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Cycloisomerization reactions of enamides and related compounds using platinum(II), gold(I), and silver(I).. 2010

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  CYCLOISOMERIZATION REACTIONS OF ENAMIDES AND RELATED COMPOUNDS USING PLATINUM(II), GOLD(I), AND SILVER(I) SALTS TO FORM COMPLEX RING SYSTEMS.  THE TOTAL SYNTHESIS OF (+)-FAWCETTIDINE.    by    Jennifer Aiden Kozak   B. Sc. (Hons.), The University of British Columbia, 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 2010  Jennifer Aiden Kozak, 2010  ii Abstract  This dissertation presents investigations of enamides as π-nucleophiles within the context of electrophilic platinum(II) and gold(I) salt catalyzed cycloisomerization reactions.   Chapter 1 provides a brief overview of electrophilic metal salt catalyzed cycloisomerization reactions with a primary focus on platinum, gold, and silver salts.  Chapter 2 describes the first total synthesis of Lycopodium alkaloid (+)-fawcettidine (2.5), completed in sixteen synthetic operations from (R)-(+)-pulegone (2.56).  The feature reaction in the sequence was a platinum(II)-catalyzed annulation of highly functionalized bicyclic enamide 2.124 to give tricycle 2.125.  This annulation reaction installed the quaternary stereocenter, placed the double bond of the enamine in the correct position, and formed an exocyclic alkene which was amenable to further manipulation.  A thiolate anion addition to an enone and a Ramberg-Bäcklund reaction were other noteworthy steps for the completion of the synthesis of (+)-fawcettidine.   Chapter 3 describes the platinum(II)- and gold(I)-catalyzed cyclorearrangement of 1,2,3,4- tetrahydropyridine derivatives containing an aromatic substituted alkyne moiety tethered at the 3-position of the ring.  The reactions proceeded by a tandem cycloisomerization/Friedel-Crafts addition process resulting from an initial 6-endo-dig cyclization, forming nitrogen-containing tetracyclic scaffolds featuring a quaternary carbon center.  The 5-exo-dig mode of cyclization was observed to be a minor pathway.  Platinum(II)-catalyzed cycloisomerization reactions formed the products in 51-98% yield.  Gold(I)-catalyzed cycloisomerization reactions were lower yielding.  An unexpected azocine derivative was observed when an enamide substrate was treated with 20 mol% of silverhexafluoroantimonate(V).   Chapter 4 describes the platinum(II)- and gold(I)-catalyzed cycloisomerization/Friedel- Crafts tandem process of acyclic enamine derivatives featuring 1-arylalkynes.  Four tricyclic products were observed: two products were formed by initial 6-endo-dig (major pathway) or 5- exo-dig (minor pathway) cyclization.  The alkene of the 6-endo product frequently isomerized under the reaction conditions to form a 1-aza-substituted indene derivative, and the 5-exo product often eliminated to form substituted naphthalene derivatives.  Catalysis with a platinum(II) salt, a gold(I) species derived from the mixture of triphenylphosphine gold(I) chloride and silver  iii hexafluoroantimonate(V), or [(2-biphenyl-bis-tbutylphosphine)Au(I)·NCCH3] +SbF6 - (1.70) gave mixtures of products in 21-100% yield.  Gold(I) catalyst 1.70 was the most effective of the catalysts tested.                            iv Preface   A portion of the research reported in Chapter 2 was published in 2008: Jennifer A. Kozak and Gregory R. Dake. “Total Synthesis of (+)-Fawcettidine.” Angew. Chem., Int. Ed. 2008, 47, 4221-4223.  This chapter is written entirely by me.  I performed all of the synthesis and characterization of the compounds.  Starting material 2.119 was donated by fellow Dake group member Tyler Harrison.  X-Ray crystallographic analyses were performed by UBC Professional Officer Brian O. Patrick.   A portion of the material reported in Chapter 3 was published in 2009: Jennifer A. Kozak, Jennifer M. Dodd, Tyler J. Harrison, Katherine J. Jardine, Brian O. Patrick, and Gregory R. Dake. “Enamides and Enesulfonamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel-Crafts Pathway.” J. Org. Chem. 2009, 74, 6929-6935.  I wrote this chapter in its entirety and performed all synthesis and characterization. X-Ray crystallographic analyses were carried out by UBC Professional Officer Brian O. Patrick.  A portion of the material reported in Chapter 4 was submitted for publication on July 2, 2010: Jennifer A. Kozak, Brian O. Patrick, and Gregory R. Dake. “Platinum(II) and Gold(I)- Catalyzed Intramolecular Tandem Addition/Friedel-Crafts Reactions between Acyclic Enamides and 1-Arylalkynes.”  I wrote the chapter in its entirety and performed all syntheses and characterizations.  Catalyst 1.70 was generously donated by fellow Dake group member Jennifer Dodd.  X-Ray crystallographic analyses were carried out by UBC Professional Officer Brian O. Patrick.          v Table of Contents Abstract .......................................................................................................................................... ii Preface ...........................................................................................................................................iv Table of Contents ........................................................................................................................... v List of Tables ...............................................................................................................................viii List of Figures ................................................................................................................................ix List of Schemes..............................................................................................................................xi List of Charts................................................................................................................................xiv List of Abbreviations and Symbols...............................................................................................xv Acknowledgements.......................................................................................................................xx  Foreword.........................................................................................................................................1  Chapter 1: Cycloisomerization Reactions Catalyzed by Platinum, Gold, and Silver Salts: A Review ........................................................................................................................................ 4 1.1 Introduction........................................................................................................................... 5 1.2 Activation of Alkynes by Late Transition Metal Coordination ............................................ 6 1.3 Investigation of π-Coordination to Platinum, Gold, and Silver Centers............................... 8 1.4 Early Metal Salt-Catalyzed Cycloisomerization Reactions ................................................ 11 1.5 Mechanistic Implications .................................................................................................... 13 1.6 Other Nucleophiles Used in Cycloisomerization Reactions ............................................... 19 1.7 Ligand Effects in Gold Catalysis ........................................................................................ 23 1.8 Previous work from the Dake group................................................................................... 25 1.9 The Use of Platinum, Gold, and Silver Catalyzed Cycloisomerization      Reactions in Total Syntheses of Natural Products......................................................................................... 28 1.10 Brønsted Acid Catalysis.................................................................................................... 31 1.11 Conclusion ........................................................................................................................ 33 1.12 References......................................................................................................................... 34  Chapter 2: The Total Synthesis of (+)-Fawcettidine................................................................ 41 2.1 Introduction......................................................................................................................... 42 2.1.1 Alkaloid Natural Products............................................................................................ 42 2.1.2 The Lycopodium Alkaloid Family ............................................................................... 42  vi 2.1.3 (+)-Fawcettidine........................................................................................................... 46 2.2 Synthetic Approaches to the Total Synthesis of Fawcettimine .......................................... 49 2.2.1 Inubushi and Coworkers’ Total Synthesis of (±)-Fawcettimine.................................. 50 2.2.2 Heathcock and  Coworkers’ Total Synthesis of (±)-Fawcettimine.............................. 51 2.2.3 Toste and Coworkers’ Total Synthesis of (+)-Fawcettimine....................................... 52 2.2.4 Sha and Coworkers’ Formal Synthesis of (+)-Fawcettimine....................................... 54 2.2.5 Mukai and Coworkers’ Total Synthesis of (+)-Fawcettimine ..................................... 55 2.2.6 Jung and Chang’s Formal Synthesis of (+)-Fawcettimine........................................... 57 2.3 Model Studies: Progress Towards the Core of Fawcettidine.............................................. 58 2.4 Retrosynthetic Analysis ...................................................................................................... 59 2.5 Synthesis of a Common Starting Material from (R)-(+)-Pulegone..................................... 61 2.6 Synthetic Studies:  Route A ................................................................................................ 65 2.7 Synthetic Studies: Route B ................................................................................................. 73 2.8 Conclusion .......................................................................................................................... 81 2.9 Experimental ....................................................................................................................... 82 2.9.1 General Experimental .................................................................................................. 82 2.9.2 Synthesis of a Common Ketoester Starting Material................................................... 83 2.9.3 Route A: Forward Synthesis ........................................................................................ 90 2.9.4 Route B: Model Studies ............................................................................................... 98 2.9.5 Route B: Forward Synthesis ...................................................................................... 103 2.10 References....................................................................................................................... 111  Chapter 3: Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel-Crafts Pathway ................................................... 115 3.1 Introduction....................................................................................................................... 116 3.2 Substrate Synthesis ........................................................................................................... 119 3.3 Reactions of Substrates ..................................................................................................... 124 3.4 Unsuccessful Cyclization Reactions ................................................................................. 129 3.5 Unexpected Formation of an Azocine Derivative ............................................................ 132 3.6 Conclusion ........................................................................................................................ 135 3.7 Experimental ..................................................................................................................... 136 3.7.1 General Experimental ................................................................................................ 136 3.7.2 Synthesis of Substrates .............................................................................................. 136  vii 3.7.3 Reactions of Substrates .............................................................................................. 152 3.8 References......................................................................................................................... 164  Chapter 4: Platinum(II) and Gold(I)-Catalyzed Intramolecular Tandem Addition/Friedel-Crafts Reactions between Acyclic Enamides and 1-Arylalkynes ........... 165 4.1 Introduction....................................................................................................................... 166 4.2 Synthesis of Substrates ..................................................................................................... 168 4.3 Reactions of Substrates ..................................................................................................... 182 4.4 Discussion ......................................................................................................................... 198 4.5 Unsuccessful Cycloisomerization Reactions of Acyclic Substrates ................................. 200 4.6 Conclusion ........................................................................................................................ 204 4.7 Experimental ..................................................................................................................... 205 4.7.1 General Experimental ................................................................................................ 205 4.7.2 Synthesis of Substrates .............................................................................................. 205 4.7.3 Reactions of Substrates .............................................................................................. 243 4.8 References......................................................................................................................... 263  Conclusions................................................................................................................................264  Appendix A: Selected Spectra for Chapter 2.............................................................................267 Appendix B: Selected Spectra for Chapter 3 .............................................................................291 Appendix C: Selected Spectra for Chapter 4.............................................................................318 Appendix D: X-ray Crystallographic Data ................................................................................359          viii List of Tables  Table 2.1:  Attempted reduction of enamide 2.86 to amide 2.106...............................................69 Table 2.2:  Optimization of the allylic oxidation of compound 2.106.........................................70 Table 2.3:  Optimization of the allylic oxidation of compound 2.125.........................................76 Table 3.1:  Sonogashira coupling reactions of enamides...........................................................123 Table 3.2:  Evaluation of substrates having para- or unsubstituted arene rings ........................125 Table 3.3:  Cyclization of veratrole derivatives .........................................................................127 Table 3.4:  Unsuccessful platinum(II)-catalyzed cycloisomerization/Friedel-Crafts reactions.. .....................................................................................................................................................130 Table 3.5:  NMR data for 3.51 ...................................................................................................162 Table 3.6:  NMR data for 3.51 ...................................................................................................163 Table 4.1:  Sonogashira coupling reactions of alkynols ............................................................169 Table 4.2:  Moffatt-Swern oxidation reactions ..........................................................................170 Table 4.3: Condensation of amides and aldehydes to form enamides .......................................172 Table 4.4: Sonogashira coupling reactions of enamides............................................................174 Table 4.5: Copper-catalyzed formation of enamides and enesulfonamides ..............................179 Table 4.6: Investigation of product ratio of enamide 4.29.........................................................187 Table 4.7:  Isomerization of products to tetrasubstituted double bond......................................197 Table 4.8:  Unsuccessful cycloisomerization reactions containing unsubstituted and para- substituted arene rings.................................................................................................................201 Table 4.9:  Unsuccessful cycloisomerization reactions of enamides containing other electron- withdrawing substituents on the nitrogen atom of the enamine derivative ................................202 Table 4.10: NMR data for 4.28A ...............................................................................................245 Table 4.11: NMR data for 4.28A ...............................................................................................246 Table 4.12: NMR data for 4.29D ...............................................................................................255 Table 4.13: NMR data for 4.29D ...............................................................................................256 Table D.1:  X-ray crystallography data for compounds 2.105, 2.123, and 2.131......................360 Table D.2:  X-ray crystallography data for compounds 3.33X/3.33N, 3.35N, and 4.65B/4.65C .....................................................................................................................................................363     ix List of Figures  Figure 1.1:  Metal-carbonyl ligand orbital interactions ................................................................. 