-yloxy)isoindoline-1,3-dione (2.1l): To a stirred solution of dec-9-yn-1-ol (2.11) (1.0 g, 6.48 mmol) in dry THF (60 mL) was sequentially added triphenylphosphine (2.55 g, 9.72 mmol) and N-hydroxyphthalimide (1.58 g, 9.72 mmol) at 0 °C. The solution was stirred until the solids had dissolved. Diisopropylazodicarboxylate (2.20 mL, 11.5 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 × 50 mL), and the combined organic layers were washed with NaHCO3 (3 × 50 mL), brine (50 mL) and dried over Na2SO4. The organics were concentrated using rotary evaporation and purified by flash column chromatography (10:1 hexanes/EtOAc) to provide N-alkoxyphthalimide 2.1l as a white crystalline solid (1.77 g, 85%). IR (film): 3282, 2934, 2860, 1800, 1726, 1460, 1369, 1195, 1134, 978, 786, 700 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 7.78 - 7.86 (m, 2 H), 7.70 - 7.77 (m, 2 H), 4.18 (t, J = 6.8 Hz, 2 H), 2.17 (td, J = 7.0, 2.7 Hz, 2 H), 1.93 (t, J = 2.7 Hz, 1 H), 1.73 - 1.82 (m, 2 H), 1.43 - 1.57 (m, 4 H), 1.28 - 1.43 (m, 6 H); 13 C NMR (125 MHz, CDCl3): δ 163.6, 134.3, 128.9, 123.4, 84.6, 78.5, 68.1, 29.1, 28.9, 28.6, 28.4, 28.1, 25.4, 18.3; HRESIMS (m/z): calcd. for C18H21NO3Na [M+Na] +  322.1419, found 322.1422. 2.5.4 General cyclization procedures      To a 0.02 M solution of cyclization precursor in degassed benzene at reflux was added a 0.2 M solution of tributyltin hydride (1.2 equiv) and AIBN (0.15 equiv) in degassed benzene by syringe pump (0.4 mL/h). The reaction was then stirred for an additional 2 h at reflux. The 70  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 and linear alcohols as a colorless oil. The product mixture was then dissolved in CH2Cl2 (0.3 M) and cooled to 0 °C. m-CPBA (3 equiv) was added in one portion. The resulting mixture was allowed to warm to ambient temperature and stirred overnight. The reaction was quenched with 2.0 M Na2S2O3 (10 mL), washed with saturated aqueous Na2CO3 (3 × 5 mL), H2O (5 mL), dried over Na2SO4, and concentrated by rotary evaporation. The cyclized products were purified by flash column chromatography. The relative configuration of the cyclized products was determined using nOe experiments and the major diastereomer is shown.       3-(2-Methylcyclopentyl)propan-1-ol (2.6a): N-Alkoxyphthalimide 2.1a (550 mg, 1.30 mmol) was subjected to the general cyclization procedure. Purification by flash chromatography (10:1 hexanes/EtOAc) gave 262 mg (79%) of 2.6a (cis:trans = 75:25) as a colorless oil. IR (neat) 3405, 2951, 2927, 1646, 1057 cm -1 ; 1 H NMR (400 MHz, CDCl3):  3.68 (t, J = 6.6 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 = 6.6 Hz ,0.7 H, trans), 0.81 (d, J = 7.1 Hz, 2.3 H, cis); 13 C NMR (100 MHz, CDCl3):  63.2, 47.4, 43.1, 40.6, 35.9, 34.7, 33.4, 32.3, 32.0, 31.7, 30.7, 29.6, 26.5, 23.4, 22.4, 19.3, 14.7; HRMS-ESI (m/z): calcd. for [M+H] +  143.1436, found 143.1434.  71        (3-(2-Benzylcyclopentyl)propoxy)(tert-butyl)dimethylsilane (2.6d, Table 2.1, entry 5): N- Alkoxyphthalimide 2.1d (230 mg, 0.63 mmol) was subjected to the general cyclization procedure. The crude mixture in CH2Cl2 (20 mL) was sequentially added triethylamine (202 mg, 2.0 mmol) and methyldiphenylsilyl chloride (218 mg, 0.94 mmol) and stirred overnight. The solvent was evaporated and the residue was dissolved in Et2O (20 mL). The organic layer was washed with NaHCO3 (10 mL), brine (10 mL) and dried over Na2SO4, concentrated using rotary evaporation. The crude product was purified using flash column chromatography (20:1 hexanes/EtOAc) to afford tetrahydrofuran 2.6d as a colorless oil (160 mg, 55%, two steps, cis:trans = 78:22). IR (film): 2960, 2869, 1430, 1369, 1256, 1121, 1069, 1004, 800, 739, 700 cm - 1 ; 1 H NMR (400 MHz, CDCl3): δ 7.26 - 7.32 (m, 2 H), 7.15 - 7.22 (m, 3 H), 3.65 (t, J = 6.5 Hz, 1.56 H), 3.61 (t, J = 6.5 Hz, 0.44 H), 2.86 (dd, J = 4.6, 13.2 Hz, 0.22 H), 2.76 (dd, J = 4.6, 13.2 Hz, 0.78 H), 2. 38 (dd, J = 4.6, 13.2 Hz, 0.22 H), 2.23 - 2.35 (m, 0.78 H), 2.13 - 2.23 (m, 0.78 H), 1.10 - 1.80 (m, 10.21 H), 0.93 (s, 9 H), 0.09 (s, 6 H); 13 C NMR (100 MHz, CDCl3): δ 142.5, 128.9, 128.1, 128.1, 125.5, 125.4, 63.6, 63.6, 47.7, 45.3, 44.2, 42.8, 41.2, 35.3, 32.1, 32.1, 32.0, 31.7, 31.1, 30.1, 29.7, 26.0, 26.0, 23.5, 22.2, 18.4, -5.2; HRMS-ESI (m/z): calcd. for C15H22O [M+Na] +  355.2433, found 355.2430.   72        33-(2-(((tert-Butyldimethylsilyl)oxy)methyl)cyclopentyl)propan-1-ol (2.6e, Table 2.1, entry 6): N-Alkoxyphthalimide 2.1e (150 mg, 0.35 mmol) was subjected to the general cyclization procedure. Purification by flash column chromatography (4:1 hexanes/EtOAc) afforded 2.6e as a colorless oil (62 mg, 62%, cis:trans = 65:35).  1 H NMR (400 MHz, CDCl3): δ 3.70 - 3.57 (m, 2.60 H), 3.54 (dd, J = 5.8, 9.9 Hz, 0.34 H), 3.50 - 3.38 (m, 1.03 H), 2.13 - 2.00 (m, 0.64 H), 1.79 - 1.49 (m, 9.57 H), 1.41 - 1.19 (m, 3.05 H), 0.9 (s, 9 H), 0.04 (s, 6 H);      33-(2-(((tert-Butyldimethylsilyl)oxy)methyl)cyclopentyl)propan-1-ol (2.6e, Table 2.1, entry 7): N-Alkoxyphthalimide 2.1e (150 mg, 0.35 mmol) was subjected to the general cyclization procedure. Purification by flash column chromatography (4:1 hexanes/EtOAc) afforded 2.6e as a colorless oil (62 mg, 62%, cis:trans = 75:25). IR (neat): 3381, 2934, 2869, 1608, 1500, 1460, 1386, 1352, 1256, 1065, 1021, 800, 752, 704 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 3.67 - 3.58 (m, 2.72 H), 3.54 (dd, J = 5.8, 9.9 Hz, 0.32 H), 3.48 - 3.42 (m, 0.96 H), 2.13 - 2.00 (m, 0.75 H), 1.95 - 1.42 (m, 9.60 H), 1.41 - 1.13 (m, 0.65 H), 0.89 (s, 9 H), 0.04 (s, 6 H); 13 C NMR (100 MHz, CDCl3): δ 66.6, 63.4, 63.3, 63.3, 47.9, 44.3, 41.9, 41.6, 32.8, 32.1, 31.8, 31.7, 31.0, 29.3, 28.1, 25.9, 25.9, 25.8, 24.4, 22.9, 18.3, 18.3, -5.3, -5.4; HRMS-ESI (m/z): calcd. for C15H32O2NaSi [M+Na] +  295.2069, found 295.2067.   73        3-(2-methyl-5-(1,3-dioxolan-2-yl)-cyclopentyl)propan-1-ol (2.6g): N-Alkoxyphthalimide 2.1g (550 mg, 1.30 mmol) was subjected to the general cyclization procedure. Purification by flash chromatography (10:1 hexanes/EtOAc) gave 262 mg (55%) of cyclopentane 2.6g (cis:trans = 56:44) as a colorless oil. IR (neat) 3420, 2947, 2921, 1455, 1023 cm -1 ; 1 H NMR (400 MHz, CDCl3):  3.77 - 3.92 (m, 4 H), 3.58 - 3.64 (m, 2 H), 2.14 - 2.23 (m, 2.8 H), 1.92 - 1.98 (m, 0.58 H), 1.72 - 1.86  (m, 2.67 H), 1.57 - 1.68 (m, 2.66 H), 1.46 - 1.54 (m, ,1.33 H), 1.30 - 1.43 (m, 2H), 1.15 - 1.25 (m, ,0.67 H), 1.01 (d, J = 6.5 Hz, 1.32 H, trans), 0.88 (d, J = 7.2 Hz, 1.68 H, cis); 13 C NMR (100 MHz, CDCl3):  118.7, 118.4, 64.9, 64.5, 64.0, 63.9, 63.4, 63.3, 52.8, 49.4, 38.4, 35.9, 35.5, 33.8, 31.6, 31.3, 30.7, 30.0, 24.6, 20.6, 20.5, 15.3; HRMS-ESI (m/z): calcd. for C36H35NO5Na [M+Na] +  223.1310, found 223.1306.       3-(2-benzylcyclohexyl)propan-1-ol (2.6j): N-Alkoxyphthalimide 2.1j (377 mg, 1.00 mmol) was subjected to the general cyclization procedure. Purification by flash column chromatography (4:1 hexanes/EtOAc) afforded cyclohexane 2.6j as a colorless oil (150 mg, 65%, cis:trans = 55:45). IR (film): 3347, 2952, 2839, 1608, 1504, 1447, 1369, 1265, 1060, 813, 743, 695 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 7.25 - 7.31 (m 2 H), 7.13 - 7.22 (m, 3 H), 3.64 - 3.69 (m, 2 H), 3.06 (dd, J = 13.4, 3.8 Hz, 0.50 H), 2.83 (dd, J = 12.0, 4.0 Hz, 0.04 H), 2.75 (dd, J = 12.0, 4.0 Hz, 0.09 H), 2.62 (dd, J = 13.5, 5.5 Hz, 0.44 H), 2.52 (dd, J = 13.4, 10.0 Hz, 0.50 H), 2.41 (dd, J = 74  12.0, 4.0 Hz, 0.07 H), 2.29 (dd, J = 12.0, 4.0 Hz, 0.12 H), 2.19 (dd, J = 13.3, 9.7 Hz, 0.54 H), 1.77 - 1.92 (m, 1 H), 1.50 - 1.74(m, 6 H), 1.28 - 1.47 (m, 5 H), 0.98 - 1.26 (m, 2 H); 13 C NMR (100 MHz, CDCl3): δ 141.9, 141.6, 129.2, 129.0, 128.9, 128.8, 128.1, 128.1, 125.1, 125.4, 63.5, 63.3, 63.1, 63.0, 44.1, 43.2, 42.9, 41.5, 41.1, 40.1, 38.8, 35.5, 35.3, 33.1, 31.6, 31.4, 30.7, 30.0, 29.8, 29.7, 29.5, 29.5, 28.4, 27.7, 26.1, 25.9, 24.7, 23.7, 23.2, 23.2; HRMS-ESI (m/z): calcd. for C16H24ONa [M+Na] +  255.1725, found 255.1727.        3-(2-(((Triisopropylsilyl)oxy)methyl)cyclohexyl)propan-1-ol (2.6k): N-Alkoxyphthalimide 2.1k (444 mg, 0.94 mmol) was subjected to the general cyclization procedure. Purification by flash column chromatography (4:1 hexanes/EtOAc) afforded tetrahydrofuran 2.6k as a colorless oil (192 mg, 62%, cis:trans = 73:27). IR (film): 3339, 2943, 2856, 1665, 1378, 1117, 1060, 1004, 873, 795, 682 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 3.54 - 3.72 (m, 4 H), 1.61 - 1.80 (m, 7.38 H), 1.43 - 1.56 (m, 2.18), 1.24 - 1.42 (m, 4.01 H), 1.17 - 1.22 (m, 4.13 H), 1.06 (s, 13.05 H), 1.06 (s, 4.81 H); 13 C NMR (100 MHz, CDCl3): δ 66.0, 64.0, 63.6, 63.2, 44.5, 42.18, 37.9, 31.6, 30.0, 29.7, 29.2, 28.7, 26.3, 26.1, 25.6, 24.2, 23.0, 18.1, 12.0; HRMS-ESI (m/z): calcd. for C19H40O2Na [M+Na] + 351.2682, found 351.2688.    75        3-(2-Methylenecyclohexyl)propan-1-ol (2.6l): N-alkoxyphthalimide 2.1l (90 mg, 0.35 mmol) was subjected to the general cyclization procedure. Purification by flash column chromatography (4:1 hexanes/EtOAc) afforded cyclohexane 2.6l as a colorless oil (35 mg, 71%). IR (film): 3334, 2926, 2834, 1643, 1443, 1056, 900 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 4.66 (s, 1 H), 4.56 (s, 1 H), 3.64 (t, J = 7.7 Hz, 2 H), 2.20 - 2.30 (m, 0.48 H), 2.00 - 2.09 (m, 1.41 H), 1.90 - 1.95 (m, 0.33 H), 1.72 - 1.80 (m, 0.82 H), 1.63 - 1.71 (m, 3.34 H), 1.42 - 1.63 (m, 4.49 H), 1.20 - 1.36 (m, 3.6 H); 13 C NMR (100 MHz, CDCl3): δ 152.7, 105.7, 63.2, 42.9, 34.6, 30.1, 28.8, 28.1, 24.1; HRMS-ESI (m/z): calcd. for C10H19O [M+H] + 155.1436, found 155.1432.    76  Chapter  3: Construction of Oxacycles using Radical Relay Cyclizations      Oxacycles, such as tetrahydropyrans and tetrahydrofurans, have received considerable synthetic attention due to their prevalence in natural products. After the successful application of our radical relay cyclization methodology to the formation of carbocycles (Chapter 2), we turned our attention to the formation of oxacycles. To explore how oxygen atom incorporation in the starting material would influence relay cyclizations, we first synthesized the required precursors with radical acceptors similar to carbon analogs (Figure 3.1).   Figure 3.1. Cyclization precursors used in the oxacycle formation. 3.1 Preparation of radical relay cyclization precursors      Preparation of precursor 3.1b commenced with SN2 displacement of 4-((tert- butyldimethylsilyl)oxy)pentyl 4-methylbenzenesulfonate by alcohol 3.8 to provide ether 3.9 (Scheme 3.1). Treatment of 3.9 with tetrabutylammonium fluoride afforded alcohol 3.10. A subsequent Mitsunobu reaction led to the formation of final N-alkoxyphthalimide 3.1b in 80% yield.  77   Scheme 3.1. Synthesis of N-alkoxyphthalimide 3.1b.  Scheme 3.2. Synthesis of N-alkoxyphthalimide 3.1c.      Preparation of precursor 3.1c began with trityl-protection of known epoxide 3.11 to afford 3.12 (Scheme 3.2). Ring-opening of epoxide 3.12 with vinylmagnesium bromide provided diol 78  3.13. Displacement followed by deprotection afforded alcohol 3.15 in 51% yield over two steps. N-Alkoxyphthalimide was then installed by a Mitsunobu reaction to afford 3.1c in 90% yield.  Scheme 3.3. Synthesis of N-alkoxyphthalimides E-enriched 3.1d.      For the synthesis of precursor 3.1d (an 80:20 ratio of E/Z isomers), we began with SN2 displacement of allyl bromide by monoprotected diol 3.16 (Scheme 3.3). Hydroboration of the resulting ether 3.17 gave 3.18 in 56% yield. Swern oxidation followed by Wittig olefination afforded 1,2-disubstituted alkene 3.19 in 56% yield over two steps. The subsequent deprotection 79  and a Mitsunobu reaction provided desired N-alkoxyphthalimide 3.1d in 81% yield over two steps. For the synthesis of the more E-enriched isomer 3.1d (a 95:5 ratio of E/Z isomer), monoprotected diol 3.21 was subjected to Swern oxidation and Wittig olefination, which afforded alkene 3.22 in 89% yield. Deprotection followed by SN2 displacement gave ether 3.19 in 30% yield over two steps. Desilylation followed by a Mitsunobu reaction resulted in the formation of a 95:5 ratio of E/Z isomers 3.1d in 73% yield over two steps.   Scheme 3.4. Synthesis of N-alkoxyphthalimide Z-enriched 3.1e.      Silyl enol ether 3.1e was synthesized from commercially available alcohol 3.8 (Scheme 3.4). Displacement reaction between 4-(tert-butyldimethylsilyloxy)butyl-4-methylbenzenesulfonate and alcohol 3.8 provided ether 3.25 in 40% yield, which was subsequently hydroborated to afford alcohol 3.26 in 88% yield. Tosylation followed by desilylation, Swern oxidation and soft 80  enolization afforded silyl enol ether 3.28. The subsequent SN2 displacement by N- hydroxyphthalimide provided 3.1e in 75% yield.      Synthesis of 3.1h started with phenol 3.29 (Scheme 3.5). The isolation of pure N- alkoxyphthalimide 3.1h was problematic by a Mitsunobu reaction. A two-step procedure involving tosylation followed by SN2 displacement successfully furnished 3.1h in 75% yield.  Scheme 3.5. Synthesis of N-alkoxyphthalimide 3.1h.      The precursors N-alkoxyphthalimides 3.1g and 3.1i were prepared from the corresponding alcohols (Scheme 3.6), utilizing the same strategy as 3.1d. The substrates 3.1g and 3.1i were obtained in 89% and 90% yield respectively. Substrates 3.1a and 3.1f were synthesized by Jason Wickenden, and 3.1c was originally synthesized by Natalie Campbell and later repeated by me.  Scheme 3.6. Synthesis of N-alkoxyphthalimides 3.1g and 3.1i. 81  3.2 Results and discussion      We began our investigation on the formation of tetrahydrofuran derivatives using the same reaction conditions as in the formation of carbocycles. Gratifyingly, cyclization of N- alkoxyphthalimide 3.1a with a simple alkene as the acceptor afforded tetrahydrofuran 3.6a in 62% yield and with a significantly higher diastereoselectivity compared to the carbon analog (Table 3.1, entry 1). Table 3.1. Radical relay 5-exo oxacyclizations.    entry substrate (a)  geometry (E/Z) product (b)  yield (c) (%)  dr (d)  1  -  62 90:10 2  -  47 (e)  93:7 3 -  64 86:14 (f) 4  80:20  75 85:15 5  95:5  75 89:11 6  45:55  71  70:30 (a) Reactions were carried out on >0.25 mmol scale. (b) The relative configuration was determined by nOe experiments.  (c) Isolated yields of the mixture of diastereomers after flash chromatography. (d) The diastereomeric ratio was determined by 1 H NMR spectroscopy of crude reaction mixtures. (e) The isolated yield corresponds to a two-step cyclization/silylation procedure. (f) The ratio of the cis isomers to all other diastereomers.      Cyclization of secondary alkoxy radical 3.1b provided tetrahydrofuran derivative 3.6b with a high diastereoselectivity (Table 3.1, entry 2). High cyclization diastereoselectivity was also 82  observed with branched substrate 3.1c, which cyclized to form trisubstituted tetrahydrofuran 3.5c in 64% yield and an 86:14 ratio of diastereomers (Table 3.1, entry 3).      We next examined the effect that altering the cyclization acceptor would have on the cyclization diastereoselectivity. In Chapter 2, we studied a cyclization onto a phenyl-substituted alkene (Table 2.1, entry 4), which provided cyclized product 2.6d in a 65:35 ratio of cis to trans cyclopentane isomers. Cyclization of the more E-enriched alkene 2.1d afforded 2.6d in higher diastereoselectivity (cis/trans = 75:25, Table 2.1, entry 5) than the less E-enriched alkene 2.1d (Table 2.1, entry 4). To determine the effects of the E/Z ratio on the cyclization diastereoselectivity for oxygen-containing analogs, we examined cyclizations with similar substrates that have different E/Z ratios (Table 3.1, entries 4 and 5). Similar to cyclization of the carbon substrate 2.1d (Table 2.1, entry 5), the cyclization of oxa-analog 3.1d also provided higher cyclization diastereoselectivity with increased enrichment of the starting E-olefin substrate (Table 3.1, entry 5). Cyclization of oxygen-containing analog 3.1d, with an 80:20 ratio of E to Z isomers, provided tetrahydrofuran derivative 3.6d in an 85:15 ratio of stereoisomers, while analog 3.1d, with a ratio of 95:5 of E/Z isomers, cyclized in an 89:11 ratio of diastereomers. Cyclization onto silyl enol ethers (Table 3.1, entry 6) provided a similar trend as the phenyl substituted derivatives, with increased cyclization diastereoselectivity with oxygen- atom incorporation. Overall, there is an increase in diastereoselectivity with oxygen atom incorporation into the substrate containing 1,2-disubstituted alkenes compared to carbon analogs, but the effect was not as significant as it was for cyclizations onto monosubstituted alkenes.      The increase in the cyclization diastereoselectivity between the carbocycles and the oxa- analogs may be explained using a model based on calculations by Beckwith and Houk. The lowest energy transition states for 5-exo radical cyclizations should be the chair-like transition 83  states depicted in Scheme 3.7. The corresponding boat-like transition states have not been depicted as they are significantly higher in energy than the two chair-like transition states depicted in Scheme 3.7. Transition state 3.36, proceeding to cis-cyclization product 3.37 should have lower energy than transition state 3.34 because orienting R 1  in the pseudo-equatorial position minimizes 1,3-diaxial strain. With an oxygen-atom incorporated in the substrate, the bond lengths in both chair-like transition states (3.38 and 3.40) are shortened. This decreased bond length should not significantly affect transition state 3.40, but should increase the 1,3- diaxial interactions in 3.38. This greater steric interaction between R 1 and the pseudo-axial protons results in a greater relative energy difference between 3.38 and 3.40 and, thus, should provide higher cis selectivity.  Scheme 3.7. Chair-like transition states for 5-exo cyclizations of oxygen-containing substrates.      The difference in diastereoselectivity for the cyclization of E-enriched and Z-enriched oxygen-containing analogs can also be explained based on the 5-exo transition states in Scheme 84  3.7. When the cyclization involves a Z-alkene (Scheme 3.7, R 2  = H, R 3  = Ph, OTBS), there is a significant A 1,3  strain in both chair-like transition states (3.38 and 3.40). This steric interaction should destabilize both of these transition states and make them closer in energy to the higher- energy boat-type transition states, thus leading to lower diastereoselectivity. The difference in bond length due to oxygen atom incorporation will not influence the allylic strain and, therefore, there is less of a difference in selectivity for the oxacycle formation when utilizing Z-enriched alkenes. In contrast, there is higher cis cyclization selectivity for the E-enriched alkenes (Scheme 3.7, R 2  = Ph, R 3  = H), as there is no significant allylic strain in either transition state (3.38 or 3.40). These transition states are still dominated by the differences in sterics of the pseudoaxial substituent (R 1 ) that strongly favors transition state 3.40, which affords cis-substituted isomer 3.41. Table 3.2. Synthesis of tetrahydropyran, benzofuran and benzopyran derivatives.    entry substrate (a)  product (b)  yield (c) (%)  dr (d)  1  41 60:40 2   65 >95:5 3  56 (e)  60:40 4  61 60:40 (a) Reactions were carried out on >0.25 mmol scale. (b) The relative configuration was determined by nOe experiments.  (c) Isolated yields of the mixture of diastereomers after flash chromatography. (d) The diastereomeric ratio was determined by 1 H NMR spectroscopy of crude reaction mixtures. (e) The isolated yield corresponds to a two-step cyclization/silylation procedure. 85       After examining the selectivity for the 5-exo formation of oxygen-containing substrates, we next attempted to utilize this radical relay methodology to form tetrahydropyran, benzofuran and benzopyran ring derivatives. As discussed in Chapter 2, the 6-membered ring formation provided only poor to moderate yields with low cyclization diastereoselectivity. While the formation of tetrahydropyran derivatives was improved compared to carbon analogs, the yields and selectivity were still low (Table 3.2, entry 1). The most significant improvement in diastereoselectivity was obtained in 6-endo cyclizations. Cyclization of the gem-disubstituted alkene 2.1m afforded the corresponding cyclohexane in a moderate 65:35 ratio of trans to cis isomers (Table 2.3, entry 4), while the oxygen-containing analog, precursor 3.1g, cyclized in good yield almost exclusively as the trans-isomer (Table 3.2, entry 2). To further evaluate the applicability of the radical relay cyclization methodology across the aryl ring, 3.1h and 3.1i were examined. The reactions only provided moderate yields and diastereoselectivity for both 5-exo and 6-exo cyclizations (Table 3.2, entries 3 and 4). 3.3 Future work      In Chapters 2 and 3, we demonstrated that our new radical relay cyclization methodology could be utilized to synthesize cyclopentane, cyclohexane, tetrahydrofuran and tetrahydropyran derivatives. We envisaged that our methodology could be extended to the synthesis of pyrrolidine and piperidine derivatives. Jason Wickenden demonstrated that cyclization of N- alkoxyphthalimide 3.42 provided pyrolidine derivative 3.43 in 63% yield (Scheme 3.8). However, cyclization of 3.44 (done by Joe Leung) provided a mixture of 6-exo and 7-endo products. Analysis of isolated products revealed approximately a 1:1 ratio of an inseparable mixture of 6-exo (3.45) and 7-endo (3.46) products. To broaden the synthetic utility, there needs to be an increase of the chemoselectivity for the final cyclization product. This is a challenging 86  problem since the rates of cyclization of secondary carbon-centered radicals onto alkenes for both 6-exo and 7-endo are on the same order (10 3 s -1 ). 73b  One method for controlling the chemoselectivity is to incorporate suitable radical acceptors into precursors, to bias the desired cyclization reaction pathway.  Scheme 3.8. Synthesis of nitrogen-containing ring systems via radical relay cyclization.      Silyl enol ethers as radical acceptors were studied in our group. 72a  The rate of intramolecular cyclizations of alkoxy radicals onto silyl enols ether proved to be fastest among the radical cyclization reactions. 72c  The studies showed that cyclization of alkoxy radicals onto silyl enol ethers exclusively provided 6-exo tetrahydropyran derivatives. From our previous radical relay cyclization studies, we exclusively synthesized the 6-exo cyclohexane derivative 2.6k from 2.1k (Table 2.3, entry 2). Cyclization of 3.47 may selectively yield 6-exo piperidine derivative 3.48 through a dative control by forming a carbon radical alpha to a nitrogen atom (Scheme 3.9). We can also potentially install more bulky, electron-rich substituents on alkenes, such as ketene-S,S- acetal 3.51, which can provide additional functional handles after cyclization. These radical relay cyclizations of substrates with substituted alkenes as acceptors may be exploited as a possible method to synthesize 2,3-disubstituted piperidine derivatives. 87   Scheme 3.9. Chemoselective synthesis of piperidine derivatives. 3.4 Conclusion      We have demonstrated that the alkoxy radical-initiated intramolecular radical relay cyclization methodology has been successfully utilized in the synthesis of oxacycles, including tetrahydrofuran, tetrahydropyran, benzofuran, and benzopyran derivatives. While the diastereoselectivity of the 6-exo cyclizations were slightly improved, the diastereoselectivity of 5-exo cyclizations with oxygen atom incorporation into the molecules was improved significantly, compared to their carbon analogs. The most significant improvement in diastereoselectivity was obtained in 6-endo cyclizations. The oxygen-containing precursor 88  exclusively cyclized as a single trans diasteromer. High diastereoselectivity in 5-exo cyclizations is presumably due to greater steric interactions resulting from short C-O-C bond lengths in the transition state.      In summary, this radical relay methodology provides a synthetically general pathway for the formation of oxacycles. The generality for the higher diastereoselectivity with oxygen atom incorporation into substrates broadens the synthetic utility of this radical relay cyclization methodology in the total synthesis of natural products.                 89  3.5 Experimental 3.5.1 General methods      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. All other solvents were used without further purification. Thin layer chromatography (TLC) was performed on Whatman Partisil K6F UV254 pre-coated TLC plates. Chromatographic separations were effected over Fluka 60 silica gel. The silica gel was basified by stirring with triethylamine prior to packing and then sequentially flushed with the solvent system of choice. All reagents were purchased from commercial sources and used as received. 3.5.2 Instrumentation      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 (IR) spectra were obtained using a Thermo Nicolet 4700 FTIR spectrometer. Proton nuclear magnetic resonance ( 1 H NMR) spectra were recorded using a Bruker AV-300 or AV-400 spectrometer. Carbon nuclear magnetic resonance ( 13 C NMR) spectra were recorded 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 d6-chloroform (7.27 ppm 1 H NMR; 77.0 ppm 13 C NMR) or d6-benzene (7.16 ppm 1 H NMR; 128.1 ppm 13 C NMR). High resolution mass spectra (HRMS) were recorded on a Waters/Micromass LCT spectrometer.    90  3.5.3 Synthesis of precursors N-hydroxyphthalimides 3.1 Synthesis of 3.1b       5-(But-3-en-1-yloxy)pentan-2-ol (3.10): To a stirred solution of NaH (60% dispersion in mineral oil, 589 mg, 14.7 mmol) in anhydrous DMF (25 mL) was added 3-buten-1-ol (0.65 mL, 554 mg, 7.38 mmol). The solution was stirred for 10 min at ambient temperature after which a solution of 4-((tert-butyldimethylsilyl)oxy)pentyl 4-methylbenzenesulfonate (2.50 g, 6.70 mmol) in anhydrous DMF (2.0 mL) was added. The solution was then heated to 75 °C and stirred for 2 h, allowed to cool to ambient temperature. The reaction was quenched via the slow addition of H2O (40 mL) followed by saturated NaHCO3 (10 mL). The reaction was extracted with Et2O (3 × 50 mL) and the combined organic layers were washed with H2O (20 mL) and brine (20 mL), dried over Na2SO4, concentrated by rotary evaporation to yield silyl ether 3.9 as a colorless oil.     To a stirred solution of the crude ether 3.9 in THF (20 mL) was added TBAF (4.55 mL, 1.0 M in THF, 4.55 mmol), and the solution was allowed to stir 12 h at ambient temperature. The reaction was quenched with H2O (20 mL) and extracted with Et2O (3 × 20 mL). The combined organic layers were washed with H2O (20 mL), brine (20 mL), dried over Na2SO4, and concentrated by rotary evaporation. The product was purified using flash column chromatography (3:1 hexanes/EtOAc) to yield alcohol 3.10 as a colorless oil (305 mg, 30%, two steps). IR (film): 3386, 2965, 2921, 2852, 1639, 1456, 1373, 1260, 1108, 1021, 917, 804 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 5.77 - 5.88 (m, 1 H), 5.00 - 5.15 (m, 2 H), 3.80 - 3.83 (m, 1 H), 3.46 - 3.52 (m, 4 H), 2.57 (br. s., 1 H), 2.35 (q, J = 6.7 Hz, 2 H), 1.67 - 1.71 (m, 2 H), 1.56 - 1.63 91  (m, 1 H), 1.45 - 1.53 (m, 1 H), 1.19 (d, J = 6.3 Hz, 3 H); 13 C NMR (100 MHz, CDCl3): δ 135.0, 116.5, 71.2, 70.3, 67.7, 36.8, 34.1, 26.4, 23.4; HRMS-ESI (m/z): calcd. for C9H19O2 [M+H]  +  159.1385, found 159.1381.       2-((5-(But-3-en-1-yloxy)pentan-2-yl)oxy)isoindoline-1,3-dione (3.1b): To a stirred solution of alcohol 3.10 (210 mg, 1.32 mmol) in regular THF (13 mL) was sequentially added triphenylphosphine (521 mg, 1.99 mmol) and N-hydroxyphthalimide (324 mg, 1.99 mmol). The solution was stirred until the solids were dissolved, at which point diisopropylazodicarboxylate (0.47 mL, 483 mg, 2.38 mmol) was added via syringe pump (0.80 mL/h). The resulting yellow solution was stirred for 12 h at ambient temperature, and was then quenched with H2O (10 mL). The aqueous layer was extracted with EtOAc (3 × 20 mL), and the combined organic layers were washed with NaHCO3 (3 × 20 mL) and brine (20 mL). The organic layer was dried over Na2SO4, concentrated using rotary evaporation, and purified by flash column chromatography (3:1 hexanes/Et2O) to provide N-alkoxyphthalimide 3.1b as a colorless oil (321 mg, 80%). IR (film): 2930, 2847, 1795, 1734, 1373, 1117, 878, 695 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 7.82 - 7.84 (m, 2 H), 7.72 - 7.76 (m, 2 H), 5.78 - 5.86 (m, 1 H), 4.96 - 5.13 (m, 2 H), 4.36 - 4.45 (m, 1 H), 3.45 - 3.53 (m, 4 H), 2.32 (q, J = 6.8 Hz, 2 H), 1.78 - 1.86 (m, 3 H), 1.65 - 1.74 (m, 1 H), 1.34 (d, J = 6.3 Hz, 3 H); 13 C NMR (100 MHz, CDCl3): δ 164.3, 135.3, 134.4, 129.0, 123.4, 116.2, 84.2, 70.4, 70.0, 34.2, 31.5, 25.4, 18.8; HRMS-ESI (m/z): calcd. for C17H22NO4 [M+H] +  304.1549, found 304.1547.  92  Synthesis of 3.1c       1-(Trityloxy)pent-4-en-2-ol (3.13): To a stirred solution of CuI (628 mg, 3.30 mmol) in dry THF (20 mL) was added vinylmagnesium bromide (50 mL, 50 mmol) at –20 °C. The mixture was stirred for half hour, and then 2-((trityloxy)methyl)oxirane (3.12) (11.1 g, 33.8 mmol) in dry THF (30 mL) was added to the mixture through additional funnel dropwise. The resulting solution was stirred for another 1.5 h at the same temperature. The reaction was quenched by addition of NH4Cl (50 mL). The mixture was added Et2O (200 mL) and stirred overnight. The organic layer was concentrated using rotary evaporation. The crude compound was purified by flash column chromatography (12:1 to 2:1 hexanes/Et2O) to provide title compound 3.13 as a colorless oil (11 g, 94%). IR (film): 3440, 3059, 3032,  2925, 2872, 1641, 1597, 1490, 1448, 1219, 1183, 1154, 1075, 1032 cm –1 ;  1 H NMR (400 MHz, CDCl3): δ 7.47 (d, J = 7.3 Hz, 6 H), 7.31 - 7.36 (m, 6 H), 7.24 - 7.27 (m, 2 H), 5.77 (ddt, J = 17.1, 10.1, 7.0, 7.0 Hz, 1 H), 5.03 - 5.12 (m, 2 H), 3.82 - 3.90 (m, 1 H), 3.21 (dd, J = 9.2, 3.9 Hz, 1 H), 3.12 (dd, J = 9.4, 7.0 Hz, 1 H), 2.31 (d, J = 3.9 Hz, 1 H), 2.22 - 2.29 (m, 2 H); 13 C NMR (100 MHz, CDCl3): δ 143.8, 134.3, 128.6, 127.8, 127.1, 117.6, 86.7, 70.2, 67.0, 38.1. HRMS-ESI (m/z): calcd. for C24H24O2Na [M+Na] +  367.1674, found 367.1682.    93        1-Methoxy-4-((4-(1-(trityloxy)pent-4-en-2-yloxy)butoxy)methyl)benzene (3.14): To a stirred solution of 1-(trityloxy)pent-4-en-2-ol (3.13) (5.67 g, 16.5 mmol) in dry DMF (32 mL) was added NaH (1.97 g, 49.4 mmol). This solution was allowed to stir for 30 min, after which it was added to a solution of 4-(4-methoxybenzyloxy)butyl 4-methylbenzenesulfonate (6.00 g, 16.5 mmol) in dry DMF (30 mL) by syringe pump over 15 min. The resulting solution was heated to 75°C and stirred overnight. The reaction was cooled to room temperature and quenched with H2O (50 mL). The aqueous layer was extracted with diethyl ether (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated by rotary evaporation. Purification by flash chromatography (10:1 hexanes/EtOAc) yielded the title product as a pale yellow oil (4.69, 53% yield). IR (film): 3059, 3032, 2932, 2857, 1613, 1586, 1513, 1490, 1448, 1359, 1302, 1173, 1093, 1034, 820, 764, 746, 705 cm –1 ;  1 H NMR (400 MHz, CDCl3):  7.46 - 7.51 (m, 6 H), 7.21 - 7.33 (m, 12 H), 6.88 (d, J = 8.5 Hz, 2 H), 5.75 (ddt, J = 17.2, 10.1, 7.0, 7.0 Hz, 1 H), 4.92 - 5.09 (m, 2 H), 4.44 (s, 2 H), 3.81 (s, 3 H), 3.59 (dt, J = 9.3, 6.0 Hz, 1 H), 3.41 - 3.52 (m, 4 H), 3.06 - 3.18 (m, 2 H), 2.25 - 2.38 (m, 2 H), 1.64 - 1.74 (m, 4 H); 13 C NMR (100 MHz, CDCl3):  159.1, 144.2, 134.9, 130.7, 129.2, 128.7, 127.7, 126.9, 116.7, 113.7, 86.5, 78.7, 72.5, 69.9, 69.9, 65.3, 55.2, 36.6, 26.9, 26.5; HRMS-ESI (m/z): calcd. for C36H40O4Na [M+Na] +  559.2824, found 559.2824.   94        4-(1-(Trityloxy)pent-4-en-2-yloxy)butan-1-ol (3.15): To a stirred solution of 1-methoxy-4- ((4-(1-(trityloxy)pent-4-en-2-yloxy)butoxy)methyl)benzene (3.14) (4.69 g, 8.73 mmol) in CH2Cl2 (87 mL) and H2O (8.7 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (2.37 g, 10.4 mmol). The resulting solution was allowed to stir for 2.5 h, and then subsequently quenched with a saturated aqueous solution of NaHCO3 (30 mL). The aqueous layer was extracted with CH2Cl2 (3 × 35 mL). The combined organic layers were washed with a saturated aqueous solution of NaHCO3 (50 mL), brine (50 mL). The resulting organic layer was dried over Na2SO4, and concentrated by rotary evaporation. Purification by flash chromatography (3:1 hexanes/EtOAc) yielded the title product as a pale yellow oil (1.86 g, 51% yield). IR (film): 3383, 3059, 3032, 2933, 2870, 1641, 1597, 1490, 1448, 1348, 1318, 1220, 1183, 1154, 1072, 1033, 1001, 913, 774, 764, 746, 706, 646, 633 cm –1 ;  1 H NMR (400 MHz, CDCl3):  7.47 (d, J = 7.5 Hz, 6 H), 7.24 - 7.33 (m, 6 H), 5.73 (ddt, J = 17.2, 10.4, 6.8, 6.8 Hz, 1H), 4.59 - 5.07 (m, 2H), 3.59 - 3.69 (m, 3H), 3.41 - 3.52 (m, 2H), 3.11 - 3.19 (m, 2H), 2.26 - 2.40 (m, 2H), 2.10 (t, J = 5.8 Hz, 1H), 1.67 (br. s, 4H); 13 C NMR (100 MHz, CDCl3):  144.1, 134.6, 128.7, 127.7, 126.9, 117.0, 86.6, 79.0, 70.1, 65.2, 62.7, 36.5, 30.1, 27.0; HRMS-ESI (m/z): calcd. for C28H32O3Na [M+Na] +  439.2249, found 439.2236.    95        2-(4-(1-(tert-Butyldimethylsilyloxy)pent-4-en-2-yloxy)butoxy)isoindoline-1,3-dione (3.1c): To a stirred solution of alcohol 3.15 (250 mg, 0.65 mmol) in regular THF (7 mL) was sequentially added triphenylphosphine (236 mg, 0.90 mmol) and N-hydroxyphthalimide (146 mg, 0.90 mmol). The solution was stirred until the solids were dissolved, at which point diisopropylazodicarboxylate (218 mL, 1.08 mmol) was added via syringe pump (0.80 mL/h). The resulting yellow solution was stirred overnight at ambient temperature, and was then quenched with H2O (10 mL). The aqueous layer was extracted with EtOAc (3 × 20 mL), and the combined organic layers were washed with NaHCO3 (3 × 5 mL), brine (5 mL), dried over Na2SO4, concentrated using rotary evaporation and purified by flash column chromatography (4:1 hexanes/EtOAc) to provide 3.1c as a colorless oil (302 mg, 90%). IR (film): 3060, 3032, 2925, 2872, 1789, 1732, 1490, 1467, 1448, 1373, 1222, 1187, 1082, 1033, 1017, 986, 912, 878, 765, 733, 700, 647, 632 cm –1 ;  1 H NMR (400 MHz, CDCl3):  7.81 - 7.87 (m, 2 H), 7.72 - 7.77 (m, 2 H), 7.47 (d, J = 7.3 Hz, 6 H), 7.27 - 7.34 (m, 7 H), 7.19 - 7.25 (m, 3 H), 5.75 (ddt, J = 17.1, 10.1, 7.0, 7.0 Hz, 1 H), 4.93 - 5.09 (m, 2 H), 4.24 (t, J = 6.5 Hz, 2 H), 3.66 (dt, J = 9.3, 5.9 Hz, 1 H), 3.54 (dt, J = 9.3, 6.2 Hz, 1 H), 3.46 (quin, J = 5.5 Hz, 1 H), 3.08 - 3.21 (m, 2 H), 2.25 - 2.41 (m, 2 H), 1.86 - 1.95 (m, 2 H), 1.75 - 1.84 (m, 2H); 13 C NMR (100 MHz, CDCl3):  163.6, 144.1, 134.8, 134.4, 128.9, 128.7, 127.7, 126.9, 123.4, 116.8, 86.5, 78.7, 78.3, 69.3, 65.3, 36.5, 26.2, 25.1; HRMS-ESI (m/z): calcd. for C36H35NO5Na [M+Na] +  584.2413, found 584.2399.   96  Synthesis of 3.1d       3-(4-((tert-Butyldimethylsilyl)oxy)butoxy)propan-1-ol (3.18): To a stirred solution of ether 3.17 (4.00 g, 16.4 mmol) in THF (60 mL) at 0 °C was added borane (1M in THF, 29.0 mL, 29.0 mmol) dropwise in 30 min. The solution was allowed to warm to room temperature and stirred overnight. The mixture was cooled to 0 °C and H2O (15 mL) was added, followed by addition of 3N NaOH (50 mL) and 30% H2O2 (50 mL). Bath removed and the resulting mixture was stirred for another 30 min. The solution was extracted with CH2Cl2 (3 × 50) and the combined organic layers were dried over Na2SO4, concentrated by rotary evaporation, and purified using flash column chromatography (6:1 hexanes/EtOAc) to yield 3.18 as a colorless oil (2.4 g, 56%). IR (neat): 3381, 2935, 2848, 1470, 1357, 1254, 1080, 841, 778, 670 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 3.78 (t, J = 5.6 Hz, 2 H), 3.62 (dt, J = 4.3, 5.9 Hz, 4 H), 3.46 (t, J = 6.4 Hz, 2 H), 2.16 (br. s., 1 H), 1.83 (quin, J = 5.6 Hz, 2 H), 1.71 - 1.51 (m, 4 H), 0.89 (s, 9 H), 0.05 (s, 6 H); 13 C NMR (100 MHz, CDCl3): δ 71.2, 70.2, 62.9, 62.3, 31.9, 29.4, 26.1, 25.9, 18.3, -5.3; HRMS-ESI (m/z) calcd. for C13H31O3Si [M+H]  +  263.2042, found 263.2045.       tert-Butyldimethyl(4-((4-phenylbut-3-en-1-yl)oxy)butoxy)silane (3.19): To a stirred solution of oxalyl chloride (0.54 mL, 6.39 mmol) in CH2Cl2 (40 mL) at –78 °C was added a solution of dimethyl sulfoxide (0.90 mL, 12.7 mmol) in CH2Cl2 (5 mL) dropwise over 30 min. The solution was allowed to stir for an additional 30 min. A solution of 3.18 (1.40 g, 5.33 mmol) 97  in CH2Cl2 (5 mL) was then added dropwise over 10 min and the resulting slurry was allowed to stir for 30 min at –78 °C. Triethylamine (3.70 mL, 26.6 mmol) was added dropwise over 10 min and the solution was stirred for 30 min at –78 °C. The bath removed and the mixture was stirred for another 2 h. The reaction was quenched with H2O (20 mL) and extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were washed with H2O (20 mL) and brine (20 mL), dried over Na2SO4, and concentrated by rotary evaporation to yield an aldehyde which was used without further purification.      To a stirred solution of benzyltriphenylphosphonium bromide (6.16 g, 14.2 mmol) in THF (40 mL) was added butyllithium (1.6 M in THF, 8.99 mL, 14.9 mmol) dropwise over 10 min at –78 °C. The cold bath was removed and the mixture was stirred for another 25 min. The reaction was cooled to –78 °C and a solution of the crude aldehyde (5.33 mmol) in THF (10 mL) was then added dropwise over 15 min. The resulting solution was stirred overnight. The reaction was quenched with saturated aqueous NH4Cl (50 mL) and extracted with Et2O (3 × 25 mL). The combined organic layers were dried over Na2SO4, concentrated by rotary evaporation and purified using flash column chromatography (1:1 hexanes/EtOAc) to yield alcohol 3.19 as a colorless oil (1.0 g, 56%). IR (neat): 2952, 2926, 2860, 1478, 1360, 1256, 1095, 830, 765 cm –1 ; 1 H NMR (400 MHz, CDCl3): δ 7.39 - 7.33 (m, 2 H), 7.33 - 7.27 (m, 2 H), 7.24 - 7.18 (m, 1 H), 6.47 (d, J = 15.8 Hz, 1 H), 6.25 (td, J = 6.8, 15.8 Hz, 1 H), 3.65 (t, J = 6.2 Hz, 2 H), 3.55 (t, J = 6.7 Hz, 2 H), 3.48 (t, J = 6.4 Hz, 2 H), 2.50 (dq, J = 1.4, 6.9 Hz, 2 H), 1.70 - 1.54 (m, 4 H), 0.91 (s, 9 H), 0.06 (s, 6 H); 13 C NMR (100 MHz, CDCl3): δ 137.6, 131.5, 128.4, 127.1, 127.0, 126.0, 70.8, 70.3, 63.0, 33.5, 29.5, 26.2, 26.0, 18.3, -5.3; HRMS-ESI (m/z) calcd. for C20H35O2Si [M+H]  +  335.2406, found 335.2416. 98        4-((4-Phenylbut-3-en-1-yl)oxy)butan-1-ol (3.20): To a stirred solution of silyl ether 19 (880 mg, 2.63 mmol) in THF (20 mL) was added tetrabutylammonium fluoride (1.0 M in THF, 6.0 mL, 6.0 mmol), and the solution was stirred for 2 h at ambient temperature. The reaction was quenched with H2O (20 mL) and extracted with Et2O (3 × 30 mL). The combined organic layers 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 (gradient from 4:1 to 1:1 hexanes/EtOAc) to yield alcohol 3.20 as a colorless oil (523 mg, 90%, E:Z = 80:20). IR (film): 3391, 2921, 2865, 1726, 1452, 1265, 1113, 800, 704 cm -1 ; 1 HNMR (400 MHz, CDCl3): δ 7.43 - 7.29 (m, 4 H), 7.28 - 7.20 (m, 1 H), 6.59 - 6.45 (m, 1 H), 6.32 - 6.22 (m, 0.8 H), 5.77 - 5.70 (m, 0.2 H, Z alkene), 3.67 (t, J = 5.8 Hz, 2 H), 3.59 (t, J = 6.7 Hz, 2 H), 3.53 (t, J = 5.8 Hz, 2 H), 2.88 (br., s, 1 H), 2.67 (q, J = 6.9 Hz, 0.4 H, Z alkene), 2.54 (q, J = 6.9 Hz, 1.6 H), 1.77 - 1.65 (m, 4 H); 13 C NMR (100 MHz, CDCl3): δ δ137.3, 137.1 (Z alkene), 131.5, 130.4 (Z alkene), 128.5 (Z alkene), 128.3 (Z alkene), 128.3, 127.9 (Z alkene), 126.8, 126.6, 126.5 (Z alkene), 125.8, 70.7, 70.6 (Z alkene), 70.2, 62.1, 33.2, 29.7, 29.7 (Z alkene), 28.9 (Z alkene), 26.3, 26.3 (Z alkene); HRMS-ESI (m/z): calcd, for C14H21O2 [M+H] + 221.1542, found 221.1539.       2-(4-((4-Phenylbut-3-en-1-yl)oxy)butoxy)isoindoline-1,3-dione (3.1d, Table 3.1, entry 4): To a stirred solution of alcohol 3.20 (283 mg, 1.28 mmol) in THF (50 mL) was sequentially added triphenylphosphine (507 mg, 1.93 mmol) and N-hydroxyphthalimide (315 mg, 1.93 99  mmol). The solution was stirred until the solids were dissolved, at which point diisopropylazodicarboxylate (483 mg, 2.39 mmol) was added via syringe pump (0.8 mL/h). The resulting yellow solution was stirred overnight at ambient temperature, and was then quenched with H2O (30 mL). The aqueous layer was extracted with EtOAc (3 × 30 mL), and the combined organic layers were washed with NaHCO3 (3 × 30 mL), brine (30 mL) and dried over Na2SO4. The organic layers were concentrated using rotary evaporation and purified by flash column chromatography (4:1 hexanes/EtOAc) to provide N-alkoxyphthalimide 3.1d as a colorless oil (420 mg, 90%, E:Z = 80:20). IR (neat): 2921, 2865, 1791, 1730, 1478, 1378, 1265, 1178, 1108, 969, 878, 700 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 7.87 - 7.80 (m, 2 H), 7.78 - 7.71 (m, 2 H), 7.37 - 7.28 (m, 4 H), 7.22 - 7.15 (m, 1 H), 6.53 - 6.41 (m, 1 H), 6.24 (td, J = 7.0, 15.8 Hz, 0.78 H), 5.70 (td, J = 7.2, 11.8 Hz, 0.16 H, Z alkene), 4.29 - 4.20 (m, 2 H), 3.60 - 3.48 (m, 4 H), 2.62 (dq, J = 1.5, 6.8 Hz, 0.4 H, Z alkene), 2.50 (dq, J = 0.9, 6.7 Hz, 1.6 H), 1.95 - 1.77 (m, 4 H); 13 C NMR (100 MHz, CDCl3): δ 163.5 (Z alkene), 163.5, 137.5, 137.3 (Z alkene), 134.3, 134.2 (Z alkene), 131.4, 130.3 (Z alkene), 128.8, 128.7 (Z alkene), 128.6 (Z alkene), 128.3, 128.0 (Z alkene), 127.0, 126.9, 126.5 (Z alkene), 125.9, 123.3, 123.3 (Z alkene), 108.7 (Z alkene), 78.1, 70.2 (Z alkene), 70.2, 70.1, 70.1 (Z alkene), 69.0 (Z alkene), 33.4, 30.7 (Z alkene), 29.1 (Z alkene), 25.7, 25.0, 22.4 (Z alkene).; HRMS-ESI (m/z) calcd. for C22H24NO4 [M+H] +  366.1705, found 366.1702.       4-Phenylbut-3-en-1-ol (3.23): To a stirred solution of oxalyl chloride (2.83 mL, 4.19 g, 33.0 mmol) in dry CH2Cl2 (100 mL) at –78 °C was added dimethylsulfoxide (5.88 mL, 6.48 g, 66.0 mmol) in CH2Cl2 (20 mL) dropwise over 10 min. The solution was stirred at –78 °C for 30 min. 100  3-((tert-Butyldimethylsilyloxy)oxy)-propan-1-ol (3.21) (5.70 g, 30.0 mmol) in CH2Cl2 (20 mL) was then added dropwise over 10 min and the solution was stirred for another 30 min. Triethylamine (21.0 mL, 15.2 g, 150 mmol) was added in one portion. The mixture was allowed to warm to ambient temperature and stirred overnight. The reaction was quenched by H2O (100 mL) and the aqueous layer was extracted with CH2Cl2 (3 × 50 mL). The organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated by rotary evaporation to yield an aldehyde as a yellow oil. This compound was used without further purification.      To a stirred solution of benzyltriphenylphosphonium bromide (6.90 g, 15.9 mmol) in dry THF (90 mL) at –78 °C was added butyllithium (9.90 mL, 1.6 M in THF, 15.9 mmol) dropwise over 10 min. The solution was stirred for an additional 1 h. Bath then removed and the mixture was stirred for another 1 h and then cooled to –78 °C. A solution of the crude aldehyde (1.00 g, 5.30 mmol) in dry THF (10 mL) was then added dropwise over 10 min. The resulting solution was stirred overnight. The reaction was quenched with saturated aqueous NH4Cl (50 mL) and extracted with Et2O (3 × 30 mL). The combined organic layers were dried over Na2SO4, concentrated by rotary evaporation and purified by flash column chromatography (25:1 hexanes/Et2O) to provide 3.22 as a colorless oil (1.2 g, 89%). IR (film): 2926, 1717, 1273, 1100, 1047,713 cm -1 ; 1 HNMR (400 MHz, CDCl3): δ 7.28 - 7.36(m, 4 H), 7.21 - 7.26 (m, 1 H), 6.48 (d, J = 15.9 Hz, 1 H), 6.27 (dt, J = 15.9, 7.0 Hz, 1 H), 3.75 (t, J = 6.7 Hz, 2 H), 2.45 (qd, J = 6.8, 1.3 Hz, 2 H), 0.92 (s, 9 H), 0.08 (s, 6 H); 13 C NMR (100 MHz, CDCl3): δ 137.7, 131.6, 128.4, 127.2, 126.9, 125.9, 62.9, 36.6, 25.9, 18.3, -5.2.     To a stirred solution of silyl ether 3.22 (1.25 g, 4.76 mmol) in THF (20 mL) was added TBAF (14.3 mL, 1.0 M in THF, 14.3 mmol), and the solution was to stir overnight at ambient temperature. The reaction was quenched with H2O (10 mL) and extracted with Et2O (3 × 20 mL). 101  The combined organic layers 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 (4:1 then 1:1 hexanes/EtOAc) to yield alcohol 3.23 as a colorless oil (606 mg, 86%). 1 H NMR (400 MHz, CDCl3): δ 7.29 - 7.41 (m, 4 H), 7.19 - 7.27 (m, 1 H), 6.62 (d, J = 15.7 Hz, 0.20 H, Z alkene), 6.52 (d, J = 15.7 Hz, 0.80 H), 6.22 (dt, J = 15.8, 7.1 Hz, 0.80 H), 5.71 (dt, J = 15.8, 7.1 Hz, 0.20 H, Z alkene), 3.73 - 3.81 (m, 2 H),  2.61 - 2.66 (m, 0.40 H, Z alkene), 2.47 - 2.54 (m, 1.60 H), 1.58 (s, 0.27 H); 13 C NMR (100 MHz, CDCl3): δ 138.1, 137.2, 132.9, 132.7, 131.5, 128.7, 128.5, 128.2, 127.2, 126.8, 126.3, 126.0, 62.5, 62.2, 36.6, 31.9.       tert-Butyldimethyl(4-((4-phenylbut-3-en-1-yl)oxy)butoxy)silane (3.19): To a stirred solution of NaH (60% dispersion in mineral oil, 281 mg, 7.04 mmol) in anhydrous DMF (19 mL) was added 4-phenylbut-3-en-1-ol (3.23) (870 mg, 5.87 mmol). The solution was stirred for 1 h, after which a solution of 4-(tert-Butyldimethylsilyloxy)butyl-3-methylbenzenesulfonate (1.03 g, 2.89 mmol) in anhydrous DMF (2.0 mL) was added. The solution was then heated to 50 °C and stirred overnight, and allowed to cool to ambient temperature. The reaction was quenched via the slow addition of H2O (10 mL) followed by saturated NaHCO3 (10 mL). The reaction was extracted with Et2O (3 × 20 mL) and the combined organic layers were dried over Na2SO4, concentrated by rotary evaporation, and purified using flash column chromatography (50:1 hexanes/Et2O) to yield silyl ether 3.19 as a colorless oil (615 mg, 35%). IR (film): 2952, 2926, 2860, 1478, 1360, 1256, 1095, 830, 765 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 7.28 - 7.38 (m, 4 H), 7.18 - 7.23 (m, 1 H), 6.46 (d, J = 15.7 Hz, 1 H), 6.20 - 6.29 (m, 1 H), 3.64 (t, J = 6.1 Hz, 2 102  H),  3.54 (t, J = 6.8 Hz, 2 H), 3.48 (t, J = 6.3 Hz, 2 H), 2.46 - 2.54 (m, 2 H), 1.59 - 1.67 (m, 4 H), 0.90 (s, 9 H), 0.06 (s, 6 H); 13 C NMR (100 MHz, CDCl3): δ 137.8, 131.6, 128.6, 127.3, 127.1, 126.2, 71.0, 70.5, 63.1, 33.7, 29.7, 26.3, 26.1, 18.5, -5.1; HRMS-ESI (m/z): calcd. for C20H35O2Si [M+H] + 335.2406, found 335.2416.       2-(4-((4-Phenylbut-3-en-1-yl)oxy)butoxy)isoindoline-1,3-dione (3.1d, Table 3.1, entry 5): To a stirred solution of silyl ether 3.19 (270 mg, 0.80 mmol) in THF (3 mL) was added TBAF (2.4 mL, 1.0 M in THF, 2.4 mmol), and the solution was to stir overnight at ambient temperature. The reaction was quenched with H2O (5 mL) and extracted with Et2O (3 × 10 mL). The combined organic layers were washed with H2O (10 mL) and brine (10 mL), dried over Na2SO4, and concentrated by rotary evaporation. The product was purified using flash column chromatography (4:1 then 1:1 hexanes/EtOAc) to yield alcohol 3.20 as a colorless oil (130 mg, 80%). IR (film): 3391, 2921, 2865, 1726, 1452, 1265, 1113, 800, 704 cm -1 ; 1 HNMR (400 MHz, CDCl3): δ 7.28 - 7.38 (m, 4 H), 7.18 - 7.23 (m, 1 H), 6.47 (d, J = 15.7 Hz, 1 H), 6.16 - 6.29 (m, 1 H), 3.62 - 3.69 (m, 2 H),  3.57 (t, J = 6.8 Hz, 2 H), 3.49 - 3.53 (m, 2 H), 2.51 (qd, J = 6.7, 1.5 Hz, 2 H), 2.34 (br, s., 1 H), 1.65 - 1.75 (m, 4 H); 13 C NMR (100 MHz, CDCl3): δ 137.7, 131.9, 128.6, 127.2, 126.9, 126.2, 71.1, 70.6, 62.9, 33.6, 30.4, 26.9; HRMS-ESI (m/z): calcd. for C14H21O2 [M+H]  + 221.1542, found 221.1539.      To a stirred solution of alcohol 3.20 (130 mg, 0.59 mmol) in regular THF (20 mL) was sequentially added triphenylphosphine (233 mg, 0.89 mmol) and N-hydroxyphthalimide (145 mg, 0.89 mmol). The solution was stirred until the solids were dissolved, at which point 103  diisopropylazodicarboxylate (0.22 mL, 222 mg, 1.10 mmol) was added via syringe pump (0.8 mL/h). The resulting yellow solution was stirred overnight at ambient temperature, and was then quenched with H2O (10 mL). The aqueous layer was extracted with EtOAc (3 × 20 mL), and the combined organic layers were washed with NaHCO3 (3 × 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 hexanes/EtOAc) to provide N-alkoxyphthalimide 3.1d as a colorless oil (200 mg, 92%, E:Z>95:5). 1 H NMR (400 MHz, CDCl3): δ 7.87 - 7.81 (m, 2 H), 7.79 - 7.72 (m, 2 H), 7.38 - 7.28 (m, 4 H), 7.22 - 7.16 (m, 1 H), 6.46 (d, J = 15.7 Hz, 1 H), 6.24 (td, J = 7.1, 15.9 Hz, 1 H), 4.25 (t, J = 6.3 Hz, 2 H), 3.62 - 3.49 (m, 4 H), 2.50 (dq, J = 1.0, 6.8 Hz, 2 H), 1.97 - 1.76 (m, 4 H); 13 C NMR (100 MHz, CDCl3): δ 163.6, 137.6, 134.4, 131.5, 129.0, 128.4, 127.1, 127.0, 126.0, 123.5, 78.3, 70.3, 70.2, 33.5, 25.8, 25.1. Synthesis of 3.1e       (4-(But-3-en-1-yloxy)butoxy)(tert-butyl)dimethylsilane (3.25): To a stirred solution of NaH (60% dispersion in mineral oil, 2.23 g, 55.7 mmol) in anhydrous DMF (90 mL) was added 3- buten-1-ol (3.24) (2.36 mL, 2.01 g, 27.8 mmol) dropwise. The solution was stirred for 1 h, after which a solution of 4-((tert-butyldimethylsilyl)oxy)butyl tosylate (10.0 g, 27.8 mmol) in anhydrous DMF (10 mL) was added. The solution was then heated to 75 °C and stirred for one and half h, and allowed to cool to ambient temperature. The reaction was quenched via the slow addition of H2O (70 mL) followed by saturated NaHCO3 (50 mL). The reaction was extracted with Et2O (3 × 50 mL) and the combined organic layers were dried over Na2SO4, concentrated 104  by rotary evaporation, and purified using flash column chromatography (50:1 hexanes/Et2O) to yield silyl ether 3.25 as a colorless oil (2.88 g, 40%). IR (film): 2965, 2921, 2856, 1730, 1634, 1256, 1100, 1017, 786 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 5.79 - 5.88 (m, 1 H), 5.00 - 5.15 (m, 2 H), 3.64 (t, J = 6.2 Hz, 2 H), 3.46 (dt, J = 9.6, 6.6 Hz, 4 H), 2.34 (q, , J = 6.8 Hz, 2 H), 1.57 - 1.68 (m, 4 H), 0.90 (s, 9 H), 0.05 (s, 6 H); 13 C NMR (100 MHz, CDCl3): δ 135.4, 116.2, 70.8, 70.1, 63.0, 34.3, 29.5, 26.2, 26.0, 18.8, -5.3; HRMS-ESI (m/z): calcd. for C14H31O2Si [M+H] +  259.2093, found 259.2088.       