7 Figure 1.2:  Metal-alkyne orbital interactions ............................................................................... 7 Figure 1.3:  Schematic representation of the anion of Zeise’s salt (1.1) ....................................... 8 Figure 1.4:  Examples of gold complexes used for cycloisomerization catalysis ....................... 23 Figure 1.5:  Enamine derivatives ................................................................................................. 26 Figure 2.1:  Lycopodium alkaloids............................................................................................... 43 Figure 2.2:  Mapping of two 8 carbon chains onto the core of annotinine (2.8) ......................... 44 Figure 2.3:  Different structural representations of (+)-fawcettidine (2.5) .................................. 47 Figure 2.4:  Numbering scheme for (+)-fawcettidine (2.5) ......................................................... 47 Figure 2.5:  ORTEP representation of the solid state structure of enone 2.105 .......................... 68 Figure 2.6:  ORTEP representation of the solid state molecular structure of model compound 2.123.............................................................................................................................................. 75 Figure 2.7:  ORTEP representation of the solid state molecular structure of olefin 2.131.......... 79 Figure 2.8:  Comparison of NMR and IR data of (+)-fawcettidine (2.5) and structurally related 8α,11α-dihydrofawcettidine (2.137) ............................................................................................ 81 Figure 3.1:  Diagnostic signals in sample 1H NMR analysis of 3.29N/3.33X and 3.29N /3.33X ..................................................................................................................................................... 124 Figure 3.2:  Variable-temperature NMR analysis of azocine 3.51 ............................................ 134 Figure 3.3:  NMR correlations for azocine product 3.51........................................................... 134 Figure 3.4:  ORTEP representation of the solid state structure of 3.33X .................................. 157 Figure 3.5:  ORTEP representation of the solid state structure of 3.33N .................................. 157 Figure 3.6:  ORTEP representation of the solid state structure of 3.35N .................................. 159 Figure 4.1:  Compounds structurally related to products of acyclic enamide cycloisomerization ..................................................................................................................................................... 167 Figure 4.2:  Opportunities for variation of the substrate set ...................................................... 167 Figure 4.3:  Steric interaction impedes formation of Z-enecarbamate ...................................... 181 Figure 4.4:  Substrates used in this study................................................................................... 183 Figure 4.5:  2D NMR COSY and HMBC correlations for tricycle 4.28A ................................ 184 Figure 4.6:  ORTEP representation of the solid state molecular structures of 6-endo product 4.65B and 5-exo product 4.65C .................................................................................................. 189  x Figure 4.7:  Diagnostic signals in sample 1H NMR analysis of 4.29A/4.29B/4.29C and 4.40A/4.40B/4.40C ..................................................................................................................... 190 Figure 4.8:  Gold complex 1.70 tested in select cycloisomerization reactions.......................... 191                            xi List of Schemes  Scheme 1.1:  Solid-state structure of the anion [PtCl3(EtC≡CEt)] − and its schematic representation (1.5) ......................................................................................................................... 8 Scheme 2.1:  Proposed biogenesis of Lycopodium alkaloid lycopodine 2.1 ............................... 44 Scheme 2.2:  Biosynthetic pathway as proposed by Spenser....................................................... 46 Scheme 2.3:  Proposed biogenesis of serratinine (2.6) and fawcettidine (2.5) ............................ 48 Scheme 2.4:  Structure elucidation of (+)-fawcettidine (2.5) based on its formation from serratinine (2.6) ............................................................................................................................. 49 Scheme 2.5:  Harayama, Takatani, and Inubushi’s total synthesis of (±)-fawcettimine (2.3) ..... 50 Scheme 2.6:  Heathcock, Blumenkopf, and Smith’s total synthesis of (±)-fawcettimine (2.3) ... 52 Scheme 2.7:  Linghu, Kennedy-Smith, and Toste’s total synthesis of (+)-fawcettimine ............ 53 Scheme 2.8:  Au(I)-catalyzed cycloisomerization as a key step in Toste’s synthesis ................. 53 Scheme 2.9:  The conclusion of Toste and co-worker’s synthesis of (+)-fawcettimine .............. 54 Scheme 2.10:  Liu, Chau, and Sha’s formal synthesis of (+)-fawcettimine................................. 55 Scheme 2.11:  Otsuka, Inagaki, and Mukai’s total synthesis of (+)-fawcettimine ...................... 56 Scheme 2.12:  Synthesis of the requisite (S)-methyl ketone 2.76 ................................................ 57 Scheme 2.13:  Completion of (+)-fawcettimine........................................................................... 58 Scheme 2.14:  Model studies for the application of the methodology towards the total synthesis of (+)-fawcettidine ........................................................................................................................ 59 Scheme 2.15:  Retrosynthetic analysis: Route A ......................................................................... 60 Scheme 2.16:  Retrosynthetic analysis: Route B.......................................................................... 61 Scheme 2.17:  Synthesis of sulfoxide 2.93................................................................................... 62 Scheme 2.18:  Synthesis of ketoester 2.94 ................................................................................... 62 Scheme 2.19:  Synthesis of the required bromide 2.97 ................................................................ 63 Scheme 2.20:  Synthesis of ketoester 2.99 ................................................................................... 63 Scheme 2.21:  Rationale for trans stereochemical outcome of compound 2.98 .......................... 65 Scheme 2.22:  Synthesis of 2.86 using a platinum(II)-catalyzed cycloisomerization.................. 66 Scheme 2.23:  Proposed mechanism for the condensation reaction leading to enamide 2.87 ..... 66 Scheme 2.24:  Postulated mechanism of the key platinum(II)-catalyzed cycloisomerization step ....................................................................................................................................................... 67 Scheme 2.25:  Allylic oxidation adjacent to the exocyclic olefin ................................................ 67 Scheme 2.26:  First test allylic oxidation reaction of substrate 2.106.......................................... 70  xii Scheme 2.27:  Synthesis of diester 2.108 and an attempted Krapcho reduction.......................... 71 Scheme 2.28:  Synthesis of amine 2.111...................................................................................... 72 Scheme 2.29:  Attempted Appel reaction of alcohol 2.111 ......................................................... 72 Scheme 2.30:  Planned steps for the completion of (+)-fawcettidine via Route A ...................... 73 Scheme 2.31:  Synthesis of amine salt 2.118 ............................................................................... 74 Scheme 2.32:  Model study of base induced cyclization to form sulfide 2.123........................... 75 Scheme 2.33:  Synthesis of 2.125 using a platinum(II)-catalyzed cycloisomerization................ 75 Scheme 2.34:  First allylic oxidation of substrate 2.125 .............................................................. 76 Scheme 2.35:  Undesired dimer formation and a solution to the problem................................... 77 Scheme 2.36:  Synthesis of compound 2.131 using a Ramberg-Bäcklund reaction .................... 78 Scheme 2.37:  Mechanism of the Ramberg-Bäcklund reaction ................................................... 79 Scheme 2.38:  Completion of the total synthesis of (+)-fawcettidine.......................................... 80 Scheme 3.1:  Platinum(II)-catalyzed synthesis of quaternary carbon centers............................ 116 Scheme 3.2:  Platinum(II)-catalyzed cyclization to form tetracyclic products .......................... 117 Scheme 3.3:  Formation of regioisomeric products ................................................................... 117 Scheme 3.4:  Rationale for observed isomer ratio of product .................................................... 118 Scheme 3.5:  Zhai and coworkers: Platinum(II)-catalyzed cycloisomerization towards the total synthesis of nakadomarin A........................................................................................................ 119 Scheme 3.6:  Synthetic route for the construction of alkyne 3.16 ............................................. 120 Scheme 3.7:  Condensation with primary amines to form enamides 3.17 and 3.18 .................. 120 Scheme 3.8:  Synthesis of non-commercially available aryl iodides ......................................... 122 Scheme 3.9:  Regioisomeric products were not observed.......................................................... 127 Scheme 3.10:  Cyclization of furan derivative 3.36 ................................................................... 128 Scheme 3.11:  Control experiments ........................................................................................... 129 Scheme 3.12:  Cyclization of 2-substituted indole derivative 3.38............................................ 129 Scheme 3.13:  Selective formation of the 5-exo product using ortho-substituted aromatic rings ..................................................................................................................................................... 131 Scheme 3.14:  Possible explanations for failure of cycloisomerization reactions when X = S, O ..................................................................................................................................................... 132 Scheme 3.15:  Formation of azocine derivative 3.50 by silver catalysis ................................... 133 Scheme 3.16:  Cycloisomerization of enamide 3.29 with silver hexafluoroantimonate as a catalyst ........................................................................................................................................ 133 Scheme 3.17:  Proposed mechanism for the formation of azocine 3.51 ....................................135  xiii  Scheme 4.1:  Cycloisomerization/Friedel-Crafts addition reactions discussed in Chapter 3..... 166 Scheme 4.2:  Acyclic version of the cycloisomerization of enamides....................................... 166 Scheme 4.3:  Synthesis of alcohols 4.5 and 3.14 ....................................................................... 168 Scheme 4.4:  Oxidation of alcohol 4.22 ..................................................................................... 171 Scheme 4.5:  Attempted oxidation of alcohol 4.33 .................................................................... 173 Scheme 4.6:  Synthesis of non-commercially available iodides 4.35 and 4.37 ......................... 173 Scheme 4.7:  Takai olefination of aldehydes 4.15 and 4.16....................................................... 176 Scheme 4.8:  Synthesis of vinyl iodide 4.49 .............................................................................. 176 Scheme 4.9:  Synthesis of iodide 4.51 ....................................................................................... 177 Scheme 4.10:  Synthesis of iodide 4.55 ..................................................................................... 177 Scheme 4.11:  Synthesis of iodide 4.59 ..................................................................................... 178 Scheme 4.12:  Synthesis of Z-iodide 4.60 .................................................................................. 178 Scheme 4.13:  Attempted synthesis of a Z-enamide derivative ................................................. 180 Scheme 4.14:  Unexpected results when attempting to for a Z-enamide derivative .................. 181 Scheme 4.15:  Attempted formation of Z-enecarbamate 4.73.................................................... 182 Scheme 4.16:  Initial test cycloisomerization of enamide 4.28.................................................. 183 Scheme 4.17:  Cycloisomerization of enamide 4.28 at lower temperature and decreased reaction time ............................................................................................................................................. 185 Scheme 4.18:  Investigation of alkene isomerization................................................................. 185 Scheme 4.19:  Initial cycloisomerization study using gold catalysis ......................................... 186 Scheme 4.20:  Treatment of cyclization products 4.29B and 4.29C with RhCl3·3H2O............. 188 Scheme 4.21:  Formation of regioisomeric products ................................................................. 188 Scheme 4.22:  Gold(I)-catalysis of enesulfonamide 4.65........................................................... 189 Scheme 4.23:  Cycloisomerization of indole substituted enamide 4.30..................................... 194 Scheme 4.24:  Proposed mechanism for the formation of naphthalene derivative 4.29D ......... 198 Scheme 4.25:  Rationale for configuration of protons in the product 4.38B ............................. 199 Scheme 4.26:  Proposed rational for stereochemical outcome of cyclization of enamide 4.46 . 200 Scheme 4.27:  Selective formation of the 5-exo product using aromatic rings substituted with an ortho-ester ................................................................................................................................... 203     xiv List of Charts Chart 4.3.1:  Cycloisomerization results for 2-pyrrolidinone derivatives .................................192 Chart 4.3.2:  Cycloisomerization results for substrates with varying groups on nitrogen ........195                           xv List of Abbreviations and Symbols  δ     chemical shift δ +     partial positive charge 1D     1 dimensional 2D     2 dimensional Ac     acetyl Ac2O     acetic anhydride AIBN    azobisisobutyronitrile Anal.     analysis APCI    atmospheric pressure chemical ionization aq.     aqueous Ar     aryl atm     atmosphere Bn     benzyl Boc     tert-butyloxycarbonyl Boc-ON    2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile bp     boiling point br     broad BRSM    based on recovered starting material Bu     butyl o C     degrees Celsius calcd     calculated cap     caprolactamate cat.     catalytic amount or catalyst cm-1     reciprocal centimeters CoA     coenzyme A COSY    correlational spectroscopy Cy     cyclohexyl d     doublet DBU     1,8-diazabicyclo[5.4.0]undec-7-ene DCC     N,N’-dicyclohexylcarbodiimide  xvi dd     doublet of doublets DEAD    diethyl azodicarboxylate dec     decomposed DIAD    diisopropyl azodicarboxylate dig     digonal DMAP    N,N-(dimethylamino)pyridine DME     dimethoxyethane DMF     N,N-dimethylformamide DMP     Dess-Martin periodinane DMS     dimethylsulfide DMSO    dimethylsulfoxide dppb     1,4-bis(diphenylphosphino)butane dr     diastereomeric ratio dt     doublet of triplets E     entgegen E1     elimination unimolecular E2     elimination bimolecular ee     enantiomeric excess EI     electron ionization endo     endocyclic eq(s)     equation(s) equiv     equivalent(s) ESI     electrospray ionization Et     ethyl EWG    electron withdrawing group exo     exocyclic g     gram(s) h     hour(s) HMBC    heteronuclear multiple bond correlation HMDS    hexamethyldisilazide HMPA    hexamethylphosphoramide HMQC    1H-detected heteronuclear multiple quantum coherence HOAc    acetic acid  xvii HRMS    high resolution mass spectrum i     iso IR     infrared IPr     1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene J     coupling constant KAPA    potassium 3-aminopropylamide L or Ln or L *   undefined ligand(s) lit.     literature LG     leaving group M     metal (generic), molarity, or parent mass m     multiplet, milli m     meta mCPBA    meta-chloroperoxybenzoic acid Me     methyl Met     metal (generic) mg     milligram(s) MHz     Mega Hertz min     minute(s) mmHg    millimeters of mercury mmol    millimole(s) µ     micro (SI) or bridging ligands mL     milliliter(s) mp     melting point NIS     N-iodosuccinimide NMO    N-methylmorpholine-N-oxide N,N-DMG    N,N-dimethylglycine hydrochloride NpH     naphthalene NMR    nuclear magnetic resonance NOE     Nuclear Overhauser Effect NR     no reaction Ns     4-nitrobenzenesulfonyl or nosyl Nuc     nucleophile [O]     oxidation  xviii o     ortho ORTEP    Oak Ridge thermal Ellipsoid plot OTf     triflate, trifluoromethanesulfonate p     para %     percent PG     protecting group Ph     phenyl pH     −log[H3O +] PhH     benzene PhCH3    toluene ppm     parts per million PPTs     pyridinium para-toluenesulfonate Pr     propyl pyr     pyridine Q     quaternary q     quartet qt     quintet R     undefined portion of a molecule R     rectus RSM     recovered starting material rt     room temperature s     singlet S     sinister Sia     siamyl SM     starting material SN2     substitution nucleophilic bimolecular t     triplet t     tertiary TBAF    tetrabutylammonium fluoride TBAI    tetrabutylammonium iodide TBS     tert-butyldimethyl silyl td     triplet of doublets Tf     trifluoromethanesulfonyl  xix TFA     trifluoroacetic acid THF     tetrahydrofuran TMS     trimethylsilyl Ts     toluenesulfonyl or tosyl TsOH    para-toluenesulfonic acid Ts2O     para-toluenesulfonic anhydride UBC     University of British Columbia wt %     weight percent Z     zusammen                        xx Acknowledgements  First and foremost, I would like to thank my research supervisor, Professor Gregory Dake, for his guidance, support, encouragement, and patience over the last five years.  