4-(4-((tert-Butyldimethylsilyl)oxy)butoxy)butan-1-ol (3.26):  To a stirred solution of alkene 3.25 (800 mg, 3.09 mmol) in dry THF (12 mL) at 0 °C  was added borane (5.80 mL, 1.0 M in THF, 5.80 mmol) dropwise, and the solution was stirred 2 h at 0 °C. The mixture was allowed to warm to ambient temperature and stirred overnight. The reaction was re-cooled to 0 °C, and H2O (5 mL) was added dropwise followed by addition of 3N NaOH (15 mL), H2O2 (15 mL). Bath was removed and the resulting mixture was stirred for additional 30 min and extracted with CH2Cl2 (3 × 20 mL). The organic layers were dried over Na2SO4, and concentrated by rotary evaporation. The product was purified using flash column chromatography (4:1 hexanes/EtOAc) to yield alcohol 3.26 as a colorless oil (757 mg, 88%). IR (film): 3382, 2939, 2847, 1469, 1356, 1252, 1078, 839, 773, 665 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 3.60 (t, J = 6.1 Hz, 4 H), 3.40 - 3.45 (m,  4 H), 2.81 (br. s., 1 H), 1.50 - 1.67 (m, 4 H), 0.82 (s, 9 H), 0.05 (s, 6 H); 13 C NMR (100 MHz, CDCl3): δ 70.8, 70.7, 62.9, 62.5, 30.2, 29.4, 26.8, 26.0, 25.9, 18.2, -5.4; HRMS-ESI (m/z): calcd. for C14H33O3Si [M+H]  +  277.2199, found 277.2206. 105        4-(4-((tert-Butyldimethylsilyl)oxy)butoxy)butyl 4-methylbenzenesulfonate (3.27): To a stirred solution of 4-(4-((tert-butyldimethylsilyl)oxy)butoxy)butan-1-ol (645 mg, 2.33 mmol) in dry CH2Cl2 (20 mL) at 0 °C was sequentially added para-toluenesulfonyl chloride (533 mg, 2.80 mmol), triethylamine (0.65 mL, 4.66 mmol) and dimethylaminopyridine (28 mg, 0.23 mmol). The resulting solution was stirred overnight. The solvent was evaporated and the residue was diluted with Et2O (50 mL). The resulting mixture was washed with aqueous saturated NaHCO3 (10 mL), brine (10 mL) and dried over Na2SO4. The organic layer was filtered and concentrated by rotary evaporation. The product was purified by flash column chromatography (20:1 hexanes/EtOAc) to yield title compound as a colorless oil (613 mg, 61%). IR (film): 2923, 2854, 1264, 1215, 1191 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 8.2 Hz, 2 H), 7.35 (d, J = 8.0 Hz, 2 H), 4.06 (t, J = 6.4 Hz, 2 H), 3.61 (t, J = 6.0 Hz, 1 H), 3.36 (q, J = 6.0 Hz, 2 H ), 2.45 (s, 3 H), 1.69 - 1.78 (m, 2 H), 1.50 - 1.61 (m, 6 H), 0.89 (s, 9 H), 0.05 (s, 6 H); 13 C NMR (100 MHz, CDCl3): δ 144.6, 133.2, 129.8, 127.9, 70.8, 70.5, 69.7, 62.9, 29.5, 26.1, 25.93, 25.9, 25.7, 21.6, 18.3, -5.3; HRMS-ESI (m/z): calcd. for C21H39O5SSi [M+H] +  431.2287, found 431.2283.       4-((4-((tert-Butyldimethylsilyl)oxy)but-3-en-1-yl)oxy)butyl4-methylbenzenesulfonate (3.28): To a stirred solution of 4-(4-((tert-butyldimethylsilyl)oxy)butoxy)butyl 4- methylbenzenesulfonate (3.27) (570 mg, 1.33 mmol) in THF (10 mL) was added tetrabutylammonium fluoride (2.66 mL, 2.66 mmol).  The resulting solution was stirred for 5 h 106  before being diluted with NH4Cl (20 mL).  The aqueous layer was extracted with Et2O (3 × 20 mL). The combined organic layers were dried over Na2SO4, concentrated using rotary evaporation, and purified by column chromatography (3:2 hexanes/EtOAc) to yield a alcohol as a colourless oil (400 mg, 95%). IR (film): 3411, 1215, 1191, 815 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ  7.79 (d, J = 8.1 Hz, 2 H), 7.35 (d, J = 8.0 Hz, 2 H), 4.06 (t, J = 6.3 Hz, 2 H), 3.62 - 3.67 (m, 2 H), 3.42 (q, J = 5.8 Hz, 4 H ), 2.46 (s, 3 H), 2.40 (br. s., 1 H), 1.70 - 1.79 (m, 2 H), 1.56 - 1.69 (m, 6 H); 13 C NMR (100 MHz, CDCl3): δ 144.7, 133.1, 129.8, 127.9, 70.9, 70.3, 69.9, 62.8, 30.1, 26.8, 25.8, 25.6, 21.6; HRMS-ESI (m/z): calcd. for C15H25O5S [M+H] +  317.1423, found 317.1421.      To a stirred solution of oxalyl chloride (95 mg, 0.75 mmol) in dry CH2Cl2 (4 mL) at –78 °C was added dimethylsulfoxide (118 mg, 1.51 mmol) dropwise over 1 min. The solution was stirred at –78 °C for 30 min, then the alcohol (200 mg, 0.63 mmol) in CH2Cl2 (1 mL) was added dropwise over 1 min. The resulting solution was stirred for 90 min at –78 °C. Triethylamine (0.44 mL, 319 mg, 3.16 mmol) was then added and the solution was allowed to warm to ambient temperature and stirred for 12 h. The reaction was poured into H2O (10 mL) and extracted with CH2Cl2 (3 × 20mL). The combined organic layers were washed with brine (30mL), dried over Na2SO4, concentrated using rotary evaporation to give an aldehyde which was used for the next step  without further purification.      To a stirred solution of the crude aldehyde in CH2Cl2 (6 mL) at 0 °C was added N,N- diisopropylethylamine (168 mg, 1.26 mmol). To this solution was added tert-butyldimethyl trifluoromethanesulfonate (249 mg, 4.20 mmol) dropwise over 5 min, and the yellow solution was allowed to stir overnight at 0 °C. The reaction was quenched by addition of NaHCO3 (10 mL), extracted with CH2Cl2 (2 × 10 mL). The organic layers were washed with brine (10 mL), 107  dried over Na2SO4, concentrated using rotary evaporation, and purified by column chromatography (3:2 hexanes/EtOAc) to yield the title product as a colourless oil (132 mg, 50% over two steps). IR (film): 2929, 1639, 1186 cm -1 ; 1 H NMR (400 MHz, C6D6): δ 7.76 (d, J = 8.02 Hz, 2 H), 6.70 (d, J = 7.85 Hz, 2 H), 6.33 (d, J = 12.0 Hz, 0.55 H), 6.22 (d, J = 7.9 Hz, 0.45 H), 5.13 - 5.19 (m, 0.55 H), 4.57 - 4.62 (m, 0.45 H), 3.87 (t, J = 6.4 Hz, 2 H), 3.29 (t, J = 6.9 Hz, 1 H ), 3.14 (t, J = 6.7 Hz, 1 H), 3.07 (t, J = 6.1 Hz, 1 H), 3.02 (t, J = 6.1 Hz, 1 H), 2.54 (q, J = 6.8 Hz, 1 H), 2.11 (q, J = 6.8 Hz, 1 H), 1.84 (s, 3 H), 1.43 - 1.52 (m, 2 H), 1.30 - 1.38 (m, 2 H), 0.94 (s, 5 H), 0.92 (s, 4 H), 0.07 (s, 3.40 H), 0.02 (s, 2.63 H); 13 C NMR (100 MHz, C6D6): δ 144.4, 144.3, 142.3, 140.3, 135.0, 135.0, 130.1, 128.5, 128.3, 108.4, 107.4, 72.0, 71.1, 70.7, 70.6, 70.2, 70.1, 28.9, 26.6, 26.6, 26.4, 26.3, 26.2, 26.1, 25.5, 21.5, 18.8, -4.8, -5.0; HRMS-ESI (m/z): calcd. for C21H36NaO5SSi [M+Na] +  451.1950, found 451.1953.       2-(4-((4-((tert-Butyldimethylsilyl)oxy)but-3-en-1-yl)oxy)butoxy)isoindoline-1,3-dione (3.1e): To a stirred solution of 4-(2-vinylphemoxy)butyl4-methylbenzenesulfonate (3.28) (220 mg, 0.60 mmol), N-hydroxyphthalimide (147 mg, 0.90 mmol) in DMF (3 mL) was added diisopropylethylamine (155 mg, 1.20 mmol). The resulting mixture was then heated to 90 °C and stirred for 2 h. The solution was cooled to room temperature. The reaction was quenched with H2O (10 mL) and extracted with Et2O (3 × 10 mL). The combined organic layers were washed with H2O (10 mL), NaHCO3 (10 mL), brine (10 mL) and dried over Na2SO4. The organic layer was filtered and concentrated by rotary evaporation. The product was purified by flash column chromatography (4:1 hexanes/EtOAc) to yield title compound as a colorless oil (520 mg, 75%, 108  E/Z = 45:55). IR (film): 2925, 1995, 1737, 1261,1216, 1192 cm -1 ; 1 H NMR (400 MHz, C6D6): δ 7.26 - 7.33 (m, 2 H), 6.76 - 6.84 (m, 2H), 6.35 (d, J = 12.0 Hz, 0.45 H), 6.22 (d, J = 7.9 Hz, 0.55 H), 5.17 - 5.23 (m, 0.45 H), 4.62 - 4.68 (m, 0.56 H), 4.05 (t, J = 6.0 Hz, 2 H), 3.39 (t, J = 6.8 Hz, 1 H ), 3.31 (t, J = 5.8 Hz, 1 H), ), 3.22 - 3.29 (m, 2 H), 2.59 (q, J = 6.7 Hz, 1 H), 2.17 (q, J = 6.8 Hz, 1 H), 1.68-1.78 (m, 4 H), 0.95 (s, 4 H), 0.93 (s, 5 H), 0.08 (s, 2.68 H), 0.03 (s, 3.29 H); 13 C NMR (100 MHz, C6D6): δ 163.7, 142.2, 140.2, 134.1, 134.0, 129.9, 128.5, 128.4, 123.3, 108.6, 107.7, 78.7, 78.6, 72.0, 71.1, 70.6, 70.6, 28.9, 26.7, 26.2, 26.1, 25.9, 25.6, 18.8, -4.8, -5.0; HRMS-ESI (m/z): calcd. for C22H34NaNO4Si [M+Na] +  420.2206, found 420.2195. Synthesis of 3.1g       2-(4-((3-Phenylbut-3-en-1-yl)oxy)butoxy)isoindoline-1,3-dione (3.1g): To a stirred solution of alcohol 3.32 (350 mg, 1.59 mmol) in regular THF (60 mL) was sequentially added triphenylphosphine (624 mg, 2.38 mmol) and N-hydroxyphthalimide (388 mg, 2.38 mmol). The solution was stirred until the solids were dissolved, at which point diisopropylazodicarboxylate (0.56 mL, 578 mg, 2.86 mmol) was added via syringe pump (0.81 mL/h). The resulting yellow solution was stirred overnight at ambient temperature, and was then quenched with H2O (10 mL). The aqueous layer was extracted with EtOAc (3 × 30 mL), and the combined organic layers were washed with NaHCO3 (3 × 25 mL), H2O (25 mL), brine (25 mL) and dried over Na2SO4. The organic layers were concentrated using rotary evaporation and purified by flash column chromatography (4:1hexanes/EtOAc) to provide N-alkoxyphthalimide 3.1g as a colorless oil (520 mg, 89%, 92% purity), contaminated with diisopropyl 1,2-hydrazinedicarboxylate. 3.1g was 109  immediately subjected to the general cyclization procedure. 1 H NMR (400 MHz, CDCl3): δ 7.82 - 7.84 (m, 2 H), 7.72 - 7.74 (m, 2 H), 7.40 - 7.42 (m, 2 H),  7.19 - 7.35 (m, 3 H), 5.32 (s, 1 H), 5.12 (s, 1 H), 4.21 (t, J = 7.2 Hz, 2 H),  3.54 (t, J = 7.2 Hz, 2 H), 3.48 (t, J = 7.2 Hz, 2 H), 2.78 (t, J = 7.1 Hz, 2 H), 1.82 - 1.89 (m, 2 H), 1.74 - 1.80 (m, 2 H); HRMS-ESI (m/z): calcd. for C22H23NO4 Na [M+Na] +  388.1525, found 388.1528.  Synthesis of 3.1h       tert-Butyldimethyl(4-(2-vinylphenoxy)butoxy)silane (3.30): To a stirred solution of alcohol 2-vinylphenol (3.29) (1.20 g, 9.99 mmol) in DMF (80 mL) was sequentially added tert-butyl(4- iodobutoxy)dimethylsilane (2.99 g, 2.46 ml, 1.00 mmol) and K2CO3 (6.56 g, 47.5 mmol). The resulting solution was stirred at ambient temperature overnight. The reaction was diluted with H2O (50 mL) and extracted with Et2O (3 × 40 mL). The combined organic layers were dried over Na2SO4 and concentrated using rotary evaporation and purified by flash column chromatography (30:1 hexanes/EtOAc) to provide title compound 3.30 as a colorless oil (2.8 g, 90% ). IR (film): 3352, 2942, 2863, 1653, 1458, 1187, 908, 725 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 7.48 - 7.51 (m,  1 H), 7.22 - 7.24 (m,  1 H), 7.05 - 7.12 (m, 1 H), 6.86 - 6.96 (m, 1 H), 4.03 (t, J = 6.4 Hz, 2 H), 3.71 (t, J = 6.4 Hz, 2 H), 1.87 - 1.94 (m, 2 H), 1.70 - 1.77 (m, 2 H), 0.92 (s, 9 H), 0.80 (s, 6 H); 13 C NMR (100 MHz, CDCl3): δ131.9, 129.5, 128.9, 126.6, 120.6, 114.3, 112.0, 68.3, 63.0, 29.7, 26.4, 26.1, 18.5, -5.1; HRMS-ESI (m/z): calcd. for C18H30O2SiNa [M+Na] +  307.2093, found 307.2097. 110        4-(2-Vinylphenoxy)butyl 4-methylbenzenesulfonate (3.31): To a stirred solution of tert- butyldimethyl(4-(2-vinylphenoxy)butoxy)silane (3.30) (2.8 g, 9.1 mmol) in THF (18 mL) was added tetrabutylammonium fluoride (18 mL, 1.0 M in THF, 18 mmol). The resulting solution was allowed to stir for 5 h before being diluted with 20 mL H2O.  The aqueous layer was extracted with Et2O (3 × 20 mL). The combined organic layers were dried over Na2SO4 and concentrated using rotary evaporation, and purified by column chromatography (7:1 hexanes/Et2O  ) to yield a alcohol as a colourless oil (0.80 g, 96%). IR (film): 3386, 2934, 2869, 1686, 1604, 1491, 1456, 1239, 1039, 813, 756 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 7.48 - 7.50 (m, 1H), 7.21 - 7.27 (m, 1H), 7.04 - 7.10 (m, 1H), 6.94 (t, J = 7.6 Hz, 1 H), 6.87 (d, J = 8.0 Hz, 1H), 5.76 (d, J = 16.0 Hz, 1H), 5.27 (d, J = 12.0 Hz, 1H), 4.04 (t, J = 4.0 Hz, 2H), 3.72 - 3.76 (m, 2H), 1.89 - 1.96 (m, 2H), 1.75 - 1.82 (m, 2H), 1.57 (bs, 1H); 13 C NMR (100 MHz, CDCl3): δ 156.2, 131.8, 128.9, 127.0, 126.7, 120.8, 114.5, 112.1, 68.2, 62.7, 29.7, 26.0; HRMS-ESI (m/z): calcd. for C12H16NaO2 [M+Na] +  193.1229, found 193.1232.      To a stirred solution of the alcohol (382 mg, 1.98 mmol) in dry CH2Cl2 (10 mL) was sequentially added para-toluenesulfonyl chloride (454 mg, 2.38 mmol) and triethylamine (0.56 mL, 3.96 mmol). The resulting solution was stirred overnight. H2O (10 mL) was added and the reaction mixture was stirred for another 10 min. The organic layer was washed with aqueous saturated NaHCO3 (10 mL), H2O (10mL), brine (10 mL), dried over Na2SO4 and concentrated using rotary evaporation. The crude oil was purified by flash column chromatography (10:1 hexanes/EtOAc) to yield title compound as a colorless oil (520 mg, 75%). IR (film): 2952, 2852, 1591, 1495, 1369, 1169, 1095, 943, 817, 743 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 111  8.4 Hz, 2 H), 7.48 (dd, J = 7.6, 1.6 Hz, 2 H), 7.34 (d, J = 8.0 Hz, 1 H ), 7.21 (dt, J = 6.4, 2.0 Hz, 1 H), 6.91 - 7.03 (m, 2H), 6.80 (d, J = 8.0 Hz, 1H), 5.72 (dd, J = 18.0, 1.6 Hz, 1 H), 5.23 (dd, J = 12.0, 1.2 Hz, 1 H), 4.13 (t, J = 5.6 Hz, 2 H), 3.94 (t, J = 5.2 Hz, 2 H), 2.44 (s, 3 H), 1.85 - 1.89 (m, 4 H; 13 C NMR (100 MHz, CDCl3): δ 155.8, 144.7, 133.0, 131.5, 129.8, 128.8, 127.8, 126.7, 126.4, 120.7, 114.3, 111.8, 70.1, 67.0, 25.8, 25.3, 21.6; HRMS-ESI (m/z): calcd. for C19H22NaSO4 [M+Na] +  369.1137, found 369.1140.       2-(4-(2-Vinylphenoxy)butyoxy)isoindoline-1,3-dione (3.1h): To a stirred solution of 4-(2- vinylphemoxy)butyl4-methylbenzenesulfonate (3.31) (220 mg, 0.60 mmol), N- hydroxyphthalimide (147 mg, 0.90 mmol) in DMF (3 mL) was added diisopropylethylamine (155 mg, 1.20 mmol). The resulting mixture was then heated to 90 °C and stirred for 2 h. The solution was cooled to room temperature. The reaction was quenched with H2O (10 mL), extracted with Et2O (3 × 10 mL). The combined organic layers were washed with H2O (10 mL), NaHCO3 (10 mL), brine (10 mL) and dried over Na2SO4. The organic layer was filtered and concentrated by rotary evaporation. The product was purified by flash column chromatography (4:1 hexanes/EtOAc) to yield title compound as a colorless oil (520 mg, 75%). IR (film): 2917, 1734, 1369, 1256, 1069, 1026 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 7.83 - 7.87 (m, 2 H), 7.75 - 7.78 (m,  2 H), 7.47 (dd, J = 7.6, 1.6 Hz, 1 H ), 7.22 (dt, J = 8.0, 1.6 Hz, 1 H), 7.02 - 7.09 (m, 1H), 6.88 - 6.95 (m, 2H), 5.73 (dd, J = 18.0, 1.6 Hz, 1 H), 5.23 (dd, J = 11.0, 1.6 Hz, 1 H), 4.31 (t, J = 6.0 Hz, 2 H), 4.11 (t, J = 6.0 Hz, 2 H), 2.17 - 2.14 (m, 2 H), 1.98 - 2.05 (m, 2 H); 13 C NMR (100 MHz, CDCl3): δ 163.6, 156.0, 134.4, 131.6, 129.1, 128.9, 126.9, 126.5, 123.6, 120.7, 112  114.4, 112.0, 78.1, 67.6, 25.7, 25.2; HRMS-ESI (m/z): calcd. for C20H19NaNO4 [M+Na] +  360.1212, found 360.1220. Synthesis of 3.1i       2-(4-(2-Allylphenoxy)butyoxy)isoindoline-1,3-dione (3.1i): To a stirred solution of 4-(2- allyphenoxy)butan-1-ol (3.33) (400 mg, 1.94 mmol) in anhydrous THF (60 mL) at 0 °C was sequentially added triphenylphosphine (763 mg, 2.91 mmol) and N-hydroxyphthalimide (474 mg, 2.91 mmol). The solution was stirred until the solids had dissolved, at which point diisopropylazodicarboxylate (0.68 mL, 3.56 mmol) was added dropwise via syringe pump (0.81 mL/h). The resulting yellow solution was stirred for 12 h at ambient temperature, and was then quenched with H2O (50 mL). The aqueous layer was extracted with EtOAc (3 × 50 mL), and the combined organic layers were washed with NaHCO3 (3 × 50 mL), brine (50 mL) and dried over Na2SO4. The organic layers were concentrated using rotary evaporation and purified by flash column chromatography (3:1 hexanes/EtOAc) to provide N-alkoxyphthalimide 3.1i as a colorless oil (615 mg, 90%). IR (film): 3065, 2939, 1791, 1734, 1595, 1495, 1452, 1373, 1247, 1186, 1130, 982, 873, 700 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 7.83 - 7.85 (m, 2 H), 7.74 - 7.76 (m,  2 H), 7.13 - 7.21 (m, 2 H ), 6.86 - 6.91 (m, 2 H), 5.93 - 6.03 (m, 1H), 4.99 - 5.07 (m, 2H), 4.31 (t, J = 6.0 Hz, 2 H), 4.08 (t, J = 4.0 Hz, 2 H), 3.39 (d, J = 8.0 Hz, 2 H), 1.98 - 2.12 (m, 4 H); 13 C NMR (100 MHz, CDCl3): δ 163.6, 156.5, 137.0, 134.4, 129.7, 128.9, 128.6, 127.2, 123.4, 120.4, 115.2, 111.1, 78.0, 67.0, 34.3, 25.6, 25.0; HRMS-ESI (m/z): calcd. for C21H21NaNO4 [M+Na] +  374.1368, found 374.1357. 113  3.5.4 General cyclization procedures      To a 0.02 M solution of cyclization precursors in degassed benzene at reflux was added a 0.2 M solution of tributyltin hydride (1.2 equiv) and AIBN (0.15 equiv) in degassed benzene by syringe pump (0.4 mL/h). The reaction was then stirred for an additional 2 h at refluxing. 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 and linear alcohols as a colorless oil. The product mixture was then dissolved in CH2Cl2 (0.3 M) and cooled to 0 °C. m-CPBA (3 equiv) was added in one portion. The resulting mixture was allowed to warm to ambient temperature and stirred overnight. The reaction was quenched with 2.0 M Na2S2O3 (10 mL), washed with saturated aqueous Na2CO3 (3 × 5 mL), H2O (5 mL), dried over Na2SO4, and concentrated by rotary evaporation. The cyclized products were purified by flash column chromatography. The relative configuration of the cyclized products was determined using nOe experiments and the major diastereomer is shown.       tert-Butyldimethyl-4-(3-methyltetrahydrofuran-2-yl)butan-2-ol (3.6b): N- Alkoxyphthalimide 3.1b (285 mg, 0.93 mmol) was subjected to the general cyclization procedure. The crude mixture in CH2Cl2 (20 mL) was sequentially added triethylamine (303 mg, 3.00 mmol) and diphenylmethylsilylchloride (349 mg, 1.50 mmol). The resulting solution was stirred overnight. The solvent was evaporated and the residue was dissolved in Et2O (20 mL). The organic layer was washed with NaHCO3 (20 mL), brine (20 mL), dried over Na2SO4, and concentrated using rotary evaporation. The crude product was purified using flash column 114  chromatography (10:1 hexanes/EtOAc) to afford tetrahydrofuran 3.6b as a colorless oil (180 mg, 55%, two steps, cis:trans = 93:7). IR (film): 2960, 2869, 1430, 1369, 1256, 1121, 1069, 1004, 800, 739, 700 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 7.61 - 7.68 (m, 4 H), 7.36 - 7.44 (m, 6 H), 3.94 - 4.04 (m, 1 H), 3.87 - 3.93 (m, 0.92 H), 3.76 - 3.84 (m, 0.11 H), 3.62 - 3.75 (m, 2 H), 2.13 - 2.23 (m, 1 H), 2.01 - 2.12 (m, 1 H), 1.66 - 1.84 (m, 1 H), 1.47 - 1.66 (m, 1 H), 1.35 - 1.47 (m, 1 H), 1.20 (d, J = 6.1 Hz, 3 H), 1.02 (d, J = 6.1 Hz, 0.21 H), 0.88 (t, J = 6.5 Hz, 2.80 H), 0.69 (d, J = 1.4 Hz, 3 H); 13 C NMR (100 MHz, CDCl3): δ 136.8, 136.8, 134.4, 134.4, 129.6, 127.7, 81.9, 81.4, 69.7, 69.1, 65.9, 65.9, 36.7, 36.2, 35.2, 35.2, 33.8, 33.8, 27.0, 26.1, 23.8, 23.5, 14.1, 14.1, - 2.3; HRMS-ESI (m/z): calcd. for C22H31SiO2 [M+H] +  355.2093, found 355.2102.       3-(3-Methyl-5-(trityloxymethyl)-tetrahydrofuran-2-yl)propan-1-ol (3.6c): N- Alkoxyphthalimide 3.1b (262 mg, 0.47 mmol) was subjected to the general cyclization procedure. Purification by flash chromatography (5:1 hexanes/EtOAc) gave 138 mg (79%) of cyclopentane 3.6c (cis:trans = 89:11) as a colorless oil. IR (film): 3383, 3059, 3032, 2933, 2870, 1641, 1597, 1490, 1448, 1348, 1318, 1220, 1183, 1154, 1072, 1033, 1001, 913, 774, 764, 746, 706, 646, 633 cm –1 ;  1 H NMR (400 MHz, CDCl3):  7.52 (d, J = 7.5 Hz, 6H), 7.24 - 7.37 (m, 9H), 4.21 - 4.39 (m, 0.12 H), 4.08 - 4.18 (m, 0.89 H), 3.91 (ddd, J = 9.8, 6.6, 2.9 Hz, 0.88H), 3.81 - 3.86 (m, 0.09 H), 3.61 - 3.77 (m, 1.93 H), 3.41 - 3.53 (m, 0.10 H), 3.26 (dd, J = 9.4, 6.1 Hz, 0.88H), 3.14 - 3.20 (m, 0.10 H), 3.09 (dd, J = 9.6, 4.4 Hz, 0.92H), 2.66 (br, s., 0.76 H), 2.34 (dt, J = 13.9, 6.9 Hz, 0.93H), 2.11 - 2.20 (m, 1H), 1.70 - 1.77 (m, 0.87H), 1.72 - 1.82 (m, 2.04 H), 1.56 - 1.71 (m, 1.52 H), 1.43 - 1.54 (m, 0.8 H), 1.23 - 1.43 (m, 2 H), 1.05 - 1.12 (m, 0.20 H), 0.95 115  (d, J = 7.0 Hz, 2.82 H); 13 C NMR (100 MHz, CDCl3):  144.1, 128.8, 127.7, 126.9, 86.4, 82.1, 77.5, 67.0, 63.0, 36.5, 35.8, 30.6, 28.4, 15.2; HRMS-ESI (m/z): calcd. for C36H40O4Na [M+Na] +  439.2249, found 439.2244.       3-(3-Benzyltetrahydrofuran-2-yl)propan-1-ol (3.6d, Table 3.1, entry 4): N- Alkoxyphthalimide 3.1d (111 mg, 0.30 mmol) was subjected to the general cyclization procedure. Purification by flash column chromatography (4:1 hexanes/EtOAc) afforded 3.6d as a colorless oil (50 mg, 75%, cis:trans = 83:17). 1 H NMR (400 MHz, CDCl3): δ 7.27 - 7.23 (m, 2 H), 7.17 - 7.22 (m, 3 H), 3.89 - 3.99 (m, 1.82 H), 3.82 - 3.85 (m, 0.24 H), 3.61 - 3.78 (m, 2.75), 3.53 - 3.57 (m, 0.14 H), 2.84 (dd, , J = 12.0, 4.0 Hz, 0.85 H), 2.76 - 2.81 (m, 0.15 H), 2.55 - 2.61 (m, 1.01 H), 2.38 – 2.52 (m, 1.75 H), 1.95 - 2.09 (m, 0.32 H), 1.82 - 1.92 (m, 0.78 H), 1.64 - 1.78 (m, 3.69 H), 1.53 - 1.62 (m, 0.84 H); 13 C NMR (100 MHz, CDCl3): δ 140.8, 128.8, 128.7, 128.4, 126.1, 126.0, 84.1, 81.5, 66.7, 66.2, 62.9, 62.8, 46.2, 43.1, 39.0, 34.6, 32.5, 31.6, 30.5, 30.4, 29.9, 27.8.      3-(3-Benzyltetrahydrofuran-2-yl)propan-1-ol (3.6d, Table 3.1, entry 5): N- Alkoxyphthalimide 3.1d (110 mg, 0.30 mmol) was subjected to the general cyclization procedure. Purification by flash column chromatography (4:1 hexanes/EtOAc) afforded 3.6d as a colorless oil (50 mg, 75%, cis:trans = 89:11). IR (neat): 3381, 2934, 2869, 1608, 1500, 1460, 1386, 1352, 1256, 1065, 1021, 800, 752, 704 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 7.27 - 7.23 (m, 2 H), 7.17 - 7.22 (m, 3 H), 3.89 - 3.99 (m, 1.83 H), 3.82 - 3.85 (m, 0.28 H), 3.61 - 3.78 (m, 2.98), 3.53 - 3.57 (m, 0.15 H), 2.84 (dd, , J = 12.0, 4.0 Hz, 0.94 H), 2.76 (br, s., 1 H), 2.38 - 2.61 (m, 1.86 H), 1.95 - 2.09 (m, 0.32 H), 1.82 - 1.92 (m, 1.44 H), 1.64 - 1.78 (m, 4.35 H), 1.53 - 1.62 116  (m, 0.92 H); 13 C NMR (100 MHz, CDCl3): δ 140.8, 128.8, 128.7, 128.4, 126.1, 126.0, 84.1, 81.5, 66.7, 66.2, 62.9, 62.8, 46.2, 43.1, 39.0, 34.6, 32.5, 31.6, 30.5, 30.4, 29.9, 27.8; HRMS-ESI (m/z): calcd. for C14H20O2Na [M+Na] +  243.1361, found 243.1363.       3-(3-(((tert-Butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)propan-1-ol (3.6e): N- Alkoxyphthalimide 3.1e (23.0 mg, 0.05 mmol) was subjected to the general cyclization procedure. Purification by flash column chromatography (3:1 hexanes/EtOAc) afforded tetrahydrofuran 3.6e as a colorless oil (8.8 mg, 60%, cis:trans = 70:30). IR (film): 3375, 2527, 2855, 1259, 1215, 1192, 749 cm -1 ; 1 H NMR (400 MHz, CDCl3) δ 3.83 (td, J = 8.3, 5.6 Hz, 0.72 H), 3.74 - 3.80 (m, 1.0 H), 3.54 - 3.73 (m, 4.33 H), 3.44 - 3.18 (m, 1 H), 2.21 - 2.27 (m, 0.69 H), 2.15 - 2.18 (m, 0.33 H), 2.04 - 2.07 (m, 0.66), 1.89 - 1.95 (m, 0.32 H), 1.66 - 1.74 (m, 5 H), 1.35 (s, 1 H), 1.06 (s, 6.34 H ), 1.05 (s, 2.67 H), 0.13 (s, 4.13 H), 0.11 (s, 1.87 H); 13 C NMR (100 MHz, CDCl3): δ 82.6, 81.3, 67.2, 66.5, 65.2, 63.2, 63.2, 62.9, 47.5, 44.7, 33.1, 32.3, 31.7, 31.0, 30.0, 29.5, 28.0, 26.4, 23.4, 18.8, 18.8, 14.7, -5.0, -5.0; HRMS-ESI (m/z): calcd. for C14H30O3Na [M+Na] +  297.1862, found 297.1859.       3-(4-Phenyltetrahydro-2H-pyran-2-yl)propan-1-ol (3.6g): N-Alkoxyphthalimide 3.1g (212 mg, 0.58 mmol) was subjected to the general cyclization procedure. Purification by flash column chromatography (1:1 hexanes/EtOAc) afforded 3.6g as a colorless oil (126 mg, 65%, cis:trans>5:95). IR (neat): 3373, 2943, 2852, 1734, 1452, 1373, 1265, 1073, 921, 800, 760, 717 117  cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 7.37 - 7.30 (m, 2 H), 7.25 - 7.20 (m, 3 H), 4.15 (td, J = 3.2, 11.3 Hz, 1 H), 3.73 - 3.56 (m, 3 H), 3.50 - 3.43 (m, 1 H), 2.85 - 2.75 (m, 1 H), 2.50 (t, J = 5.8 Hz, 1 H), 1.86 - 1.46 (m, 10 H); 13 C NMR (100 MHz, CDCl3): δ 145.6, 128.5, 126.7, 126.3, 77.9, 68.2, 62.9, 41.7, 39.5, 33.5, 33.3, 29.3; HRMS-ESI (m/z): calcd. for C14H20O2Na [M+Na] + 243.1361, found 243.1357.       tert-Butyldimethyl(3-(3-methyl-2,3-dihydrobenzofuran-2yl)propoxy)silane (3.6h): N- Alkoxyphthalimide 3.1h (88.0 mg, 0.33 mmol) was subjected to the general cyclization procedure. The crude mixture was sequentially added imidazole (45.0 mg, 0.66 mmol) and tert- butyldimethylsilylchloride (137 mg, 0.50 mmol) and stirred overnight. The solvent was evaporated and the residue was dissolved in Et2O (50 mL). The organic layer was washed by brine (20 mL), dried over Na2SO4, and concentrated using rotary evaporation. The crude product was purified using flash column chromatography (4:1 hexanes/EtOAc) to afford silyl ether 3.6h as a colorless oil (28 mg, 28%, two steps). IR (film): 2917, 1734, 1369, 1256, 1069, 1026 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 7.12 - 7.16 (m, 2H), 6.77 - 6.88 (m, 2H), 4.64 - 4.70 (m, 0.61 H), 4.27 - 4.31 (m, 0.37 H), 3.95 - 4.05 (m, 0.33 H), 3.67 - 3.77 (m, 2.43 H), 3.38 - 3.42 (m, 0.60 H), 3.13 - 3.20 (m, 0.37 H), 1.72 - 1.84, (m, 4.71 H), 1.19 (d, J = 6.8 Hz, 1.07 H), 1.87 (d, J = 7.2 Hz, 1.72 H) 0.92 (s, 9 H), 0.08 (s, 6 H); 13 C NMR (100 MHz, CDCl3): δ 158.7, 133.6, 132.4, 127.9, 127.9, 124.1, 123.8, 120.3, 120.1, 109.4, 109.3, 90.9, 86.4, 62.9, 62.8, 42.2, 39.0, 31.4, 29.7, 28.8, 26.3, 26.0, 19.0, 18.3, 15.2, -5.3; LRMS-ESI (m/z): calcd. for C12H17O2 [M+H] +  193.1, found 193.4. 118        3-(3-Methylchroman-2-yl)propan-1-ol (3.6i): N-Alkoxyphthalimide 3.1i (62 mg, 0.18 mmol) was subjected to the general cyclization procedure. Purification by flash column chromatography (4:1 hexanes/EtOAc) afforded benzopyran 3.6i as a colorless oil (34 mg, 60%, cis:trans = 43:57). 