In particular I am thankful for the time he took to help prepare this manuscript.  Editing can be a very mundane exercise and I am nothing but grateful for his thorough proofreading.   I would like to acknowledge Jennifer Love for additional assistance in proofreading this document.  Any errors that remain, either scientific in nature or grammatical, are my own.   I give a special thank you to those who shared this experience with me: Jenny, Julien, Emmanuel, Krystle, Tyler, Paul, Leah, and Erik, and the many visiting and undergraduate students we have had.  Much of what I learned about chemistry (knowledge and technique) can only be attributed to helpful discussion with fellow group members.  These people made my time in the lab enjoyable and I would have never survived without their companionship on late nights or early mornings.  There is nothing more therapeutic than being able to vent about work, study, or life in general over a box of wine and some terrible TV.  For this privilege I must thank my Wednesday night friends (team models): Jackie, Brownyn, Shiva, Courtney, Louisa, Ali, Jaime, and Roxan. I want to thank to Ali and Louisa for taking me under their wing, Jackie for never-ending amusement involving slot machines, venn diagrams, and eating, Bronwyn for memorable quotations and her photogenicity, Shiva for always doing the mental math, and CT for her cardigans and mismatched socks.  The majority of us has parted or will be parting ways, and I sincerely hope to continue the friendship no matter where we are.   I would like to thank my parents, Brian and Elizabeth Kozak, for their continued support and interested in my education.  They have always taken an interest in everything that I do and have never hesitated to help me if I’ve needed it.  Thanks to my brother Michael for not making too much fun of me for still being in school and for making visits home always entertaining.   The last two years have been some of the happiest I can remember.  For this I have to thank Jay Turcot, whose love and support during the culmination of my career as a graduate student was unwavering.  xxi   Last but not least, I would like to thank the staff of the NMR Laboratory, the Mass Spectrometry/Microanalysis Laboratory, and the Mechanical Shop.  Their continued support made the work presented in this dissertation possible.  A special thank you to Ken Love for scooping tar out of our group’s pumps on more than one occasion, while continuing to be kind and patient.  Thanks to Brian Patrick for the successful X-ray structure determination of my tiny, organic crystals.  I would like to thank the Natural Sciences and Engineering Research Council (NSERC) and the University of British Columbia for funding leading up to and throughout my graduate degree.          1                   Foreword                            Foreword   2  Synthetic organic chemistry can be divided into two closely related subdivisions: methodology and target-oriented synthesis.  Methodology describes the development of a reaction method used to perform a particular chemical transformation.  Target-oriented synthesis involves the selection of a molecule, often either a product of nature or a compound of practical interest, to be synthesized in the laboratory.  A successful target-oriented synthesis, or total synthesis, begins with a strategic synthetic plan.  It is common for the plan to be altered in the course of the synthesis, as certain reactions can fail and specific pathways prove to be unsuccessful.  It is also possible that a particular chemical transformation is required for which there is no known methodology.  This can lead to the development of new methods, and highlights the relationship between the two subdivisions of synthetic organic chemistry.   The following dissertation describes target-oriented synthesis as well as the development of chemical methods.  Both topics highlight the use of enamine derivatives as π-nucleophiles within the context of electrophilic metal salt cycloisomerization reactions.  This thesis is divided into four chapters.  Chapter 1 provides a brief overview of the field of electrophilic metal salt- catalyzed cycloisomerization, focusing on reactions involving platinum, gold, and silver salts.  A section dedicated to the use of this methodology within the context of target-oriented synthesis is provided.  In chapter 2, methodology developed in the Dake laboratory is applied to the total synthesis of (+)-fawcettidine.  Initially, a discussion of previous synthetic routes towards structurally related fawcettimine is given.  Two synthetic plans for the synthesis of (+)- fawcettidine are then described, followed by the implementation of these plans in two following sections.  Problems that arise are methodologically solved before the description of the synthetic route continues.  In chapter 3, methodology studies on the platinum(II)-catalyzed addition/Friedel-Crafts tandem process of cyclic enamides is described.  The chapter begins with a detailed description of the synthesis of the substrates.  The following section describes the reactions of the substrates. Inefficient or non-existent platinum(II)-catalyzed cycloisomerization of particular substrates is described for the sake of completion in the final section.  Foreword   3  Chapter 4 describes initial methodology studies on the platinum(II)- or gold(I)-catalyzed cycloisomerization of acyclic enamine derivatives.  The format follows that of chapter 3, with an added discussion section to describe general trends and justify observed products.  The concluding chapter reiterates the successes of the research presented in the body chapters of the thesis.  The significance and applicability of the research in the field of synthetic organic chemistry are discussed.                                        4                  Chapter 1: Cycloisomerization Reactions Catalyzed by Platinum, Gold, and Silver Salts: A Review                             Chapter 1:  Cycloisomerizations catalyzed by Platinum, Gold, and Silver Salts: A Review   5 1.1 Introduction The science of the synthesis of complex molecules is an integral part of the pharmaceutical industry and of academic synthetic organic laboratories.  Chemists from both fields rise to the challenge of constructing target molecules from readily available starting materials.  Industrial and academic groups approach the synthesis of these molecules differently. Interestingly, academic laboratories focus on original and elegant methods of bond construction that may be applied in total synthesis.  An arguable goal of an academic synthesis is creativity within a scholarly exercise.  In an industrial process setting, the goal is to drive the synthesis towards commercial production.  From both an academic or industrial perspective, the challenges of synthesis are often met by the implementation of methods that improve synthetic efficiency.  A synthetically efficient process can be defined by having one or more of the following characteristics: a) high yields, b) theoretical stoichiometry, c) a minimum number of physical operations, d) an increase in molecular complexity, e) high selectivity, and f) a small amount of byproducts or waste formed. One method employed by chemists to improve efficiency is through the use of catalysts.  Jones defines a catalyst as “a species that functions to increase the rate of a chemical reaction by providing a lower energy pathway between the starting material and the product, while remaining unchanged by the reaction”.1  Types of catalysis include, but are not limited to, biocatalysis (enzymatic catalysis),2 organocatalysis,3, 4 electrocatalysis,5, 6 and transition metal catalysis.7, 8  Transition metal-catalysts can often enable reactions that are impossible by traditional methods.  Homogenous transition metal-catalyzed reactions have been successful in achieving a certain level of synthetic efficiency.  One set of transition metal catalyzed reactions are cycloisomerization reactions. Cycloisomerization reactions traditionally describe the cyclization (cyclorearrangement) of 1,n- enynes and dienes.  Within this review, cycloisomerization will describe the reaction where a portion of a molecule containing a carbon or carbon-heteroatom chain with at least two units of unsaturation is isomerized with the simultaneous formation of at least one ring.8  These reactions are synthetically efficient since all of the atoms of the reactant are found in the product, and the only other reactant is used catalytically.  Chapter 1:  Cycloisomerizations catalyzed by Platinum, Gold, and Silver Salts: A Review   6  Cycloisomerization reactions involving transition metal catalysis have been thoroughly studied and reviewed in the last 15 years.  Thus, this review will not be comprehensive and readers are directed to one of the many reviews in the primary literature.8-30  This introduction will provide a brief historical perspective and only cover the aspects of platinum, gold, and silver catalysis within cycloisomerization reactions that are directly related to the body of work described in the thesis.   1.2   Activation of Alkynes by Late Transition Metal Coordination  The alkyne is an electron rich moiety that often acts as a nucleophile.  It reacts with functional groups such as Brønsted acids and Lewis acids, including electrophilic metal salts derived from Pt(II), Au(I), and Au(III).  Electrophilic metal salts react with the π-system of the alkyne as traditional Lewis acids would, and are therefore also called “π-acids”.16, 20  Classic Inorganic Definition It should be noted that “π-acid” is a term within inorganic chemistry that is used to describe particular ligands of metal-ligand complexes.  An example is the carbonyl ligand. There are two predominant types of orbital interactions between a transition metal and a carbonyl ligand (Figure 1.1).  The first is a weak σ-donation by the carbonyl ligand to an empty metal d orbital.  Taking only this interaction into account, the role of the metal is that of a Lewis acid and the role of the ligand is that of a Lewis base.  The roles are reversed as a second, stronger orbital interaction takes place: the filled d orbital on the metal donates electron density to the π* orbital of the ligand.31  This back donation from metal to ligand is described by the Dewar-Chatt- Duncanson model.32-34  Since the carbonyl ligand is a weak σ-donor and a strong π-acceptor, it is referred to as a “π-acid” (i.e., the π-system of the ligand accepts electrons).  The measurement of the CO stretching frequency can be used as a measure of electron density on a metal center.  CO and related ligands are used to pull electron density away from the metal center, making the metal more electropositive. Chapter 1:  Cycloisomerizations catalyzed by Platinum, Gold, and Silver Salts: A Review   7 COσ - CO as electron-donating ligand COπ ∗ - CO as electron-accepting ligand M C O M C O 1 1 1 1  Figure 1.1:  Metal-carbonyl ligand orbital interactions  Contemporary Organic Definition  Alkynes also act as ligands to form complexes with metal centers (Figure 1.2).  The alkyne ligand donates electron density from the filled π-orbital to a metal d orbital, forming a σ-bond. In contrast to carbonyl ligands, there is little back donation from the filled metal d orbital to the empty π*-orbital of the ligand.  The σ-donation is therefore the dominant interaction and the metal remains the Lewis acid and the ligand a Lewis base.  The Lewis acidic metal is interacting with a π-system; it is therefore a “π-acid” (i.e., the metal is accepting electrons from the π- system).16, 20  Back-donation to the alkyne can be augmented by altering the ligands around the metal center.  More electron-donating ligands will increase electron density at the metal center, thereby increasing its ability to back-donate.  The measurement of the carbon-carbon bond length as well as the stretching frequency can be used as a measure of the electron density on the metal center.  CCσ - alkyne as electron-donating ligand CCπ ∗ - alkyne as electron-accepting ligandM 1 1 1 1 M  Figure 1.2:  Metal-alkyne orbital interactions Transition metal coordination renders the alkyne electrophilic.  This alkyne activation is the basis for many Pt(II), Au(I), and Ag(I) cycloisomerization reactions. Chapter 1:  Cycloisomerizations catalyzed by Platinum, Gold, and Silver Salts: A Review   8 1.3   Investigation of π-Coordination to Platinum, Gold, and Silver Centers  The isolation and characterization of organometallic complexes give insight into the orbital interactions and ultimate reactivity of the complex.  The first example of a metal π complex – and of an organometallic complex in general – was potassium trichloro(ethane)platinate(II), or Zeise’s salt 1.1 (Figure 1.3).35  The complex was prepared in 1827, although its solid state molecular structure was not solved until 1954.36  It was shown that the bound ethylene is oriented perpendicular to PtCl3 - plane and the carbon-carbon double bond length is only 2 pm longer than that of ethylene.37, 38  Removal of electron density from the olefin renders it electrophilic and it can be attacked by nucleophiles, a reactivity that is mirrored in analogous palladium complexes. This is the basis for the Wacker-Hoechst oxidation.39  Cl Pt Cl Cl H H H H 1.1 K+  Figure 1.3:  Schematic representation of the anion of Zeise’s salt (1.1)35  The synthesis of acetylenic platinum complexes was attempted following the successful complexation of olefins to platinum.  Steinborn and coworkers reacted potassium tetrachloroplatinate 1.2 (K2[PtCl4]) and 18-crown-6 in water to give complex 1.3 as stable and isolable pink crystals (Scheme 1.1).40  Compound 1.3 was then reacted with 3-hexyne (1.4) to give platinum-acetylene complex 1.5, which was amenable to X-ray crystallographic analysis to give structure 1.5S.  The potassium crown-ether counterion is removed for clarity.  Cl Pt Cl Cl 1.5 K2[PtCl4] 18-crown-6 H2O [K(18-cr-6)]2[Pt2Cl6] CH2Cl2, rt 89%59% 1.5S1.31.2 1.4  Scheme 1.1:  Solid-state structure of the anion [PtCl3(EtC≡CEt)] − and its schematic representation (1.5)40  Similarities between the coordination of an olefin and that of an alkyne are apparent when comparing structures 1.1 and 1.5.  The π-system of 1.5 is again oriented perpendicular to the PtCl3 - plane.  Because there is only a small amount of back-donation by platinum, the carbon- Chapter 1:  Cycloisomerizations catalyzed by Platinum, Gold, and Silver Salts: A Review   9 carbon triple bond is only slightly elongated relative to that of the uncoordinated alkyne. The back-donation is also responsible for the distortion of the alkyne away from linearity.  M R R M R R R R M I II Pt Ph3P Ph3P Ph Ph Glanville and coworkers 1.6  Scheme 1.2:  Representations of metal-alkyne complexes Depending on the environment around platinum, the π-ligand can be represented as a bound alkyne complex (I), or a metallocyclopropene (II) (Scheme 1.2).  Metal-alkyne complexes with strong metal back-donation are best represented by structure II.  Alteration of the ligands changes the ability of platinum to back-donate to a coordinated π-system.  An example is the platinum(0)-acetylene complex 1.6 synthesized and structurally characterized by Glanville and coworkers.41  The electron-donating triphenylphosphine ligands increase the electron density at the metal, augmenting its ability to back-donate.  Complex 1.6 is best represented as a metallocyclopropene.   Although gold has been used extensively in cycloisomerization reactions for the last 15 years with simple terminal and internal alkynes, the only gold-alkyne complexes determined by X-ray crystallography are those containing strained alkynes and alkynes in a tethered framework.42, 43   Recently, a simple gold complex of 3-hexyne was isolated and structurally characterized (Scheme 1.3).44  Complex 1.7 was synthesized by reaction of 3-hexyne 1.4 with AuCl in dichloromethane at low temperature.  