1 H NMR (400 MHz, CDCl3): δ 7.05 - 7.12 (m, 3.4 H), 6.80 - 6.88 (m, 3.4 H), 4.04 - 4.07 (m, 0.7 H), 3.71 - 3.74 (m, 4.76 H), 2.99 (dd, J = 16.0, 4.0 Hz, 0.69 H ), 2.79 (, J = 16.0, 4.0 Hz, 1 H), 2.45 - 2.53 (m, 1.75 H), 2.23 (br. s, 1.6 H), 2.1 - 2.2 (m, 1.24 H), 1.85 - 1.95 (m, 4 H), 1.61 - 1.84 (m, 5 H), 1.06 (d, J = 8.0 Hz, 3 H), 0.99 (d, J = 8.0 Hz, 2.1 H); 13 C NMR (100 MHz, CDCl3): δ 154.2, 153.9, 130.0, 129.3, 127.0, 127.0, 121.9, 121.0, 120.2, 12.0, 116.3, 116.2, 80.6, 78.4, 62.7, 62.6, 33.0, 32.6, 30.7, 29.6, 29.3, 29.0, 28.1, 27.6, 17.6, 13.3; HRMS-ESI (m/z): calcd. for C13H18NaO2 [M+Na] +  229.1204, found 229.1209.        119  Chapter  4: Diastereoselective Construction of Functionalized Tetrahydrofurans using a New Substrate Substitution Pattern      We have previously demonstrated that radical relay cyclizations initiated by alkoxy radicals are powerful methods for rapid construction of carbo- and oxacycles. However, one drawback of alkoxy radical-initiated 5-exo cyclizations is that the precursor needs a seven-atom chain between the alkoxy radical and the radical acceptor (4.1 in Figure 4.1). Long chains between the alkoxy radical and the acceptor, such as 4.2 in Figure 4.1, require an initial 1,6-hydrogen atom translocation to enable the subsequent 5-exo cyclization. Because the rate of 1,5-hydrogen atom transfer by alkoxy radicals is on the order of 10 8 s -1 , 66 the rate of 1,6-hydrogen atom abstraction by alkoxy radicals must be at least on the order of 10 9 s -1 for relay cyclization substrate 4.2 to be synthetically viable.  Figure 4.1. Radical relay cyclization challenges.      Another limitation of these radical relay cyclizations is branched substrates, as shown in Figure 4.1 (4.3, Type B). For these substrates, direct cyclization reactions are usually faster and outcompete the desired 1,5-HAT. 76 A competition study, performed by Joe Leung in the Sammis group, showed that the ratio of the direct cyclization intermediate (4.5) and the 1,5-hydrogen atom translocation intermediate (4.6) is approximately 15:1 (Scheme 4.1). 120   Scheme 4.1. Competition between 5-exo cyclization and 1,5-HAT.      For these alkoxy-initiated 1,5- or 1,6-hydrogen atom translocation and subsequent cyclization reactions to be synthetically useful, there needs to be a general controlling factor to increase the chemoselectivity of the initial hydrogen atom translocation. One possible solution to increase the chemoselectivity is through the strategic incorporation of an oxygen atom into the cyclization precursors. It is well known that oxygen atoms stabilize radicals on adjacent carbons. 77 This stabilization can be described in Valence Bond Theory by electron delocalization through the formation of a resonance structure (Figure 4.2). 78  The stability of the α-carbon radical adjacent to an oxygen atom can also be explained by Linnett Theory, 79 whereby both oxygen and carbon atoms have filled their valence shells.  Figure 4.2. Stabilization of an α-carbon radical. 4.1 Results and discussion 4.1.1 Competition of 1,6-HAT and 1,5-HAT      To overcome these challenging problems and further expand the reaction scope, we first investigated chemoselective 1,6-hydrogen atom translocation over 1,5-hydrogen atom translocation through strategic oxygen atom incorporation into the substrates. We began our investigations with a simple system (Scheme 4.2). Alkoxy radical 4.10 may lead to different 121  oxacycles through two possible pathways. It may undergo 1,5-hydrogen atom translocation and subsequent 6-exo cyclization to obtain tetrahydropyran derivative 4.12 (Scheme 4.2, Path A). Alternatively, the dative control contributed by an oxygen atom would offer the opportunity of 1,6-hydrogen atom translocation to form radical intermediate 4.13, which would then undergo 5- exo cyclization to afford tetrahydrofuran derivative 4.14 (Scheme 4.2, Path B). 80   Scheme 4.2. Two possible radical relay cyclization pathways.      To investigate whether the oxygen’s dative stabilization can enable the 1,6-hydrogen atom translocation to outcompete the generally dominant 1,5-hydrogen atom translocation, we tested the cyclization of precursor 4.16 (Scheme 4.3). Using the previously optimized relay cyclization conditions, precursor 4.16 cleanly cyclized to tetrahydrofuran 4.14 in 66% isolated yield as an 80:20 ratio of isomers. It is noteworthy that no trace of tetrahydropyran 4.12 was observed by 1 H NMR spectroscopic analysis.   Scheme 4.3. Radical relay cyclization initiated by 1,6-HAT. 122       The fact that no cyclization product tetrahydropyran derivative 4.12 was observed does not eliminate the possibility of 1,5-hydrogen atom transfer. Since a small amount of the direct reduction product 4.15 was also obtained, it may be possible that this reduced linear product came from the quenching of the radical intermediate 4.11. To examine if this linear product came from the radical intermediate 4.11 or another radical intermediate 4.13, we then tested the cyclization of allyl ether radical 4.17 (Scheme 4.4), in which the oxygen atom was one carbon shorter to the radical acceptor than in previous cyclization precursor 4.10. If the 1,5-hydrogen atom translocation outcompetes the 1,6-hydrogen atom translocation, then the reaction would proceed through path A, and the resulting radical intermediate 4.20 would undergo a 5-exo cyclization, which is faster than the direct hydrogen quench, to lead to final tetrahydrofuran derivative 4.21. However, if 1,6-hydrogen atom transfer is dominant, then the resulting radical intermediate (4.18) would not be able to cyclize to form the oxacycle, as the radical is too close to the radical acceptor and the reaction would go through path B to get the direct quenched product (4.19). Under our radical relay cyclization conditions, N-alkoxyphthalimide 4.22 was transformed exclusively to the corresponding linear alcohol 4.19 (Scheme 4.5).  Scheme 4.4. Competition between 1,6-HAT and 1,5-HAT. 123   Scheme 4.5. Reaction of oxygen-transposed substrate 4.22. 4.1.2 Altering the substitution pattern of the radical relay cyclization precursors      We next turned our attention to the radical relay cyclization initiated by alkoxy radicals of branched substrates. As discussed in Chapter 1.4, other than 1,5-hydrogen atom translocation reactions, there are two other significant competing radical pathways: (1) direct 5-exo cyclization with the radical acceptors and (2) β-fragmentation (Scheme 4.6). When the oxygen atom is replaced with methylene group (X = CH2, 4.23, Scheme 4.6), the rate of direct cyclization initiated by an alkoxy radical onto an alkene would be sufficiently fast to compete with the desired 1,5-hydrogen atom translocation. The dominant reaction would be through the direct cyclization pathway to afford 4.27. Another competing reaction is the β-fragmentation reaction, which would provide 4.29. Incorporation of an oxygen atom into the substrates should increase the rate of the 1,5-HAT pathway relative to direct cyclization through dative stabilization, to bias the formation of cyclization product 4.25. 124   Scheme 4.6. Competing radical pathways initiated by alkoxy radicals.      The precursors (4.23) (X = O) can be easily prepared in only a few steps from commercially available epoxides or aldehydes. Secondary alcohols 4.32 were synthesized through the ring- opening of epoxides (4.30) with metal alkenes or alkynes, or through allylation of aldehydes (4.31). The following alkylation, desilylation and a Mitsunobu reaction afforded branched substrates 4.23. This synthetic route allows for the formation of enantioenriched products as the corresponding starting chiral epoxides are readily available (Scheme 4.7).  Scheme 4.7. Synthesis of enantioenriched tetrahydrofurans 4.25. 125   Table 4.1. Competition study among relay cyclization, direct cyclization and fragmentation.   entry substrate 4.25 (%) (a)  4.27 (%) (a),(d)  4.29 (%) (a)  T (°C) (e)  1  >95(74) (b)  <5 <5 90 2  88(70) (b)  12 0 90 3  25(20) (c) 44 31 90 4 25 53 22 70 5 27 53 20 60  6  30(25) (c)  27 43 90 7 39 21 40 60    8  41(34)  (c) 32 27 90 9 60 19 21 70 10 72(62)  (c)  11 17 60    11  38(25)  (c)  38 24 90 12 61 22 17 60 (a) Determined by 1 H NMR analysis. (b) The number in bracket indicates the isolated yield after flash column chromatography. (c) The relay cyclization products are volatile, so the substrates were protected first as tertbutyldiphenylsilyl ethers prior to isolation. The number in the bracket indicates the isolated yield after this two- step procedure. (d) The direct cyclization product can undergo several subsequent radical reactions. The reported yield represents all subsequent products resulting from an initial direct cyclization. See Appendix E for details. (e) This number refers to the temperature of the oil bath, not the internal reaction temperature.      We first examined the cyclization of the substrates with a phenyl group alpha to an oxygen atom (Table 4.1, entry 1). With the presence of the oxygen atom and the phenyl group, the resulting benzylic radicals (4.24, R = Ph, Scheme 4.6) should provide capto-dative 79  stabilization 126  to compete with the formation of 4.26 and 4.28, which result from the direct cyclization and the β-fragmentation, respectively. Cyclization of 4.23a afforded the formation of the radical relay cyclization product (4.25a) in 74% isolated yield as 53:45:2 mixtures of diastereomers, with no formation of either direct cyclization or β-fragmentation products. Cyclization of substrate 4.23b with an alkyne as the acceptor provided the radical relay product (4.25b) in 88% NMR yield (70% isolated yield) as a single all-cis stereoisomer. Direct cyclization product was also formed in 12% NMR yield.      We next tested substrates containing only the alkyl group alpha to the oxygen atom. These substrates have only dative stabilization effect with no other functional groups alpha to the oxygen atom. Cyclization of 4.23c (entry 3) provided the radical relay cyclization product (4.25c) as the minor product (25% NMR yield), as well as the direct cyclization product (44% NMR yield) and the β-fragmentation product (31% NMR yield). We then performed the reactions at various specific lower temperatures. At 70 °C, cyclization of 4.23c provided the radical relay cyclization product with no yield change (entry 4). Decreasing the temperature further to 60 °C, the yield of the radical relay cyclization product slightly increased (entry 5). Further lowering the temperature did not initiate the reactions effectively using tributyltin hydride or triethylborane. When the radical acceptor was changed to an alkyne, similar results in temperature effects were observed (entries 6 and 7).      Finally, the substrates with a longer alkyl chain alpha to the oxygen atom were examined under different temperature conditions. Under the standard thermal condition (90 °C), cyclization of 4.23e provided radical relay cyclization product 4.25e with a higher yield compared to 4.23c, but only 41% NMR yield was obtained (entry 8). Lowering the temperature to 70 °C resulted in the formation of the radical cyclization product in a higher NMR yield with a small decrease in 127  the formation of the direct cyclization and the β-fragmentation products (entry 9). When we further decreased the temperature to 60 °C, the yield of the radical relay cyclization product increased dramatically. The desired radical relay cyclization product (4.25e) was obtained as a 93:7 mixture favoring the all-cis diastereoisomer (entry 10). With an alkyne as the acceptor, cyclization of substrate 4.23f provided radical relay cyclization product 4.25f in 38% NMR yield (entry 11). When the temperature decreased to 60 °C, a similar trend was observed with a 61% NMR yield of the radical relay cyclization product in an 85:15 ratio of cis to trans isomers (entry 12). 4.2 Future work      We demonstrated that a higher yield of radical relay cyclization products could be achieved compared to both 5-exo direct cyclization products and β-fragmentation products by decreasing the reaction temperature to 60 °C. While all three radical pathways are related to different temperature conditions, we proposed that lowering the temperature could further increase the yields of the radical relay cyclization products. However, neither tributyltin hydride and AIBN nor triethylborane initiated radical relay cyclizations effectively at temperature lower than 60 °C. A suitable low temperature initiator is the key to control the reaction pathways. Fortunately, a combination of tributyltin hydride and triethylborane is known to initiate radical reactions at room temperature. 82c  This combination will enable us to investigate how varying temperature will affect the three reaction pathways: radical relay cyclization, 5-exo direct cyclization and β- fragmentation reactions at temperatures lower than 60 °C. 4.3 Conclusion      We successfully demonstrated that we can expand the scope of alkoxy radical-initiated radical relay cyclizations by utilizing dative stabilization with strategic placement of an oxygen atom 128  into the cyclization precursors. This dative effect can not only increase the rate of 1,6-hydrogen atom transfer over the well-known 1,5-hydrogen atom transfer, but also it can lead to the desired 1,5-hydrogen atom transfer over both the dominant 5-exo cyclization and the competing β- fragmentation pathways.      In summary, our studies in this chapter clearly proved that the dative effect through the strategic incorporation of an oxygen atom into the cyclization precursors significantly increases the scope of the radical relay cyclization methodology and provides a general strategy for the synthesis of functionalized tetrahydrofuran derivatives.                129  4.4 Experimental 4.4.1 General methods      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. All other solvents were used without further purification. Thin layer chromatography (TLC) was performed on Whatman Partisil K6F UV254 pre-coated TLC plates. Chromatographic separations were effected over Fluka 60 silica gel. The silica gel was basified by stirring with triethylamine prior to packing and then sequentially flushed with the solvent system of choice. All reagents were purchased from commercial sources and used as received. 4.4.2 Instrumentation      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 (IR) spectra were obtained using a Thermo Nicolet 4700 FTIR spectrometer. Proton nuclear magnetic resonance ( 1 H NMR) spectra were recorded using a Bruker AV-300 or AV-400 spectrometer. Carbon nuclear magnetic resonance ( 13 C NMR) spectra were recorded 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 d6-chloroform (7.27 ppm 1 H NMR; 77.0 ppm 13 C NMR) or d6-benzene (7.16 ppm 1 H NMR; 128.1 ppm 13 C NMR). High resolution mass spectra (HRMS) were recorded on a Waters/Micromass LCT spectrometer.    130  4.4.3 Synthesis of precursors N-hydroxyphthalimides Synthesis of 4.16       2-((5-(But-3-en-1-yloxy)pentyl)oxy)isoindoline-1,3-dione (4.16): To a stirred solution of alcohol 4.36 (130 mg, 0.82 mmol) in regular THF (20 mL) was sequentially added triphenylphosphine (322 mg, 1.23 mmol) and N-hydroxyphthalimide (200 mg, 1.23 mmol). The solution was stirred until the solids were dissolved, at which point diisopropylazodicarboxylate (0.29 mL, 297 mg, 1.47 mmol) was added via syringe pump (0.8 mL/h). The resulting yellow solution was stirred for 12 h at ambient temperature, and was then quenched with H2O (10 mL). The aqueous layer was extracted with EtOAc (3 × 20 mL), and the combined organic layers were washed with NaHCO3 (3 × 20 mL), brine (20 mL) and dried over Na2SO4. The organics were concentrated using rotary evaporation and purified by flash column chromatography (4:1 hexanes/EtOAc) to provide N-alkoxyphthalimide 4.15 as a colorless oil (186 mg, 69%). IR (film): 2943, 2856, 1795, 1726, 1473, 1378, 1191, 1117, 982, 886, 704 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 7.82 - 7.84 (m, 2 H), 7.72 - 7.74 (m, 2 H), 5.78 - 5.86 (m, 1 H), 5.02 - 5.07 (m, 2 H), 4.21 (t, J = 6.7 Hz, 2 H), 3.43 - 3.49 (m, 4 H), 2.30 - 2.36 (m, 2 H), 1.82 (quin, J = 7.1 Hz, 2 H), 1.62 - 1.69 (m, 2 H), 1.53 - 1.61 (m, 2 H); 13 C NMR (100 MHz, CDCl3): δ 163.6, 135.3, 134.4, 128.9, 123.4, 116.2, 78.4, 70.6, 70.1, 34.2, 29.3, 27.9, 22.2; HRMS-ESI (m/z): calcd. for C17H21NNaO4 [M+H] + 304.1549, found 304.1544.   131  Synthesis of 4.22       2-((5-(Allyloxy)pentyl)oxy)isoindoline-1,3-dione (4.22): To a stirred solution of alcohol 4.19 (310 mg, 2.15 mmol) in regular THF (20 mL) was sequentially added triphenylphosphine (844 mg, 3.22 mmol) and N-hydroxyphthalimide (525 mg, 3.22 mmol). The solution was stirred until the solids were dissolved, at which point diisopropylazodicarboxylate (0.76 mL, 782 mg, 3.86 mmol) was added via syringe pump (0.8 mL/h). The resulting yellow solution was stirred for 12 h at ambient temperature, and was then quenched with H2O (10 mL). The aqueous layer was extracted with EtOAc (3 × 20 mL), and the combined organic layers were washed with NaHCO3 (3 × 20 mL), brine (20 mL) and dried over Na2SO4. The organics were concentrated using rotary evaporation and purified by flash column chromatography (5:1 hexanes/EtOAc) to provide N-alkoxyphthalimide 4.22 as a colorless oil (400 mg, 64%). IR (film): 2943, 2860, 1791, 1730, 1465, 1365, 1191, 1126, 1078, 986, 873, 704 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 7.79 - 7.84 (m, 2 H), 7.70 - 7.76 (m, 2 H), 5.82 - 5.97 (m, 1 H), 5.12 - 5.27 (m, 2 H), 4.19 (t, J = 6.7 Hz, 2 H), 3.94 (d, J = 5.4 Hz, 2 H), 3.44 (t, J = 6.4 Hz, 2 H), 1.76 - 1.86 (m, 2 H), 1.61 - 1.69 (m, 2 H), 1.51 - 1.60 (m, 2 H); 13 C NMR (100 MHz, CDCl3): δ 163.5, 134.9, 134.5, 128.8, 123.3, 116.4, 78.3, 71.7, 69.9, 29.3, 27.9, 22.2; HRMS-ESI (m/z): calcd. for C16H20NO4 [M+H] + 290.1392, found 290.1397.    132  Synthesis of  4.23a       1-((tert-Butyldimethylsilyl)oxy)pent-4-en-2-ol (4.32a): To a stirred solution of CuI (474 mg, 2.50 mmol) in dry THF (25 mL) was added vinylmagnesium bromide (50 mL, 50 mmol). The mixture was stirred at room temperature for half h, and was then cooled to –78 °C. tert- Butyldimethyl(oxiran-2-ylmethoxy)silane (4.30) (4.70 g, 24.9 mmol) in dry THF (15 mL) was added to the mixture dropwise through additional funnel. The resulting solution was warmed to room temperature and stirred overnight. The reaction was quenched by addition of NH4Cl (50 mL) at 0 °C. The mixture was extracted with Et2O (3 × 50 mL). The combined organic layers were washed with H2O (50 mL), brine (50 mL), dried over Na2SO4, and concentrated using rotary evaporation. The crude compound was purified by flash column chromatography (10:1 hexanes/EtOAc) to provide title compound 4.32a as a colorless oil (4.04 g, 75%). IR (film): 3428, 2933, 2853, 1478, 1432, 1108, 917, 817 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 5.81 - 5.89 (m, 1H), 5.07 - 5.14 (m, 2 H), 3.69 - 3.75 (m, 1 H), 3.63 (dd, J = 12.0, 4.0 Hz, 1 H), 3.45 (dd, J = 12.0, 4.0 Hz, 1 H), 2.43(d, J = 4.0 Hz, 1 H), 2.22 - 2.26 (m, 2 H), 0.91 (s, 9 H), 0.08 (s, 6 H); 13 C NMR (100 MHz, CDCl3): δ 134.5, 117.4, 71.1, 66.5, 37.6, 25.9, 18.3, -5.4; HRMS-ESI (m/z): calcd. for C13H29NaSiO2 [M+Na] +  245.1937, found 245.1935.   133        2-((2-(Benzyloxy)pent-4-en-1-yl)oxy)isoindoline-1,3-dione (4.23a): To a stirred solution of NaH (554 mg, 13.8 mmol) in dry DMF/THF (25/5 mL) at room temperature was added a solution of 1-((tert-butyldiphenylsilyl)oxy)pent-4-en-2-ol (4.32a) (2.00 g, 9.24 mmol) in dry THF (5 mL) dropwise over 10 min. The solution was stirred for an additional 30 min. BnBr (1.73 g, 10.1 mmol) was added and the solution was stirred overnight. The reaction was quenched with H2O (20 mL), and the aqueous layer was extracted with Et2O (3 × 20 mL). The combined organic layers were washed with H2O (50 mL), brine (25 mL), dried over Na2SO4, concentrated by rotary evaporation to afford a benzyl silyl alkene which was used for the next step without further purification.      The crude alkene in THF (20 mL) was added TBAF (12 mL, 12 mmol). The solution was stirred overnight. The reaction was quenched with H2O (20 mL), and the aqueous layer was extracted with Et2O (3 × 20 mL). The combined organic layers were washed with H2O (20 mL), brine (20 mL), dried over Na2SO4, concentrated by rotary evaporation, and purified by flash column chromatography (6:1 hexanes/EtOAc) to provide an alcohol as a colorless oil (800 mg, 45%). IR (film): 3404, 2921, 2865, 1717, 1634, 1456, 1352, 1269, 1069, 913, 743, 686 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 7.31 - 7.39 (m, 5H), 5.78 - 5.88 (m, 1H), 5.08 - 5,16 (m, 2H), 4.62 (AB quartet, νB = 4.6, νA = 4.5, JAB = 12.0 Hz, 2H), 3.68 - 3.72 (m, 1H), 3.54 - 3.61 (m, 2 H), 2.31 - 2.45 (m, 2H), 1.96 (t, J = 4 Hz, 1 H); 13 C NMR (100 MHz, CDCl3): δ 138.3, 134.0, 128.5, 134  127.8, 127.8, 117.6, 79.1, 71.6, 64.1, 35.3; HRMS-ESI (m/z): calcd. for C12H16NaO2 [M+Na] + 215.1048, found 215.1051.      To a stirred solution of the alcohol (170 mg, 0.88 mmol) in dry CH2Cl2 (5 mL) was sequentially added para-toluenesulfonyl chloride (202 mg, 1.06 mmol) and triethylamine (0.24 mL, 1.76 mmol). The resulting solution was stirred overnight. H2O (5 mL) was added and the reaction mixture was stirred for another 10 min. The organic layer was washed with aqueous saturated NaHCO3 (5 mL), H2O (5mL), brine (5 mL), and dried over Na2SO4. The organic layer was filtered and concentrated by rotary evaporation. The product was purified by flash column chromatography (10:1 hexanes/EtOAc) to yield the tosylate as a colorless oil (254 mg, 83%). IR (film): 2926, 1726, 1595, 1447, 1356, 1173, 1091, 978, 913, 813  cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 7.78 - 7.80 (m, 2 H), 7.26 - 7.35 (m, 7 H), 5.72 - 5.79 (m, 1 H), 5.05 - 5.09 (m, 2H), 4.54 (s, 2 H), 4.01 - 4.11 (m, 2 H), 3.66 - 3.71 (m, 1 H), 2.44 (s, 3 H), 2.29 - 2.32 (m, 2 H); 13 C NMR (100 MHz, CDCl3): δ 144.8, 137.9, 133.0, 129.8, 128.3, 127.9, 127.7, 127.7, 118.3, 98.9, 76.0, 72.0, 70.9, 35.6, 21.6; HRMS-ESI (m/z): calcd. for C19H22NaSO4 [M+Na] + 369.1137, found 369.1131.      To a stirred solution of the tosylate (242 mg, 0.69 mmol), N-hydroxyphthalimide (170 mg, 1.05 mmol) in DMF (3.5 mL) was added diisopropylethylamine (180 mg, 1.39 mmol). The resulting mixture was then heated to 90 °C and stirred overnight. The solution was cooled to room temperature and was quenched with H2O (20 mL), extracted with Et2O (3 × 20 mL). The combined organic layers were washed with H2O (10 mL), NaHCO3 (10 mL), brine (10 mL), and dried over Na2SO4. The organic layer was filtered and concentrated by rotary evaporation. The product was purified by flash column chromatography (6:1 hexanes/EtOAc) to yield title compound as a colorless oil (80 mg, 57%). IR (film): 3069, 2926, 2860, 1786, 1730, 1473, 1373, 135  1186, 1130, 1026, 991, 917, 878, 704 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 7.80 - 7.82 (m, 2 H), 7.72 - 7.74 (m, 2 H), 7.21 - 7.36 (m, 5 H), 5.84 - 5.94 (m, 1H), 5.11 - 5.20 (m, 2H), 4.71 (AB quartet, νB = 4.7, νA = 4.7, JAB = 12.0 Hz, 2H), 4.26 - 4.33 (m, 2 H), 3.91 - 3.96 (m, 1 H), 2.44 - 2.54 (m, 2 H); 13 C NMR (100 MHz, CDCl3): δ 163.4, 138.3, 134.4, 133.6, 128.9, 128.2, 127.8, 127.5, 123.5, 118.0, 79.9, 76.5, 71.9, 35.9; HRMS-ESI (m/z): calcd. for C20H20NO4 [M+H] + 338.1392, found 338.1385. Synthesis of 4.23b       1-((tert-Butyldimethylsilyl)oxy-5-(triethylsilyl)pent-4-yn-2-ol (4.32b): To a stirred solution of triethylsilylacetylene (1.11 g, 7.95 mmol) in dry THF (20 mL) at –78 °C was added a 1.6 M solution of butyllithium (5.00 mL, 7.95 mmol) dropwise over 10 min. The solution was stirred for an additional 30 min at –78 °C. Boron trifluoride diethyl etherate (1.00 mL, 1.13 g, 7.95 mmol) was added dropwise over 5 min and the solution was stirred for another 20 min. A solution of epoxide 4.30 (1.0 g, 5.3 mmol) in anhydrous THF (2.6 mL) was then added dropwise over 5 min. The resulting mixture was stirred for 1 h. The reaction was quenched with saturated aqueous NH4Cl (25 mL) and extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with brine (25 mL), dried over Na2SO4, concentrated by rotary evaporation, and purified by flash chromatography (20:1  hexanes/EtOAc) to afford alcohol 4.32b as a colorless oil (1.44 g, 83%). IR (film): 3421, 2956, 2873, 2169, 1460, 1265, 1121, 1017, 852, 817, 773, 717 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 3.74 - 3.63 (m, 2H), 3.64 - 3.68 (m, 1H), 2.43 - 2.56 (m, 3H), 0.99 (t, J = 8.0 Hz, 9 H), 0.92 (s, 9 H), 0.59 (q, J = 8.0 Hz, 6 H), 0.09 (s, 6H); 13 C NMR 136  (100 MHz, CDCl3): δ 103.7, 84.3, 70.2, 65.4, 25.8, 24.5, 18.3, 7.45, 4.4, -5.4, -5.4; HRMS-ESI (m/z): calcd. for C17H37NaSi2O2 [M+Na] + 329.2332, found 329.2327.       2-((2-(Benzyloxy)pent-4-yn-1-yl)oxy)isoindoline-1,3-dione (4.23b): To a stirred solution of NaH (292 mg, 60% dispersion in mineral oil, 7.3 mmol) in anhydrous DMF (20 mL) was added 4.32b (1.00 g, 3.04 mmol) in anhydrous DMF (1.4 mL). This solution was stirred for 30 min at ambient temperature. BnBr (914 mg, 5.34 mmol) in anhydrous DMF was added in one portion. The resulting solution was stirred overnight. The reaction was quenched with H2O (25 mL), and the aqueous layer was extracted with Et2O (3 × 25 mL). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, and concentrated by rotary evaporation. The crude product was used in the next step without further purification.      To a stirred solution of the resulting mixture in anhydrous THF (5 mL) was added a 1.0 M solution of tetrabutylammonium fluoride (9.6 mL, 9.6 mmol), and the mixture was then stirred for 12 h at ambient temperature. The reaction was quenched with saturated aqueous NH4Cl (10 mL) and extracted with Et2O (3 × 15 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated using rotary evaporation. Purification by flash column chromatography (4:1 hexanes/EtOAc) afforded an alcohol as a clear oil (0.57 g, 45% over 2 steps). IR (film): 3425, 2930, 2851, 1478 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 7.32 - 7.39 (m, 5 H), 4.70 (AB quartet, ∆νAB = 56, JAB = 12 Hz, 2H), 3.79 - 3.85 (m, 1H), 3.66 - 3.71 (m, 2H), 2.44 - 2.57 (m, 2H), 2.04 (t, J = 2.7 Hz, 1 H), 1.94 - 1.95 (m, 1 H); 13 C NMR (100 MHz, 137  CDCl3): δ 137.8, 128.5, 127.9, 127.8, 80.3, 77.6, 71.8, 70.4 63.7, 20.6; HRMS-ESI (m/z): calcd. for C12H14NaO2 [M+Na] + 213.0891, found 213.0895.      To a stirred solution of the alcohol (200 mg, 1.05 mmol) in THF (11 mL) was sequentially added triphenylphosphine (413 mg, 1.57 mmol) and N-hydroxyphthalimide (257 mg, 1.57 mmol). The solution was stirred until the solids had dissolved, at which point diisopropylazodicarboxylate (0.57 mL, 2.80 mmol) was 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 (10 mL). The aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with NaHCO3 (3 × 20 mL), brine (20 mL), and dried over Na2SO4. The organics were concentrated using rotary evaporation and purified by flash column chromatography (6:1 hexanes/EtOAc) to provide N-alkoxyphthalimide 4.23b as a colorless oil (280 mg, 79%). IR (film): 3286, 2956, 1786, 1726, 1465, 1373, 1265, 1186, 1104, 1030, 878, 804, 700 cm -1 ; 1 H NMR (400 MHz, C6D6): δ 7.25 - 7.29 (m, 4 H), 7.07 - 7.11 (m,  3 H), 6.76 - 6.78 (m, 2H), 4.48 (quartet, ∆νAB = 28.0, JAB = 12.0 Hz, 2H), 4.27 - 4.33 (m, 2 H), 3.82 - 3.85 (m, 1 H), 2.37 - 2.48 (m, 2 H), 1.70 (t, J = 4.0 Hz, 1 H); 13 C NMR (100 MHz, CDCl3): δ 163.4, 139.1, 134.0, 129.7, 128.7, 128.6, 127.9, 123.3, 80.5, 79.6, 76.3, 72.4, 71.2, 21.7; HRMS-ESI (m/z): calcd. for C20H17NaNO4 [M+Na] + 358.1055, found 358.1066. Synthesis of 4.23c       1-((tert-Butyldiphenylsilyl)oxy)pent-4-en-2-ol (4.32c): To a stirred solution of 2-(2,2- dimethyl-1,1-diphenyl-1-silapropoxy)ethanal (4.31) (2.0 g, 6.7 mmol) in dry Et2O (30 mL) at – 138  78 °C was added allylmagnesium bromide (13.4 mL, 13.4 mmol) dropwise. The resulting solution was warmed to ambient temperature and stirred overnight. The reaction was quenched by addition of 1M HCl (20 mL). The mixture was extracted with Et2O (3 × 50 mL). The combined organic layers were washed with H2O (50 mL), brine (50 mL), dried over Na2SO4 and concentrated using rotary evaporation. The crude compound was purified by flash column chromatography (10:1 hexanes/EtOAc) to provide title compound 4.32c as a colorless oil (1.62 g, 71%). IR (film): 3569, 3426, 3069, 2934, 2852, 1656, 1586, 1478, 1434, 1395, 1356, 1104, 917, 817, 695, 621 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 7.69 - 7.71 (m, 4 H), 7.40 - 7.47 (m,  6 H), 5.75 - 5.88 (m, 1H), 5.07 - 5.13 (m, 2 H), 3.80 - 3.83 (m, 1 H), 3.71 (dd, J = 8.0, 4.0 Hz, 1 H), 3.59 (dd, J = 8.0, 4.0 Hz, 1 H), 2.51(d, J = 4.0 Hz, 1 H), 2.26 - 2.29 (m, 2 H), 1.11 (s, 9 H); 13 C NMR (100 MHz, CDCl3): δ 135.5, 134.3, 133.1, 129.8, 127.7, 117.4, 71.2, 67.3, 37.5, 26.8, 19.2; HRMS-ESI (m/z): calcd. for C20H26NaSiO2 [M+Na] + 363.1749, found 363.1751.       2-((2-Methoxypent-4-en-1-yl)oxy)isoindoline-1,3-dione (4.23c): To a stirred solution of NaH (282 mg, 7.05 mmol) in dry THF (60 mL) at 0 °C was added a solution of 1-((tert- butyldiphenylsilyl)oxy)pent-4-en-2-ol (4.32c) (1.6 g, 4.7 mmol) in dry THF (8 mL) dropwise over 10 min. The solution was stirred for an additional 30 min at 0 °C. MeI (1.09 g, 7.05 mmol) was added dropwise over 5 min and the solution was warmed to ambient temperature and stirred overnight. The reaction was quenched with H2O (20 mL), and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (25 mL), dried over Na2SO4, concentrated by rotary evaporation, and purified by flash chromatography (50:1 139  hexanes/EtOAc) to afford a protected alcohol as a colorless oil (1.08 g, 65%). IR (film): 2930, 2856, 1469, 1434, 1352, 1108, 826, 739, 700, 621 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 7.71 - 7.74 (m, 4H), 7.40 - 7.46 (m, 6H), 5.80 - 5.89 (m, 1H), 5.05 - 5,13 (m, 2H), 3.66 - 3.73 (m, 2H), 3.43 (s, 3H), 3.34 - 3.39 (m, 1H), 2.30 - 2.42 (m, 2H), 1.10 (s, 9 H),; 13 C NMR (100 MHz, CDCl3): δ 135.5, 134.7, 133.5, 129.6, 127.6, 116.8, 81.4, 64.9, 57.5, 35.7, 26.8, 19.2; HRMS-ESI (m/z): calcd. for C22H30NaSiO2 [M+Na] + 377.1913, found 377.1918.      To a stirred solution of the alcohol (1.06 g, 2.98 mmol) in anhydrous THF (30 mL) at 0 °C was added TBAF (4.5 mL, 4.5 mmol). The mixture was allowed to warm to ambient temperature and stirred overnight. The reaction was quenched with saturated aqueous NH4Cl (10 mL) and extracted with Et2O (3 × 20 mL). The combined organic layers were dried over Na2SO4 and concentrated using rotary evaporation. Purification by flash column chromatography (3:1 hexanes/EtOAc) afforded a volatile alcohol.      To this alcohol (100 mg, 0.88 mmol) in dry THF (30 mL) was sequentially added triphenylphosphine (345 mg, 1.32 mmol) and N-hydroxyphthalimide (215 mg, 1.32 mmol). The solution was stirred until the solids had dissolved, at which point diisopropylazodicarboxylate (0.31 mL, 1.8 mmol) was 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 (20 mL). The aqueous layer was extracted with EtOAc (3 × 30 mL), and the combined organic layers were washed with NaHCO3 (3 × 30 mL), brine (30 mL) and dried over Na2SO4. The organics were concentrated using rotary evaporation and purified by flash column chromatography (6:1 hexanes/EtOAc) to provide N-alkoxyphthalimide 4.23c as a colorless oil (160 mg, 70%). IR (film): 2930, 1786, 1730, 1473, 1382, 1186, 1134, 1082, 986, 873, 717 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 7.83 - 7.87 (m, 2 H), 7.73 - 7.76 (m,  2 H), 5.80 - 5.88 (m, 1H), 5.10 - 5.19 (m, 140  2H), 4.19 - 4.26 (m, 2 H), 3.69 - 3.73 (m, 2 H), 3.47 (s, 3 H), 2.40 - 2.44 (m, 2 H); 13 C NMR (100 MHz, CDCl3): δ 163.3, 134.4, 133.4, 128.9, 123.5, 118.0, 79.3, 78.2, 57.5, 35.2; HRMS- ESI (m/z): calcd. for C15H15NaN2O [M+Na] + 262.1082, found 262.1087. Synthesis of 4.23d       2-((2-Methoxypent-4-yn-1-yl)oxy)isoindoline-1,3-dione (4.23d): To a stirred solution of NaH (456 mg, 60% dispersion in mineral oil, 11.4 mmol) in anhydrous THF (50 mL) was added 4.32b (2.5 g, 7.6 mmol) in anhydrous THF (5 mL) at 0 °C. This solution was stirred for 30 min then MeI (1.61 g, 11.4 mmol) was added in one portion. The resulting solution was stirred overnight. The reaction was quenched with H2O (30 mL), and the aqueous layer was extracted with Et2O (3 × 30 mL). The combined organic extracts were washed with brine (25 mL), dried over Na2SO4 and concentrated by rotary evaporation to provide silyl ether which was used in the next step without further purification.      To a stirred solution of the crude silyl ether (1.9 g, 5.5 mmol) in anhydrous THF (11 mL) at 0 °C was added TBAF (15 mL, 15 mmol). The mixture was allowed to warm to ambient temperature and stirred overnight. The reaction was quenched with saturated aqueous NH4Cl (10 mL) and extracted with Et2O (3 × 20 mL). The combined organic layers were dried over Na2SO4 and concentrated using rotary evaporation. Purification by flash column chromatography (2:1 hexanes/EtOAc) afforded a volatile alcohol.      To the alcohol (430 mg, 3.6 mmol) in dry THF (55 mL) was sequentially added triphenylphosphine (1.43 g, 5.44 mmol) and N-hydroxyphthalimide (888 mg, 5.44 mmol). The 141  solution was stirred until the solids had dissolved, at which point diisopropylazodicarboxylate (1.9 mL, 9.8 mmol) was 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 (30 mL). The aqueous layer was extracted with EtOAc (3 × 50 mL), and the combined organic layers were washed with NaHCO3 (3 × 30 mL), brine (30 mL), and dried over Na2SO4. The organic layers were concentrated using rotary evaporation and purified by flash column chromatography (4:1 hexanes/EtOAc) to provide N-alkoxyphthalimide 4.23d as a colorless oil (559 mg, 60%). IR (film): 2982, 2926, 1791, 1734, 1473, 1382, 1269, 1182, 1108, 1030, 991, 882, 708 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 7.65 (td, J = 5.0, 3.1 Hz, 2 H), 7.42 (td, J = 5.6, 2.5 Hz, 2 H), 4.21 - 4.32 (m, 2 H), 3.67 (dd, J = 5.8, 4.4 Hz, 2 H), 3.35 (s, 3 H), 2.48 (dd, J = 5.9, 2.7 Hz, 2 H), 1.90 (t, J = 2.7 Hz, 1 H); 13 C NMR (100 MHz, CDCl3): δ 163.1, 134.1, 128.8, 123.2, 79.5, 78.6, 77.1, 70.5, 57.4, 21.5, 20.4; HRMS-ESI (m/z): calcd. for C14H15N2O [M+H] + 260.0923, found 260.0925. Synthesis of 4.23e       2-((2-(benzyloxy)pent-4-en-1-yl)oxy)isoindoline-1,3-dione(4.23e): To a stirred solution of NaH (924 mg, 23.1 mmol) in dry THF (60 mL) at 0 °C was added a solution of 1-((tert- butyldimethylsilyl)oxy)pent-4-en-2-ol (4.32a) (2.0 g, 9.2 mmol) in dry THF (2 mL) dropwise over 5 min. The solution was stirred for an additional 30 min at 0 °C. EtI (2.15 g, 13.8 mmol) was added dropwise over 5 min and the solution was warmed to ambient temperature and stirred overnight. The reaction was quenched with H2O (20 mL), and the aqueous layer was extracted 142  with Et2O (3 × 20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, concentrated by rotary evaporation, and purified by flash chromatography (50:1 hexanes/Et2O) to afford a protected alcohol as a colorless oil (1.14 g, 51%). IR (film): 2956, 2847, 1634, 1255, 1099 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 5.83 - 5.90 (m, 1H), 5.04 - 5,12 (m, 2H), 3.37 - 3.63 (m, 4H), 3.34 - 3.56 (m, 1H), 2.22 - 2.32 (m, 2H), 1.19 (t, J = 12.0 Hz, 3 H), 0.90 (s, 9 H), 0.06 (s, 6 H); 13 C NMR (100 MHz, CDCl3): δ 135.1, 134.3, 116.7, 79.7, 65.4, 65.0, 36.1, 33.1, 25.9, 15.6, -5.3, -5.4; HRMS-ESI (m/z): calcd. for C13H29SiO2 [M+H] + 245.1937, found 245.1935.      To this protected alcohol (1.14 g, 4.66 mmol) in THF (15 mL) was added TBAF (6.9 mL, 6.9 mmol). The solution was stirred overnight. The reaction was quenched with H2O (20 mL), and the aqueous layer was extracted with Et2O (3 × 20 mL). The combined organic layers were washed with H2O (20 mL), brine (20 mL), dried over Na2SO4, concentrated by rotary evaporation, and purified by flash column chromatography (6:1 hexanes/EtOAc) to provide a volatile alcohol as a colorless oil (485 mg, 80%). To the alcohol (200 mg, 1.04 mmol) in THF (10 mL) was sequentially added triphenylphosphine (409 mg, 1.56 mmol) and N- hydroxyphthalimide (254 mg, 1.56 mmol). The solution was stirred until the solids had dissolved, at which point diisopropylazodicarboxylate (0.38 mL, 1.87 mmol) was 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 (20 mL). The aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with NaHCO3 (3 × 20 mL), brine (20 mL), and dried over Na2SO4. The organics were concentrated using rotary evaporation and purified by flash column chromatography (6:1 hexanes/EtOAc) to provide N- alkoxyphthalimide 4.23e (contaminated with 3% of DIAD) as a colorless oil (305 mg, 70%, two 143  steps). IR (film): 2978, 2891, 1795, 1734, 1473, 1373, 1256, 1195, 1108, 1026, 878, 791, 704 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 7.88 (dd, J = 3.0, 5.2 Hz, 2 H), 7.79 (dd, J = 3.2, 5.3 Hz, 2 H), 5.90 (tdd, J = 7.0, 10.1, 17.2 Hz, 1 H), 5.19 (d, J = 17.1 Hz, 1 H), 5.14 (d, J = 10.1 Hz, 1 H), 4.32 - 4.20 (m, 2 H), 3.86 - 3.78 (m, 1 H), 3.75 - 3.60 (m, 2 H), 2.49 - 2.36 (m, 2 H), 1.19 (t, J = 7.0 Hz, 3 H); 13 C NMR (100 MHz, CDCl3): δ 163.0, 134.3, 133.7, 129.4, 122.9, 117.5, 79.8, 77.0, 65.2, 36.1, 21.8, 16.0; HRMS-ESI (m/z): calcd. for C15H18NO4 [M+H] +  276.1234, found 276.1236. Synthesis of 4.23f       2-((2-Ethoxypent-4-yn-1-yl)oxy)isoindoline-1,3-dione (4.23f): To a stirred solution of 4.32b (1.23 g, 4.29 mmol) in anhydrous DMF (21 mL) was added NaH (429 mg, 60% dispersion in mineral oil, 10.7 mmol). This solution was stirred for 30 min then EtI (1.0 g, 6.4 mmol) was added in one portion. The resulting solution was stirred overnight. The reaction was quenched with H2O (30 mL), and the aqueous layer was extracted with Et2O (3 × 30 mL). The combined organic layers were washed with brine (25 mL), dried over Na2SO4, and concentrated by rotary evaporation to provide a silyl ether which was used in the next step without further purification.     To a stirred solution of the crude silyl ether (516 mg, 2.12 mmol) in anhydrous THF (7 mL) at 0 °C was added TBAF (6.4 mL, 6.4 mmol). The mixture was allowed to warm to ambient temperature and stirred overnight. The reaction was quenched with saturated aqueous NH4Cl (10 mL) and extracted with Et2O (3 x 20 mL). The combined organic layers were dried over Na2SO4 and concentrated using rotary evaporation. Purification by flash column chromatography (2:1 144  hexanes/EtOAc) afforded a volatile alcohol. To the alcohol (280 mg, 2.12 mmol) in dry THF (30 mL) was sequentially added triphenylphosphine (393 g, 3.20 mmol) and N-hydroxyphthalimide (244 mg, 3.20 mmol). The solution was stirred until the solids had dissolved, at which point diisopropylazodicarboxylate (0.75 mL, 3.80 mmol) was 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 (10 mL). The aqueous layer was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with NaHCO3 (3 × 30 mL), brine (30 mL), and dried over Na2SO4. The organic layers were concentrated using rotary evaporation and purified by flash column chromatography (4:1 hexanes/EtOAc) to provide N-alkoxyphthalimide 4.23f as a colorless oil (200 mg, 35%). IR (film): 2982, 2926, 1791, 1734, 1473, 1382, 1269, 1182, 1108, 1030, 991, 882, 708 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 7.81 - 7.87 (m, 2 H), 7.72 - 7.79 (m, 2 H), 4.29 - 4.41 (m, 2 H), 3.85 - 3.93 (m, 1 H), 3.59 - 3.74 (m, 2 H), 2.61 (dd, J = 6.0, 2.7 Hz, 2 H), 2.02 (t, J = 2.6 Hz, 1 H), 1.15 (t, J = 7.0 Hz, 3 H); 13 C NMR (100 MHz, CDCl3): δ 163.3, 134.5, 128.9, 123.5, 79.9, 78.9, 75.7, 70.5, 65.5, 21.1, 15.3; HRMS-ESI (m/z): calcd. forC15H15NaNO4 [M+Na] + 296.0899, found 296.0897. 4.4.4 General cyclization procedures      A: To a stirred 0.02 M solution of cyclization precursors (1 equiv) in degassed benzene at reflux was added a 0.2 M solution of tributyltin hydride (1.2 equiv) and AIBN (0.15 equiv) in degassed benzene by syringe pump (0.4 mL/h). The reaction was then stirred for an additional 1 h at reflux.      B: To a stirred 0.02 M solution of cyclization precursors (1 equiv) in degassed d6-benzene at 70 °C was added a 0.2 M solution of tributyltin hydride (1.8 equiv) and AIBN (0.15 equiv) in 145  degassedd6-benzene by syringe pump (0.4 mL/h). The reaction was then stirred for an additional 1 h at 70 °C.      C: To a stirred 0.02 M solution of cyclization precursors (1 equiv) in degassed d6-benzene at 60 °C was added a 0.2 M solution of tributyltin hydride (1.8 equiv) and AIBN (0.15 equiv) in degassed d6-benzene by syringe pump (0.4 mL/h). The reaction was then stirred for an additional 1 h at 60 °C.       4-(3-Methyltetrahydrofuran-2-yl)butan-1-ol (4.14): N-Alkoxyphthalimide 4.16 (100 mg, 0.30 mmol) was subjected to general cyclization procedure A. Purification by flash column chromatography (1:1 hexanes/EtOAc) afforded 4.14 (major isomer) as a colorless oil (31 mg, 66%, ratio 80:20). IR (neat): 3385, 2934, 2870, 1709, 1458, 1375, 1055 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 3.95 - 3.87 (m, 1 H), 3.77 - 3.70 (m, 2 H), 3.67 (t, J = 6.4 Hz, 2 H), 2.30 - 2.17 (m, 1 H), 2.15 - 2.01 (m, 1 H), 1.68 - 1.37 (m, 8 H), 0.91 (d, J = 7.0 Hz, 3 H); 13 C NMR (100 MHz, CDCl3): δ 81.6, 65.9, 62.7, 35.3, 33.9, 32.8, 30.1, 22.9, 14.2; HRMS-ESI (m/z): calcd. for C9H19O2  [M+H] + 159.1385, found 159.1382.       (4-Methyl-5-phenyltetrahydrofuran-2-yl)methanol (4.25a): N-Alkoxyphthalimide 4.23a (62 mg, 0.18 mmol) was subjected to general cyclization procedure A. Purification by flash column chromatography (4:1 hexanes/EtOAc) afforded 4.25a as a colorless oil (42 mg, 74%, ratio 53:45:2). IR (neat): 3404, 2917, 2865, 1713, 1456, 1273, 1069, 1021, 704 cm -1 ; 1 H NMR 146  (400 MHz, CDCl3): δ 7.31 - 7.15 (m, 5 H), 5.01 (d, J = 5.5 Hz, 0.02 H), 4.95 (d, J = 7.0 Hz, 0.44 H), 4.43 - 4.36 (m, 0.02 H), 4.36 - 4.29 (m, 0.09 H), 4.26 (d, J = 8.5 Hz, 0.5 H), 4.22 - 4.14 (m, 0.39 H), 4.12 - 4.03 (m, 0.4 H), 3.84 - 3.75 (m, 0.42 H), 3.73 - 3.63 (m, 1 H), 3.62 - 3.54 (m, 0.42 H), 3.51 (td, J = 6.0, 11.7 Hz, 0.14 H), 2.55 (spt, J = 7.2 Hz, 0.45 H), 2.21 - 1.89 (m, 2.45 H), 1.77 - 1.66 (m, 0.51 H), 1.55 - 1.45 (m, 0.09 H), 1.45 - 1.33 (m, 0.47 H), 0.95 (d, J = 6.1 Hz, 1.6 H), 0.56 (d, J = 7.0 Hz, 0.12 H), 0.54 - 0.49 (m, 1.33 H); 13 C NMR (100 MHz, CDCl3): δ 140.7, 140.1, 128.4, 128.4, 127.9, 127.8, 127.1, 126.5, 126.4, 126.3, 88.7, 87.7, 83.9, 79.6, 79.1, 78.3, 65.8, 65.3, 65.2, 43.8, 42.0, 37.6, 36.8, 36.2, 35.4, 16.6, 16.2, 15.3; HRMS-ESI (m/z): calcd. for C12H16NaO2 [M+Na] + 215.1048, found 215.1046.       (4-methylene-5-phenyltetrahydrofuran-2-yl)methanol (4.25b): N-Alkoxyphthalimide 4.23b (70 mg, 0.21 mmol) was subjected to general cyclization procedure A. Solvent was evaporated and the mixture was purified by flash column chromatography (4:1 hexanes/EtOAc) afforded 4.25b as a colorless oil (28 mg, 70%, cis:trans>95:5). IR (neat): 3391, 2921, 1717, 1447, 1260, 1095, 1026, 800, 700 cm -1 ; 1 H NMR (400 MHz, C6D6): δ 7.33 - 7.27 (m, J = 6.8 Hz, 2 H), 7.21 - 7.00 (m, 3 H), 5.11 (s, 1 H), 4.82 (q, J = 2.2 Hz, 1 H), 4.60 (q, J = 2.0 Hz, 1 H), 3.92 - 3.82 (m, 1 H), 3.59 (ddd, J = 3.1, 6.4, 11.7 Hz, 1 H), 3.41 (td, J = 5.9, 11.4 Hz, 1 H), 2.45 - 2.33 (m, 1 H), 2.21 (dd, J = 6.4, 15.6 Hz, 1 H), 1.56 (t, J = 6.5 Hz, 1 H); 13 C NMR (100 MHz, CDCl3): δ 151.4, 141.2, 128.6, 128.2, 127.5, 107.8, 84.1, 78.9, 64.6, 34.7; HRMS-ESI (m/z): calcd. for C12H15NaO2 [M+Na] +   191.1072, found 191.1074.  147        tert-Butyl((4-methyltetrahydrofuran-2-ol)methoxydiphenylsilane (4.25c): N- Alkoxyphthalimide 4.23c (88 mg, 0.33 mmol) was subjected to general cyclization procedure A. To the crude mixture was sequentially added imidazole (45 mg, 0.66 mmol), then tert- butyldiphenylsilylchloride (137 mg, 0.50 mmol) and stirred overnight. The solvent was evaporated and the residue was dissolved in Et2O (50 mL). The organic layer was washed by brine (20 mL) and dried over Na2SO4, concentrated using rotary evaporation. The crude product was purified using flash column chromatography (4:1 hexanes/EtOAc) to afford 4.25c as a colorless oil (28 mg, 20%, two steps, cis:trans> 95:5). IR (neat): 2969, 2921, 2856, 1739, 1478, 1434, 1117, 708 cm -1 ; 1 H NMR (400 MHz, C6D6): δ 7.91 - 7.80 (m, 4 H), 7.27 - 7.20 (m, 6 H), 4.11 - 4.00 (m, 1 H), 3.86 - 3.66 (m, 3 H), 3.29 (t, J = 8.2 Hz, 1 H), 2.07 - 1.90 (m, 1 H), 1.82 - 1.70 (m, 1 H), 1.27 - 1.13 (m, 10 H), 0.79 (d, J = 6.6 Hz, 3 H); 13 C NMR (100 MHz, C6D6/CDCl3 ~2/1): δ 135.7, 133.7, 129.5, 127.6, 80.1, 74.8, 75.5, 66.6, 36.6, 34.4, 26.8, 19.2, 16.8; HRMS-ESI (m/z): calcd. for C22H30NaSiO2 [M+Na] +  377.1913, found 377.1911.       tert-Butyl((4-methylenetetrahydrofuran-2-yl)methoxy)diphenylsilane (4.25d): N- Alkoxyphthalimide 4.23d (160 mg, 0.61 mmol) was subjected to general cyclization procedure A. To the crude mixture was sequentially added imidazole (81 mg, 1.2 mmol), then tert- butyldiphenylsilylchloride (202 mg, 0.74 mmol) and the mixture was stirred overnight. The 148  solvent was evaporated and the residue was dissolved in Et2O (50 mL). The organic layer was washed by brine (20 mL), dried over Na2SO4, and concentrated using rotary evaporation. The crude product was purified using flash column chromatography (25:1 hexanes/EtOAc) to afford 4.25d as a colorless oil (60 mg, 25%, two steps). IR (neat): 2982, 2926, 1791, 1734, 1473, 1382, 1269, 1182, 1108, 1030, 991, 882, 708 cm -1 ; 1 H NMR (400 MHz, C6D6): δ 7.84 - 7.77 (m, 4 H), 7.23 (t, J = 2.9 Hz, 6 H), 4.83 (quin, J = 2.2 Hz, 1 H), 4.70 (t, J = 2.1 Hz, 1 H), 4.36 - 4.28 (m, 1 H), 4.21 - 4.14 (m, 1 H), 4.10 - 4.03 (m, 1 H), 3.71 (dd, J = 2.6, 4.7 Hz, 2 H), 2.37 - 2.31 (m, 2 H), 1.17 (s, 9 H); 13 C NMR (100 MHz, CDCl3): δ 147.9, 135.6, 133.6, 129.6, 127.6, 104.2, 79.8, 71.3, 66.0, 34.9, 26.8, 19.2; HRMS-ESI (m/z): calcd. for C22H28NaSiO2 [M+Na] + 375.1756, found 375.1753.       tert-Butyl((4,5-dimethyltetrahydrofuran-2-yl)methoxy)diphenylsilane (4.25e): N- Alkoxyphthalimide 4.23e (250 mg, 0.91 mmol) was subjected to general cyclization procedure C. To the crude mixture was sequentially added imidazole (116 mg, 1.70 mmol), then tert- butyldiphenylsilylchloride (370 mg, 1.36 mmol) and the mixture was stirred overnight. The solvent was evaporated and the residue was dissolved in Et2O (50 mL). The organic layer was washed by brine (20 mL), dried over Na2SO4, and concentrated using rotary evaporation. The crude product was purified using flash column chromatography (30:1 hexanes/Et2O) to afford 4.25e (major isomer) as a colorless oil (200 mg, 62%, two steps, ratio 93:7 mixture of isomers). IR (neat): 2965, 2921, 2843, 1469, 1426, 1378, 1265, 1113, 830, 795, 739, 704 cm -1 ; 1 H NMR (400 MHz, C6D6): δ 7.90 - 7.81 (m, 4 H), 7.26 - 7.21 (m, 6 H), 4.04 - 3.95 (m, 1 H), 3.92 (quin, J 149  = 6.5 Hz, 1 H), 3.81 - 3.73 (m, 2 H), 2.01 - 1.89 (m, 1 H), 1.78 (td, J = 7.2, 12.3 Hz, 1 H), 1.28 (td, J = 8.0, 12.4 Hz, 1 H), 1.20 (s, 9 H), 1.03 (d, J = 6.4 Hz, 3 H), 0.73 (d, J = 7.0 Hz, 3 H); 13 C NMR (100 MHz, CDCl3): δ 135.7, 135.7, 133.8, 133.7, 129.5, 127.6, 78.8, 77.6, 67.0, 36.2, 35.9, 26.8, 19.2, 16.8, 14.9; HRMS-ESI (m/z): calcd. for C23H32NaSiO2 [M+Na] + 391.2069, found 391.2064.       tert-Butyl((5-methyl-4-methylenetetrahydrofuran-2-yl)methoxy)diphenylsilane (4.25f): N-Alkoxyphthalimide 4.23f (100 mg, 0.36 mmol) was subjected to general cyclization procedure A. To the crude mixture was sequentially added imidazole (49 mg, 0.73 mmol), then tert- butyldiphenylsilylchloride (120 mg, 0.44 mmol) and stirred overnight. The solvent was evaporated and the residue was dissolved in Et2O (30 mL). The organic layer was washed by brine (20 mL), dried over Na2SO4, and concentrated using rotary evaporation. The crude product was purified using flash column chromatography (25:1 hexanes/EtOAc) to afford 4.25f as a colorless oil (60 mg, 25%, two steps, cis:trans = 85:15). IR (neat): 2982, 2926, 1791, 1734, 1473, 1382, 1269, 1182, 1108, 1030, 991, 882, 708 cm -1 ; 1 H NMR (400 MHz, C6D6): δ 7.87 - 7.78 (m, 4 H), 7.25 - 7.20 (m, 6 H), 4.85 - 4.79 (m, 1 H), 4.69 (q, J = 2.1 Hz, 1 H), 4.56 - 4.47 (m, 0.17 H), 4.32 (s, 0.80 H), 4.16 (s, 0.17 H), 3.98 (tdd, J = 4.5, 6.7, 8.7 Hz, 0.82 H), 3.80 - 3.72 (m, 1.67 H), 3.68 (dd, J = 3.5, 4.7 Hz, 0.31 H), 2.47 - 2.35 (m, 1.82 H), 2.35 - 2.31 (m, 0.17 H), 1.27 (d, J = 6.4 Hz, 2.55 H), 1.23 (d, J = 6.4 Hz, 0.89 H), 1.18 (s, 7.4 H), 1.17 (s, 2.1 H); 13 C NMR (100 MHz, CDCl3): δ 152.9, 135.8, 135.8, 133.8, 133.8, 129.7, 127.8, 104.3, 104.3, 78.2, 150  77.3, 76.6, 66.3, 66.2, 35.6, 35.0, 27.0, 21.0, 20.7, 19.4; HRMS-ESI (m/z): calcd. For C15H30NaO2Si [M+Na] +  293.1913, found 293.1913.  151  Chapter  5: Application to the Synthesis of the Tetrahydrofuran Fragment of (–)-Amphidinolide K      Substituted tetrahydrofurans are common motifs in many bioactive polyketide natural products. 81  One such example is amphidinolide K 82 (Scheme 5.1, 5.1), isolated from the Okinawan flatworm Amphiscolops sp, which contains a 2,3,5-trisubstituted tetrahydrofuran in the macrocyclic core. This chapter will give a brief overview of the different routes for the synthesis of the tetrahydrofuran fragment within amphidinolide K. 5.1 Synthesis of the tetrahydrofuran fragment by Meyer and Lee  Scheme 5.1. Synthesis of the tetrahydrofuran fragment within (+)-amphidinolide K by Meyer.      The first total synthesis of (+)-amphidinolide K was completed by Meyer and co-workers (Scheme 5.1), 82b  in which they synthesized the tetrahydrofuran fragment through an intramolecular displacement reaction. 152   Scheme 5.2. Retrosynthetic analysis of (–)-amphidinolide K by Lee.      