The complex was air and temperature sensitive, but was stable for a few hours in solution at low temperature.  Chapter 1:  Cycloisomerizations catalyzed by Platinum, Gold, and Silver Salts: A Review   10 Au Cl 1.7 AuCl CH2Cl2, -20 oC 1.4 1.7S Scheme 1.3:  Solid-state molecular structure of a linear gold(I)-alkyne complex (1.7S) and its schematic representation (1.7)44  Analyses of the structure show that the gold coordination environment is nearly linear, with a Cl-Au-centroidC≡C angle of 176.3 o.  The alkyne is oriented perpendicular to the gold- chloride bond and is distorted from complete linearity due to some back donation from the metal to the alkyne.  Density functional theory45-48 (DFT) calculations suggest that the alkyne of complex 1.7 is a strong σ-donor but a weak π-acceptor, which correlates with observations of other π-complexes with metals of moderate ability to back-donate.  Ag Ag O O S S O OF F F O O F F F 1.9 Ag(SO3CF3) THF 44% 1.9S1.8 Scheme 1.4:  Solid-state structure of a silver trifluoromethanesulfonate-alkyne complex 1.9S and its schematic representation (1.9)49  The ability of silver(I) to coordinate to alkenes was discovered in the 1930’s by Lucas and Winstein.50, 51  Determination of the amount of alkene coordinated to the silver was performed using distribution measurements.  Coordination of silver(I) to an alkyne was first reported in 1956 using similar measurements.52  The coordination of alkenes and alkynes to silver(I) was studied by Lewandos and coworkers using IR spectroscopic and NMR techniques in 1976.53  A common silver catalyst used in cycloisomerization reactions is silver(I) trifluoromethanesulfonate (triflate).  Recently, Gleiter and coworkers isolated and structurally characterized a silver(I) triflate alkyne complex (1.9) (Scheme 1.4).49  The complex was formed Chapter 1:  Cycloisomerizations catalyzed by Platinum, Gold, and Silver Salts: A Review   11 by treatment of 1 equivalent of silver(I) triflate with 1 equivalent of dialkyne 1.8 in THF at room temperature with the strict exclusion of light.  The product precipitated out of solution and after removal of the solvent, compound 1.9 was isolated as a pale yellow solid.  A crystal amenable to X-ray analysis was isolated by recrystallization from acetone.  With the unambiguous structure in hand, the authors compared the bond lengths between the uncoordinated dialkyne 1.8 and that of the complex 1.9.  They found after complexation, the bond lengths of the alkyne increased from 1.202 Å to 1.204 Å.  The coordination of the alkyne to silver weakens the C(sp)-C(sp) bond, thereby lowering the LUMO and allowing the alkyne to become electrophilic and able to undergo subsequent reactions.   1.4   Early Metal Salt-Catalyzed Cycloisomerization Reactions  The first transition metal catalyzed cycloisomerization of 1,6-dienes was performed in 1971 by Malone and coworkers.54  The first platinum-catalyzed cycloisomerization reaction was discovered by Blum and coworkers over 20 years later (Scheme 1.5).55  Blum treated various allyl propargyl ethers (1.10) with a catalytic amount of platinum(IV) chloride at room temperature which gave 3-oxabicyclo[4.1.0]hept-4-ene derivatives 1.11.  The yields varied from 20-97% depending on the nature of substituents R and R1.  R O R1 O R R1 5 mol % PtCl4 PhH, rt 20-97% 1.10 1.11 Scheme 1.5:  Blum’s platinum(IV) catalyzed cycloisomerization of allyl propargyl ethers55  The first platinum(II)-catalyzed reaction was carried out by Shinji Murai and coworkers in 1996.56  In this elegant study, Murai found that 1,6-enynes (1.12) underwent cyclorearrangement when treated with a catalytic amount of platinum(II) chloride to yield 1-vinylcycloalkenes (1.13) (Scheme 1.6).  The authors successfully cycloisomerized 13 different substrates using catalytic platinum(II) chloride in high yields (66-98 %).  Treating 1,7-enynes under the same reaction conditions also gave cycloisomerized product, although the reaction time was long and the yield was poor.  In the same study, the authors performed a deuterium labeling study and found that two distinct mechanistic pathways were operating for the single reaction.  The nature of the Chapter 1:  Cycloisomerizations catalyzed by Platinum, Gold, and Silver Salts: A Review   12 substituents on the alkene or the alkyne functionality determined the course of the reaction. Mechanistic phenomena will be discussed in more detail in section 1.5.  E E 4 mol % PtCl2 PhCH3, 80 oC 3 h E = COOEt 86% E E 1.12 1.13  Scheme 1.6:  Murai’s cyclorearrangement of enynes using platinum(II)-catalysis56  Silver catalyzed cycloisomerization has origins dating before the first cycloisomerization of enynes.  Castañer and Pascual demonstrated in 1958 that propargylidene malonic acid underwent cycloisomerization in the presence of silver nitrate to form a carboxybutenolide.57 Later, it was found that treatment of propargylidene malonic acids such as 1.14 with a catalytic amount of silver nitrate formed either carboxybutenolides depicted by 1.15 or α-pyrones such as 1.16 (Scheme 1.7, eq 1).58  If R was aromatic, only carboxybutenolides were formed.  If R was aliphatic, mixtures of butenolides and α-pyrones were formed.  H15C7 n O H3C H CH3 20 mol% AgBF4 CH3CN, 90 oC 0.5 h 99% OH3C H15C7 n CH3 1.17 1.18 HOOC COOH R 2-3 drops 0.1 N AgNO3 MeOH, rt 70-90% O O COOH R O OR COOH 1.14 1.15 1.16 Belil, Pascual, Sarratosa: 1964 Marshall and Robinson: 1990 (1) (2)  Scheme 1.7:  Silver-catalyzed cycloisomerization to form substituted furans58, 59  Although Belil and coworkers performed a cycloisomerization reaction that was presumably catalytic in silver salt, the amount of salt added was an inexact measure.  It wasn’t until much later that a rigorously measured catalytic silver(I) cycloisomerization was performed (Scheme 1.7, eq 2).59  Marshall and Robinson found that allenone 1.17 reacted with a 20 mol% of silver(I) tetrafluoroborate to form furan 1.18 in high yield.  The authors found that a variety of allenals and allenones react with a catalytic amount of either silver nitrate or silver(I) tetrafluoroborate to give furans in good yields ranging from 72-99 %. Chapter 1:  Cycloisomerizations catalyzed by Platinum, Gold, and Silver Salts: A Review   13 1.5 Mechanistic Implications In the last decade the mechanism of electrophilic metal salt catalyzed cycloisomerization reactions has been extensively probed.  One unifying mechanistic framework has arisen from experimental data and DFT calculations (Scheme 1.8).16, 18, 20, 24  The proposed mechanism is complicated.  Depending on catalyst and substrate structure, the reactive intermediates on one hand can be described as non-classical carbocations.  On the other hand, they can display carbene-like character.  The proposed structures can be thought of as a series of resonance forms, the predominant form differing from reaction to reaction.  It is likely that the reactive intermediate invokes more than one of these canonical-forms.  It should be noted that there is no direct evidence of any of the proposed intermediates, and the mechanistic framework depicted in Scheme 1.8 is largely the result of interpretation of experimental results and theoretical calculations.16, 20  At the outset of a metal catalyzed reaction of a 1,6-enyne, the metal can coordinate to both the alkene and the alkyne (A), or to only the alkyne (B).  It is likely that A and B are in equilibrium with each other.  If the metal coordinates to both π-systems it is likely that it will go through a metallocyclopentene pathway (not shown) as described by Trost and coworkers in the context of palladium and ruthenium catalysis.9, 13  When the metal is coordinated to only the alkyne, the mechanistic rationale described in Scheme 1.8 can be invoked.  Depending on the nature of the metal and of substituents on the alkyne, the metal bound alkyne complex can be drawn as a metallocyclopropene (C).  The metal can also “slip” along the alkyne (going from η2 towards η1) and polarize it.  In the case of complex D, the partial positive charge is formed on the carbon situated closest to the center of the molecule (proximal carbon). If Z = carbon, a nucleophilic alkene will attack to undergo a 5-exo-dig cyclization.  Less common but observed pathways are 6-endo-dig cyclizations.  These are omitted from this mechanistic scheme. Chapter 1:  Cycloisomerizations catalyzed by Platinum, Gold, and Silver Salts: A Review   14 Z R1 R M Z R1 R M metallocyclopentene pathway (Pd, Ru, Rh) A B Z R1 C M R 1,2-hydride shift Z = O, N Z R1 O M- Z R1 P M Z Q M R Z R R Z R1 D M R δ+ 5-exo-dig Z = C M = PtCl2 or AuL* E Z M R R1 I Z M R F Z M R G Z R M H Z R M R1 R1 R1 R1 R1 R1 J Z R1 M R K Z R1 fragmentation elimination R L Z M R R1 [1,2-alkyl shift] M Z M R R1 N Z R fragmentation elimination [1,2-alkyl shift] R1 RR or  Scheme 1.8:  A mechanistic rationale for the cycloisomerization of 1,6-enynes  After the initial cyclization takes place, carbocationic intermediate E can be invoked. This intermediate is in resonance with structures F-I.  Structures E, F, G, and I represent resonance structures of a non-classical carbocation.  Structure H represents the carbene rendition, and is said to be invoked if there is enough back donation from the metal to the alkyne.20  In an alternate explanation by Kozmin, the carbocationic pathway is a concerted process whereas the carbene pathway is a step-wise process.18  The carbene type intermediate can be indirectly Chapter 1:  Cycloisomerizations catalyzed by Platinum, Gold, and Silver Salts: A Review   15 observed through trapping experiments.  A functional group appropriately placed to trap the carbene will generate cyclopropane rings or C-H insertion products.  Products resulting from the carbocationic resonance structures will be absent.  EtO2C EtO2C 1.19 EtO2C CO2Et EtO2C EtO2C CO2Et CO2Et 1.24 EtO2C EtO2C 1.20 EtO2C CO2Et Pt2+ EtO2C EtO2C 1.21 EtO2C CO2Et Pt EtO2C EtO2C 1.22 EtO2C CO2Et Pt EtO2C EtO2C 1.23 Pt EtO2C CO2Et 4 mol% PtCl2 PhCH3, 80 oC, 1 h 61%  Scheme 1.9:  Murai and coworkers: Trapping of a carbene intermediate using an olefin60  Another insightful study by Murai provides experimental support for the intermediary metal carbene (Scheme 1.9).60  If an alkene was strategically placed within the substrate, it trapped the transient metal carbene to form a cyclopropane ring.  Murai and coworkers treated dienyne 1.19 with a 4 mol% of platinum(II) chloride to give the complex tetracyclic product 1.24.  He speculated that after initial complexation of platinum to the alkyne in an η2-fashion (1.20), the platinum slips to form η1-complex 1.21.  This complex is in resonance with carbenoid 1.22.  Carbenoid 1.22 then attacks the pendant alkene, forming cycopropyl derivative 1.23. Further trapping of the metal carbene by another alkene led to the formation of a tetracyclo[6.4.0.01,902,4]dodecane derivative 1.24.  As mentioned in section 1.4, Murai and coworkers discovered two operating mechanistic pathways in their cycloisomerizations of 1,n-enynes.56  From resonance structure I, two options are possible: first, fragmentation can occur to open the cyclobutane ring, and subsequent elimination gives product K.  Alternatively, from intermediate I, a 1,2-alkyne shift can occur to give a cyclopropyl intermediate (L).  Fragmentation of this ring gives structure M that undergoes Chapter 1:  Cycloisomerizations catalyzed by Platinum, Gold, and Silver Salts: A Review   16 a second alkyl shift and elimination to give final product N.  The experiment performed by Murai and coworkers is shown in Scheme 1.10.  Treatment of enyne 1.25 with 8 mol% of platinum(II) chloride led to dienes 1.26 and 1.27 formed in 84 % yield as an 8:1 mixture.  The mechanism described above accounts for the mixture of products observed.  EtO2C EtO2C 1.25 Me EtO2C EtO2C Me EtO2C EtO2C Me 1.26 1.27 8 mol% PtCl2 PhCH3, 80 oC, 3 h 84% (8:1) Scheme 1.10:  Murai’s discovery of two operating mechanistic pathways56 In Scheme 1.8, if Z = nitrogen or oxygen, then a 1,2-hydride migration occurs to form an alkenyl carbene O that is stabilized by the adjacent heteroatom Z.  From resonance structure P one can envisage a [2+2] cycloaddition to form metallocyclobutane Q.  Reductive elimination gives the bicycle[4.1.0]heptene products typically observed for 1,6-enynes containing a heteroatom in the tether.  A specific example using gold catalysis comes from the work of Echavarren (Scheme 1.11).61  He found that 1,6-enyne 1.28 reacted with the cationic gold catalytic system to afford products 1.33 and 1.34 in 78 % yield in a 14:1 ratio, with 1.33 being the major observed product.  The major product arose from initial coordination of the gold to the alkyne, as in 1.29, followed by a 1,2-hydride shift to give stabilized allenyl carbene 1.30 and its resonance structure 1.31.  Cycloaddition followed by reductive elimination of gold (1.32) yielded the major product 1.33.  The minor 1.34 product arose from initial 5-exo-dig attack of the alkene on the electrophilic alkyne. TsN [Ph3PAuCl]/AgSbF6 (cat). 78% (14:1) 1.28 TsN 1.33 TsN 1.29 AuLn + TsN 1.31 AuLnTsN 1.30 AuLn TsN 1.32 AuLn [Au] cat. 1.34 TsN  Scheme 1.11:  Gold-catalyzed cycloisomerization of nitrogen-tethered enyne 1.2861 Chapter 1:  Cycloisomerizations catalyzed by Platinum, Gold, and Silver Salts: A Review   17  The reaction outcome is strongly dependent on reaction conditions and substrate structure (Scheme 1.12).  After initial 5-exo-dig cyclization, putative carbene intermediate S is presumably formed.  If an external nucleophile such as R3OH is present in the reaction media, it can react with carbene S to form intermediate T.  Protodemetallation will give alkene U.  If the substituent is R1 = CH3 or CH2TMS, loss of either a proton (as shown in W) or of the TMS group will open the cyclopropane ring to give intermediate X.  Protodemetallation gives diene Y.  X Z M R R2 T Z M R R1 R2 OR3 S Z R M R1 R2 R1 = CH3 CH2TMS W Z R M R2 H proto- demetallation Y Z H R R2 R3OH U Z H R R1 R2 OR3 proto- demetallation  Scheme 1.12:  Mechanistic rationale for observed product outcomes using an external nucleophile or a trisubstituted olefin Echavarren and coworkers reported the platinum(II)-catalyzed alkoxy- and hydroxycyclizations on a series of 1,6-enynes.62-64  In a specific example, the authors reacted trisubstituted olefin 1.35 with a 5 mol% of platinum(II) chloride in methanol (Scheme 1.13). The platinum coordinates to the alkyne to give η2-complex 1.36.  Attack by the trisubstituted alkene gives metal carbene intermediate 1.37 or its cationic representation 1.39.  In either case, methanol acts as a nucleophile and either fragments the cyclopropane ring or attacks the tertiary carbocation to give complex 1.40.  Protodemetallation gives the product 1.41.  Chapter 1:  Cycloisomerizations catalyzed by Platinum, Gold, and Silver Salts: A Review   18 PhO2S PhO2S Me Me PhO2S PhO2S 1.35 1.41 PhO2S PhO2S Me Me 1.36 Pt2+ PhO2S PhO2S Me 1.39 Pt PhO2S PhO2S 1.40 Pt proto- demetallation PhO2S PhO2S 1.37 Pt Me Me 5 mol% PtCl2 MeOH, 60 oC 88% H O Me Me H O Me Me Me OMe Me Me OMe  Scheme 1.13:  Platinum-catalyzed alkoxycyclization of enyne 1.3562  In a related reaction, Echavarren and coworkers ran the same reaction as in Scheme 1.13, but without methanol (Scheme 1.14).64  After the formation of the two resonance related intermediates 1.42 and 1.43, the C-H bond of the methyl substituent was eliminated to form a disubstituted double bond (1.44).  Protodemetallation gave the final product 1.45.  PhO2S PhO2S Me Me PhO2S PhO2S Me 1.35 1.45 5 mol% PtCl2 dioxane, 70 oC 89% PhO2S PhO2S Me Me Pt2+ PhO2S PhO2S Me 1.43 Pt H PhO2S PhO2S Me 1.44 Pt proto- demetallation PhO2S PhO2S 1.42 Pt Me Me  Scheme 1.14:  Platinum-catalyzed cycloisomerization of an 1,6-enyne containing a trisubstituted olefin 1.35 64       Chapter 1:  Cycloisomerizations catalyzed by Platinum, Gold, and Silver Salts: A Review   19 1.6 Other Nucleophiles Used in Cycloisomerization Reactions  A common nucleophile in the cycloisomerization of 1,n-enynes is the alkene functional group.  Once the π-system has been activated, nucleophiles other than alkenes can attack. Heteroatoms are an obvious choice as they have lone pairs of electrons which can react with electrophilic species.  As an example, Fürstner and coworkers exploited the oxygen atom of phenols as a nucleophile to form benzofurans.  Phenol derivative 1.46 containing a pendent alkyne at the 2-position was reacted with 1 mol% of platinum(II) chloride to give benzofuran 1.47 in 98% yield (Scheme 1.15, eq 1).65  No external base was necessary to promote the reaction in contrast to similar reactions reported in the past.66  The authors also found that substitution on oxygen did not prevent cycloisomerization (Scheme 1.15, eq 2).  Allyl ether 1.48 was treated with 5 mol% of platinum(II) chloride to give benzofuran 1.49 in 98% yield.  The oxygen substituent was transferred to the 3-position of the benzofuran during the course of the reaction.  The reactions proceeded under platinum(II)-catalysis but were accelerated under an atmosphere of carbon monoxide.67, 68  Ph OH O Ph 1 mol% PtCl2 CO (1 atm) PhCH3, 80 oC 98% 1.46 1.47 Ph O O Ph 5 mol% PtCl2 CO (1 atm) PhCH3, 80 oC 94% 1.48 1.49 (1) (2)  Scheme 1.15:  Fürstner’s hydroxylation of alkynes65  Nitrogen is a nucleophile used extensively in coinage metal catalyzed cycloisomerizations. Gold-catalyzed hydroamination reactions have received a lot of attention in the last year.30, 69-79 Silver and platinum-catalyzed hydroamination reactions are less common.80-85  An example of a gold-catalyzed double hydroamination reaction is shown in Scheme 1.16, eq 1.86  o- Alkynylaniline 1.50 reacted with phenyl acetylene 1.51 under gold(III) catalysis to afford N- alkenylindole 1.52 in 82% yield.  