The first total synthesis of the unnatural enantiomer, (–)-amphidinolide K, was accomplished by Lee and co-workers in 2009. Unlike Meyer’s strategy, Lee utilized a radical cyclization method to synthesize the tetrahydrofuran fragment (Scheme 5.2). 82c  Lee’s synthesis of the tetrahydrofuran fragment within (–)-amphidinolide K started with the ring-opening of epoxide 5.7, using a lithiated alkyne (Scheme 5.3). A subsequent desilylation and ether formation provided alcohol 5.6. A following key radical cyclization of 5.6 using tributyltin hydride and triethylborane afforded intermediate 5.10, which was then transformed to protected alcohol 5.5 in three steps.   Scheme 5.3. Synthesis of tetrahydrofuran 5.5 by Lee and co-workers. 153  5.2 Synthesis of the tetrahydrofuran fragment by our methodologies  Scheme 5.4. Retrosynthetic analysis of (–)-amphidinolide K by Sammis’s group.      From our radical relay cyclization studies in Chapter 3, we successfully synthesized the trisubstituted tetrahydrofuran 3.5c from 3.1c (Table 3.1, entry 3). We envisioned that the core system (5.5) in (–)-amphidinolide K could be synthesized through our radical relay cyclization method as they both have a similar structure (2,5-cis-disubstitution pattern) (Scheme 5.4). Instead of an alkene as the acceptor, precursor 5.13 containing an alkyne as the acceptor could easily enable access to tetrahydrofuran fragment 5.5, using our radical relay cyclization methodology.  Scheme 5.5. Synthesis of the tetrahydrofuran fragment within (–)-amphidinolide K using radical relay cyclization. 154       Synthesis of tetrahydrofuran fragment 5.5 within (–)-amphidinolide K was completed by Natalie Campbell in five steps starting with the commercially available, enantiomerically enriched trityl-protected epoxide (Scheme 5.5). 83  Epoxide ring opening with a TES-protected lithiated alkyne afforded chiral alcohol 5.16 in 82% yield. Ether formation followed by TBAF- mediated deprotection provided free alcohol 5.18 in 45% yield over two steps. Installation of the N-alkoxyphthalimide using a Mitsunobu reaction provided N-alkoxyphthalimide 5.19 in 67% yield. The key radical relay cyclization led to tetrahydrofuran fragment 5.20 in 64% yield as an 89:11 ratio of cis to trans isomers.      After we established the alternative radical relay cyclization pattern as described in Chapter 4, we envisaged that it would be valuable to access the core motif of (–)-amphidinolide K using our new route. This new route has the advantage of providing a different protection pattern compared to our first generation route (Scheme 5.5). Synthesis of the key tetrahydrofuran began with the ring-opening of the commercially available, enantioenriched epoxide 5.7 with a TES-protected lithiated alkyne to afford alcohol 5.21 in 95% yield. Ether formation by nucleophilic displacement followed by TBAF-mediated deprotection provided free alcohol 5.23 in 45% yield over two steps.  Installation of the phthalimide moiety using a Mitsunobu reaction provided N- alkoxyphthalimide 5.24 in 67% yield.  The key radical relay cyclization under the new reaction conditions outlined in Chapter 4 led to (–)-amphidinolide K fragment 5.25 in 60% yield, with an >95:5 ratio of cis to trans isomers (Scheme 5.6). Overall, the tetrahydrofuran core within (–)- amphidinolide K was synthesized in five steps from the commercially available starting material. 155   Scheme 5.6. Synthesis of the tetrahydrofuran core within (–)-amphidinolide K. 5.3 Conclusion      An efficient diastereoselective synthesis of the tetrahydrofuran fragment within (–)- amphidinolide K was achieved using our newly developed radical relay cyclization methodology through a dative control. Compared to Lee’s radical method, our approach to the synthesis of the tetrahydrofuran core moiety required fewer steps. While our second generation route for the synthesis of the tetrahydrofuran fragment within (–)-amphidinolide K provided the comparable yield and diastereoselectivity to the first generation route, the new approach allows for the direct access to a new protection pattern.       156  5.4 Experimental 5.4.1 General methods      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. All other solvents were used without further purification. Thin layer chromatography (TLC) was performed on Whatman Partisil K6F UV254 pre-coated TLC plates. Chromatographic separations were effected over Fluka 60 silica gel. The silica gel was basified by stirring with triethylamine prior to packing and then sequentially flushed with the solvent system of choice. All reagents were purchased from commercial sources and used as received. 5.4.2 Instrumentation      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 (IR) spectra were obtained using a Thermo Nicolet 4700 FTIR spectrometer. Proton nuclear magnetic resonance ( 1 H NMR) spectra were recorded using a Bruker AV-300 or AV-400 spectrometer. Carbon nuclear magnetic resonance ( 13 C NMR) spectra were recorded 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 d6-chloroform (7.27 ppm 1 H NMR; 77.0 ppm 13 C NMR) or d6-benzene (7.16 ppm 1 H NMR; 128.1 ppm 13 C NMR). High resolution mass spectra (HRMS) were recorded on a Waters/Micromass LCT spectrometer.    157  5.4.3 Synthesis of the tetrahydrofuran fragment       (R)-1-((tert-Butyldiphenylsilyl)oxy)-5-(triethylsilyl)pent-4-yn-2-ol (5.21): To a stirred solution of triethylsilylacetylene (3.45 g, 24.1 mmol) in dry THF (70 mL) at –78 °C was added a solution of butyllithium (1.6 M in hexane, 15.0 mL, 24.1 mmol) dropwise over 10 min. The solution was stirred for an additional 10 min at –78 °C. Boron trifluoride diethyl etherate (3.00 mL, 3.43 g, 24.1 mmol) was added dropwise over 5 min and the solution was stirred for additional 20 min. A solution of epoxide 5.7 (5.00 g, 16.1 mmol) in anhydrous THF (30 mL) was then added dropwise over 10 min. The resulting mixture was stirred for 2 h at –78 °C. The reaction was quenched with saturated aqueous NH4Cl (25 mL) and extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with brine (25 mL), dried over Na2SO4, concentrated by rotary evaporation, and purified by flash chromatography (20:1 hexanes/EtOAc) to afford alcohol 5.21 (with trace amounts of EtOAc) as a colorless oil (6.47 g, 88%). [α]D 21 – 10.5 (c 1.56, CHCl3); IR (neat): 3447, 3069, 3043, 2956, 2926, 2869, 2173, 1469, 1421, 1260, 1113, 1004, 821, 739, 695, 621 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 7.5 Hz, 4 H), 7.50 - 7.35 (m, 6 H), 3.90 (sxt, J = 5.6 Hz, 1 H), 3.81 (dd, J = 4.4, 10.2 Hz, 1 H), 3.72 (dd, J = 6.1, 9.9 Hz, 1 H), 2.62 - 2.48 (m, 3 H), 1.09 (s, 9 H), 0.95 (t, J = 7.9 Hz, 9 H), 0.55 (q, J = 7.7 Hz, 6 H); 13 C NMR (100 MHz, CDCl3): δ 135.5, 135.5, 133.1, 133.1, 129.8, 127.8, 103.5, 84.4, 70.3, 66.4, 26.8, 24.7, 19.3, 7.4, 4.4; HRMS-ESI (m/z): calcd. for C27H40NaSi2O2 [M+Na] +  475.2465, found 475.2470. 158        (S)-2-(4-(Trityloxy)butoxy)pent-4-yn-1-ol (5.23): To a suspension of sodium hydride (60 wt% dispersion in mineral oil, 247 mg, 6.18 mmol) in anhydrous DMF (12 mL) was added 5.21 (1.87 g, 4.12 mmol) in anhydrous DMF (2 mL). This solution was stirred for 1 h at ambient temperature. 4-(Trityloxy)butyl 4-methylbenzenesulfonate (2.06 g, 4.12 mmol) in anhydrous DMF (10 mL) was added dropwise in 60 min. The resulting solution was stirred overnight. The reaction was quenched with H2O (25 mL), and the aqueous layer was extracted with Et2O (3 × 30 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, and concentrated by rotary evaporation. The crude product was used in the next step without further purification. To a solution of the resulting mixture in anhydrous THF (20 mL) was added tetrabutylammonium fluoride (1.0M in THF, 6.8 mL, 6.8 mmol), and the solution was then stirred for 12 h. The reaction was quenched with saturated aqueous NH4Cl (10 mL) and extracted with Et2O (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated using rotary evaporation. Purification by flash column chromatography (5:1 hexanes/EtOAc) afforded alcohol 5.23 as a clear oil (440 mg, 48% over 2 steps). [α]D 21 – 4.5 (c 1.23, CHCl3); IR (neat): 3430, 3295, 3086, 3052, 3021, 2921, 2860, 1491,1443, 1213, 1073, 752, 708, 634 cm -1 ; 1 H NMR (400 MHz, C6D6): δ 7.56 (d, J = 7.5 Hz, 6 H), 7.14 (t, J = 7.9 Hz, 6 H), 7.08 - 7.00 (m, 3 H), 3.63 - 3.45 (m, 2 H), 3.27 - 3.17 (m, 2 H), 3.16 - 3.03 (m, 3 H), 2.18 (dd, J = 2.7, 6.5 Hz, 2 H), 1.70 (t, J = 2.7 Hz, 1 H), 1.68 - 1.46 (m, 5 H); 13 C NMR (100 MHz, C6D6): δ 145.4, 129.5, 128.4, 127.5, 87.2, 81.3, 79.0, 70.8, 69.9, 64.1, 63.9, 27.5, 27.4, 21.1; HRMS-ESI (m/z) calcd. for C28H30NaO3 [M+Na] +  437.2093, found 437.2102. 159       2-((2-(4-(trityloxy)butyoxy)pent-4-yn-1-yl)oxy)isoindoline-1,3-dione (5.24): To alcohol 5.23 (100 mg, 0.24 mmol) in dry THF (2 mL) was sequentially added triphenylphosphine (90 mg, 0.34 mmol) and N-hydroxyphthalimide (55 mg, 0.34 mmol). The solution was stirred until the solids were dissolved, at which point diisopropylazodicarboxylate (83 mg, 0.41 mmol) was 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 (2 mL). The aqueous layer was extracted with EtOAc (3 × 10 mL), and the combined organic extracts were washed with NaHCO3 (3 × 10 mL), brine (10 mL) and were dried over Na2SO4. The organic layers were concentrated using rotary evaporation and purified by flash column chromatography (5:1 hexanes/EtOAc) to provide N-alkoxyphthalimide 5.24 as a colorless oil (107 mg, 80%). [α]D 21 – 6.5 (c 2.56, CHCl3); IR (neat): 3282, 2947, 2865, 1800, 1730, 1443, 1373, 1186, 1078, 1078, 1008, 878, 704 cm -1 ; 1 H NMR (400 MHz, CDCl3): δ 7.85 - 7.79 (m, 2 H), 7.73 - 7.69 (m, 2 H), 7.45 - 7.39 (m, 6 H), 7.32 - 7.27 (m, 5 H), 7.25 - 7.19 (m, 3 H), 4.39 - 4.26 (m, 2 H), 3.86 - 3.78 (m, 1 H), 3.60 - 3.51 (m, 2 H), 3.01 (t, J = 5.6 Hz, 2 H), 2.61 - 2.54 (m, 2 H), 1.99 (t, J = 2.7 Hz, 1 H), 1.61 (d, J = 5.8 Hz, 4 H); 13 C NMR (100 MHz, CDCl3): δ 163.3, 144.4, 134.4, 128.9, 128.7, 127.7, 126.8, 123.5, 86.2, 79.9, 78.7, 75.8, 70.5, 69.9, 63.1, 26.7, 26.5, 21.0; HRMS-ESI (m/z) calcd. for C36H33NaNO5 [M+Na] +  582.2266, found 582.2249.  160        ((2S,5S)-4-Methylene-5-(3-trityloxy)propyl)tetrahydrofuran-2-yl)methanol (5.25): To a 0.02 M solution of N-alkoxyphthalimide 5.24 (170 mg, 0.30 mmol) in degassed d6-benzene at 60 °C was added a 0.2 M solution of tributyltin hydride (1.8 equiv) and AIBN (0.15 equiv) in degassed d6-benzene by syringe pump (0.4 mL/h). The reaction was then stirred for an additional 1 h at 60 °C. Solvent was evaporated and the mixture was purified by flash column chromatography (3:2 hexanes/Et2O) afforded 5.25 as a colorless oil (78 mg, 60%, cis:trans> 95:5). [α]D 21 +8.65 (c 10.5, CHCl3); IR (neat): 3413, 2965, 2917, 2847, 1737, 1447, 1265, 1073 cm -1 ; 1 H NMR (400 MHz, C6D6): δ 7.60 - 7.56 (m, 6 H), 7.12 (t, J = 7.5 Hz, 6 H), 7.06 - 7.00 (m, 3 H), 4.78 (q, J = 2.0 Hz, 1 H), 4.67 (q, J = 2.3 Hz, 1 H), 4.20 - 4.15 (m, 1 H), 3.74 - 3.67 (m, 1 H), 3.55 - 3.48 (m, 1 H), 3.34 - 3.26 (m, 1 H), 3.21 (t, J = 6.4 Hz, 2 H), 2.28 - 2.18 (m, 1 H), 2.09 (dd, J = 6.1, 15.8 Hz, 1 H), 1.96 - 1.84 (m, 1 H), 1.82 - 1.66 (m, 2 H), 1.62 - 1.44 (m, 2 H); 13 C NMR (100 MHz, C6D6): δ 152.3, 145.4, 129.5, 128.3, 127.5, 104.9, 87.3, 81.4, 78.9, 64.8, 64.3, 35.1, 32.7, 26.9; HRMS-ESI (m/z) calcd. for C28H30NaO3 [M+Na] +  437.2093, found 437.2102.    161  Bibliography 1. Gomberg, M. J. Am. Chem. Soc. 1900, 22, 757-771. 2. Curran, D. P. 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Commun. 1993, 1723-1725. 58. Kim, S.; Lee, T. A.; Song, Y. Synlett 1998, 471-472. 59. Barton, D. H. R.; Motherwell, R. S. H.; Motherwell, W. B. J. Chem. Soc. Perkin. Trans. 1 1981, 2363-2367. 60. Čeković, Ž.; Ilijev, D. Tetrahedron Lett. 1988, 29, 1441-1444. 61. Rawal, V. H.; Newton, C. H.; Krishnamurthy, V. J. Org. Chem. 1990, 55, 5181-5183. 61. Rawal, V. H.; Krishnamurthy, V.; Fabre, A. Tetrahedron Lett. 1993, 34, 2899-2902. 63. Rawal, V. H.; Krishnamurthy, V. Tetrahedron Lett. 1992, 33, 3439-3442. 64. Begley, M. J.; Housden, N.; Johns, A.; Murphy, J. A. Tetrahedron 1991, 39, 8417-8430. 166  65. Kim, S.; Lee, S.; Koh, J. S. J. Am, Soc, Chem. 1991, 113, 5106-5107. 66. For kinetic studies pertaining to alkoxy radical 1,5-HATs, see: Horner, J. H.; Choi, S.-Y.; Newcomb, M. Org. Lett. 2000, 2, 3369–3372. 67. Barton, D. H. R.; Blundell, P.; Jaszberenyl, J. C. Tetrahedron Lett. 1989, 30, 2341-2344. 68. Okada, K.; Okamoto, K.; Oda, M. J. Am. Chem. Soc. 1998, 110, 8736-8738. 69. Chatgilialoglu, C.; Griller, D.; Lesage, M. J. Org. Chem. 1988, 53, 3641–3642. 70. Schlosser, M.; Christmann, K. F. Angew. Chem. Int. Ed. Engl. 1966, 5, 126-126. 71. (a) Wittig, G.; Schollkopf, U. Chem. Ber. 1954, 97, 1318-1330. (b) Wittig, G.; Haag, W. Chem. Ber. 1955, 88, 1654-1666. 72. (a) Zlotorzynska, M; Zhai, H; Sammis, G. M. Org. Lett. 2008, 10, 5083-5086. (b) Zlotorzynska, M; Zhai, H; Sammis, G. M. J. Org. Chem. 2010, 75, 864-872. (c) Rueda-Becerril, M.; Leung, J. C. T.; Dunbar, C. R.; Sammis, G. M.  J. Org. Chem. 2011,76, 7720-7729. 73. (a) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron Lett. 1985, 26, 373-376. (b) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985, 41, 3925-3941. 74. Spellmeyer, D. C.; Houk, K. N. J. Org. Chem. 1987, 52, 959-974. 75. (a) Faul, M. M.; Huff, B. E. Chem. Rev. 2000, 100, 2407-2474. (b) Kang, E. J.; Lee, E. Chem. Rev. 2005, 105, 4348-4378. (c) Wolfe, J. P.; Hay, M. B. Tetrahedron 2007, 63, 261-290. 76. For representative examples of kinetic studies pertaining to alkoxy radical cyclizations, see: (a) Beckwith, A. L. J.; Hay, B. P. J. Am. Chem. Soc. 1988, 110, 4415-4416. (b) Beckwith, A. L. J.; Hay, B. P.; Williams, G. M. J. Chem. Soc. Chem. Commun. 1989, 1202-1203. (c) Hartung, J.; Gallou, F. J. Org. Chem. 1995, 60, 6706-6716. (d) Ziegler, F. E.; Petersen, A. K. J. Org. Chem. 1995, 60, 2666-2667. 77. For a review, see: Davidson, R. S. Rev. Chem. Soc. 1967, 21, 249-258. 167  78. For a review on the capto-dative effect, see: Viehe, H. G.; Merenyi, R.; Stella, L.; Janousek, Z. Angew. Chem. Int. Ed. Engl. 1979, 18, 917-932. 79. (a) Linnett, J. W. J. Am. Chem. Soc. 1961, 83, 2643-2653. (b) Firestone, R. A. J. Org. Chem. 1969, 34, 2621-2627. 80. For examples of 1,6-HATs preferred over 1,5-HATs see: (a) Sperry, J.; Liu, V.-C.; Brimble, M. A. Org. Biomol. Chem. 2010, 8, 29-38. (b) Mićović, B. M.; Stojčić, S.; Bralović, M.; Mladenović, S.; Jeremić, D.; Stefanović, M. Tetrahedron 1969, 25, 985-993. (c) Dorta, R. L.; Martín, A.; Prangé, T.; Suárez, E. Tetrahedron: Asymmetry 1996, 7, 1907-1910. (d) Martín, A.; Salazar, J. A.; Suárez, E. J. Org. Chem. 1996, 61, 3999-4006. (e) Dorta, R. L.; Martín, A.; Salazar, J. A.; Suárez, E.; Prangé, T. Tetrahedron Lett. 1996, 37, 6021-6024. (f) Dorta, R. L.; Martín, A.; Prangé, T.; Salazar, J. A.; Suárez, E. J. Org. Chem. 1998, 63, 2251-2261. (g) Francisco, C. G.; Freire, R.; Herrera, A. J.; Suárez, E. Tetrahderon Lett. 2007, 63, 8910-8920. (h) Martín, A.; Pérez-Martín, I.; Quintanal, L. M.; Suárez, E. Tetrahedron Lett. 2008, 49, 5179- 5181. (i) Brown, P; Albert, A. H.; Pettit, G. R. J. Am. Chem. Soc. 1970, 92, 3212-3214.  (j) Albert, A. H.; Pettit, G. R.; Brown, P. J. Org. Chem., 1973, 38, 2197-2201. (k) Francisco, C. G.; Freire, R.; Hernández, R.; Medina, M., C.; Suárez, E.  Tetrahedron Lett. 1983, 4621-46324. 81. For representative reviews, see: (a) Rupprecht, J. K.; Hui, Y.-H.; McLaughlin, J. L. J. Nat. Prod. 1990, 53, 237-278. (b) Kobayashi, J.; Tsuda, M. Nat. Prod. Rep. 2004, 21, 77-93. 82. (a) Ishibashi, M.; Sato, M.; Kobayashi, J. J. Org. Chem. 1993, 58, 6928-6929. (b) For a synthesis of (+)-amphidinolide K, see: Williams, D. R.; Meyer, K. G. J. Am. Chem. Soc. 2001, 123, 765-766. (c) For a synthesis of (–)-amphidinolide K, see: Ko, H. M.; Lee, C. W.; Kwon, H. K.; Chung, H. S.; Choi, S. Y.; Chung, Y. K.; Lee, E. Angew. Chem. Int. Ed. 2009, 48, 2364- 2366. (d) For synthetic efforts toward the synthesis of (–)-amphidinolide K, see: (e) Williams, D. 168  R.; Meyer, K. G. Org. Lett. 1999, 1, 1303-1305. (f) Andreou, T.; Costa, A. M.; Esteban, L.; Gonzàlez, L.; Mas, G.; Vilarrasa, J. Org. Lett. 2005, 7, 4083-4086. 83. Zhu, H; Wickenden, J. G.; Campbell, N. E.; Leung, J. C. T.; Johnson, K. M.; Sammis, G. M. Org. Lett. 2009, 11, 2019-2022.    169  Appendices         Appendix A  : Selected 1 H NMR and 13 C NMR spectra for Chapter 2     170  12 11 10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N o rm a li z e d  I n te n s it y 6 .5 2 2 .3 4 2 .2 4 2 .2 1 2 .1 6 1 .0 2 1 .0 6 1 .0 2 2 .0 4 2 .0 7 7 .7 6 7 .7 1 5 .7 4 4 .9 6 4 .8 9 4 .1 5 1 .9 8 1 .7 1 1 .4 4 1 .3 0     220 200 180 160 140 120 100 80 60 40 20 0 -20 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N o rm a li z e d  I n te n s it y 1 6 3 .7 1 1 3 9 .1 5 1 3 4 .5 3 1 2 9 .0 8 1 2 3 .5 4 1 1 4 .3 3 7 8 .6 5 3 3 .8 5 2 9 .2 4 2 8 .9 0 2 8 .2 5 2 5 .6 1  171  11 10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N o rm a li z e d  I n te n s it y 4 .0 3 4 .1 6 2 .0 6 1 .5 0 0 .5 9 2 .0 6 0 .2 7 0 .7 4 1 .0 0 0 .9 5 4 .1 2 2 .0 0 1 .9 4 7 .8 4 7 .8 4 7 .8 3 7 .7 5 7 .7 5 7 .7 4 7 .7 3 7 .3 4 7 .2 9 7 .2 7 7 .1 7 6 .4 0 6 .3 7 6 .2 5 6 .2 1 5 .6 8 5 .6 5 4 .2 3 4 .2 1 4 .1 9 4 .1 8 2 .2 5 2 .2 3 2 .2 1 1 .8 1 1 .7 9 1 .5 1 1 .4 9 1 .4 8 1 .4 0 1 .4 0 1 .3 9 1 .3 6     200 180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N o rm a li z e d  I n te n s it y 1 6 3 .6 4 1 3 7 .8 8 1 3 4 .3 8 1 3 1 .0 5 1 2 9 .7 3 1 2 8 .9 4 1 2 8 .6 9 1 2 8 .4 0 1 2 8 .0 5 1 2 6 .6 9 1 2 5 .8 7 1 2 3 .4 3 7 8 .5 4 3 2 .9 5 2 9 .7 9 2 9 .2 2 2 9 .1 2 2 9 .0 0 2 8 .5 0 2 8 .1 0 2 5 .4 7  172  11 10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N o rm a li z e d  I n te n s it y 1 0 .2 3 1 .1 6 2 .0 2 2 .0 2 2 .9 6 1 .9 9 2 .0 0 1 .9 0 1 .8 7 7 .8 0 7 .7 8 7 .3 5 7 .3 3 4 .0 3 4 .0 2 4 .0 0 3 .6 4 3 .6 3 3 .6 1 2 .4 5 1 .6 3 1 .6 1 1 .5 4 1 .4 7 1 .3 0 1 .2 9 1 .2 7 1 .2 6 1 .2 4     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N o rm a li z e d  I n te n s it y 1 4 4 .6 0 1 3 3 .1 8 1 2 9 .7 6 1 2 7 .8 3 7 0 .6 4 6 2 .9 3 3 2 .6 8 2 9 .2 5 2 9 .1 8 2 8 .7 4 2 5 .6 1 2 5 .2 5 2 1 .5 8  173  11 10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N o rm a li z e d  I n te n s it y 5 .9 9 9 .0 1 9 .1 8 2 .4 0 2 .0 0 3 .0 6 2 .1 8 1 .0 0 0 .9 4 2 .1 2 2 .1 4 7 .8 1 7 .7 9 7 .3 6 7 .3 4 6 .1 7 6 .1 6 4 .4 4 4 .4 2 4 .4 1 4 .3 9 4 .0 4 4 .0 2 4 .0 0 2 .4 5 2 .0 5 2 .0 4 1 .6 5 1 .6 3 1 .6 2 1 .6 0 1 .3 0 1 .2 8 1 .2 6 1 .2 5 1 .2 4 0 .9 2 0 .1 2     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N o rm a li z e d  I n te n s it y 1 4 4 .5 7 1 3 8 .4 5 1 3 3 .2 4 1 2 9 .7 7 1 2 7 .8 6 1 1 0 .5 3 7 0 .6 8 2 9 .4 5 2 8 .9 8 2 8 .7 8 2 5 .6 2 2 5 .2 7 2 3 .4 6 2 1 .6 0 1 8 .2 6 -5 .3 9  174  11 10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N o rm a li z e d  I n te n s it y 6 .2 9 9 .7 7 6 .0 9 2 .0 6 2 .2 9 2 .1 1 2 .0 7 1 .0 4 1 .0 0 2 .1 1 2 .1 1 H2O 7 .8 6 7 .8 5 7 .8 4 7 .8 4 7 .7 6 7 .7 6 7 .7 5 7 .7 4 6 .1 8 6 .1 6 4 .4 7 4 .4 5 4 .4 4 4 .4 2 4 .2 2 4 .2 0 4 .1 9 2 .0 9 2 .0 8 2 .0 6 1 .8 2 1 .8 0 1 .7 8 1 .7 6 1 .5 0 1 .4 8 1 .4 7 1 .3 5 0 .9 3 0 .1 2     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N o rm a li z e d  I n te n s it y 1 6 3 .6 8 1 3 8 .4 1 1 3 4 .3 9 1 2 9 .0 0 1 2 3 .4 7 1 1 0 .7 2 7 8 .6 6 2 9 .5 6 2 9 .1 9 2 9 .1 2 2 8 .1 4 2 5 .6 4 2 5 .5 0 2 3 .5 3 1 8 .2 8 -5 .3 8  175  10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N o rm a li z e d  I n te n s it y 6 .1 8 9 .0 4 6 .2 8 2 .0 9 2 .1 6 1 .4 6 0 .6 4 2 .0 6 0 .3 0 0 .7 0 0 .3 0 0 .7 0 2 .0 5 1 .9 9 7 .8 5 7 .8 5 7 .8 4 7 .8 3 7 .7 6 7 .7 5 7 .7 5 7 .7 4 6 .2 4 6 .2 1 6 .1 8 6 .1 6 5 .0 2 5 .0 0 4 .9 9 4 .9 8 4 .9 7 4 .9 5 4 .4 7 4 .4 5 4 .4 3 4 .2 2 4 .2 0 4 .1 8 2 .0 7 1 .8 9 1 .8 7 1 .8 1 1 .7 9 1 .7 8 1 .5 0 1 .4 8 1 .4 6 1 .3 4 1 .3 3 0 .9 2 0 .1 3     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N o rm a li z e d  I n te n s it y 1 6 3 .6 7 1 4 0 .0 4 1 3 8 .3 9 1 3 4 .3 9 1 2 8 .9 8 1 2 6 .5 7 1 2 3 .4 6 1 1 1 .5 9 7 8 .6 0 3 0 .3 2 2 9 .1 1 2 8 .8 6 2 8 .1 3 2 7 .2 3 2 5 .7 2 2 5 .6 3 2 5 .5 0 2 3 .5 2 1 8 .3 3 -5 .2 3 -5 .3 8  176  11 10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N o rm a li z e d  I n te n s it y 4 .0 6 2 .1 0 4 .1 0 2 .0 6 2 .0 1 0 .9 9 2 .1 0 2 .0 3 M04(t)M07(m) M08(m) M01(m)M03(m) M02(m) M05(m)M06(m) 7 .8 1 7 .8 0 7 .7 9 7 .7 8 7 .7 7 7 .7 3 7 .7 2 7 .7 2 7 .2 7 5 .8 2 5 .8 1 5 .7 9 5 .7 8 5 .7 6 5 .7 5 5 .7 5 5 .7 4 5 .0 1 4 .9 7 4 .9 5 4 .9 2 4 .1 8 4 .1 7 4 .1 5 2 .5 3 2 .5 2 2 .5 1 2 .5 0 2 .4 8 2 .3 2 2 .3 1 2 .2 9 1 .7 8 1 .7 7 1 .7 6     200 180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N o rm a li z e d  I n te n s it y 2 0 9 .6 2 1 6 3 .4 6 1 3 7 .0 4 1 3 4 .3 7 1 2 8 .8 4 1 2 3 .3 6 1 1 5 .0 8 7 7 .9 7 4 1 .9 3 4 1 .6 7 2 7 .6 6 2 7 .4 2 1 9 .8 1  177  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.25 0.50 0.75 1.00 N o rm a li z e d  I n te n s it y 2 .2 1 4 .0 2 1 .9 7 1 .9 3 4 .0 0 2 .0 9 2 .0 2 0 .9 6 2 .0 2 1 .9 3 M10(m) M09(m) M01(m) M03(m) M02(m) M06(t) M05(s) M04(m) M08(m) M07(m) 7 .8 4 7 .8 3 7 .8 3 7 .8 2 7 .7 5 7 .7 4 7 .7 3 7 .7 2 5 .9 0 5 .8 8 5 .8 4 5 .8 2 5 .8 1 5 .8 0 5 .7 9 5 .0 5 5 .0 5 5 .0 0 4 .9 9 4 .9 5 4 .9 1 4 .2 2 4 .2 0 4 .1 8 3 .9 4 2 .1 7 2 .1 2 1 .8 1 1 .7 5 1 .7 2 1 .7 1 1 .7 0 1 .6 9 1 .6 7 1 .5 9 1 .5 9     160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N o rm a li z e d  I n te n s it y 1 6 3 .7 9 1 3 8 .7 5 1 3 4 .5 9 1 2 9 .1 7 1 2 3 .6 5 1 1 4 .4 2 1 1 1 .4 2 7 8 .5 0 6 5 .1 8 3 6 .9 8 3 6 .4 6 2 8 .4 9 2 8 .2 6 2 0 .1 5  178  11 10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N o rm a li z e d  I n te n s it y 0 .7 9 4 .3 3 4 .0 7 2 .0 2 0 .9 0 0 .4 7 2 .0 0 0 .3 5 2 .0 3 2 .0 3 2 .0 7 7 .8 4 7 .8 3 7 .8 2 7 .8 2 7 .7 5 7 .7 4 7 .7 4 7 .7 3 4 .2 1 4 .1 9 4 .1 8 2 .1 9 2 .1 8 1 .9 4 1 .9 3 1 .7 9 1 .7 7 1 .5 4 1 .5 2 1 .5 0 1 .4 2 1 .4 1     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N o rm a li z e d  I n te n s it y 1 6 3 .6 1 1 3 4 .3 8 1 2 8 .9 6 1 2 3 .4 2 8 4 .5 8 7 8 .4 7 6 8 .1 2 2 8 .6 8 2 8 .4 8 2 8 .2 8 2 8 .0 4 2 5 .3 7 1 8 .3 0  179  10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N o rm a li z e d  I n te n s it y 8 .1 8 2 .1 4 2 .0 5 2 .0 1 2 .0 6 1 .9 7 0 .9 5 4 .0 0 7 .7 7 7 .7 2 5 .7 4 4 .9 6 4 .8 9 4 .1 5 1 .9 8 1 .7 4 1 .4 4 1 .2 8     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N o rm a li z e d  I n te n s it y 1 6 3 .7 2 1 3 9 .2 3 1 3 4 .5 3 1 2 9 .0 9 1 2 3 .5 5 1 1 4 .2 7 7 8 .6 8 3 3 .8 9 2 9 .3 6 2 9 .0 0 2 8 .2 6 2 5 .6 4  180  10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N o rm a li z e d  I n te n s it y 6 .1 9 9 .2 0 1 0 .2 3 4 .1 5 0 .9 9 4 .0 0 3 .5 7 3 .5 5 3 .5 4 3 .5 3 2 .5 2 1 .5 2 1 .5 0 1 .4 8 1 .4 6 1 .4 4 1 .3 0 1 .2 9 1 .2 5 1 .2 5 0 .8 5 0 .0 0     130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N o rm a li z e d  I n te n s it y 6 3 .0 0 6 2 .3 9 3 2 .5 5 3 2 .4 4 2 9 .3 0 2 9 .1 2 2 5 .6 8 2 5 .4 9 1 8 .0 4 -5 .5 8  181  10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N o rm a li z e d  I n te n s it y 6 .2 6 4 .0 1 2 .0 1 1 .2 3 0 .6 8 2 .0 0 0 .3 4 0 .6 3 0 .9 2 0 .8 8 4 .0 4 1 .9 9 1 .9 7 7 .8 5 7 .8 4 7 .8 3 7 .8 3 7 .7 5 7 .7 5 7 .7 4 7 .7 3 7 .2 8 7 .2 7 6 .4 0 6 .3 6 6 .2 5 6 .2 3 6 .2 1 5 .6 8 5 .6 5 4 .2 3 4 .2 2 4 .2 1 4 .2 0 4 .1 9 4 .1 8 2 .3 4 2 .2 2 2 .2 0 1 .8 0 1 .5 0 1 .4 8 1 .4 8 1 .3 7 1 .3 6 1 .3 4 1 .3 3 1 .3 3     160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) -0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N o rm a li z e d  I n te n s it y 1 6 3 .8 1 1 3 4 .5 5 1 3 3 .3 4 1 2 9 .8 9 1 2 9 .1 7 1 2 8 .8 9 1 2 8 .5 9 1 2 8 .2 4 1 2 6 .8 7 1 2 6 .5 5 1 2 6 .0 6 1 2 3 .6 1 7 8 .7 6 3 3 .1 7 3 0 .0 7 2 9 .4 8 2 9 .3 9 2 9 .2 7 2 8 .7 5 2 8 .3 1 2 5 .7 0  182  10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N o rm a li z e d  I n te n s it y 1 2 .3 5 2 .0 3 2 .0 7 1 .0 5 3 .0 2 2 .0 0 2 .0 4 1 .9 9 1 .9 6 7 .7 5 7 .7 3 7 .3 2 7 .3 0 3 .9 9 3 .9 7 3 .9 6 3 .5 9 3 .5 7 3 .5 5 2 .4 0 1 .6 0 1 .5 9 1 .2 5 1 .2 5 1 .2 3 1 .2 2 1 .2 2 1 .2 0 1 .1 9 1 .1 8     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) -0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N o rm a li z e d  I n te n s it y 1 4 4 .5 1 1 3 2 .9 9 1 2 9 .6 5 1 2 7 .6 4 7 0 .5 7 6 2 .6 2 3 2 .5 3 2 9 .1 5 2 9 .0 8 2 8 .6 6 2 8 .6 0 2 5 .5 4 2 5 .1 0 2 1 .4 1  183  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.25 0.50 0.75 1.00 N o rm a li z e d  I n te n s it y 1 8 .2 3 1 0 .7 3 3 .1 9 3 .6 1 1 .9 2 3 .1 4 2 .1 3 0 .9 2 0 .0 9 0 .9 4 2 .0 8 2 .0 5 M03(s)M06(s) M01(s) M09(m)M11(m(para)) M07(m) M10(m(para)) M04(m) M05(m) M08(m) M02(m) 7 .8 1 7 .7 8 7 .3 6 7 .3 3 6 .2 8 6 .2 7 6 .2 7 6 .2 6 6 .2 5 5 .0 0 4 .9 9 4 .9 8 4 .9 7 4 .4 0 4 .3 8 4 .3 7 4 .3 5 4 .0 4 4 .0 3 4 .0 2 4 .0 1 2 .4 5 2 .1 0 2 .0 9 2 .0 7 1 .6 5 1 .6 3 1 .3 5 1 .3 0 1 .2 9 1 .2 7 1 .2 6 1 .2 3 1 .0 9 1 .0 6     160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 45 50 55 60 N o rm a li z e d  I n te n s it y 1 3 9 .1 2 1 2 9 .9 2 1 2 8 .0 4 1 1 0 .0 0 7 0 .8 5 2 9 .7 4 2 9 .3 3 2 9 .0 7 2 8 .9 8 2 5 .4 7 2 3 .6 6 2 1 .7 7 1 7 .8 5 1 2 .4 6 1 2 .1 4  184  10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 45 50 55 60 A b s o lu te  I n te n s it y 1 8 .9 9 9 .2 1 2 .0 5 2 .0 7 1 .9 9 2 .1 6 1 .0 4 1 .0 7 2 .1 0 2 .0 7 7 .8 4 7 .8 3 7 .8 3 7 .8 2 7 .7 5 7 .7 3 7 .7 2 6 .2 6 6 .2 6 6 .2 5 6 .2 5 6 .2 4 4 .4 0 4 .3 9 4 .3 7 4 .3 7 4 .3 5 4 .2 0 4 .1 9 4 .1 7 2 .0 9 2 .0 8 2 .0 8 1 .8 0 1 .7 8 1 .7 6 1 .4 7 1 .3 5 1 .3 1 1 .2 9 1 .0 8 1 .0 6     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 8 16 24 32 40 48 56 64 72 80 N o rm a li z e d  I n te n s it y 1 6 3 .8 1 1 3 9 .0 4 1 3 4 .5 3 1 2 9 .1 5 1 2 3 .5 9 1 1 0 .1 1 7 8 .7 9 2 9 .7 9 2 9 .5 1 2 9 .4 0 2 9 .1 0 2 8 .3 2 2 5 .6 9 2 3 .7 1 1 7 .8 8 1 2 .4 6  185  10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N o rm a li z e d  I n te n s it y 6 .2 8 3 .9 5 2 .0 0 0 .8 7 1 .9 3 1 .9 7 1 .9 7 1 .9 0 7 .8 3 7 .8 2 7 .8 2 7 .8 1 7 .7 5 7 .7 4 7 .7 3 7 .7 2 4 .2 0 4 .1 8 4 .1 7 2 .1 7 2 .1 6 1 .9 3 1 .7 8 1 .5 2 1 .5 0 1 .4 8 1 .3 8 1 .3 5 1 .3 4 1 .3 4 1 .3 3     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N o rm a li z e d  I n te n s it y 1 6 3 .5 8 1 3 4 .3 5 1 2 8 .9 4 1 2 3 .4 0 8 4 .6 4 7 8 .4 9 6 8 .0 6 2 9 .0 7 2 8 .8 5 2 8 .5 5 2 8 .3 6 2 8 .0 6 2 5 .4 2 1 8 .3 0  186  10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 45 50 55 60 N o rm a li z e d  I n te n s it y 2 .2 9 0 .7 0 3 .9 7 0 .5 7 6 .9 5 0 .7 3 2 .0 0 3 .6 8 3 .6 6 3 .6 3 2 .0 2 1 .7 9 1 .7 3 1 .6 0 1 .5 9 1 .5 6 1 .5 5 1 .2 9 1 .2 8 1 .2 7 0 .9 8 0 .9 6 0 .8 1 0 .7 8     140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 45 50 55 60 N o rm a li z e d  I n te n s it y 6 3 .2 2 4 7 .4 0 4 3 .0 9 4 0 .6 1 3 5 .9 0 3 4 .7 1 3 3 .4 4 3 2 .3 1 3 1 .9 5 3 1 .7 3 3 0 .6 5 2 9 .6 4 2 6 .5 2 2 3 .3 6 2 2 .4 1 1 9 .3 4 1 4 .6 8  187  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 45 50 55 60 N o rm a li z e d  I n te n s it y 5 .9 8 9 .0 6 1 0 .2 1 0 .9 8 0 .7 8 0 .7 8 0 .2 2 0 .7 9 0 .2 2 0 .4 4 1 .5 7 2 .9 2 2 .1 3 7 .3 1 7 .2 9 7 .2 8 7 .2 7 7 .2 7 7 .2 0 7 .1 9 7 .1 7 3 .6 7 3 .6 5 3 .6 4 3 .6 2 3 .6 0 2 .7 7 2 .7 5 2 .7 4 2 .3 2 2 .2 9 2 .2 6 1 .5 9 1 .5 7 1 .5 5 1 .5 4 1 .5 4 1 .5 3 1 .5 2 1 .5 0 1 .2 8 1 .0 9 0 .9 3 0 .0 9     160 140 120 100 80 60 40 20 0 -20 Chemical Shift (ppm) 0 8 16 24 32 40 48 56 64 72 80 88 96 N o rm a li z e d  I n te n s it y 1 4 2 .4 8 1 2 8 .9 0 1 2 8 .1 4 1 2 5 .5 3 1 2 5 .4 5 6 3 .5 9 4 7 .7 2 4 5 .2 5 4 4 .2 1 4 2 .7 5 4 1 .2 4 3 5 .2 7 3 2 .1 0 3 1 .9 7 3 0 .1 1 2 9 .6 9 2 6 .0 2 2 6 .0 0 2 3 .5 2 2 2 .1 7 1 8 .3 9 -5 .2 2  188  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 8 16 24 32 40 48 56 64 72 80 88 96 N o rm a li z e d  I n te n s it y 6 .0 0 9 .1 7 3 .4 4 1 0 .3 8 0 .7 0 1 .0 7 0 .3 3 2 .7 5 3 .6 6 3 .6 5 3 .6 4 3 .6 3 3 .6 1 3 .6 0 3 .5 9 3 .4 7 3 .4 5 2 .0 6 1 .6 8 1 .5 6 1 .5 5 1 .5 3 1 .5 2 1 .5 1 1 .5 1 1 .5 0 1 .4 9 1 .2 6 0 .9 0 0 .0 4     112 104 96 88 80 72 64 56 48 40 32 24 16 8 0 -8 Chemical Shift (ppm) 0 8 16 24 32 40 48 56 64 72 80 88 96 N o rm a li z e d  I n te n s it y 6 6 .6 5 6 3 .4 1 6 3 .3 3 6 3 .2 7 4 7 .8 7 4 4 .3 2 4 1 .8 9 4 1 .6 0 3 2 .8 3 3 2 .1 3 3 1 .8 1 3 1 .7 0 3 0 .9 9 2 9 .3 4 2 8 .0 6 2 5 .9 3 2 5 .7 7 2 4 .3 8 2 2 .8 8 1 8 .2 6 -5 .3 8  189  11 10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 20 40 60 80 100 N o rm a li z e d  I n te n s it y 1 .6 8 1 .3 2 0 .6 7 2 .2 8 1 .3 3 2 .6 6 2 .6 7 0 .5 8 1 .9 9 2 .1 6 4 .0 6 M02(d) M01(d) M08(m) M07(m) M05(m) M03(m) M06(m) M09(m) 3 .9 0 3 .9 0 3 .8 9 3 .8 8 3 .8 7 3 .6 3 3 .6 1 3 .6 0 3 .6 0 2 .1 9 2 .1 9 1 .7 7 1 .7 6 1 .6 3 1 .6 2 1 .6 0 1 .0 2 1 .0 0 0 .8 9 0 .8 7     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) -8 0 8 16 24 32 40 48 56 64 72 80 88 96 N o rm a li z e d  I n te n s it y 1 5 .2 6 2 0 .5 1 2 0 .5 7 2 4 .6 3 3 0 .0 3 3 0 .7 0 3 1 .3 2 3 1 .5 8 3 3 .7 5 3 5 .4 8 3 5 .8 5 3 8 .4 4 4 9 .4 4 5 2 .8 3 6 3 .2 8 6 3 .4 2 6 3 .8 6 6 3 .9 6 6 4 .4 5 6 4 .9 6 1 1 8 .3 7 1 1 8 .7 0  190  10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 8 16 24 32 40 48 56 64 72 80 88 96 N o rm a li z e d  I n te n s it y 0 .4 0 1 .7 2 3 .6 6 6 .2 7 0 .8 0 0 .6 3 0 .6 1 0 .1 2 0 .0 7 0 .4 9 0 .4 8 0 .0 9 0 .0 4 0 .5 2 2 .1 3 3 .0 0 2 .0 5 7 .2 9 7 .2 8 7 .2 7 7 .2 6 7 .1 9 7 .1 8 7 .1 7 7 .1 6 3 .6 8 3 .6 7 3 .6 5 3 .0 4 2 .7 3 2 .6 1 2 .5 5 2 .5 2 2 .2 0 1 .7 3 1 .6 1 1 .6 1 1 .6 0 1 .6 0 1 .5 4 1 .5 3 1 .5 3 1 .3 5 1 .1 8 0 .9 2     160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 8 16 24 32 40 48 56 64 72 80 88 96 N o rm a li z e d  I n te n s it y 1 4 1 .9 1 1 4 1 .5 6 1 2 9 .2 1 1 2 8 .9 9 1 2 8 .8 4 1 2 8 .1 0 1 2 8 .0 0 1 2 5 .4 8 1 2 5 .4 3 6 3 .4 7 6 3 .2 7 6 2 .9 6 4 4 .0 7 4 3 .2 1 4 1 .4 8 4 1 .0 6 4 0 .1 0 3 1 .5 9 3 1 .3 5 3 0 .7 1 2 9 .4 8 2 8 .4 4 2 7 .7 0 2 6 .0 8 2 5 .9 2 2 2 .1 6  191  10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 8 16 24 32 40 48 56 64 72 80 88 96 N o rm a li z e d  I n te n s it y 4 .8 1 1 3 .0 3 3 .2 2 3 .1 2 1 .7 0 5 .7 5 3 .9 8 3 .6 9 3 .6 8 3 .6 7 3 .6 6 3 .6 4 3 .6 3 3 .6 3 3 .6 2 1 .7 9 1 .7 0 1 .6 5 1 .6 3 1 .3 3 1 .3 3 1 .2 2 1 .2 1 1 .1 9 1 .0 6 1 .0 6     104 96 88 80 72 64 56 48 40 32 24 16 8 0 Chemical Shift (ppm) 0 8 16 24 32 40 48 56 64 72 80 88 96 N o rm a li z e d  I n te n s it y 6 6 .0 0 6 3 .9 8 6 3 .5 6 6 3 .2 4 4 4 .4 9 4 2 .1 8 3 7 .8 8 3 1 .5 6 3 0 .8 6 3 0 .0 0 2 9 .6 7 2 9 .1 8 2 8 .7 4 2 6 .2 6 2 6 .1 3 2 5 .6 1 2 4 .2 4 2 2 .9 9 1 8 .0 6 1 2 .0 0  192  10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 8 16 24 32 40 48 56 64 72 80 88 96 N o rm a li z e d  I n te n s it y 9 .6 0 1 .8 8 1 .3 4 2 .0 0 0 .6 4 0 .7 7 0 .2 2 0 .2 1 4 .8 7 4 .7 7 4 .6 6 4 .5 7 3 .6 7 3 .6 5 3 .6 4 2 .3 2 2 .2 2 2 .0 5 2 .0 4 2 .0 2 1 .6 2 1 .6 0 1 .5 8 1 .5 7 1 .5 6 1 .3 3 1 .2 8 1 .2 6     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 8 16 24 32 40 48 56 64 72 80 88 96 N o rm a li z e d  I n te n s it y 1 5 6 .9 9 1 5 2 .7 0 1 0 5 .6 6 1 0 4 .0 0 6 3 .2 2 6 2 .9 7 4 3 .9 1 4 2 .9 5 3 4 .6 3 3 4 .2 4 3 3 .8 7 3 3 .1 8 3 3 .0 0 3 0 .7 6 2 8 .7 8 2 8 .1 3 2 4 .1 3 2 3 .9 7  193            Appendix B  : Selected 1 H NMR and 13 C NMR spectra for Chapter 3             194  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 8 16 24 32 40 48 56 64 72 80 88 96 N o rm a li z e d  I n te n s it y 3 .3 4 1 .3 0 1 .1 2 2 .2 6 2 .0 1 1 .0 9 3 .9 5 1 .1 3 0 .3 3 0 .2 3 1 .9 7 0 .3 1 0 .2 5 0 .9 9 5 .8 5 5 .8 3 5 .8 1 5 .7 8 5 .1 2 5 .1 2 5 .0 8 5 .0 7 5 .0 7 5 .0 6 5 .0 4 3 .8 3 3 .8 2 3 .8 2 3 .8 0 3 .5 1 3 .4 9 3 .4 8 3 .4 6 2 .3 7 2 .3 5 2 .3 4 1 .7 2 1 .7 1 1 .7 0 1 .7 0 1 .7 0 1 .6 9 1 .6 8 1 .6 6 1 .2 0 1 .1 8     160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 8 16 24 32 40 48 56 64 72 80 88 96 N o rm a li z e d  I n te n s it y 1 3 5 .0 2 1 1 6 .4 9 7 1 .1 6 7 0 .2 6 6 7 .7 0 3 6 .8 3 3 4 .0 8 2 6 .3 7 2 3 .4 0  195  10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 10 20 30 40 50 60 70 80 90 100 N o rm a li z e d  I n te n s it y 3 .0 1 0 .1 3 4 .4 3 1 .6 9 3 .6 0 0 .1 7 0 .1 1 0 .9 4 1 .6 2 0 .7 8 1 .7 9 1 .7 1 H2O 7 .8 5 7 .8 5 7 .8 4 7 .8 3 7 .7 7 7 .7 6 7 .7 5 5 .8 8 5 .8 6 5 .8 3 5 .8 2 5 .7 9 5 .1 1 5 .0 7 5 .0 6 5 .0 4 5 .0 1 4 .4 2 4 .4 1 3 .5 3 3 .5 2 3 .5 1 3 .5 0 3 .4 9 3 .4 7 2 .3 6 2 .3 4 2 .3 2 2 .3 1 1 .8 4 1 .8 3 1 .8 2 1 .8 0 1 .7 2 1 .7 0 1 .3 7 1 .3 5     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 8 16 24 32 40 48 56 64 72 80 88 96 N o rm a li z e d  I n te n s it y 1 6 4 .2 9 1 3 5 .2 9 1 3 4 .3 5 1 2 8 .9 5 1 2 3 .3 8 1 1 6 .1 8 8 4 .1 5 7 0 .3 6 7 0 .0 4 3 4 .1 5 3 1 .5 2 2 5 .3 9 1 8 .8 4  196  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 8 16 24 32 40 48 56 64 72 80 88 96 N o rm a li z e d  I n te n s it y 6 .2 2 9 .6 2 4 .5 5 2 .0 8 2 .3 4 2 .0 5 2 .0 1 1 .0 0 5 .9 6 5 .9 4 5 .9 2 5 .9 0 5 .8 9 5 .8 7 5 .2 8 5 .2 4 5 .2 3 5 .1 7 5 .1 4 3 .9 6 3 .9 5 3 .9 5 3 .6 4 3 .6 3 3 .6 1 3 .4 6 3 .4 4 3 .4 2 1 .6 4 1 .6 2 1 .6 1 1 .6 0 1 .5 8 1 .5 8 1 .5 6 1 .5 6 0 .8 9 0 .0 4     160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 8 16 24 32 40 48 56 64 72 80 88 96 N o rm a li z e d  I n te n s it y 1 3 4 .7 1 1 1 6 .2 7 7 1 .4 0 6 9 .9 0 6 2 .6 1 2 9 .1 7 2 5 .8 9 2 5 .6 0 1 7 .9 7 -5 .6 7  197  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 8 16 24 32 40 48 56 64 72 80 88 96 N o rm a li z e d  I n te n s it y 5 .7 8 8 .9 5 4 .0 5 1 .9 9 1 .0 0 1 .9 6 3 .9 5 2 .0 0 7 .2 7 3 .7 9 3 .7 8 3 .7 6 3 .6 4 3 .6 3 3 .6 3 3 .6 2 3 .6 0 3 .4 6 2 .1 6 1 .8 5 1 .8 3 1 .8 2 1 .6 3 1 .6 2 1 .5 8 1 .5 7 1 .5 6 1 .5 6 0 .9 2 0 .8 9 0 .8 6 0 .0 5     120 110 100 90 80 70 60 50 40 30 20 10 0 -10 Chemical Shift (ppm) 0 8 16 24 32 40 48 56 64 72 80 88 96 N o rm a li z e d  I n te n s it y 7 1 .2 1 7 0 .2 3 6 2 .8 7 6 2 .2 6 3 1 .9 4 2 9 .4 1 2 6 .1 4 2 5 .9 2 1 8 .3 0 -5 .3 3  198  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 8 16 24 32 40 48 56 64 72 80 88 96 N o rm a li z e d  I n te n s it y 5 .8 2 9 .0 3 4 .5 6 2 .0 1 1 .9 9 1 .9 9 2 .0 0 0 .9 7 0 .9 5 0 .8 7 4 .0 7 7 .4 0 7 .4 0 7 .3 8 7 .3 5 7 .3 3 7 .3 1 7 .3 0 7 .2 4 6 .5 2 6 .4 8 6 .3 0 6 .2 8 6 .2 6 3 .6 9 3 .6 8 3 .6 6 3 .6 0 3 .5 8 3 .5 6 3 .5 1 3 .5 0 2 .5 5 2 .5 4 2 .5 3 2 .5 2 1 .6 9 1 .6 7 1 .6 6 1 .6 5 1 .6 5 1 .6 3 0 .9 4 0 .0 9     160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 8 16 24 32 40 48 56 64 72 80 88 96 N o rm a li z e d  I n te n s it y 1 3 7 .6 1 1 3 1 .4 7 1 2 8 .4 4 1 2 7 .1 1 1 2 6 .9 7 1 2 6 .0 0 7 0 .8 4 7 0 .3 0 6 2 .9 8 3 3 .5 3 2 9 .5 1 2 6 .1 7 2 5 .9 5 1 8 .3 3 -5 .3 0  199  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 8 16 24 32 40 48 56 64 72 80 88 96 N o rm a li z e d  I n te n s it y 4 .0 9 1 .6 2 0 .4 2 0 .9 6 2 .1 3 1 .9 7 2 .0 4 0 .2 0 0 .8 0 1 .0 0 0 .9 5 4 .0 6 7 .4 0 7 .3 8 7 .3 5 7 .3 3 7 .3 1 7 .2 6 7 .2 4 6 .5 2 6 .4 8 6 .3 0 6 .2 8 6 .2 6 6 .2 4 5 .7 5 5 .7 3 5 .7 2 3 .6 8 3 .6 7 3 .6 5 3 .6 1 3 .5 9 3 .5 8 3 .5 3 3 .5 2 2 .8 8 2 .5 5 2 .5 3 1 .7 4 1 .7 3 1 .7 2 1 .7 1 1 .7 0 1 .6 9 1 .6 8     160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 8 16 24 32 40 48 56 64 72 80 88 96 N o rm a li z e d  I n te n s it y 1 3 7 .2 9 1 3 7 .1 1 1 3 1 .4 8 1 2 8 .4 8 1 2 8 .3 2 1 2 8 .2 5 1 2 7 .9 4 1 2 6 .8 3 1 2 6 .5 5 1 2 6 .4 6 1 2 5 .8 0 7 0 .6 8 7 0 .6 5 7 0 .2 0 6 2 .1 4 3 3 .1 8 2 9 .7 0 2 8 .9 3 2 6 .3 3 2 6 .3 0  200  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 10 20 30 40 50 60 70 80 90 100 N o rm a li z e d  I n te n s it y 4 .0 9 1 .6 4 0 .4 1 4 .2 2 2 .0 5 0 .2 1 0 .7 9 1 .0 0 1 .0 1 4 .4 1 2 .1 1 2 .1 3 H2O 7 .8 4 7 .8 4 7 .8 3 7 .7 6 7 .7 5 7 .7 5 7 .7 4 7 .3 4 7 .3 0 7 .2 8 7 .1 9 6 .4 8 6 .4 4 6 .2 6 6 .2 4 6 .2 2 5 .7 2 5 .6 9 5 .6 7 4 .2 6 4 .2 5 4 .2 4 4 .2 3 4 .2 2 3 .5 8 3 .5 6 3 .5 5 3 .5 5 3 .5 4 3 .5 2 2 .5 1 2 .4 9 1 .9 2 1 .9 0 1 .8 8 1 .8 6 1 .8 5 1 .8 3 1 .8 1     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 8 16 24 32 40 48 56 64 72 80 88 96 N o rm a li z e d  I n te n s it y 1 6 3 .5 0 1 3 7 .4 5 1 3 4 .3 1 1 3 1 .3 9 1 2 8 .8 2 1 2 8 .5 9 1 2 8 .3 3 1 2 8 .0 2 1 2 6 .9 8 1 2 6 .8 6 1 2 5 .8 8 1 2 3 .3 3 1 0 8 .6 7 7 8 .1 2 7 0 .2 1 7 0 .0 9 7 0 .0 6 6 9 .0 1 3 3 .4 0 3 0 .6 9 2 9 .1 4 2 5 .7 2 2 4 .9 9 2 2 .4 3  201  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 8 16 24 32 40 48 56 64 72 80 88 96 N o rm a li z e d  I n te n s it y 6 .0 7 9 .1 2 3 .9 1 1 .9 8 4 .0 3 2 .0 0 1 .9 1 0 .9 2 5 .8 7 5 .8 6 5 .8 5 5 .8 3 5 .8 2 5 .8 0 5 .1 2 5 .0 8 5 .0 7 5 .0 5 5 .0 3 3 .6 5 3 .6 4 3 .4 9 3 .4 7 3 .4 6 3 .4 6 3 .4 5 3 .4 3 2 .3 5 2 .3 3 1 .6 3 1 .6 2 1 .6 1 1 .6 1 1 .6 0 1 .5 9 1 .5 8 1 .5 8 0 .9 0 0 .0 5     160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 45 A b s o lu te  I n te n s it y 1 3 5 .3 7 1 1 6 .2 1 7 0 .7 8 7 0 .0 8 6 3 .0 0 3 4 .2 5 2 9 .5 2 2 6 .1 5 2 5 .9 7 2 0 .7 5 -5 .2 9  202  10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 5 10 15 20 25 N o rm a li z e d  I n te n s it y 6 .0 3 9 .0 9 8 .0 0 0 .9 6 4 .0 0 4 .0 0 3 .6 1 3 .6 0 3 .5 8 3 .4 4 3 .4 3 3 .4 1 2 .8 1 1 .6 5 1 .6 4 1 .6 3 1 .6 2 1 .6 1 1 .6 0 1 .6 0 1 .5 9 0 .8 6 0 .0 2     140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 Chemical Shift (ppm) 0 8 16 24 32 40 48 56 64 72 N o rm a li z e d  I n te n s it y 7 0 .8 3 7 0 .7 4 6 2 .8 5 6 2 .5 1 3 0 .1 9 2 9 .3 8 2 6 .7 8 2 6 .0 4 2 5 .8 8 1 8 .2 4 -5 .3 9  203  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 N o rm a li z e d  I n te n s it y 6 .0 4 9 .0 9 5 .9 6 2 .0 5 3 .0 1 4 .0 0 1 .9 9 2 .0 0 1 .9 7 1 .9 4 7 .8 0 7 .7 8 7 .3 6 7 .3 4 4 .0 7 4 .0 6 4 .0 4 3 .6 3 3 .6 1 3 .6 0 3 .3 9 3 .3 7 3 .3 6 3 .3 4 2 .4 5 1 .7 7 1 .7 4 1 .7 2 1 .6 0 1 .5 8 1 .5 7 1 .5 7 1 .5 6 1 .5 5 0 .8 9 0 .0 5     160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 45 50 55 60 65 N o rm a li z e d  I n te n s it y 1 4 4 .6 2 1 3 3 .1 8 1 2 9 .7 8 1 2 7 .8 6 7 0 .7 5 7 0 .4 5 6 9 .6 5 6 2 .9 3 2 9 .4 7 2 6 .1 3 2 5 .9 3 2 5 .8 7 2 5 .6 8 2 1 .6 0 1 8 .3 1 -5 .3 2  204  10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 45 50 N o rm a li z e d  I n te n s it y 2 .6 3 3 .3 9 4 .0 6 5 .0 7 2 .1 7 2 .1 2 3 .1 3 1 .1 4 0 .9 0 1 .1 5 0 .9 6 1 .1 4 0 .9 2 2 .1 4 0 .4 7 0 .5 5 0 .4 5 0 .5 5 2 .0 8 2 .0 6 H2O 7 .7 7 7 .7 5 6 .7 1 6 .6 9 6 .3 4 6 .3 1 6 .2 3 6 .2 1 5 .1 7 5 .1 6 5 .1 5 5 .1 4 4 .6 2 4 .6 0 4 .5 9 3 .8 8 3 .8 7 3 .8 5 3 .2 9 3 .1 6 3 .1 4 3 .1 2 3 .0 7 3 .0 4 3 .0 2 3 .0 1 2 .1 2 2 .1 0 1 .8 4 1 .4 8 1 .4 7 1 .4 6 1 .4 6 1 .3 5 1 .3 4 0 .9 4 0 .9 2 0 .0 7     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) -1.0 -0.5 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 N o rm a li z e d  I n te n s it y 1 4 4 .3 5 1 4 4 .3 1 1 4 2 .2 5 1 4 0 .2 7 1 3 5 .0 0 1 3 0 .1 0 1 2 8 .5 0 1 2 8 .2 7 1 0 8 .3 8 1 0 7 .4 1 7 2 .0 1 7 1 .1 4 7 0 .5 9 7 0 .1 7 2 8 .8 6 2 6 .5 9 2 6 .3 5 2 6 .3 3 2 6 .1 9 2 6 .1 2 2 5 .5 0 2 1 .4 6 1 8 .8 0 -4 .7 9  205  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 5 10 15 20 25 N o rm a li z e d  I n te n s it y 3 .2 9 2 .6 8 5 .0 9 4 .0 0 4 .0 2 0 .9 1 1 .1 2 1 .9 2 1 .1 9 1 .1 2 2 .0 7 0 .5 6 0 .4 3 0 .5 5 0 .4 4 2 .0 5 2 .0 1 H2O 7 .3 1 7 .3 0 7 .2 9 7 .2 9 7 .2 8 6 .8 1 6 .8 1 6 .8 0 6 .7 9 6 .3 6 6 .3 3 6 .2 3 6 .2 2 5 .2 3 5 .2 2 4 .6 6 4 .6 4 4 .0 7 4 .0 5 4 .0 4 3 .4 1 3 .3 9 3 .3 7 3 .3 2 3 .3 0 3 .2 9 3 .2 7 3 .2 5 2 .6 0 2 .5 8 2 .1 8 1 .7 6 1 .7 4 1 .7 3 1 .7 2 1 .7 1 0 .9 5 0 .9 3 0 .0 8 0 .0 3     160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 1 2 3 4 5 6 7 N o rm a li z e d  I n te n s it y 1 6 3 .7 0 1 4 2 .2 2 1 4 0 .1 6 1 3 4 .0 6 1 3 4 .0 4 1 2 9 .8 7 1 2 8 .5 0 1 2 8 .2 7 1 2 3 .3 2 1 0 8 .5 6 1 0 7 .7 1 7 8 .6 6 7 8 .6 0 7 2 .0 3 7 1 .1 6 7 0 .5 6 2 8 .9 4 2 6 .6 8 2 6 .1 4 2 5 .8 9 2 5 .5 8 1 8 .8 1 -4 .7 8 -5 .0 0  206  10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.0000001 0.0000002 0.0000003 0.0000004 0.0000005 0.0000006 0.0000007 0.0000008 0.0000009 0.0000010 N o rm a li z e d  I n te n s it y 4 .0 5 0 .8 4 2 .1 0 1 .9 4 1 .9 9 1 .9 5 1 .0 2 1 .0 0 2 .9 3 1 .9 1 7 .4 3 7 .4 3 7 .4 1 7 .4 1 7 .3 5 7 .3 3 7 .3 1 7 .2 7 5 .3 5 5 .3 5 5 .1 3 3 .6 3 3 .6 1 3 .5 7 3 .5 5 3 .5 3 3 .4 5 3 .4 4 3 .4 2 2 .8 2 2 .8 1 2 .7 9 1 .6 5 1 .6 5 1 .6 4 1 .6 3 1 .6 3 1 .6 3     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 0.0000001 0.0000002 0.0000003 0.0000004 0.0000005 0.0000006 0.0000007 0.0000008 0.0000009 0.0000010 N o rm a li z e d  I n te n s it y 1 4 4 .9 6 1 4 0 .7 3 1 2 8 .2 0 1 2 7 .3 5 1 2 5 .9 3 1 1 3 .8 0 7 0 .7 8 6 9 .5 5 6 2 .4 0 3 5 .4 5 3 0 .0 1 2 6 .5 6  207  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) -2 0 2 4 6 8 10 12 14 16 N o rm a li z e d  I n te n s it y 1 .8 9 1 .8 2 1 .8 9 1 .7 8 1 .7 5 2 .4 6 0 .9 4 1 .0 0 2 .9 5 2 .4 2 2 .5 7 2 .4 1 H2O 7 .8 6 7 .8 5 7 .8 4 7 .8 4 7 .7 7 7 .7 6 7 .7 5 7 .4 3 7 .4 1 7 .3 2 5 .3 4 5 .1 3 4 .2 4 4 .2 2 4 .2 0 3 .5 9 3 .5 7 3 .5 5 3 .5 3 3 .5 0 3 .4 9 3 .4 7 2 .8 1 2 .8 0 2 .7 8 1 .9 2 1 .8 7 1 .8 5 1 .8 4 1 .7 9 1 .7 7 1 .7 6     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 0.0000001 0.0000002 0.0000003 0.0000004 0.0000005 0.0000006 0.0000007 0.0000008 0.0000009 0.0000010 N o rm a li z e d  I n te n s it y 1 6 3 .5 7 1 4 5 .2 5 1 4 0 .9 2 1 3 4 .3 6 1 2 8 .9 2 1 2 8 .2 2 1 2 7 .3 3 1 2 5 .9 8 1 2 3 .4 0 1 1 3 .6 6 7 8 .2 0 7 0 .0 8 6 9 .5 6 3 5 .5 4 2 5 .7 5 2 5 .0 2  208  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 45 N o rm a li z e d  I n te n s it y 4 .1 1 3 .1 5 2 .0 3 2 .0 7 1 .0 2 1 .0 4 0 .9 7 1 .9 5 0 .9 6 1 .9 5 0 .9 2 1 .9 4 7 .8 2 7 .8 0 7 .4 8 7 .4 7 7 .4 6 7 .3 5 7 .3 3 6 .9 6 6 .9 3 6 .8 1 6 .7 9 5 .7 5 5 .7 5 5 .7 1 5 .7 0 5 .2 5 5 .2 5 5 .2 3 5 .2 2 4 .1 4 4 .1 3 4 .1 3 4 .1 1 3 .9 5 3 .9 4 3 .9 4 3 .9 3 2 .4 4 1 .8 9 1 .8 8 1 .8 8 1 .8 7 1 .8 6 1 .8 5 1 .8 5     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 45 50 55 60 N o rm a li z e d  I n te n s it y 1 5 5 .7 7 1 4 4 .7 2 1 3 3 .0 3 1 3 1 .4 6 1 2 9 .8 2 1 2 8 .7 6 1 2 7 .8 2 1 2 6 .6 9 1 2 6 .4 0 1 2 0 .6 9 1 1 4 .2 6 1 1 1 .7 6 7 0 .1 0 6 7 .0 3 2 5 .7 7 2 5 .3 4 2 1 .5 8  209  10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 45 N o rm a li z e d  I n te n s it y 4 .0 7 2 .0 9 2 .0 0 0 .9 9 1 .0 0 1 .9 8 0 .9 4 0 .9 3 0 .9 1 2 .0 0 1 .9 1 7 .8 6 7 .8 6 7 .8 5 7 .8 4 7 .7 7 7 .7 6 7 .7 6 7 .7 5 7 .4 7 6 .9 3 6 .9 1 6 .8 9 5 .7 5 5 .7 1 5 .7 1 5 .2 5 5 .2 4 5 .2 2 4 .3 2 4 .3 1 4 .2 9 4 .1 2 4 .1 1 4 .0 9 2 .1 1 2 .0 9 2 .0 5 2 .0 4 2 .0 4 2 .0 3 2 .0 2 2 .0 2     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) -2 0 2 4 6 8 10 12 14 16 N o rm a li z e d  I n te n s it y 1 6 3 .6 3 1 5 6 .0 1 1 3 4 .4 5 1 3 1 .6 4 1 2 8 .9 5 1 2 8 .7 9 1 2 6 .8 0 1 2 6 .4 0 1 2 3 .4 9 1 2 0 .5 8 1 1 4 .2 0 1 1 1 .8 8 7 8 .0 1 6 7 .4 8 2 5 .6 3 2 5 .0 7  210  10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 45 50 N o rm a li z e d  I n te n s it y 2 .0 9 2 .1 2 2 .0 6 2 .0 4 2 .1 3 2 .0 0 0 .9 5 2 .0 6 2 .0 1 H2O 7 .1 9 7 .1 9 7 .1 7 7 .1 5 6 .9 3 6 .9 1 6 .8 7 6 .8 5 6 .0 1 6 .0 0 5 .9 7 5 .0 9 5 .0 9 5 .0 6 5 .0 6 5 .0 5 5 .0 4 4 .0 4 4 .0 2 4 .0 1 3 .7 6 3 .7 5 3 .7 3 3 .4 2 3 .4 1 3 .4 0 3 .4 0 1 .9 3 1 .9 2 1 .9 1 1 .8 9 1 .8 1 1 .8 0 1 .7 9 1 .7 7     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 45 50 55 60 N o rm a li z e d  I n te n s it y 1 5 6 .5 2 1 3 7 .0 2 1 2 9 .7 7 1 2 8 .6 7 1 2 7 .2 6 1 2 0 .4 6 1 1 5 .3 3 1 1 1 .1 9 6 7 .6 5 6 2 .5 9 3 4 .3 9 2 9 .5 7 2 5 .8 7  211  10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 N o rm a li z e d  I n te n s it y 4 .2 1 2 .0 3 2 .0 1 2 .0 4 1 .9 8 0 .9 6 2 .0 0 2 .0 0 2 .0 4 2 .0 1 H2O 7 .8 5 7 .8 5 7 .8 4 7 .8 3 7 .7 6 7 .7 6 7 .7 5 7 .7 4 7 .1 8 6 .8 9 6 .8 8 6 .8 6 5 .9 9 5 .9 7 5 .9 4 5 .0 7 5 .0 6 5 .0 2 5 .0 2 5 .0 0 5 .0 0 4 .3 2 4 .3 1 4 .2 9 4 .0 9 4 .0 8 4 .0 7 3 .4 0 3 .3 8 2 .0 8 2 .0 8 2 .0 7 2 .0 5 2 .0 3 2 .0 2 2 .0 2 2 .0 2     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 45 50 55 60 N o rm a li z e d  I n te n s it y 1 6 3 .5 6 1 5 6 .4 5 1 3 6 .9 8 1 3 4 .3 9 1 2 9 .6 8 1 2 8 .8 8 1 2 8 .6 0 1 2 7 .2 2 1 2 3 .4 2 1 2 0 .3 6 1 1 5 .2 2 1 1 1 .0 8 7 7 .9 7 6 7 .0 3 3 4 .3 3 2 5 .6 0 2 5 .0 3  212  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 8 16 24 32 40 48 56 64 72 80 88 96 N o rm a li z e d  I n te n s it y 3 .0 4 2 .8 0 0 .2 1 3 .0 9 0 .9 5 2 .6 6 0 .8 9 1 .0 8 0 .9 4 1 .9 3 0 .1 1 0 .9 2 0 .9 7 6 .3 2 4 .0 0 0 .6 9 0 .7 0 0 .8 6 0 .8 8 0 .9 0 1 .1 9 1 .2 1 1 .5 4 1 .5 4 1 .5 5 1 .5 6 1 .5 6 2 .0 7 2 .0 7 2 .1 7 3 .6 6 3 .6 9 3 .7 0 3 .7 1 3 .7 2 3 .7 2 3 .8 9 3 .9 1 4 .0 0 7 .3 8 7 .3 9 7 .4 0 7 .4 1 7 .4 3 7 .4 4 7 .6 3 7 .6 4 7 .6 5     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 8 16 24 32 40 48 56 64 72 80 88 96 N o rm a li z e d  I n te n s it y 1 3 6 .8 0 1 3 4 .3 7 1 2 9 .5 8 1 2 7 .7 0 8 1 .8 5 8 1 .3 9 6 9 .7 2 6 9 .0 8 6 5 .8 6 3 6 .6 8 3 6 .1 9 3 5 .2 4 3 5 .2 2 3 3 .8 3 3 3 .7 9 2 6 .9 7 2 6 .0 6 2 3 .8 3 2 3 .5 2 1 4 .1 1 -2 .3 1  213  10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 8 16 24 32 40 48 56 64 72 80 88 96 N o rm a li z e d  I n te n s it y 3 .0 0 0 .1 4 3 .0 5 1 .0 6 0 .6 2 2 .3 2 1 .0 0 1 .0 5 0 .8 5 1 .0 1 0 .1 1 1 .0 0 0 .1 0 2 .1 7 0 .9 7 1 .0 0 1 0 .7 3 6 .9 7 7 .5 3 7 .5 2 7 .3 6 7 .3 4 7 .3 2 7 .3 0 7 .2 8 7 .2 7 4 .1 3 3 .9 2 3 .9 1 3 .7 1 3 .7 0 3 .6 8 3 .2 7 3 .2 6 3 .2 5 3 .1 1 3 .1 0 3 .0 9 2 .3 4 2 .1 4 1 .7 8 1 .7 6 1 .7 5 1 .3 9 1 .3 7 1 .3 6 0 .9 7 0 .9 6 0 .9 4    haiVIII4-C(400D)_003001r.esp 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 Chemical Shift (ppm) 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N o rm a li z e d  I n te n s it y 1 5 .1 9 2 8 .3 7 3 0 .5 6 3 5 .8 4 3 6 .4 8 6 3 .0 3 6 7 .0 0 7 7 .4 6 8 2 .0 7 8 6 .4 1 1 2 6 .8 6 1 2 7 .7 0 1 2 8 .7 8 1 4 4 .1 1  214  10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 8 16 24 32 40 48 56 64 72 80 88 96 N o rm a li z e d  I n te n s it y 0 .8 4 3 .6 9 0 .7 8 0 .3 2 1 .7 5 1 .0 1 0 .1 5 0 .8 5 0 .1 4 2 .7 5 0 .2 4 1 .8 2 3 .0 8 2 .2 7 Grease 7 .3 2 7 .3 0 7 .2 8 7 .2 7 7 .2 3 7 .2 1 7 .1 9 7 .1 7 3 .9 8 3 .9 8 3 .9 6 3 .9 4 3 .7 6 3 .7 5 3 .7 3 3 .7 1 3 .7 0 2 .8 6 2 .8 3 2 .8 2 2 .4 4 1 .7 5 1 .7 4 1 .7 2 1 .7 0 1 .6 9 1 .6 7     160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 8 16 24 32 40 48 56 64 72 80 88 96 N o rm a li z e d  I n te n s it y 1 4 0 .8 0 1 2 8 .7 5 1 2 8 .3 7 1 2 6 .1 0 1 2 5 .9 5 8 4 .1 3 8 1 .5 1 6 6 .7 1 6 6 .1 5 6 2 .8 9 4 3 .1 3 3 9 .0 4 3 4 .6 2 3 2 .4 4 3 1 .5 7 3 0 .4 9 3 0 .4 3 2 9 .9 1 2 7 .7 8  215  10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 5 10 15 20 N o rm a li z e d  I n te n s it y 1 .8 3 4 .1 7 2 .7 1 6 .2 5 5 .2 9 0 .3 6 0 .6 4 0 .3 2 0 .6 9 0 .0 0 1 .2 4 6 .1 1 H2O Hexane Hexane 3 .7 6 3 .5 9 3 .5 7 3 .5 6 3 .5 5 3 .5 5 3 .5 4 3 .4 9 3 .3 7 3 .3 5 1 .6 9 1 .6 9 1 .6 5 1 .6 3 1 .5 9 1 .5 8 1 .5 7 1 .5 5 0 .9 6 0 .9 5 0 .0 3     160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 N o rm a li z e d  I n te n s it y Hexane Hexane 8 2 .5 7 8 1 .2 6 6 7 .2 1 6 6 .5 4 6 5 .1 6 6 3 .1 6 6 2 .8 7 4 7 .5 4 4 4 .7 4 3 3 .0 7 3 2 .3 0 3 1 .6 5 3 0 .9 5 2 9 .9 5 2 9 .4 5 2 8 .0 0 2 6 .4 2 1 8 .7 8 1 8 .7 5 -4 .9 9  216  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 N o rm a li z e d  I n te n s it y 0 .9 5 7 .5 0 1 .0 0 1 .1 2 0 .9 9 3 .2 3 1 .0 0 3 .1 7 2 .6 6 H2O 7 .3 6 7 .3 5 7 .3 3 7 .3 1 7 .2 4 7 .2 3 7 .2 2 7 .2 2 4 .1 7 4 .1 6 4 .1 4 3 .7 0 3 .6 8 3 .6 7 3 .6 6 3 .6 3 3 .4 7 2 .5 1 2 .5 0 2 .4 8 1 .7 9 1 .7 8 1 .7 7 1 .7 6 1 .7 4 1 .7 3 1 .6 6 1 .6 4 1 .5 7     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 8 16 24 32 40 48 56 64 72 80 88 96 N o rm a li z e d  I n te n s it y 1 4 5 .6 2 1 2 8 .5 2 1 2 6 .7 0 1 2 6 .3 4 7 7 .8 7 6 8 .2 0 6 2 .9 4 4 1 .7 3 3 9 .5 1 3 3 .4 9 3 3 .2 9 2 9 .3 1  217  10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 N o rm a li z e d  I n te n s it y 6 .5 2 1 0 .5 3 1 .8 7 1 .1 9 4 .7 1 0 .3 2 0 .3 7 0 .6 0 2 .4 3 0 .3 3 0 .3 7 0 .6 1 2 .1 4 2 .0 0 7 .1 6 7 .1 5 7 .1 4 7 .1 4 7 .1 2 6 .8 8 6 .8 6 6 .7 9 6 .7 7 6 .7 7 4 .7 0 4 .6 8 4 .6 6 4 .0 0 3 .7 6 3 .7 4 3 .7 3 3 .7 1 3 .7 0 3 .6 9 3 .6 8 3 .6 7 3 .4 0 3 .1 5 1 .8 4 1 .8 3 1 .8 1 1 .7 9 1 .7 8 1 .7 6 1 .7 2 1 .3 5 1 .3 4 1 .1 9 1 .1 7 0 .9 2 0 .0 8     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 45 50 55 N o rm a li z e d  I n te n s it y 1 5 8 .6 8 1 3 3 .5 5 1 3 2 .3 8 1 2 7 .9 2 1 2 4 .0 6 1 2 3 .7 4 1 2 0 .3 2 1 2 0 .1 4 1 0 9 .4 3 1 0 9 .3 1 9 0 .9 0 8 6 .3 7 6 2 .8 5 4 2 .1 7 3 8 .9 9 3 1 .3 6 2 9 .7 3 2 8 .7 7 2 6 .3 1 2 5 .9 5 1 8 .9 8 1 8 .3 4 1 5 .1 6 -5 .3 0  218  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 8 16 24 32 40 48 56 64 72 80 88 96 N o rm a li z e d  I n te n s it y 1 .2 2 1 .7 7 2 .9 2 2 .3 1 0 .7 2 0 .9 4 1 .0 1 0 .0 5 0 .5 8 0 .0 4 0 .3 9 0 .0 8 2 .7 4 0 .4 0 0 .0 8 0 .0 4 1 .9 9 0 .0 5 2 .0 1 0 .1 0 7 .1 0 7 .0 8 7 .0 5 7 .0 4 7 .0 3 6 .8 6 6 .8 5 6 .8 2 6 .8 0 4 .0 6 3 .7 4 3 .7 4 3 .7 3 3 .7 2 3 .7 1 3 .7 1 2 .7 7 2 .5 2 2 .4 8 2 .4 5 1 .9 1 1 .9 1 1 .8 9 1 .8 9 1 .8 8 1 .8 7 1 .7 6 1 .7 5 1 .0 7 1 .0 5 1 .0 0 0 .9 8     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 8 16 24 32 40 48 56 64 72 80 88 96 N o rm a li z e d  I n te n s it y 1 5 4 .2 2 1 5 3 .8 7 1 2 9 .9 7 1 2 9 .2 6 1 2 7 .0 4 1 2 6 .9 9 1 2 1 .9 3 1 2 0 .9 7 1 2 0 .1 9 1 2 0 .0 1 1 1 6 .3 4 1 1 6 .2 3 8 0 .6 2 7 8 .4 0 6 2 .7 0 6 2 .5 5 3 2 .9 8 3 2 .5 8 3 0 .7 0 2 9 .5 7 2 9 .3 2 2 8 .9 9 2 8 .1 4 2 7 .6 2 1 7 .5 8 1 3 .2 5  219              Appendix C  : Selected 1 H NMR and 13 C NMR spectra for Chapter 4           220  10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 45 N o rm a li z e d  I n te n s it y 2 .1 5 4 .1 8 1 .0 7 2 .1 6 4 .2 1 2 .1 9 2 .1 0 1 .0 3 5 .8 4 5 .8 3 5 .8 0 5 .7 8 5 .7 7 5 .7 7 5 .7 6 5 .0 8 5 .0 8 5 .0 4 5 .0 2 4 .9 9 3 .6 1 3 .6 0 3 .5 8 3 .4 6 3 .4 4 3 .4 2 3 .4 1 3 .3 9 2 .3 1 2 .2 9 2 .0 7 1 .6 0 1 .5 8 1 .5 6 1 .5 4 1 .5 4 1 .4 1 1 .3 9     