The authors found the reaction to work well with both electron rich and electron deficient arylacetylenes, but were less reactive towards aliphatic and alkenyl acetylenes.  A bulky substituent on o-alkynylaniline 1.53 prevented the second hydroamination reaction, thereby giving imine 1.54 as the sole product (Scheme 1.16, eq 2). Chapter 1:  Cycloisomerizations catalyzed by Platinum, Gold, and Silver Salts: A Review   20  NH2 Ph 5 mol% AuCl3 15 mol% AgOTf rt, neat 82% 1.50 N Ph Ph 1.52 Ph 1.51 NH2 Si(CH3)3 5 mol% AuCl3 15 mol% AgOTf rt, neat 51% 1.53 1.54 MeO N Si(CH3)3 H3C OMe (1) (2)  Scheme 1.16:  Gold-catalyzed hydroamination: nitrogen as a nucleophile86  A silver-catalyzed cycloisomerization employing a nucleophilic ester comes from the Toste laboratory.87  Toste and coworkers aimed to develop a transition-metal catalyzed Myers- Saito cyclization88-91 of enyne allenes to form naphthyl ketones.  They envisaged that an efficient synthesis of the required enyne allene could come from the transition metal-catalyzed rearrangement of propargyl acetates such as 1.55 (Scheme 1.17).  Toste and coworkers reacted propargyl esters such as 1.55 with 5 mol% of silver(I) hexafluoroantimonate, 2 mol% of triphenylphosphine, and 1.5 equivalents of magnesium oxide at room temperature to form naphthylketones 1.58 in 51 to 94% yield.  The proposed mechanism begins with the coordination of the metal to the alkyne followed by a 3,3-sigmatropic rearrangement to give enyne allene 1.56, the required substrate for the Myers-Saito cyclization.  6-endo-dig Cyclization of the activated alkyne furnishes naphthylene 1.57.  Upon workup, naphthyl ketone 1.58 is formed. The reaction also forms complex ring systems such as binaphthyl and anthracene derivatives. The specific catalytic system used by the authors was found serendipitously when running control reactions.  The purpose of the magnesium oxide was to avoid the destruction of the silver catalyst by acetic acid produced during the course of the reaction.  Chapter 1:  Cycloisomerizations catalyzed by Platinum, Gold, and Silver Salts: A Review   21 O R2 R1 O M O R2 O R2 R1 O O R1 M R2 O R1 O M R2 R1 O [3,3] 6-endo- dig 5 mol% AgSbF6 2 mol% PPh3 1.5 equiv MgO 51-94% CH2Cl2, rt 1.55 1.56 1.58 M R2 R1 O O 1.57 H2O  Scheme 1.17:  Silver-catalyzed cycloisomerization with acetate as the nucleophile87 Cycloisomerizations have been performed in tandem with Friedel-Crafts reactions.92-99 One example of a Friedel-Crafts reaction coupled with a gold-catalyzed cycloisomerization reaction comes from the laboratory of Echavarren (Scheme 1.18).93, 94  Aryl enynes such as 1.59 were treated with 2 mol% of cationic gold catalyst 1.63 and 2 mol% of silver(I) hexafluoroantimonate to form naphthyl derivatives 1.62 via formal [4+2] cycloadditions.  The reaction presumably occurs by initial 5-exo-dig cyclization to form gold carbene 1.60.  The authors speculate that a Nazarov type cyclization could then occur to form intermediate 1.61, although it can also be viewed as opening of the cyclopropyl ring by the electron-rich aromatic ring.  For a number of the substrates only one stereoisomer was formed during the course of the reaction, implying that the initial alkene configuration was retained.  Chapter 1:  Cycloisomerizations catalyzed by Platinum, Gold, and Silver Salts: A Review   22 R1 R2 H3CO2C H3CO2C R4 R3 H3CO2C H3CO2C R4 R3 R2 R1 H 2 mol% [Au(I)] (1.63) 2 mol% AgSbF6 CH2Cl2, rt [Au(I)] P Au Cy Cy Cl H3CO H3CO 1.63 ≡ 1.59 1.62 R2 R1 H Au(L) R3 R4 H3CO2C H3CO2C H3CO2C H3CO2C R4 R3 R2 R1 H 1.61 Au(L) 1.60 -[Au(L)]+  Scheme 1.18:  A cycloisomerization reaction coupled with a Friedel-Crafts reaction93  Gold-catalyzed cycloisomerizations coupled to Friedel-Crafts reactions also extend to intermolecular reactions.  Michelet and coworkers reacted enyne 1.64 with a gold(I)-catalytic system and veratrole (1.65) as an external nucleophile to form compound 1.66 in high yield (Scheme 1.19, eq 1).96  The authors speculate that the reaction mechanism is analogous to that described by Echavarren (Scheme 1.18).  In the absence of veratrole (1.65), the reaction of enyne 1.67 forms the well-documented diene products 1.68 and 1.69 were observed (Scheme 1.19, eq 2).  Diene 1.68 was the result of the metathesis-type pathway whereas 1.69 arose from 6-endo- dig cyclization.  With veratrole present, alkene 1.66 was the only observable product.  The reaction also took place with other electron-rich aromatics such as indole and pyrrole.  The authors did not comment on the use of electron deficient aromatics. O H 1.64 1.65 3 mol% [PPh3AuCl] 3 mol% AgSbF6 Et2O, rt, 0.5 h O O OCH3 OCH3 O O O H OCH3 OCH3 1.6691% Ph 1.67 MeO2C MeO2C 3 mol% [PPh3AuCl] 3 mol% AgSbF6 Et2O, rt, 0.2 h 55% MeO2C MeO2C Ph Ph MeO2C MeO2C 1.68 1.69(1.1:1) (1) (2)  Scheme 1.19:  Cycloisomerization coupling with an intermolecular Friedel-Crafts reaction96 Chapter 1:  Cycloisomerizations catalyzed by Platinum, Gold, and Silver Salts: A Review   23 1.7   Ligand Effects in Gold Catalysis  Catalysts are continually being modified in an attempt to make them more effective. Academic and industry groups have synthetic programs designed with the sole purpose of creating libraries of catalysts.  The hope is that by changing the properties of the catalyst, one will emerge that is more efficient than the rest.  Metal catalysts are altered in a number of ways. The ligands around the metal center are important for reactivity and selectivity, and can be modified by changing their steric and electronic properties.  Placing electron-donating or electron-withdrawing groups on a ligand can change its electronic properties.  Increasing the bulk of the ligand set, or by modifying the coordination number around the metal center can change the steric environment around the catalyst.  The counter ion employed in cationic catalyst systems can also be altered.   Following the initial successes of gold(I)-catalyzed cycloisomerization, effort is underway to increase reactivity and impart selectivity by changing the environment around the gold center. Depicted in Figure 1.4 are a series of gold catalysts recently synthesized.  Gold has been coordinated to Buchwald-type ligands such as 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos) to give neutral gold complex 1.63.  Cationic gold(I) complexes such as 1.70 have also been prepared and are reported to be active catalysts towards a number of skeletal rearrangement reactions.  Their use eliminates the need to run the reaction with a silver(I) salt, which in some cases leads to unwanted side products.  Another desirable feature is that they are isolable white solids, making them easy to handle.100-102  P Au Cy Cy Cl H3CO H3CO 1.63 P Au 1.70 N C CH3 SbF6 N OH AuCl O Cl O 1.71 N N iPr iPr iPr iPr Au Cl 1.72 Figure 1.4:  Examples of gold complexes used for cycloisomerization catalysis Gold(III)-catalysis is also utilized in cycloisomerization reactions, although it is not as popular as gold(I).  Hashmi and coworkers found gold(III) catalysts to be effective for the cycloisomerization of alkynyl furans to phenols, but catalyst stability was a concern.103  They therefore created a set of gold(III) complexes with stabilizing ligands derived from pyridine Chapter 1:  Cycloisomerizations catalyzed by Platinum, Gold, and Silver Salts: A Review   24 (Figure 1.4, 1.71).104  The ligand supported catalysts had turnover numbers of 1180 compared to 20-50 for gold(III) chloride.  In an attempt to further increase the activity of gold(I) catalysts bearing biphenyl ligands, Widenhoefer turned to N-heterocyclic carbene based ligands (Figure 1.4, 1.72).105  Complex 1.72 allowed him to cyclize urea based substrates at room temperature rather than at 80 oC with phosphine supported gold catalysts.   As previously mentioned, the change of the ligand support system of a metal catalyst can alter its selectivity and reactivity in a reaction.  Echavarren found that indole 1.73 could be catalytically transformed to either azepino[4,5-b]indole derivative 1.74 via a 7-exo-dig cyclization, or to indoloazocines 1.75 via a 8-endo-dig cyclization, depending on which catalyst is used (Scheme 1.20).106, 107  Gold(I) chloride and gold(III) chloride gave the indoloazocine product 1.75 whereas cationic gold catalyst 1.70 formed only the azepino[4,5-b]indole product 1.74.  N H N Ar CO2Me 5 mol% cat. CH2Cl2 N H N H N N CO2Me CO2Me Ar Ar1.73 1.74 1.75 catayst     yield (%)  1.74:1.75   AuCl         75             0:100   AuCl3       70             0:100   1.70          82            100:0 Ar = 2,4-dinitrobenzenesulfonyl  Scheme 1.20:  Echavarren: 7-exo-dig vs. 8-endo-dig gold catalyzed hydroarylation106, 107  Extensive studies have been performed in an effort to understand ligand effects on the mechanism of cationic gold(I)-catalysis.23  As mentioned in section 1.5, a possible intermediate along the mechanistic pathway is carbene-like in character.  An isolable gold complex with carbenoid character has so far not been discovered despite experimental and theoretical accounts that they are indeed plausible.28, 108  Studies done by Toste and Goddard determined that the amount of carbene character of a gold species is dictated by the ligands as well as the carbene substituents.109  Based on their model, they speculate that there is a correlation between bonding and reactivity.  Ancillary ligands that are largely σ-donating increase the amount of carbene character of the intermediate.  Examples of strongly σ-donating ligands are N-heterocyclic Chapter 1:  Cycloisomerizations catalyzed by Platinum, Gold, and Silver Salts: A Review   25 carbene type ligands.  In contrast, ligands that are highly π-acidic will decrease the overall amount of σ-donation, resulting in an intermediate that is carbocationic in nature.  O O Ph Ph 5 mol% LAuCl 5 mol% AgSbF6 CD2Cl2 O O Au L O O Ph Ph 1.76 1.77 1.78 1.79 L = P(OMe)3          0%       P(Me)3             56%  (1.4:1 cis:trans)       IPr                    80% (11:1 cis:trans) decreasing π-acidity  Scheme 1.21:  Ligand effects on the reactivity of gold(I) carbenes109  As an example, Toste and coworkers looked at the correlation between bonding and reactivity in gold-catalyzed cyclopropanation reactions (Scheme 1.21).109  The reaction of compound 1.76 and cis-stilbene 1.77 was expected to proceed through a gold-carbene intermediate 1.78.  The authors found that when a highly π-acidic ligand such as trimethyl phosphite was used, no product was formed.  However when a strongly σ-donating N- heterocyclic carbene ligand was used, the product 1.79 was formed in excellent yield and selectivity.     The use of chiral ligands to render a reaction asymmetric has also had a prominent role in electrophilic metal salt catalyzed cycloisomerization reactions.  Although it will not be discussed here, readers are directed to examples of asymmetric gold-catalyzed110-118 and platinum- catalyzed97, 119, 120 cycloisomerization reactions in the primary literature.   1.8   Previous work from the Dake group  A long term goal of the Dake laboratory is to create complex nitrogen-containing ring systems which can be used towards the total synthesis of alkaloid natural products.  The group has had success using the mild and functional group tolerant metal-catalyzed cycloisomerization reactions.  Uniquely, Dake and coworkers form new carbon-carbon bonds through the use of Chapter 1:  Cycloisomerizations catalyzed by Platinum, Gold, and Silver Salts: A Review   26 enamides, enesulfonamides, and enecarbamates as nucleophiles (Figure 1.5).  Enamide derivatives are useful because they are bifunctional: they can first be used as a mild nucleophile, and then harnessed as an electrophile to neutralize the positive charge of the azacarbenium ion. Enamines are unstable and are usually prepared in situ.  Derivitization of the nitrogen atom with an electron withdrawing group renders the functionalized enamine stable and isolable, while still taking advantage of its reactivity.  Enamides, enecarbamates, and enesulfonamides have generally been used as precursors to electrophilic species.121-131  The mild nucleophilicity of derivatized enamines has also been exploited.132-138  Transition metal catalyzed processes where the enamide reacts as a π-nucleophile have been studied to a lesser extent.139-151  Readers interested in the use of enamides in organic synthesis are directed to a recent review by Carbury.152  NO R N EWG EWG = R O = CO2R     enecarbamate = SO2Ar    enesulfonamide enamide enamide Figure 1.5:  Enamine derivatives  The pioneering work of the Dake group was the metal catalyzed cycloisomerization of tetrahydropyridines (1.80) substituted with a tethered alkyne at the 4-position (Scheme 1.22).153 Treatment of these substrates with a catalytic amount of platinum(II) or silver(I) salts caused them to cyclorearrange to 1,3-dienes.  If R = CH3, the double bond migrated into the ring to give 1.81 as the only product.  If R = phenyl, a 1:1 mixture of products 1.81 and 1.82 were formed.  If R = CO2CH3 the double bond stayed exocyclic to the newly formed 5-memebered ring and only 1.82 was isolated.  The initial testing of these substrates was done with platinum(II) chloride, [(dppb)Pt(µ-OH)]2(BF4)2, and silver trifluoromethanesulfonate.  N PG R 10 mol% PtCl2 N PG R N PG R 1.80 1.81 1.82      R        yield (%) 1.81:1.82     CH3        58             1:0     Ph          52             1:1 CO2CH3     69             0:1 PhCH3  Scheme 1.22:  Cycloisomerization of enesulfonamides and enecarbamates to form 1,3-dienes153 Chapter 1:  Cycloisomerizations catalyzed by Platinum, Gold, and Silver Salts: A Review   27  The proposed mechanism for the cycloisomerization of enamine derivatives is analogous to other cycloisomerization reactions in the literature.154  Initial complexation of the metal salt to the alkyne of substrate 1.80 gives the activated complex 1.83 (Scheme 1.23).  The alkyne is now sufficiently electron deficient for the nucleophilic enamide to attack in a 5-exo-dig fashion, forming a new carbon-carbon bond and 5-membered ring (1.84).  A proton is lost to reform the enamide (1.85) since there is no other nucleophile to react with the putative azacarbenium ion. Protodemetallation gives compound 1.86.  Based on nuclear Overhauser effect (NOE) experiments (1.81N), it is likely that isomerization occurs at this stage to give 1,3-diene 1.81.  N PG R 1.80 Met (cat.) N PG R 1.83 M+ N PG M 1.84 proto- demetallation N PG M 1.85 5-exo-dig H R Relimination N PG 1.86 R isomerization N PG 1.81 R N PG 1.81N R H H NOE  Scheme 1.23:  Proposed mechanism for the cycloisomerization of enamides, enecarbamates, and enesulfonamides154  The most effective combination of substrate and catalyst is shown in Scheme 1.24. Functionalizing the alkyne with an electron withdrawing group (1.87) was found to give the exocyclic alkene 1.88 as the sole product.  Silver triflate was the best catalyst for the system, forming the product in a 99% yield compared to 69% with platinum(II) chloride and 86% with [(dppb)Pt(µ-OH)]2(BF4)2.  N Ts CO2CH3 N Ts CO2CH3 1.87 1.88 2 mol % AgOTf THF/CH2Cl2 60 oC, 4.5 h 99%  Scheme 1.24:  Cycloisomerization of enesulfonamide 1.87 to form 1,3-diene 1.88153 Chapter 1:  Cycloisomerizations catalyzed by Platinum, Gold, and Silver Salts: A Review   28  The 1,3-diene formed could be a handle to build further complexity.  As an example, diene 1.88 was used in a Diels-Alder reaction to give a highly functionalized, nitrogen containing tricycle.  The cycloisomerization and Diels-Alder reactions were optimized to a one-pot reaction with yields as high as 75% for the 2 steps.   1.9   The Use of Platinum, Gold, and Silver Catalyzed Cycloisomerization Reactions in Total Syntheses of Natural Products Other academic groups besides the Dake group are interested in using cycloisomerization towards the total synthesis of natural products.  Applications of these reactions in total syntheses are not as common as the number of methodology publications put forward, but there have been some great successes.  The first use of platinum(II)-catalysis in the context of a total synthesis was performed by Fürstner when synthesizing the molecules streptorubin B and metacycloprodigiosin (Scheme 1.25).155, 156  Fürstner treated enyne 1.89 with 5 mol% of platinum(II) chloride to give product 1.92 in 79% yield.  The authors speculate that the reaction occurs through a pathway where one of the mesomeric intermediary carbocations is cyclobutane 1.90.  This intermediate can fragment to give carbocation 1.91, which upon loss of the metal gives the ring expanded product 1.92. Diene 1.92 was further elaborated to pyrrole containing natural product streptorubin B.  N Ts O 5 mol % PtCl2 toluene, 50 oC 79% N Ts O NH N H3CO H N streptorubin B 1.89 1.92 1.90 N Ts LnPtO 1.91 N Ts LnPtO -PtLn  Scheme 1.25:  Fürstner and co-workers formal synthesis of streptorubin B155 Chapter 1:  Cycloisomerizations catalyzed by Platinum, Gold, and Silver Salts: A Review   29  Fürstner and coworkers applied their methodology to a number of other total syntheses.  In an elegant study, they completed the total synthesis of both (−)-cubebol and (−)-α-cubebene from one intermediary compound 1.94 (Scheme 1.26).157  The syntheses of these natural products began with the functionalization of (R)-(−)-carvone to propargyl acetate 1.93.  Acetate 1.93 was then treated with 2 mol% of platinum(II) chloride in toluene at 80 oC to form cyclopropyl acetate 1.94 in 92% yield.  At this stage, the acetate was converted to the corresponding ketone and treated with methyllithium to afford (−)-cubebol.  Alternatively, acetate 1.94 was converted to the enol triflate and then cross coupled to form (−)-α-cubebene. The synthesis of (−)-cubebol using platinum, gold, and copper catalysis is also described in a separate publication by Fehr.158  O AcO 2 mol % PtCl2 toluene, 80 oC 92% AcO H H H H HO H H H3C (−)-cubebol (−)-α-cubebene 1.93 1.94  Scheme 1.26:  Fürstner and co-workers synthesis of (−)-cubebol and (−)-α-cubebene157  In an effort to investigate the regiochemistry of the cycloisomerization reaction, Fürstner and coworkers investigated the total synthesis of sesquicarone (Scheme 1.27).157  Acetate 1.95 was prepared as the key cyclization substrate from geranylacetone by two routine operations. Acetate 1.95 was tested first with platinum(II) chloride, and although the product was obtained, an allenylester byproduct was also formed.  Silver catalysis gave solely the undesired allenylester.  Treatment of acetate 1.95 with 1.5 mol% of gold(III) chloride gave the desired cycloisomerization product, with only minimal amounts of the byproduct. The acetate was removed to give product 1.96 in 74% yield over 2 steps.  Ketone 1.96 was further elaborated to the natural product sesquicarone.  Chapter 1:  Cycloisomerizations catalyzed by Platinum, Gold, and Silver Salts: A Review   30 O OAc 1. 5 mol % AuCl3 1,2-dichloroethane 2. K2CO3, MeOH 74% (2 steps), dr 6.7:1 O H H H H sesquicarone1.95 1.96 Scheme 1.27:  Fürstner and co-workers synthesis of sesquicarone157  An interesting application of gold catalysis is demonstrated by Toste in his total synthesis of angular triquinane ventricosene (Scheme 1.28).159  Commercially available ester 1.97 was first elaborated to cyclopropane 1.98.  Cyclopropane 1.98 was treated with 3 mol% [Ph3PAuCl] and 3 mol% silver hexafluoroantimonate to afford cyclobutanone 1.101 in 87% yield.  The authors speculate that the stereochemical outcome of the reaction can be rationalized by reaction through a boat transition state (1.100).  Cycloisomerization of the enyne would give cyclohexyl cation 1.99.  A Wagner-Meerwein shift would then furnish the cyclobutanone product 1.100.  This key step can be viewed as a gold-catalyzed ring-expanding cycloisomerization reaction.  Compound 1.101 was further elaborated to give the natural product ventricoscene.  CO2CH3 HO 3 mol % Ph3PAuCl 3 mol % AgSbF6 CH2Cl2, rt, 2 h 87% H O H H H ventricosene1.98 1.101 1.99 HO [Au] 1.97 ≡ H OH Au ≡ OH H [Au] 1.100 Scheme 1.28:  Toste’s total synthesis of ventricosene159  A recent example using silver catalysis in a total synthesis comes from the group of Bates (Scheme 1.29).160  Their program towards the synthesis of natural product porantheridine began with the elaboration of epichlorohydrin to allene 1.102.  Allene 1.102 was treated with 10 mol% of silver tetrafluoroborate to yield isoxazolidine 1.103 in 94% yield with 11.5:1 diastereoselectivity.  Isoxazolidine 1.103 was used as an intermediate in the total synthesis of porantheridine. Chapter 1:  Cycloisomerizations catalyzed by Platinum, Gold, and Silver Salts: A Review   31  O Cl n-Pr ONHBoc 10 mol % AgBF4 94%, dr 11.5:1 CH2Cl2 n-Pr O NBoc N O H H CH3 n-Pr porantheridine 1.102 1.103  Scheme 1.29:  Bates’ and co-workers formal synthesis of porantheridine160   1.10 Brønsted Acid Catalysis  Water often plays a significant role in reactions.  Side reactions involving water are avoided by rigorously drying glassware and solvents, and performing the reactions under an inert atmosphere.  There is still the possibility that water may be formed during the reaction, or that adventitious water remains on the glassware.  Transition metal catalysts with weakly coordinating anions are well known to undergo hydrolysis reactions with water to form metal hydroxide salts and protic species “H+”.161  An ongoing controversy in metal catalyzed reactions is whether the metal itself is catalyzing the reaction, or whether “H+” is responsible for catalysis.  Mz+ H2O M(OH) (z-1)+ H+   Fürstner and coworkers found that certain enynes cyclorearranged just as effectively with BF3·OEt2 and HBF4 as they did with PtCl2. 162  Krische obtained similar results; his silver(I) catalyzed coupling of alkynes and carbonyl compounds in some cases was more effective using the Lewis acid BF3 or Brønsted acid HBF4. 163  The work by Krische was extended to an intramolecular coupling of alkynes with ketones using triflic acid catalysis by Yamamoto and coworkers.164  Fürstner argued that the ability of Lewis and Brønsted acids to catalyze the same reactions as metal salts lends support to the proposed cationic nature of the reaction pathway, discussed in section 1.5.   The debate over metal versus proton-catalysis is more evident in the areas of metal catalyzed hydroamination and hydroalkoxylation.165  Hii found copper(II) triflate to be a good catalyst for the hydroalkoxylation and hydroamination of alkenes.  Experimental evidence led her to believe that triflic acid was being generated and was responsible for the catalytic activity Chapter 1:  Cycloisomerizations catalyzed by Platinum, Gold, and Silver Salts: A Review   32 observed.166, 167  Shortly after, Hartwig168 and He169 found that triflic acid alone catalyzed hydroamination and hydroalkoxylation reactions.  On the other hand, theoretical calculations performed on hydroamination reactions using catalytic PPh3AuOTf suggest that the active pathway is the binding of the metal to the alkene.170  Persuasive evidence of the participation of the metal in hydroamination reactions comes from the laboratory of Widenhoefer.171  He found that urea 1.104 underwent hydroamination with 1-octene (1.105) in the presence of 2.5 mol% of a chiral gold catalyst and 5 mol% of silver triflate to form urea 1.106 in 86% and 76% ee (Scheme 1.30).  This lends support to gold playing a role and not only a proton, otherwise no ee’s would have been observed.  N NH O H3C Me 5 N N O H3C Me Me 5 MeO MeO P P Ar Ar Ar Ar OMeAr = 1.107 = 2.5 mol% [(S)-1.107](AuCl)2 5 mol% AgOTf m -xylene, 100 oC, 48 h 1.104 1.105 1.10686%, 76% ee  Scheme 1.30:  Widenhoefer’s enantioselective hydroamination171  A number of accounts of Brønsted acid catalysis are available for reactions other than hydroamination.  Spencer found that the hetero-Michael addition of nitrogen, oxygen, and sulfur to α,β-unsaturated ketones was readily catalyzed by Brønsted acids,172 and provides evidence that protons could be the active catalysts in Lewis-acid catalyzed reactions.173  On the other hand, Kobayashi found in his metal-catalyzed aldol reaction that metal salts, even scandium(III) triflate were stable in water.174, 175   No matter how rigorously “dry” transition metal salt catalyzed reactions are performed, control experiments must be done to avoid misinterpretation of results.  The most common control experiments are to run the reaction without the metal catalyst, to run the reaction with an acid in the place of a metal catalyst, or to run the reaction with an added base to test for metal- catalysis.  Mechanistic pathways for both metal-catalysis and H+-catalysis exist based on Chapter 1:  Cycloisomerizations catalyzed by Platinum, Gold, and Silver Salts: A Review   33 experimental evidence: it is difficult a priori to discern which catalytic system would be most beneficial for a given reaction.   1.11 Conclusion  Transition metal catalyzed cycloisomerization reactions, in particular coinage metal- catalyzed reactions, have increased in popularity in the last decade.  Despite the many advances, metal catalyzed cycloisomerizations are far from reaching their full potential.  There are still many discoveries to be made and likely alternate mechanistic pathways to be uncovered. Cycloisomerization reactions are garnering such attention because they are able to create complex molecules, including the formation of ring systems, from relatively simple starting materials.  The major disadvantage of this chemistry is that there is, as of yet, no predictive ability.  It is difficult to foresee which of the mechanistic pathways a particular reaction will follow, making it difficult to predict the product.  Research is beginning to focus on DFT calculations of hypothetical reactive intermediates to discern which pathway a reaction will take, thereby predicting a product.  The ability to envisage the product will render this chemistry more useful towards total synthesis of natural products and in the pharmaceutical industry.  As ever, the “holy grail” of transition metal catalyzed cycloisomerization reactions is to have predictive ability coupled with high regio-, chemo-, diastereo-, and enantioselectivity.              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Kobayashi, S.; Nagayama, S.; Busujima, T. J. Am. Chem. Soc. 1998, 120, 8287-8288.    41                  Chapter 2: The Total Synthesis of (+)-Fawcettidine1                   1 Some material in this chapter has been published.  See: Kozak, J. A.; Dake, G. R. “Total Synthesis of (+)- Fawcettidine” Angew. Chem. Int. Ed. 2008, 47, 4221-4223. Chapter 2:  The Total Synthesis of (+)-Fawcettidine   42 2.1   Introduction  2.1.1 Alkaloid Natural Products Alkaloid is a term used to describe a large family of structurally diverse natural products, many of which are pharmacologically significant.  The term alkaloid was derived from the fact that the natural products are alkali-like, or basic in nature, and contain a minimum of one basic nitrogen atom.1  After studies of the biogenetic origin of alkaloids, the definition of an alkaloid was extended to include its being derived from an amino acid, and that the nitrogen atom is confined to a heterocyclic ring.  The discovery of alkaloids that were neutral or even acidic (i.e. colchicines, quaternary alkaloids), or contained the nitrogen atom in a chain (i.e. polyamines) illustrates difficulties in attempting to classify all alkaloids under one encompassing definition.  Alkaloids are a class of natural products that humans have contact with on what is likely a daily basis.  Some specific examples are nicotine in tobacco, caffeine in coffee and tea, theobromine in chocolate, and capsaicin (spicy flavor) in various peppers, to name only a few. Other alkaloids are poisons, hallucinogenic agents, or are active as medicines.  The pharmaceutical industry has had a longstanding interest in the use of alkaloids for medicinal applications and drug discovery because of their rich biological activity.1-3  The complex structures and diversity of the nitrogen-containing ring systems within alkaloids make them inspiring targets for the synthetic organic community.4-7  2.1.2 The Lycopodium Alkaloid Family  One large family of alkaloids is the Lycopodium alkaloid family, members of which are depicted in Figure 2.1.  Lycopodium alkaloids feature interesting and unusual skeletons that continue to pique the interest of researchers from both biological and total synthesis standpoints.4, 8, 9  The first account of an isolation of a Lycopodium alkaloid is from Bödeker in 1881.10  The natural product was isolated from the clubmoss Lycopodium complanatum (ground cedar) and is believed to be the substance now known as lycopodine (2.1) (Figure 2.1).11 Between the years 1881 and 1994, there have been 201 Lycopodium alkaloids from 54 species of Lycopodium reported, with more being discovered every year.4  The Lycopodium alkaloids are divided into four classes: the lycopodine class, the lycodine class, the fawcettimine class, and a Chapter 2:  The Total Synthesis of (+)-Fawcettidine   43 miscellaneous class.  The representative compounds from these classes are lycopodine (2.1), lycodine (2.2), fawcettimine (2.3), and phlegmarine (2.4), respectively (Figure 2.1)  H3C H O N H H H3C H O N H H HO N O H H OH OH N H O (+)-fawcettidine (2.5) fawcettimine (2.3)lycopodine (2.1) serratinine (2.6) N H N Me lycodine (2.2) N H H H Me N H H phlegmarine (2.4) NH O NH2 huperzine A (2.7) Figure 2.1:  Lycopodium alkaloids  The structures of Lycopodium alkaloids have inspired many total syntheses.  Prominent examples of these include the syntheses of lycopodine by Stork,12 Ayer,13 Heathcock,14 Wenkert,15 Kraus,16, 17 Padwa,18 and Grieco,19 as well as the studies of lycopodine and annotinine by Weisner.20-22  The total syntheses of fawcettimine will be discussed later in the chapter.   Some Lycopodium alkaloids display biological activity, typically in the form of acetocholinesterase inhibition.4  Acetylcholine is a neurotransmitter active in the nervous systems of the human body.  Degradation of acetylcholine or inhibition of acetylcholine receptors can lead to illnesses such as Alzheimer’s disease.  A number of alkaloids have been found to prevent the cholinesterase enzyme from degrading acetylcholine, leading to an increased level and duration of acetylcholine in the body.  The most potent and biologically active member of the Lycopodium genus is huperzine A (2.7, Figure 2.1) a member of the lycopodine class.  Huperzine A (2.7) has been investigated as a drug (an acetylcholinesterase inhibitor) that increases the efficiency for learning and memory in mammals and also shows promise in the treatment of Alzheimer’s disease.4, 23   There have been many proposed biosynthetic pathways for the construction of Lycopodium alkaloids.  There has been evidence to support aspects of these hypotheses, although the biosynthesis of these molecules has not been entirely elucidated.  Based on the structure of Chapter 2:  The Total Synthesis of (+)-Fawcettidine   44 annotinine (2.8), Conroy suggested that the biogenetic formation of many of the structurally related Lycopodium alkaloids starts with the condensation of two 8-carbon units (Figure 2.2).24 He proposed that the 8-carbon units are similar to the polyacetate straight chains involved in fatty acid biosynthesis.  The numbering system used for lycopodine is based on its biosynthesis from these 8-carbon units.  N O O O H annotinine (2.8) N 2 5 7 8 6 4 1 3 1' 2' 3' 4' 8' 7' 6' 5'  Figure 2.2:  Mapping of two 8 carbon chains onto the core of annotinine (2.8)  Conroy’s speculated biosynthesis of lycopodine (2.1) from two molecules of 3,5,7-triketo- octanoic acid (2.9) is shown in Scheme 2.1.  The author notes that the order of the proposed steps is not certain, but are used rather for illustration.  The two straight chain acids (2.9) first undergo an aldol condensation and dehydration to give diacid 2.10.  A second aldol condensation forms a 6-membered ring (2.11).  After reduction of the double bond, a Mannich reaction occurs with a molecule of ammonia to give highly oxidized compound 2.12.  Reduction at carbons 1, 1’, 3, 3’, and 7’ gives lycopodine (2.1).  O O O OH O 2 aldol condensation HOOC O O O HOOC O 2.102.9 HOOC O O O HOOC 2.11 aldol condensation 1. reduction 2. Mannich reaction     with ammonia OO NO O O O O 2.12 HO HO reduction N O lycopodine (2.1) H  Scheme 2.1:  Proposed biogenesis of Lycopodium alkaloid lycopodine 2.124  The investigation of the biosynthesis of lycopodine (2.1) and lycodine (2.2) by Spenser and coworkers suggests a very different pathway (Scheme 2.2).25-28  The Lycopodium species of Chapter 2:  The Total Synthesis of (+)-Fawcettidine   45 clubmoss from which lycopodine (2.1) was isolated could not be cultivated in a laboratory, making investigation of the biosynthetic pathway difficult.  Spenser and coworkers fed 14C- and 13C-labeled precursors to the shoots of the plants as they were growing in their natural environment.  After a few days, the shoots of the plants were harvested and the tissues were analyzed for incorporation of the label into the final alkaloid products or into potential pathway precursors.  Evidence from these experiments led Spenser and coworkers to believe that the decarboxylation of lysine (2.13) produces cadaverine (2.14).  Exposure to diamine oxidase converts one of the amine groups into an aldehyde (2.15) and intramolecular condensation gives piperideine (2.16).  Two molecules of malonyl CoA (2.17) are condensed using a ketosynthase enzyme to give acetone dicarboxylic acid (2.18).  Decarboxylation of one of the acids and reaction with piperideine (2.16) gives compound 2.19.  Decarboxylation of 2.19 leads to pelletierine (2.20).  Further condensation of pelletierine (2.20) with compound 2.19 yields diamine 2.21.  It should be noted that this is the skeleton of Lycopodium alkaloid phlegmarine (2.4), meaning Lycopodium alkaloids from the miscellaneous class could also be accessed via this biosynthetic pathway through oxidations and other skeletal rearrangements.  As shown in Scheme 2.2, oxidation of 2.21 could possibly lead to the formation of lycodine (2.2). Lycopodine (2.1) is hypothesized to also be derived from 2.21.  Chapter 2:  The Total Synthesis of (+)-Fawcettidine   46 H2N CO2HH2N H -CO2 H2N NH2 diamine oxidase H2N O N malonyl CoA (2.17) HO OH O O O -CO2 NH OH O O -CO2 HN OHN NH ≡ N H NH [O] N H N N O H 2.16lysine (2.13) cadaverine (2.14) 2.15 2.18 2.19 2.19 2.21 pelletierine (2.20) lycodine (2.2) lycopodine (2.1) Scheme 2.2:  Biosynthetic pathway as proposed by Spenser  Both researchers believe that two 8-carbon chains are involved, but Conroy suggests that a molecule of ammonia is incorporated whereas Spenser claims the nitrogen atom originates from an amino acid.  The fact that most alkaloids are derived from amino acids, and not ammonia, is also noted in other reviews.1  Spenser also supports his pathway with experimental evidence, leading me to believe that his proposed pathway is more plausible than that proposed by Conroy.  