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 45 50 55 60 N o rm a li z e d  I n te n s it y 1 3 5 .1 6 1 1 6 .2 0 7 0 .7 3 7 0 .0 7 6 2 .5 2 3 4 .0 8 3 2 .3 6 2 9 .2 5 2 2 .3 2  221  10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 45 N o rm a li z e d  I n te n s it y 2 .0 7 2 .1 6 2 .0 7 2 .0 2 4 .1 7 2 .1 0 2 .0 0 1 .0 0 2 .0 6 2 .0 0 7 .8 7 7 .8 7 7 .8 6 7 .8 5 7 .8 4 7 .7 9 7 .7 8 7 .7 7 5 .8 9 5 .8 8 5 .8 6 5 .8 4 5 .8 4 5 .8 2 5 .1 4 5 .1 3 5 .0 9 5 .0 7 5 .0 4 4 .2 5 4 .2 4 4 .2 2 3 .5 1 3 .5 0 3 .4 8 3 .4 7 2 .3 7 2 .3 5 1 .8 7 1 .8 5 1 .8 3 1 .7 0 1 .6 8 1 .6 6 1 .6 2 1 .6 1 1 .5 9     200 180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 45 N o rm a li z e d  I n te n s it y 1 6 3 .6 0 1 3 5 .3 1 1 3 4 .3 9 1 2 8 .9 3 1 2 3 .4 3 1 1 6 .1 9 7 8 .3 9 7 0 .5 5 7 0 .0 9 3 4 .1 8 2 9 .2 8 2 7 .9 3 2 2 .2 4  222  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 45 50 N o rm a li z e d  I n te n s it y 2 .0 8 5 .5 1 2 .1 7 2 .1 6 2 .1 3 2 .0 9 1 .0 0 5 .9 4 5 .9 2 5 .9 0 5 .8 9 5 .8 7 5 .2 9 5 .2 8 5 .2 4 5 .1 8 5 .1 8 5 .1 5 3 .9 7 3 .9 5 3 .6 5 3 .6 4 3 .6 2 3 .4 5 3 .4 4 3 .4 2 1 .6 7 1 .6 4 1 .6 2 1 .6 1 1 .6 0 1 .5 9 1 .5 7 1 .4 5 1 .4 3     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 45 50 55 60 N o rm a li z e d  I n te n s it y 1 3 4 .9 2 1 1 6 .7 7 7 1 .8 0 7 0 .2 3 6 2 .7 2 3 2 .4 6 2 9 .4 0 2 2 .3 9  223  10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 45 N o rm a li z e d  I n te n s it y 4 .1 3 2 .1 4 2 .0 2 1 .9 8 2 .0 9 2 .0 3 1 .0 0 2 .0 5 2 .1 0 7 .8 2 7 .8 1 7 .8 1 7 .8 0 7 .7 4 7 .7 3 7 .7 2 7 .7 2 5 .9 2 5 .9 1 5 .9 0 5 .8 8 5 .8 7 5 .8 5 5 .2 7 5 .2 6 5 .2 2 5 .1 5 5 .1 2 4 .2 0 4 .1 9 4 .1 7 3 .9 5 3 .9 4 3 .4 6 3 .4 4 3 .4 2 1 .8 2 1 .8 0 1 .7 8 1 .6 7 1 .6 5 1 .6 3 1 .5 7 1 .5 6 1 .5 5     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 45 50 55 60 N o rm a li z e d  I n te n s it y 1 6 3 .5 3 1 3 4 .9 2 1 3 4 .3 5 1 2 8 .8 6 1 2 3 .3 7 1 1 6 .6 2 7 8 .3 0 7 1 .6 9 6 9 .9 6 2 9 .2 7 2 7 .8 8 2 2 .2 1  224  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 45 50 55 60 N o rm a li z e d  I n te n s it y 6 .0 8 9 .6 7 2 .0 9 0 .9 8 1 .1 8 1 .0 7 1 .0 4 2 .0 3 1 .0 1 5 .8 8 5 .8 5 5 .8 3 5 .8 1 5 .1 4 5 .1 4 5 .1 1 5 .1 0 5 .1 0 5 .0 9 5 .0 8 5 .0 8 3 .7 0 3 .6 5 3 .6 4 3 .6 2 3 .6 1 3 .4 8 3 .4 7 3 .4 6 2 .4 4 2 .4 3 2 .2 6 2 .2 5 2 .2 4 2 .2 4 2 .2 2 0 .9 1 0 .0 8     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 45 50 55 60 N o rm a li z e d  I n te n s it y 1 3 4 .4 5 1 1 7 .3 5 7 1 .0 9 6 6 .5 3 3 7 .5 8 2 5 .8 6 1 8 .2 7 -5 .3 8  225  10 9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 N o rm a li z e d  I n te n s it y 1 .9 7 0 .9 7 1 .9 5 1 .9 7 1 .9 4 0 .9 3 1 .5 1 1 .3 5 1 .8 5 1 .8 8 1 .8 1 H2O 7 .8 2 7 .8 1 7 .8 0 7 .7 4 7 .7 4 7 .7 3 7 .7 2 7 .3 4 7 .3 3 7 .2 8 5 .9 2 5 .9 0 5 .8 8 5 .2 0 5 .2 0 5 .1 5 5 .1 4 5 .1 1 4 .7 6 4 .7 3 4 .6 9 4 .6 6 4 .3 1 4 .2 9 4 .2 8 3 .9 4 2 .5 3 2 .5 1 2 .4 9 2 .4 8 2 .4 8 2 .4 7 2 .4 6 2 .4 6     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 2 4 6 8 10 12 14 16 N o rm a li z e d  I n te n s it y 1 6 3 .3 5 1 3 8 .2 9 1 3 4 .3 9 1 3 3 .6 0 1 2 8 .9 3 1 2 8 .2 4 1 2 7 .7 6 1 2 7 .4 9 1 2 3 .4 7 1 1 8 .0 4 7 9 .8 5 7 6 .5 3 7 1 .9 2 3 5 .8 8  226  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 2 4 6 8 10 12 N o rm a li z e d  I n te n s it y 5 .8 8 5 .8 5 8 .9 9 8 .8 0 2 .9 4 1 .0 3 1 .9 5 H2O 3 .8 0 3 .7 8 3 .7 7 3 .7 5 3 .7 4 3 .6 8 3 .6 6 3 .6 5 2 .5 1 2 .5 0 2 .4 9 2 .4 7 2 .4 7 2 .4 7 2 .4 6 1 .0 1 0 .9 9 0 .9 7 0 .9 2 0 .6 1 0 .6 0 0 .5 8 0 .5 6 0 .0 9     140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 2 4 6 8 10 12 14 N o rm a li z e d  I n te n s it y 1 0 3 .7 5 8 4 .2 9 7 0 .2 3 6 5 .4 5 2 5 .8 6 2 4 .5 3 1 8 .3 0 7 .4 4 4 .4 2 -5 .4 5  227  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 2 4 6 8 10 N o rm a li z e d  I n te n s it y 0 .1 9 1 .0 6 2 .4 8 1 .2 0 2 .4 6 2 .4 5 2 .5 7 3 .5 9 2 .3 4 2 .4 3 H2O DIisopropyl-1,2-dihydrazinedicarboxylate 7 .2 7 7 .2 5 7 .2 5 7 .2 4 7 .2 3 7 .1 6 7 .0 9 6 .7 8 6 .7 7 6 .7 6 4 .5 3 4 .5 0 4 .4 6 4 .4 3 4 .3 3 4 .3 2 4 .3 1 4 .3 0 3 .8 5 3 .8 4 3 .8 4 2 .4 4 2 .4 3 2 .4 2 2 .4 2 2 .4 1 2 .4 0 2 .4 0 2 .3 7 1 .7 0 1 .7 0 1 .6 9     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0.5 1.0 1.5 2.0 N o rm a li z e d  I n te n s it y 1 6 3 .4 0 1 3 9 .1 1 1 3 4 .0 6 1 2 9 .7 0 1 2 8 .7 4 1 2 8 .2 6 1 2 7 .9 3 1 2 3 .3 8 8 0 .5 3 7 9 .6 5 7 6 .3 7 7 2 .4 4 7 1 .2 5 2 1 .7 6  228  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 2 4 6 8 10 12 14 16 18 20 22 24 N o rm a li z e d  I n te n s it y 1 .9 7 2 .9 8 0 .9 0 0 .8 9 0 .9 8 2 .0 0 0 .9 4 2 .2 3 2 .1 5 7 .3 1 7 .3 0 7 .3 0 7 .2 9 7 .2 8 7 .2 8 6 .8 1 6 .8 0 6 .8 0 6 .7 9 5 .7 9 5 .7 8 5 .7 8 5 .7 5 5 .0 8 5 .0 4 5 .0 2 4 .9 9 4 .2 0 4 .1 8 4 .1 6 4 .1 0 4 .0 8 4 .0 7 3 .5 4 3 .5 4 3 .5 3 3 .2 6 2 .2 9 2 .2 7 2 .2 6 2 .2 3 2 .2 2     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 45 50 55 60 N o rm a li z e d  I n te n s it y 1 6 3 .3 3 1 3 4 .4 5 1 3 3 .4 2 1 2 8 .9 3 1 2 3 .5 0 1 1 8 .0 4 7 9 .3 3 7 8 .1 8 5 7 .4 6 3 5 .1 9  229  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 N o rm a li z e d  I n te n s it y 0 .9 2 2 .0 0 3 .0 1 1 .0 5 2 .0 0 2 .0 1 1 .9 3 H2O Diisopropyl-1,2-dihydrazinecarboxylate 7 .2 8 7 .2 8 7 .2 7 7 .2 6 6 .7 9 6 .7 8 6 .7 8 6 .7 7 4 .2 7 4 .2 6 3 .6 1 3 .5 9 3 .5 8 3 .5 7 3 .5 5 3 .1 5 2 .3 5 2 .3 4 2 .3 3 2 .3 3 1 .6 9 1 .6 8 1 .6 8     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 5 10 15 20 25 30 35 40 N o rm a li z e d  I n te n s it y 1 6 3 .0 9 1 3 4 .1 2 1 2 8 .8 2 1 2 3 .2 2 7 9 .5 4 7 8 .6 2 7 7 .0 5 7 0 .5 4 5 7 .4 4 2 1 .5 1 2 0 .4 7  230  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 1 2 3 4 5 N o rm a li z e d  I n te n s it y 3 .0 4 0 .4 3 2 .0 9 2 .0 2 1 .0 1 2 .0 9 2 .0 1 1 .0 0 2 .0 3 1 .9 6 Diisopropyl-1,2-dihydrazinecarboxylate EtOAc 7 .8 6 7 .8 5 7 .8 4 7 .8 4 7 .7 7 7 .7 6 7 .7 5 7 .7 4 5 .9 0 5 .8 9 5 .8 8 5 .8 6 5 .8 5 5 .1 8 5 .1 4 5 .1 2 5 .1 0 4 .2 4 4 .2 2 4 .2 1 3 .8 0 3 .7 9 3 .7 9 3 .7 8 3 .6 7 3 .6 6 3 .6 5 3 .6 3 2 .4 7 2 .4 5 2 .4 3 2 .4 1 2 .4 0 2 .3 8 1 .1 7 1 .1 6 1 .1 4     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 1 2 3 4 5 6 7 8 9 10 11 N o rm a li z e d  I n te n s it y 1 6 3 .0 1 1 3 4 .2 8 1 3 3 .6 6 1 2 9 .3 5 1 2 2 .9 2 1 1 7 .5 4 7 9 .8 0 7 6 .9 7 6 5 .1 9 3 6 .0 9 2 1 .7 7 1 5 .5 8  231  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 45 50 55 N o rm a li z e d  I n te n s it y 2 .9 9 0 .8 7 2 .0 0 2 .0 2 0 .9 6 2 .1 3 2 .0 7 2 .0 3 H2O 7 .8 6 7 .8 5 7 .8 5 7 .8 4 7 .7 7 7 .7 6 7 .7 6 7 .7 5 4 .3 7 4 .3 6 4 .3 5 4 .3 3 3 .9 0 3 .8 8 3 .8 7 3 .6 8 3 .6 6 3 .6 6 3 .6 4 3 .6 0 2 .6 2 2 .6 2 2 .6 1 2 .6 0 2 .0 3 2 .0 2 2 .0 2 1 .1 7 1 .1 5 1 .1 3     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 2 4 6 8 10 12 14 16 N o rm a li z e d  I n te n s it y 1 6 3 .3 1 1 3 4 .4 7 1 2 8 .9 3 1 2 3 .5 2 7 9 .9 0 7 8 .8 9 7 5 .6 7 7 0 .5 2 6 5 .5 2 2 1 .1 4 1 5 .3 0  232  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 45 N o rm a li z e d  I n te n s it y 2 .4 1 0 .3 1 0 .3 0 1 0 .4 5 0 .2 2 0 .1 1 0 .9 2 0 .8 0 0 .1 2 0 .3 0 2 .2 0 1 .6 2 0 .3 4 0 .9 0 3 .9 2 3 .9 0 3 .7 5 3 .7 4 3 .7 3 3 .7 1 3 .6 8 3 .6 7 3 .6 5 2 .2 3 2 .0 8 2 .0 6 1 .6 2 1 .6 1 1 .6 0 1 .5 8 1 .4 8 1 .4 6 1 .4 5 1 .4 4 0 .9 4 0 .9 2 0 .9 1     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 N o rm a li z e d  I n te n s it y 8 1 .6 5 6 5 .9 2 6 2 .7 4 3 5 .3 4 3 3 .8 6 3 2 .7 7 3 0 .0 6 2 2 .9 4 1 4 .1 8  233  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 5 10 15 20 25 N o rm a li z e d  I n te n s it y 1 .3 4 1 .6 9 0 .5 2 0 .3 2 0 .4 0 0 .7 7 1 .5 7 0 .4 3 0 .4 2 1 .0 6 0 .4 8 0 .4 3 0 .4 1 0 .5 3 0 .4 6 5 .1 5 7 .3 7 7 .3 6 7 .3 5 7 .3 4 7 .3 2 7 .2 8 7 .2 8 7 .2 7 5 .0 4 5 .0 2 4 .3 5 4 .3 3 4 .1 6 4 .1 5 3 .8 7 3 .7 8 3 .7 7 3 .7 6 3 .7 5 3 .6 8 2 .6 4 2 .2 2 2 .2 2 2 .2 0 2 .1 9 2 .1 9 2 .1 7 2 .1 6 2 .1 5 1 .8 0 1 .7 4 1 .5 0 1 .4 4 1 .0 5 1 .0 3 0 .6 1 0 .5 9     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 2 4 6 8 10 12 14 16 18 20 22 24 N o rm a li z e d  I n te n s it y 1 4 0 .7 4 1 4 0 .0 4 1 2 8 .3 8 1 2 7 .9 4 1 2 7 .8 2 1 2 7 .0 5 1 2 6 .4 4 8 8 .7 1 8 7 .7 3 8 3 .9 2 7 9 .5 8 7 9 .0 5 7 8 .3 4 6 5 .8 3 6 5 .3 2 6 5 .2 2 4 1 .9 9 3 7 .6 1 3 6 .2 4 3 5 .4 4 1 6 .6 3 1 6 .1 9  234  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 N o rm a li z e d  I n te n s it y 1 .1 5 0 .9 7 0 .9 9 1 .0 8 1 .0 5 1 .0 0 1 .0 1 1 .0 2 1 .0 5 1 .7 4 2 .2 2 2 .1 4 H2O 7 .3 6 7 .3 1 7 .2 9 7 .2 2 7 .1 9 7 .1 2 7 .1 1 7 .1 0 7 .0 8 5 .1 1 4 .8 3 4 .5 9 3 .8 8 3 .6 2 3 .6 0 3 .5 6 3 .4 3 2 .4 3 2 .4 2 2 .3 9 2 .3 8 2 .3 6 2 .2 4 2 .2 2 2 .1 9 2 .1 8 1 .5 7 1 .5 6 1 .5 4     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 45 50 55 60 N o rm a li z e d  I n te n s it y 1 5 1 .4 4 1 4 1 .2 1 1 2 8 .6 2 1 2 8 .2 3 1 2 7 .5 1 1 0 7 .7 7 8 4 .0 8 7 8 .9 2 6 4 .5 5 3 4 .7 1  235  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 5 10 15 20 N o rm a li z e d  I n te n s it y 3 .0 7 9 .8 0 1 .0 6 1 .1 9 1 .1 0 1 .0 3 3 .1 8 1 .0 6 6 .0 0 4 .1 0 H2O 7 .8 7 7 .8 6 7 .8 6 7 .8 5 7 .8 5 7 .8 4 7 .2 5 7 .2 4 7 .2 3 7 .2 3 7 .1 6 4 .0 7 4 .0 5 3 .8 3 3 .8 1 3 .7 8 3 .7 6 3 .7 5 3 .7 4 3 .7 2 3 .3 2 3 .2 9 3 .2 6 2 .0 0 1 .9 7 1 .8 1 1 .7 9 1 .7 7 1 .7 6 1 .7 5 1 .7 2 1 .3 6 1 .2 6 1 .2 0 0 .8 0 0 .7 7     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 N o rm a li z e d  I n te n s it y CDCl3 C6D6 1 3 5 .6 7 1 3 3 .7 1 1 2 9 .5 5 1 2 7 .6 3 8 0 .0 8 7 4 .7 7 6 6 .6 3 3 6 .5 5 3 4 .3 5 2 6 .7 8 1 9 .2 0 1 6 .8 2  236  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 2 4 6 8 10 12 14 16 18 20 N o rm a li z e d  I n te n s it y 9 .0 5 1 .9 6 2 .0 2 0 .9 9 0 .9 4 1 .0 1 0 .9 9 0 .9 7 6 .0 1 4 .2 1 H2O 7 .8 1 7 .8 0 7 .2 3 7 .2 2 4 .8 3 4 .7 0 4 .3 4 4 .3 0 4 .1 9 4 .1 6 4 .0 6 3 .7 2 3 .7 1 3 .7 0 2 .3 5 2 .3 3 1 .1 7     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 45 50 55 60 N o rm a li z e d  I n te n s it y 1 4 7 .9 4 1 3 5 .6 1 1 3 3 .5 6 1 2 9 .6 2 1 2 7 .6 3 1 0 4 .1 6 7 9 .8 5 7 1 .2 9 6 5 .9 9 3 4 .9 0 2 6 .7 9 1 9 .2 3  237  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 2 4 6 8 10 12 14 N o rm a li z e d  I n te n s it y 3 .0 3 2 .9 8 9 .1 9 1 .0 2 0 .9 9 1 .0 0 1 .9 9 0 .9 6 0 .9 4 6 .2 1 4 .0 8 H2O 7 .8 7 7 .8 6 7 .8 5 7 .8 5 7 .2 4 7 .2 3 7 .2 3 3 .9 8 3 .9 7 3 .9 3 3 .9 2 3 .9 0 3 .7 8 3 .7 7 3 .7 7 3 .7 6 1 .9 7 1 .9 5 1 .9 3 1 .8 0 1 .7 8 1 .7 7 1 .3 1 1 .2 9 1 .2 6 1 .2 0 1 .0 4 1 .0 3 0 .7 4 0 .7 2     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 5 10 15 20 25 N o rm a li z e d  I n te n s it y 1 3 5 .6 8 1 3 3 .7 8 1 2 9 .5 3 1 2 7 .5 7 7 8 .7 6 7 7 .6 6 6 7 .0 3 3 6 .2 0 3 5 .9 4 2 6 .8 5 1 9 .2 6 1 6 .8 0 1 4 .9 2  238  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 1 2 3 4 5 6 7 8 9 N o rm a li z e d  I n te n s it y 9 .2 5 0 .5 5 2 .6 7 2 .0 2 0 .3 1 1 .6 9 0 .8 4 0 .1 8 0 .8 1 0 .1 7 1 .0 0 0 .9 9 6 .2 9 4 .0 9 H2O 7 .8 3 7 .8 2 7 .8 1 7 .8 0 7 .2 3 7 .2 2 4 .8 2 4 .8 1 4 .6 9 4 .6 9 4 .3 2 4 .3 1 4 .0 0 3 .9 8 3 .9 6 3 .7 6 3 .7 5 3 .6 9 3 .6 8 2 .4 6 2 .4 4 2 .4 2 2 .4 1 2 .3 8 2 .3 6 2 .3 4 1 .2 8 1 .2 6 1 .2 4 1 .2 2 1 .1 8    180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 1 2 3 4 5 6 7 8 9 N o rm a li z e d  I n te n s it y 1 5 2 .8 4 1 3 5 .8 1 1 3 5 .7 6 1 3 3 .8 2 1 3 3 .7 6 1 2 9 .7 3 1 2 7 .7 5 1 0 4 .3 2 1 0 4 .2 5 7 8 .2 4 7 7 .3 3 7 6 .6 1 6 6 .2 9 6 6 .2 1 3 5 .5 9 3 4 .9 8 2 6 .9 7 2 0 .9 8 2 0 .6 6 1 9 .4 2   239         Appendix D  : Selected 1 H NMR and 13 C NMR spectra for Chapter 5                240  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 2 4 6 8 10 12 14 16 N o rm a li z e d  I n te n s it y 9 .3 8 1 .0 1 1 .0 3 1 .0 0 1 .0 6 1 .0 7 6 .1 4 4 .2 4 7 .7 8 7 .7 7 7 .7 5 7 .7 5 7 .4 7 7 .4 7 7 .4 6 7 .4 5 7 .4 5 7 .2 7 3 .9 4 3 .9 1 3 .9 0 3 .8 0 3 .7 9 3 .7 5 3 .1 8 2 .8 0 2 .7 9 2 .7 8 2 .7 7 2 .6 8 2 .6 7 2 .6 6 1 .1 4     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 5 10 15 20 25 30 35 40 45 50 55 60 N o rm a li z e d  I n te n s it y 1 3 5 .4 9 1 3 3 .2 1 1 2 9 .6 9 1 2 7 .6 7 6 4 .2 4 5 2 .2 0 4 4 .3 3 2 6 .7 0 1 9 .1 8  241  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 2 4 6 8 10 12 14 16 18 20 N o rm a li z e d  I n te n s it y 5 .9 6 8 .9 6 8 .9 9 2 .3 0 1 .0 2 0 .9 6 1 .0 0 6 .0 9 4 .0 7 7 .6 9 7 .6 8 7 .6 7 7 .6 7 7 .6 6 7 .4 3 7 .4 2 7 .4 1 7 .4 0 3 .9 1 3 .9 0 3 .8 2 3 .8 1 3 .8 0 3 .7 9 3 .7 4 3 .7 3 3 .7 2 2 .5 7 2 .5 6 2 .5 4 2 .5 4 2 .5 2 1 .0 9 0 .9 7 0 .9 5 0 .9 3 0 .5 8 0 .5 6 0 .5 4 0 .5 2     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 45 50 55 60 N o rm a li z e d  I n te n s it y 1 3 5 .4 8 1 3 3 .0 7 1 2 9 .7 9 1 2 7 .7 6 1 0 3 .5 4 8 4 .3 9 7 7 .0 0 7 0 .2 8 6 6 .4 2 2 6 .8 4 2 4 .6 7 1 9 .2 8 7 .4 3 4 .3 7  242  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 45 50 55 60 N o rm a li z e d  I n te n s it y 2 .0 4 2 .0 5 0 .9 7 1 .0 1 2 .0 1 0 .9 5 2 .1 6 2 .0 2 1 .0 0 1 .0 4 1 .0 1 8 .6 5 6 .3 9 7 .7 0 7 .6 9 7 .6 8 7 .6 8 7 .2 8 7 .2 7 7 .2 6 7 .2 4 7 .1 6 3 .6 8 3 .6 3 3 .3 4 3 .3 3 3 .2 7 3 .2 5 3 .2 4 3 .2 1 2 .3 2 2 .3 1 2 .3 0 2 .2 9 1 .8 3 1 .8 2 1 .7 3 1 .7 1 1 .6 5 1 .6 3     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 2 4 6 8 10 12 14 16 18 20 22 24 N o rm a li z e d  I n te n s it y 1 4 5 .3 6 1 2 9 .4 9 1 2 8 .4 3 1 2 7 .5 3 8 7 .2 0 8 1 .3 0 7 8 .9 7 7 0 .7 7 6 9 .9 1 6 4 .0 9 6 3 .8 9 2 7 .4 9 2 7 .3 8 2 1 .0 8  243  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 5 10 15 20 25 30 35 40 45 50 55 60 N o rm a li z e d  I n te n s it y 4 .1 3 0 .9 4 1 .9 9 2 .0 1 2 .0 3 1 .0 0 2 .0 7 3 .3 4 7 .1 7 6 .6 8 2 .0 4 2 .1 4 7 .8 2 7 .8 1 7 .7 1 7 .4 3 7 .4 3 7 .4 1 7 .3 1 7 .2 9 7 .2 7 7 .2 4 7 .2 2 4 .3 6 4 .3 4 4 .3 3 4 .3 1 4 .3 0 3 .8 3 3 .8 2 3 .5 6 3 .5 5 3 .0 2 3 .0 1 2 .9 9 2 .5 8 2 .5 8 2 .5 7 2 .5 7 2 .5 7 1 .9 9 1 .9 9 1 .9 8 1 .6 2 1 .5 6     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 N o rm a li z e d  I n te n s it y 1 6 3 .2 6 1 4 4 .3 9 1 3 4 .4 3 1 2 8 .9 0 1 2 8 .6 7 1 2 7 .6 6 1 2 6 .7 9 1 2 3 .4 7 8 6 .2 3 7 9 .9 1 7 8 .7 4 7 5 .8 5 7 0 .4 9 6 9 .9 1 6 3 .1 2 2 6 .7 2 2 6 .5 3 2 0 .9 9  244  9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm) 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 N o rm a li z e d  I n te n s it y 4 .0 6 0 .9 5 0 .9 9 1 .0 4 1 .9 8 1 .1 6 1 .0 4 0 .9 8 1 .0 0 1 .0 2 1 .0 6 4 .2 0 5 .1 1 7 .1 1 H2O 7 .5 9 7 .5 7 7 .1 3 7 .1 1 7 .0 5 7 .0 3 7 .0 1 4 .7 8 4 .6 7 4 .1 9 4 .1 8 4 .1 7 4 .1 7 3 .7 1 3 .7 0 3 .3 2 3 .3 0 3 .2 9 3 .2 3 3 .2 1 3 .2 0 2 .2 3 2 .1 2 2 .1 0 1 .7 7 1 .7 6 1 .7 5 1 .7 3 1 .5 8 1 .4 8 1 .3 8     180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 N o rm a li z e d  I n te n s it y Grease 1 5 2 .2 9 1 4 5 .4 2 1 2 9 .5 3 1 2 8 .2 8 1 2 7 .5 1 1 0 4 .8 5 8 7 .2 7 8 1 .4 1 7 8 .9 3 6 4 .7 6 6 4 .3 0 3 5 .1 2 3 2 .6 5 2 6 .8 8  245            Appendix E  : Selected crude 1 H NMR analysis for the cyclization of substrates 4.23             246  Cyclization of  4.23d  Analysis of cyclization substrate 4.23d at 90 °C     Cyclization of substrate 4.23d was conducted under general cyclization procedure A.  The analysis below is divided into analysis of the five potential compounds in the crude reaction mixture (starting material, and products resulting from relay cyclization, β-fragmentation, interrupted relay cyclization, and direct cyclization). Evidence for the complete conversion of starting material     The following are 1 H NMR spectra of the starting material (Figure 1, top spectrum) and the crude reaction mixture (lower spectrum).           247    Figure 1. a) 1 H NMR (400MHz, C6D6) spectra of the starting material. b) The crude reaction mixture.     Analysis of the two spectra indicates that the reaction went to completion as (1) the proton peaks alpha to the alkoxyphthalimide (H5 and H6 at 4.25 - 4.27 ppm in the top spectrum) are not present in the lower spectrum, and (2) the N-alkoxyphthalimide proton peaks at 6.81- 6.84 ppm on the top spectrum are no longer present and new phthalimide peaks (presumably from a tin- bound phthalimide) appear at 6.89 - 6.95 ppm. Analysis to provide the NMR yield of relay cyclization product 4.25d     The following are 1 H NMR spectra of the crude reaction mixture (Figure 2, top spectrum) and the purified protected relay cyclization product (lower spectrum). 248   Figure 2. a) 1 H NMR (400MHz, C6D6) spectra of the crude reaction mixture. b) Purified protected relay cyclization product 4.25d.     There is a slight shift between the peaks of the relay cyclization product in the upper and lower spectra as the lower spectrum corresponds to the silylated product.  The NMR yield was determined using the phthalimide peaks at 6.89 - 6.95 ppm (corresponding to 2H) as the internal standard.  The peak at 4.77 ppm corresponds to one of alkene proton (H1) on the top spectrum (Figure 5), thus setting the yield of relay cyclization product 4.25d to be 30%.  This integration is consistent with the other relay cyclization product peaks at 4.10 - 4.23 and 3.77 - 3.85, and 3.31 - 3.35.  Further supporting this yield calculation, the isolated yield (25%) closely matches the NMR yield even after a subsequent protection step. Analysis to provide the NMR yield of β-fragmentation product 4.29d and evidence against the formation of interrupted cyclization product 4.44     The following are 1 H NMR spectra of the crude reaction mixture (Figure 3, top spectrum) and the expansion of the same spectrum between 2.21 and 2.35 ppm (lower spectrum).  249   Figure 3. a) Crude 1 H NMR (400MHz, C6D6) of cyclization product of 4.23d. b) Starting material. c) Splitting pattern of methylene protons adjacent to alkyne (H1 and H2).     The singlet peak at 2.98 ppm corresponds to methyl group in compound 4.29d (H3, H4 and H5).  The triplet of doublets at 2.21 corresponds to the methylene alpha to the alkyne (H1 and H2).  The 3:2 ratio of integration of these two peaks is consistent with this assignment. The only other product in the crude reaction mixture that would have peaks in this same region corresponds to alcohol 4.44, which would arise from an initial 1,5-HAT followed by quenching with tributyltin hydride prior to cyclization. Compound 4.29d and alcohol 4.44 can be differentiated by the splitting pattern of the peaks between 2.18 and 2.24 ppm.  Alcohol 4.44 would provide a doublet of doublets (similar to what was observed in cyclization precursor 4.23d, bottom left spectrum).  A doublet of doublets is not present anywhere from 2 -2 .5 ppm. The observed triplet of doublets is consistent with the β-fragmentation product.  Furthermore, the splitting pattern is consistent with literature data for 4.29d. 1  Using the same phthalimide peaks as  1  Shaw. K. F.; Welch. A. J.; Polyhedron 1992, 11, 157-167. 250  the internal standard (see previous analysis), the NMR yield of β–fragmentation product 4.29d is 27%.  Figure 4. Interrupted relay cyclization product 4.44 Analysis to provide the NMR yield of direct cyclization product 4.27d     After direct cyclization onto the alkyne, the resulting alkenyl radical may undergo several radical reactions, such as a subsequent hydrogen atom transfer or quenching with tributyltin hydride.  Analysis of the crude reaction mixture indicates that more than one of these pathways is occurring under the reaction conditions. Given that we have identified all products resulting from an initial 1,5-HAT and from an initial β-fragmentation, it is assumed that the remaining products in the crude reaction mixture arise from an initial direct cyclization onto the alkyne. The NMR yields of 4.25d and 4.29d are 30% and 27% respectively, the yield of the combined direct cyclization products is 43%.          251  Analysis of cyclization substrate 4.23d at 60 °C  Figure 5. a) 1 H NMR (400MHz, C6D6) spectra of the starting material. b) The crude reaction mixture.      Analysis (similar as previous one at 90 °C) indicates that the NMR yields of relay cyclization product 4.25d, fragmentation product 4.29d and direct cyclization 4.27d are 39%, 21% and 40% respectively. 252  Cyclization of 4.23c  Analysis of cyclization substrate 4.23c at 90 °C Evidence for the complete conversion of starting material     The following are 1 H NMR spectra of the starting material (Figure 6, top spectrum) and the crude reaction mixture (lower spectrum).  Figure 6. a) 1 H NMR (400MHz, C6D6) spectra of the starting material. b) The crude reaction mixture.     Analysis of the two spectra indicates that the reaction went to completion as (1) the proton peaks alpha to the alkoxyphthalimide (H5 and H6 at 4.25-4.27 ppm in the top spectrum) are not present in the lower spectrum, and (2) the N-alkoxy phthalimide proton peaks at 6.81- 6.84 ppm on the top spectrum are no longer present and new phthalimide peaks (presumably from a tin- bound phthalimide) appear at 6.89-6.95 ppm. 253  Analysis to provide the NMR yield of relay cyclization product 4.25c     The following are 1 H NMR spectra of the crude reaction mixture (Figure 7, top spectrum), 1 H NMR spectra of the crude reaction mixture from 4.23c (lower left spectrum), and the purified protected relay cyclization product (lower right spectrum).  Figure 7. a) 1 H NMR (400MHz, C6D6) spectra of the crude reaction mixture. b) Splitting pattern of methyl protons. c) Splitting pattern of methyl protons of protected isolated product.     There is a slight shift between the peaks of the relay cyclization product in the lower left and lower right spectra as the lower right spectrum corresponds to the silylated product.  The NMR yield was determined using the phthalimide peaks at 6.89 - 6.95 ppm (corresponding to 2H) as the internal standard.  The peak at 0.72 ppm corresponds to three methyl protons on the top spectrum (Figure 7), thus setting the yield of relay cyclization product 4.25d to be 25%.  Further supporting this yield calculation, the isolated yield (20%) closely matches the NMR yield even after a subsequent protection step.  254  Analysis to provide the NMR yield of β–fragmentation product 30c and evidence against the formation of interrupted cyclization product 4.45     The following are 1 H NMR spectra of the crude reaction mixture (Figure 8, top spectrum) and the expansion of the same spectrum between 2.12 and 2.28 ppm (lower spectrum).   Figure 4.8. a) Crude 1 H NMR spectra of the crude reaction mixture. b) Splitting pattern of methylene protons (H 1  and H 2 ) of the starting materal. C) Splitting pattern of methylene protons of fragmentation product.     The singlet peak at 3.07 ppm corresponds to methyl group in compound 4.27c (H3, H4 and H5).  The quartet of triplets at 2.23 corresponds to the methylene alpha to the alkene (H1 and H2). The 3:1 ratio of integration of these two peaks is consistent with this assignment.   The only other product in the crude reaction mixture that would have peaks in this same region correspond to alcohol 4.45, which would arise from an initial 1,5-HAT followed by quenching with tributyltin hydride prior to cyclization.  Compound 4.29c and alcohol 4.45 can be differentiated by the splitting pattern of the peaks between 2.23 and 2.27 ppm.  Alcohol 4.45 would provide a 255  triplet of multiplets (similar to what was observed in cyclization precursor 4.23c, bottom left spectrum).  A triplet of multiplets is not present anywhere from 2 - 2.5 ppm. The observed quartet of triplets is consistent with the β-fragmentation product. Using the same phthalimide peaks as the internal standard (see previous analysis), the NMR yield of β–fragmentation product 4.29c is 31%.  Figure 4.9.  Interrupted relay cyclization product 4.45 Analysis to provide the NMR yield of direct cyclization product 4.27c     After direct cyclization onto the alkene, the resulting alkyl radical may undergo several radical reactions, such as a subsequent hydrogen atom transfer or quenching with tributyltin hydride. Analysis of the crude reaction mixture indicates that more than one of these pathways is occurring under the reaction conditions.  Given that we have identified all products resulting from an initial 1,5- -fragmentation, it is assumed that the remaining products in the crude reaction mixture arise from an initial direct cyclization onto the alkyne. The NMR yields of 4.25c and 4.29c are 25% and 31% respectively, and the yield of the combined direct cyclization products is 44%.      256    Analysis of cyclization substrate 4.23c at 60 °C  Figure 4.10. a) 1 H NMR (400MHz, C6D6) spectra of the starting material. b) The crude reaction mixture.     Analysis (similar as previous one at 90 °C) indicates that the NMR yields of relay cyclization product 4.25c, fragmentation product 4.29c and direct cyclization 4.27c are 27%, 20% and 53% respectively.  

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