2.1.3 (+)-Fawcettidine  (+)-Fawcettidine (2.5) is a member of the Lycopodium alkaloid family in the fawcettimine class.  It was isolated by Burnell and coworkers in the late 1950’s from a Jamaican Lycopodium plant Lycopodium fawcetti.29, 30  There have been no reports about the biological activity of fawcettidine itself.  Fawcettidine has a molecular mass of 245 and features a tetracyclic core and a quaternary stereocenter.  It also contains an enamine functional group that is reported to be sensitive to aqueous acid.4  The structural representation of (+)-fawcettidine can be drawn a number of ways, four of which are represented in Figure 2.3. Chapter 2:  The Total Synthesis of (+)-Fawcettidine   47 H3C H N H H O N O CH3 ≡ N O ≡ N O ≡  Figure 2.3:  Different structural representations of (+)-fawcettidine (2.5)  Two different structural representations of (+)-fawcettidine are shown with its numbering pattern in Figure 2.4.  The numbering system shown is consistent for all fawcettimine based Lycopodium alkaloids.  H3C H N H H O ≡ N O 13 12 11 10 9 8 7 6 5 4 3 2 114 15 16 1 13 12 11 10 9 8 7 6 5 4 3 2 14 1516  Figure 2.4:  Numbering scheme for (+)-fawcettidine (2.5)  As mentioned in section 2.1.1, the proposed biogenesis of the Lycopodium class of alkaloids comes from two 8-carbon units which can be hypothetically reacted to form lycopodine 2.1.  Lycodoline (2.22) differs from lycopodine (2.1) by one hydroxyl group, suggesting they are biogenetically related.  Inubushi postulates that serratinine (2.6), fawcettidine (2.5), and fawcettimine (2.3) are formed from lycodoline (2.22) (Scheme 2.3).31  It is hypothesized that attack of a water molecule could occur at the tetrasubstituted carbon adjacent to the nitrogen atom in lycodoline, causing a carbon shift to occur to eliminate a hydroxyl group as water, affording compound 2.23.  The hydroxyl moiety of 2.23 could then form a carbonyl, breaking the carbon-nitrogen bond, forming a nitrogen-containing 9-membered ring (2.24).  At this point compound 2.24 could form two new compounds, serratinine (2.6) and fawcettidine (2.5) as indicated by the arrows a and b.  These arrows do not indicate electron movement, rather the bond that will be formed biosynthetically.  If a C-N bond is formed between the nitrogen and the carbon α to the carbonyl indicated, serratinine (2.6) is formed (path a).  If a C-N bond is formed between the nitrogen and the carbon of the carbonyl indicated, followed by dehydration of the alcohol, fawcettidine (2.5) is formed (path b).  If dehydration does not occur, or water reacts with fawcettidine (2.5), fawcettimine is formed (2.3).  One reported method to turn fawcettimine (2.3) into fawcettidine (2.5) is to treat it with phosphoryl chloride.32  It should be noted that the hypothesis described in Scheme 2.3 has not been tested experimentally. Chapter 2:  The Total Synthesis of (+)-Fawcettidine   48  N O lycodoline (2.22) OH H2O N O 2.23 O H HN O 2.24 O a b a b O N CH3 OH H HO serratinine (2.6) fawcettidine (2.5) H2O POCl3 pyridine fawcettimine (2.3) N O N O OH  Scheme 2.3:  Proposed biogenesis of serratinine (2.6) and fawcettidine (2.5)  Scheme 2.3 indicates one proposed biosynthetic pathway from lycodoline (2.22) a member of the lycopodine class of Lycopodium alkaloids, to serratinine (2.6), fawcettidine (2.5) and fawcettimine (2.3), members of the fawcettimine class.  The structure of fawcettidine was elucidated by Inubushi and coworkers based on its formation from and correlation with serratinine (Scheme 2.4).32, 33  Serratinine (2.6) was first acetylated to give diacetate 2.25. Treatment with a dilute solution of aqueous hydrochloric acid selectively deacetylated one of the hydroxyl groups (2.26).  Jones’ oxidation then converted the alcohol to a ketone (2.27).  The ketone on the 6-membered ring was then removed by conversion to the dithiane and reduction with Raney-nickel to give compound 2.28.  The second ester was then hydrolyzed and oxidized to give ketone 2.29.  At this stage, treatment of compound 2.29 with zinc under acidic conditions gave a structural rearrangement.  The proposed mechanism is as follows: the zinc interacts with the carbonyl of the 5-membered ring forming the zinc enolate and breaking the C-N bond to form the nitrogen-containing 9-membered ring.  The nitrogen then attacks the carbonyl of the 6- membered ring.  Elimination of the zinc oxide species gives fawcettidine (2.5). Chapter 2:  The Total Synthesis of (+)-Fawcettidine   49 H3C H N H H (+)-fawcettidine (2.5) O O N CH3 OH H HO serratinine (2.6) Ac2O pyridine 100 oC O N CH3 OAc H AcO 2.25 10% HCl (aq.) O N CH3 OH H AcO 2.26 O N CH3 H AcO 2.27 O CrO3, H2SO4 (aq.) acetone HS SH 1. BF3 .OEt2 2. Raney-Ni O N CH3 H AcO 2.28 1. NaOH, H2O 2. CrO3, H2SO4 (aq.)     acetone O N CH3 H 2.29 O Zn AcOH Zn N O CH3 ≡ N O CH3 O Zn H Base Zn  Scheme 2.4:  Structure elucidation of (+)-fawcettidine (2.5) based on its formation from serratinine (2.6)  Fawcettidine has only ever been formed by semisynthesis from other Lycopodium alkaloid natural products.  There has yet to be a reported total synthesis of the tetracyclic molecule.   2.2   Synthetic Approaches to the Total Synthesis of Fawcettimine  To date there have been four total syntheses and two formal syntheses of the Lycopodium alkaloid fawcettimine (2.3).  Two of the total syntheses are racemic and two are enantioselective. The two formal syntheses are both enantioselective.  Despite its near structural identity to (+)- fawcettimine, there have been no total syntheses reported for (+)-fawcettidine.  The synthetic approaches used in creating (±)- and (+)-fawcettimine will be described in the following section. An abbreviated discussion of the total syntheses of fawcettimine will be presented, focusing on interesting or important transformations.  These include formation of stereocenters, key steps as indicated by the authors, ring formation, or major structural changes.  Synthetic studies towards the core of fawcettimine will not be described but interested readers are directed to a report in the primary literature.34   Chapter 2:  The Total Synthesis of (+)-Fawcettidine   50 2.2.1 Inubushi and Coworkers’ Total Synthesis of (±)-Fawcettimine  The first synthetic effort towards (±)-fawcettimine is described by Harayama, Takatani, and Inubushi (Scheme 2.5).35  Their synthesis began with a Diels-Alder reaction between racemic enone 2.30 and 1,4-butadiene to give compound 2.31.  Ketalization, hydroboration, and primary alcohol protection gave ketal 2.32.  Inubushi and coworkers used the formation of a six- membered ring to set the relative stereochemistry, and subsequently oxidative cleaved the ring to give dialdehyde 2.33.  Intramolecular aldol condensation followed by Wadsworth-Emmons’ homologation gave a mixture of nitriles 2.34 and 2.35, favoring the desired product 2.34.  O 0.5 BF3 .OEt2 29% (53% BRSM) O H 2.30 2.31 H O O OH 1.  ketalization 2. a) H B b)  H2O2, NaOH 51% (2 steps) H 2.32 O O OBn NaH, nBu4NI benzylbromide THF/HMPA 83% CHO CHO H 2.33 O O OBn a) OsO4, NMO b) HIO4 .2H2O 92% H 2.34 O O H 2.35 O O OBnBnO CN CN 1. morpholine-     camphoric acid     Et2O/HMPA 2. (EtO)2POCH2CN 38% 2.34 and 2% 2.35 H 2.36 O O BnO 2.34 NHBoc (Ph3P)3RhCl 1. H2 2. LiAlH4 3. N3CO2 tBu 72% (3 steps) H 2.37 O H NO 1. Li, NH3(l) 2. CrO3, H2SO4 (aq.) 3. DCC, CF3CO2H, N-hydroxysuccinimide, nBu3N, CH3CN 41% (3 steps) H 2.38 O N COCF3 1. mCPBA (98%) 2. BF3 .OEt2 3. CrO3, H2SO4 (aq.) 58% (2 steps) H 2.39 O N COCF3 O H O HO N = H3C H O N H H OH fawcettimine (2.3) Scheme 2.5:  Harayama, Takatani, and Inubushi’s total synthesis of (±)-fawcettimine (2.3)35 Selective hydrogenation of the least substituted olefin with Wilkinson’s catalyst, reduction of the nitrile to the primary amine, and protection as the tert-butyl carbonate gave compound 2.36 in 72% yield over three operations.  The nine-membered ring lactam 2.37 was then formed Chapter 2:  The Total Synthesis of (+)-Fawcettidine   51 following a three step procedure.  Standard reactions furnished ketone 2.38 from 2.37.  Oxidation of 2.38 with meta-chloroperbenzoic acid (mCPBA) followed by treatment with a Lewis acid and oxidation gave enone 2.39.  Enone 2.39 was structurally similar to the keto-form of fawcettimine.  After reduction of the olefin and hydrolysis of the nitrogen protecting group, the nitrogen atom of the nine-membered ring amine spontaneously condensed with the adjacent ketone functional group to give fawcettimine (2.3) in its natural carbinolamine form.  2.2.2 Heathcock and  Coworkers’ Total Synthesis of (±)-Fawcettimine The second total synthesis of (±)-fawcettimine (2.3) was completed a decade later by Heathcock, Blumenkopf, and Smith (Scheme 2.6).36  Their synthesis began with racemic cyano enone 2.40.37  Hosomi-Sakurai addition38 of bis-silane 2.41 to cyano enone 2.40 gave compound 2.42 in excellent yield.  Although the diastereomeric mixture formed α to the carbonyl was inconsequential, the reaction displayed high facial selectivity, resulting in product 2.42 with a solely trans relationship between the remaining two substituents.  These reaction conditions were selected due to the high selectivity of this reaction compared to other known conditions.  Oxidation and Wittig homologation of 2.42 followed by treatment with base gave the 6,5- ring system 2.43.  The transformation from 2.42 to 2.43 was carried out in one-pot due to the low solubility of the diene intermediate on large-scale.  Ester 2.43 was homologated by one carbon atom to give ester 2.44 using a three operation Arndt-Eistert sequence.39, 40  Standard synthetic operations gave compound 2.45 containing a nine-membered nitrogen containing ring.  At this stage Heathcock and coworkers removed the para-toluenesulfonyl protecting group, oxidized the alcohol to the ketone, transformed the free amine to its perchlorate salt, and cleaved the exocyclic olefin to a ketone using ozone to give compound 2.46.  They found that perchlorate salt 2.46 only existed as the amino ketone tautomer.  When the perchlorate salt was neutralized with base, the nitrogen collapsed onto the ketone (as seen in Inubushi’s synthesis, Scheme 2.5) to give the carbinolamine form of fawcettimine (2.3). Chapter 2:  The Total Synthesis of (+)-Fawcettidine   52 O CN OSi(CH3)3 Si(CH3)3 TiCl4, CH2Cl2 100%2.41 O OH CN 2.42 1. CrO3, pyridine (95%) 2. EtOC(O)CH2PPh3 O CN CO2Et NaOEt, EtOH DMF 90% (2 steps) O H CN CO2Et 2.43 O H CN 2.44 CO2Et 1. LiAlH4, THF 2. Ts2O, DMAP    (68%) 3. nBu4NOH     PhH (69%) H 2.45 N HO Ts 1. Na, NpH,     DME (94%) 2. CrO3, HOAc (87%) 3. HClO4 4. O3 95%(2 steps) H 2.46 N O O H H ClO4 NaHCO3 95% H O HO N = H3C H O N H H OH fawcettimine (2.3) 2.40  Scheme 2.6:  Heathcock, Blumenkopf, and Smith’s total synthesis of (±)-fawcettimine (2.3)36  2.2.3 Toste and Coworkers’ Total Synthesis of (+)-Fawcettimine The first asymmetric synthesis of (+)-fawcettimine was achieved by Toste and coworkers in 2007 (Scheme 2.7).41  The stereocenter at C15 was set by an organocatalytic Robinson annulation between keto ester 2.47 and crotonaldehyde (2.48) to give enone (R)-(−)-2.30 in 72% yield and an enantiomeric excess of 88%.  This reaction was successful on multigram scale. Enone (R)-(−)-2.30  was then subjected to conjugate propargylation and iodination to give enyne 2.49.  Toste and coworkers then used chemistry developed by their group involving cationic gold(I)-catalysis to form the 6,5-ring system with a cis-ring junction (2.50).  Chapter 2:  The Total Synthesis of (+)-Fawcettidine   53 OC(CH3)3 O O H O N H OSi(CH3)3 Ar Ar Ar = 3,5-(CF3)2C6H3 1. 10 mol%      0 oC, 60 h 2. TsOH, PhCH3 72% (88% ee) 2.47 2.48 O (R)-(-)-2.30 1. TBSOTf, CH2Cl2 O 2.50 I 2. NIS, AgNO3, DMF H Bu3Sn OTBS 2.49 I 10 mol% [Ph3PAuCl] 10 mol% AgBF4 CH2Cl2/MeOH 10:1 H  Scheme 2.7:  Linghu, Kennedy-Smith, and Toste’s total synthesis of (+)-fawcettimine41  The gold(I)-catalyzed annulation used is of particular interest as similar chemistry is employed in the Dake group.  In this case, the silyl enol ether was used as a nucleophile as opposed to an enamine derivative (Scheme 2.8).  First the gold presumably coordinates to the alkyne to give the activated complex 2.51.  The silyl enol ether can then attack the activated alkyne in a 5-endo-dig fashion to form the 5-membered ring intermediate 2.52.  Loss of the silyl group and protodemetallation gives the product 2.50.  OTBS 2.51 I AuLn + O 2.52 I H [Au]- TBS O 2.50 I H  Scheme 2.8:  Au(I)-catalyzed cycloisomerization as a key step in Toste’s synthesis  A series of simple operations transformed vinyl iodide 2.50 into primary alcohol 2.53 (Scheme 2.9).  The primary alcohol of 2.53 was then converted to an iodide using an Appel reaction.42  Deprotonation of the nitrogen with base followed by SN2 displacement of the iodide formed the 9-membered nitrogen-containing ring (2.54).  Three functional group manipulations provided compound 2.55, an intermediate that closely resembled the intermediates used by Inubushi (2.39) and Heathcock (2.46).  Conversion of carbamate 2.55 into the natural product was performed in a similar manner.  The nitrogen atom was deprotected using trifluoroacetic acid, causing the nitrogen to collapse onto the ketone to form the carbinolamine form of (+)- fawcettimine (2.3). Chapter 2:  The Total Synthesis of (+)-Fawcettidine   54  O 2.50 I H H 2.53 O O HO NHBoc 1. Ph3P, I2,     imidazole, CH2Cl2     (97%) 2. tBuOK, THF (62%) H 2.54 N Boc O O H 2.55 N O Boc O TFA, CH2Cl2 83% H O HO N = H3C H O N H H OH fawcettimine (2.3) Scheme 2.9:  The conclusion of Toste and co-worker’s synthesis of (+)-fawcettimine  2.2.4 Sha and Coworkers’ Formal Synthesis of (+)-Fawcettimine  Methodology developed in the Sha laboratory relates to intramolecular cyclization of α- carbonyl radicals.  They have been successful in applying this methodology to a series of total syntheses.43-48  Recently, they discovered the intermolecular radical addition of α-iodo cycloalkenones to electron deficient alkenes.  To display the utility of their methodology within the context of total synthesis the authors applied it to the formal synthesis of (+)-fawcettimine.49 This work was published just prior to our work on the total synthesis of (+)-fawcettidine (2.5).   Sha and coworkers started their formal synthesis from chiral pool starting material (R)-(+)- pulegone 2.56 (Scheme 2.10).  (R)-(+)-Pulegone 2.56 was elaborated to enone 2.57 following established literature procedures.50  The requisite vinyl iodide was installed by treatment of enone 2.57 with iodine and pyridine to give iodide 2.58 in 95% yield.  The key step was then carried out on iodide 2.58.  α-Iodo alkenone 2.58 was treated under radical initiation conditions in the presence of acrylonitrile to form cyanoenone 2.40 in 70% yield.  Conjugate addition of a trimethylsilyl protected alkyne functional group followed by insertion of an unstable α-iodide gave compound 2.59 in 78% yield over two steps.  α-Iodo compound 2.59 was converted to compound 2.60 using other methodology developed by the Sha laboratory.  α-Iodo compound 2.59 was treated under radical initiation conditions to form a radical α to the carbonyl.  A 5-exo- dig cyclization then occured followed by hydrogen abstraction from the tributyl tin hydride to Chapter 2:  The Total Synthesis of (+)-Fawcettidine   55 give the 6,5-membered ring system 2.60 with the correct stereochemistry.  Removal of the trimethylsilyl group, allylic oxidation, and Jones’ oxidation gave cyano enone 2.61 in moderate yield.  Lithium perchlorate mediated conjugate addition of a ketene silyl acetal to enone 2.61 gave compound 2.62.  O 2.57 O 2.56 I2, pyridine CH2Cl2 95% O 2.58 I O 2.40 CN CN AIBN, Bu3SnH PhH 70% O 2.59 CN I Si(CH3)3 a) Cl Si(CH3)3 Mg, CuI, TMSCl HMPA, THF b) NaI, mCPBA, THF 78% (2 steps) O 2.60 CN TMS AIBN, Bu3SnH PhH, 60 oC 64% O 2.62 CN CO2CH3 O O 2.61 CN O 1. TFA, CH2Cl2, 78% 2. a) SeO2, tBuOOH,         CH2Cl2     b) CrO3, H2SO4 52% (2 steps) a) OCH3 OTBS LiClO4, Et2O b) AcOH, THF,     H2O 40% (2 steps) similar to Heathcock's approach H O HO N = H3C H O N H H OH fawcettimine (2.3)  Scheme 2.10:  Liu, Chau, and Sha’s formal synthesis of (+)-fawcettimine49  Compound 2.62 is nearly structurally identical to an intermediate isolated by Heathcock in his total synthesis of (±)-fawcettimine.  Sha and coworkers used intermediate 2.62 and followed steps similar to Heathcock’s to complete the formal synthesis of (+)-fawcettimine (2.3).  2.2.5 Mukai and Coworkers’ Total Synthesis of (+)-Fawcettimine  Mukai and coworkers have a program devoted to the total synthesis of naturally occurring alkaloids.  Many of their syntheses use the same precursor, oxatricyclo[7.3.0.01,5]dodecanedione 2.65 (Scheme 2.11).52, 53  This intermediate was synthesized commencing from chiral pool compound diethyl L-tartarate followed by elaboration to chiral enyne 2.63.  Enyne 2.63 was reacted under Pauson-Khand54, 55 conditions to form cyclopentenone 2.64.  After a series of operations, intermediate 2.65 was formed. Chapter 2:  The Total Synthesis of (+)-Fawcettidine   56  OTBS TBSO TBSO O O H O 2.63 2.65 Co2(CO)8, Me2S ClCH2CH2Cl, 45 oC 89% TBSO O H 2.64 OTBS 1. NaBH4, MeOH, -40 oC 2. BnBr, NaH, TBAI,     THF/HMPA, 60 oC 76% (2 steps) TBSO O H O 2.66 OBn 1. LiAlH4, THF, 0 oC     then 10% aq. HCl 2. TBSCl, imid., CH2Cl2, rt 3. MOMCl, iPr2NEt, CH2Cl2,     reflux 4. (Sia)2BH, THF, rt;     then NaOH and H2O2 45% (4 steps) TBSO MOMO TBSO OH OBn HH 2.67 1. NsNH2, PPh3,     DIAD, THF, 70 oC 2. TBAF, THF, rt 86% (2 steps) TBSO MOMO OH NHNs OBn HH 2.68 TBSO MOMO NHNs OBn HH 2.69 HO DEAD, PPh3 PhH, rt 96% TBSO MOMO OBn HH 2.70 NNs HO OBn HH 2.71 NH 1. Boc-ON, NEt3     CH2Cl2, rt 2. DMP, CH2Cl2, rt 3. MeLi, CuCN, LiBr,     Et2O, 0 oC O OBn HH 2.72 NBoc H H3C H3C H O N H H fawcettimine (2.3) HO  Scheme 2.11:  Otsuka, Inagaki, and Mukai’s total synthesis of (+)-fawcettimine53  This year, Mukai and coworkers elaborated intermediate 2.65 to the natural product (+)- fawcettimine.53  After selective carbonyl reduction and benzylation, compound 2.66 was formed. The lactone of compound 2.66 was then reduced and two hydroxyl groups were selectively protected as the tert-butyldimethyl silyl ethers.  The remaining secondary hydroxyl group was protected as a methoxymethyl (MOM) ether.  Hydroboration of the alkene resulted in compound 2.67.  A key step as described by the authors is their use of the Mitsunobu reaction.56-58  They first employed the reaction to convert the primary hydroxyl into a nosyl-protected nitrogen in an intermolecular Mitsunobu reaction.  The TBS-protected primary alcohol was selectively deprotected to give alcohol 2.68.  A one-carbon homologation was then performed under standard procedures to give alcohol 2.69.  At this stage the second intramolecular Mitsunobu reaction took place to form the nitrogen-containing 9-membered ring (2.70) in excellent yield.  A series of operations gave amine 2.71.  The nitrogen of 2.71 was protected as the tert- Chapter 2:  The Total Synthesis of (+)-Fawcettidine   57 butylcarbamate and the alcohol was oxidized to give an enone.  A methyl substituent was then introduced using a copper-mediated conjugate addition reaction of methyllithium to give compound 2.71 in a highly stereoselective manner.  Three more synthetic operations afforded the natural product (+)-fawcettimine (2.3).  2.2.6 Jung and Chang’s Formal Synthesis of (+)-Fawcettimine  The most recent synthesis of (+)-fawcettimine comes from the laboratory of Jung and coworkers.59  Jung’s inspiration for the formal synthesis of (+)-fawcettimine was conceived from previous work done by the group on the acid-promoted Mukaiyama-Michael addition of hindered silyoxy dienes to hindered enones.60  The formation of the hydrindanone core of (+)- fawcettimine was envisaged to come from this reaction.  N O PhO 1. NaHMDS,     MeO2CCl 2. NaHMDS, PhSeBr 3. H2O2 77% (3 steps)2.73 N O CH3 PhO 2.74 MeO2C Me S O Me Me 71% N O CH3 PhO 2.75 H MeO2C 1. H2SO4, MeOH,     reflux; 78% 2. TBSOTf, iPr2NEt,     CH2Cl2 97% CO2Me CO2Me OTBS 2.76 Scheme 2.12:  Synthesis of the requisite (S)-silyl enol ether 2.76  First the silyl enol ether (2.76) was built (Scheme 2.12).  Jung and coworkers started from the known bicyclic lactam61 2.73 and elaborated it to methyl ester 2.74 using a modification of a Meyers’ procedure.62  The enone 2.74 was then cyclopropanated using the Corey-Chaykovsky reagent63, 64 to give compound 2.75 in 71% yield as a single diastereomer.  Hydrolysis of 2.75 gave a methyl ketone that was then deprotonated using Hünig’s base and trapped using TBS triflate to give the desired cyclopropane 2.76.   The coupling partner to cyclopropane 2.76 was derived from (R)-(+)-pulegone 2.56 (Scheme 2.13).  Modification of known literature procedures gave cyano enone 2.40.50, 65, 66 Cyano enone 2.40 and cyclopropane 2.76 were then coupled in the presence of triflimide to yield the desired compound 2.77 in 85% yield as a single diastereomer.  Wittig olefination afforded alkene 2.78 in 75% based on recovered starting material.  Treatment of alkene 2.78 with scandium(III) triflate gave the desired ring opened product 2.79 in 77% yield.  Krapcho decarboxylation67-69 of compound 2.79 gave intermediate 2.80 which was nearly identical to that used by Heathcock in his total synthesis of (±)-fawcettimine (Section 2.2, Scheme 2.6). Chapter 2:  The Total Synthesis of (+)-Fawcettidine   58 Intermediate 2.80 was then elaborated following Heathcock’s procedure in 8 steps to the final product (+)-fawcettimine (2.3).  O 2.56 O 2.40 CN CO2Me CO2Me OTBS 2.76 Tf2NH, CH2Cl2 -78 oC 85% TBSO NC O H H CO2Me CO2Me 2.77 Ph3P CH2 75% BRSM TBSO NC H H CO2Me CO2Me 2.78 Sc(OTf)3 CH2Cl2, rt 77% O CN H CO2Me CO2Me wet DMF µ-wave 73% 2.79 O CN H CO2Me 2.80 8 steps H O HO N = H3C H O N H H OH fawcettimine (2.3) Scheme 2.13:  Completion of (+)-fawcettimine59  It should be noted that every synthesis of either (±)- or (+)-fawcettimine uses the same bond formation as the final step.  All groups synthesize the azonane ring, and have it react with the carbonyl to form the final C13-N bond and to give fawcettimine in its natural carbinolamine form.   2.3   Model Studies: Progress Towards the Core of Fawcettidine An ongoing project in the Dake laboratory is the platinum(II)-catalyzed cycloisomerization of enesulfonamides, enecarbamates, and enamides.  This methodology has been successful in forming tricyclic nitrogen-containing compounds from less complex bicyclic enamides.70  For example, enamides of structure 2.81 were treated with 5 mol% of platinum(II) chloride in toluene at 80 oC to give tricycles (2.82) containing a quaternary carbon center (Scheme 2.14). Application of this methodology could provide an effective route towards alkaloid ring systems structurally related to fawcettidine (2.5).  Chapter 2:  The Total Synthesis of (+)-Fawcettidine   59 N O R 5 mol% PtCl2 PhCH3, 80 oC 2.822.81 N O N O R (+)-fawcettidine (2.5)  Scheme 2.14:  Model studies for the application of the methodology towards the total synthesis of (+)- fawcettidine70  One goal of my PhD research was to extend the initial model studies to a completed total synthesis of (+)-fawcettidine (2.5).  The remainder of the chapter will describe these efforts in detail.  In the next section, two retrosynthetic analyses (Route A and Route B) of (+)- fawcettidine will be outlined.  The subsequent section will describe the synthetic studies of Route A, followed by the synthetic studies of Route B.  The experimental details of the project will be described in the final section of the chapter.   2.4   Retrosynthetic Analysis  A direct approach to (+)-fawcettidine was envisioned based on the model studies presented in Section 2.3.70  The routes differ markedly from previous syntheses of (+)-fawcettimine (2.3), despite their structural similarity.  Every reported synthesis of (+)-fawcettimine leaves the formation of the C13-N bond until the final step.  The retrosynthetic routes described herein form this bond early, and leave the formation of the 7-membered ring to a later stage in the sequence.  Route A:  In Route A, the double bond of the enamine functional group would be installed in a final step to form (+)-fawcettidine (2.5) (Scheme 2.15).  The disconnection of the 7-membered ring in compound 2.83 leaves a protected nitrogen atom and a carbon chain terminated with an appropriate leaving group (2.84).  A potential solution for ring closure would be a direct SN2 displacement of the leaving group by the nitrogen atom (N-alkylation).  The reactivity of the amine in intermediate 2.84 would then be attenuated to give tricycle 2.85.  Functional group conversions and a change in oxidation state of the C13-C14 bond of intermediate 2.85 gave tricycle 2.86 that could undergo the key retro-annulation disconnection.  Alkyne 2.87 could be converted directly to tricycle 2.86 using platinum(II)-catalysis.  If successful, this transformation Chapter 2:  The Total Synthesis of (+)-Fawcettidine   60 would form the necessary quaternary carbon center and provide an exocyclic alkene as a handle to add further functionalization that would facilitate the formation of the final 7-memebered ring of 2.5.  Chiral pool reagent (R)-(+)-pulegone 2.56 was identified as an appropriate starting material.  (R)-(+)-pulegone H3C H O N H H 2.5 H3C H O N H H 2.83 H3C H O N H 2.84 Bn BnN O 2.85 H O BnN O 2.86 H BnN O 2.87 H PtCl2 O 2.56 LG remove C=O group attenuate N reactivity change oxidation state  Scheme 2.15:  Retrosynthetic analysis: Route A  Route B:  Retrosynthetic analysis of Route B uncovered the formation of the 7-membered ring at a late stage of the synthesis, as in Route A (Scheme 2.16).  Disconnection of the 7-membered ring of 2.5 would give intermediate 2.88.  A Ramberg-Bäcklund reaction emerged as a potential solution for ring closure.71-74  Functional group conversions of intermediate 2.88 would give tricycle 2.89 that could undergo the key retro-annulation disconnection.  Alkyne 2.90 differs from alkyne 2.87 (Scheme 2.15) only in the protecting group on the nitrogen atom.  Alkyne 2.90 could be converted directly to tricycle 2.89 using platinum(II)-catalysis.  If successful, this transformation would install the C13-C14 double bond and establish the quaternary carbon center.  The formation of the exocyclic alkene also provides a handle for further functionalization that would enable closure of the 7-membered ring.  (R)-(+)-Pulegone (2.56) was again determined to be a suitable non-racemic starting material.   Of the two synthetic pathways envisaged, Route B is the more efficient.  The platinum(II)- catalyzed annulation strategy installs three important features, one being the C13-C14 double Chapter 2:  The Total Synthesis of (+)-Fawcettidine   61 bond.  In Route A, the double bond is immediately removed to avoid functional group compatibility issues throughout the remainder of the synthesis.  The extra steps involved in removing and replacing the key double bond are disadvantageous.  In Route B, the C13-C14 double bond would remain throughout the synthesis, reducing the number of overall operations.  H3C H O N H H H3C H O N H PGS N O 2.89 PGS H N O 2.90 PGS H O 2.882.5 2.56 Ramberg-Bäcklund  reaction attenuate N reactivity remove C=O group PtCl2 (R)-(+)-pulegone Scheme 2.16:  Retrosynthetic analysis: Route B  At the outset of the project, the retrosynthetic analyses of both Routes A and B were established.  It was unclear which route would be superior, therefore work began on both Route A and Route B simultaneously.   2.5   Synthesis of a Common Starting Material from (R)-(+)-Pulegone  Both Routes A and B began with elaboration of chiral pool starting material (R)-(+)- pulegone (2.56).  (R)-(+)-Pulegone (2.56) was transformed to sulfoxide 2.93 by adaptation of established literature procedures (Scheme 2.17).50, 65  Nucleophilic epoxidation afforded a 1:1 mixture of diastereomeric epoxides (2.91) in 96% yield on a 93 gram scale.  A retro-aldol reaction of epoxide mixture 2.91 using sodium hydride and thiophenol gave a 1:1 diastereomeric mixture of sulfides (2.92).  The crude mixture of sulfides (2.92) was moved onto the next reaction immediately as purification by column chromatography was inefficient and awkward. Treatment of sulfide mixture 2.92 with sodium perborate tetrahydrate in acetic acid gave sulfoxide 2.93 in 88% yield as an inconsequential mixture of diastereomers.  Each step of this Chapter 2:  The Total Synthesis of (+)-Fawcettidine   62 sequence was performed on an approximate 90 gram scale, resulting in the formation of a large amount of sulfoxide 2.93 necessary for elaboration to the natural product (2.5).  O H2O2, LiOH .H2O (R)-(+)-pulegone (2.56) MeOH 93 g, 96% O O 2.91 NaH, PhSH THF 96 g O 2.92 SPh NaBO3 .4H2O AcOH 90 g, 88% O 2.93 S O Ph  Scheme 2.17:  Synthesis of sulfoxide 2.93 Next, sulfoxide 2.93 was treated with pyridine in toluene as a solvent under reflux conditions, resulting in thermal elimination of the sulfoxide and introduction of the enone functional group (2.57) (Scheme 2.18).  Formation of the methyl ester 2.94 from enone 2.57 was attempted following a literature procedure.75  Enone 2.57 was mixed with methyl acrylate and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in N,N-dimethylformamide in a thick-walled sealable tube.  The sealed tube was heated in an oil bath at 180 oC for 24 hours.  After work-up and purification, 32% of methyl ester 2.94 was isolated.  This low yield was reproducible over several attempts as well as in the hands of fellow Dake group member Tyler Harrison.  Changing the solvent from N,N-dimethylformamide to 1,3-dimethyl-2-imidazolidinone (as described in the literature procedure) also did not increase the reaction yield.  Under these conditions, the reaction could be carried out on no more than a 3 gram scale due to practical considerations involving the volume allowed in the sealable tube.  An alternate route was sought to increase the efficiency of formation of the methyl ester 2.94.  O 2.93 S O Ph O 2.57 O 2.94 OCH3 O previous literature route O 2.93 S O Ph O 2.94 OCH3 O pyridine PhH, reflux 70% DBU, DMF 3 g, 32% a) DBU, DMF, -40 oC b) methyl acrylate methyl acrylate c) 40 oC 8-85 g, 50-63% optimized route  Scheme 2.18:  Synthesis of ketoester 2.94 It was recognized that the acidity of the α-proton between the ketone and the sulfoxide in compound 2.93 could be exploited to add functionality at that position (Scheme 2.18).  Sulfoxide Chapter 2:  The Total Synthesis of (+)-Fawcettidine   63 2.93 was treated with DBU at low temperature to deprotonate the α-proton, and then alkylated with methyl acrylate.  Warming of the reaction mixture to 40 oC succeeded in the thermal elimination of the sulfoxide, affording methyl ester 2.94 in 50-63% yields depending on the scale of the process.  Formation of the product was verified by the introduction of a 1-proton multiplet at a chemical shift of 6.72 ppm in the 1H NMR spectrum, attributable to the vinyl proton of the enone moiety. A 3-proton singlet at a chemical shift of 3.63 ppm was also observed and is consistent with the introduction of a methyl ester.  Important features of this optimized route are the following: a) it can be performed on a scale anywhere between 8 and 85 grams, b) it is a one- pot procedure, c) the yield is consistently higher than the 2-step procedure, and d) it is safer since it can be carried out in standard glassware rather than a high pressure sealable glass tube.  HO HO Si(CH3)3 Br Si(CH3)3 a) nBuLi (2 equiv) THF, -78 oC b) Si(CH3)3Cl c) 1M HCl 1) TsCl, pyr, CH2Cl2, rt 2) NaBr, DMF, 60 oC 2.95 2.96 2.97 Scheme 2.19:  Synthesis of the required bromide 2.97 Methyl ester 2.94 was next elaborated to ketoester 2.99, the final intermediate common to both Routes A and B.  The alkyne portion of the substrate was introduced to methyl ester 2.94 via a cuprate addition of an appropriate Grignard reagent.  The requisite bromide 2.97 was prepared following a literature procedure described by Holmes and coworkers (Scheme 2.19).76 The dianion of 4-pentyn-1-ol (2.95) was generated by deprotonation with 2 equivalents of n- butyllithium and subsequently quenched with excess trimethylsilyl chloride to give a bis-silyl protected compound.  Treatment with aqueous acid removed the silyl group from the alcohol, giving mono-silyl species 2.96.  Tosylation of alcohol 2.96 followed by displacement of the tosylate with a bromide ion gave bromide 2.97.  This series of reactions was carried out on a 20 gram scale.  O 2.94 OCH3 O O 2.98 OCH3 O Si(CH3)3 BrMg Si(CH3)3 CuBr.DMS, THF 19 g, 84% O 2.99 OCH3 O TBAF THF 24 g, 96% H  Scheme 2.20:  Synthesis of ketoester 2.99 Chapter 2:  The Total Synthesis of (+)-Fawcettidine   64 Bromide 2.97 was converted to a Grignard reagent and treated with copper(I) bromide dimethyl sulfide to form the cuprate reagent (Scheme 2.20).  Addition of methyl ester 2.94 to a solution containing the cuprate reagent resulted in the formation of silylalkyne 2.98 in 84% yield as a 1:1 mixture of diastereomers at the carbon α to the carbonyl.  The substituents at the 3- and 5-position of the cyclohexane ring were found to have a trans relationship.  The rationale for the stereochemical outcome of the cuprate addition is described in Scheme 2.21.77, 78  It is plausible that enone 2.94 can assume two different half chair conformations, A and B.  The cuprate reagent must coordinate with the π-system of the enone functional group.  For each conformation A and B then, attack can occur from two possible faces.  This will lead to four possible intermediates (C, D, E, and F) and two products.  Each of the two products can assume a different conformation (G and I = conformers; H and J = conformers).  For each conformer, two of the possible transition states must assume boat conformations (C and F).  Since the chair conformation is more stable than the boat conformation, paths a and d are ruled out.  While both paths b and c lead to chair transition states, there is serious steric interference between the incoming nucleophile and the axial methyl substituent of B (pathway c).  This leaves path b as the only operating pathway, resulting in a trans-relationship between the nucleophile and the methyl substituent (H).   Chapter 2:  The Total Synthesis of (+)-Fawcettidine   65 H H3C R Nuc H H CH3R OM CH3 H O O R O 2.94 R Nuc Nuc H H H H a b a b O CH3 Nuc H R D H B A CH3 OMR O CH3 Nuc R G H C R = CH2CH2COOCH3 Nuc c d I JF Nuc Nuc d Nuc H CH3 H OM E R ONuc H CH3 H R c O R Nuc OM CH3 RNuc CH3 H H H H  Scheme 2.21:  Rationale for trans stereochemical outcome of compound 2.9877, 78 Removal of the trimethylsilyl group of compound 2.98 by treatment with tetrabutylammonium fluoride gave alkyne 2.99 in 96% yield as a 1:1 mixture of diastereomers.   2.6   Synthetic Studies:  Route A  With the synthesis of alkyne 2.99 completed, the route diverged to follow either Route A or Route B.  This section will outline the efforts towards the total synthesis of (+)-fawcettidine (2.5) by Route A (Scheme 2.15).  Following the procedure of Duval and Gomès, ketoester 2.99 was condensed with benzyl amine to afford enamide 2.87 in 99% yield (Scheme 2.22).79  The mechanism of the condensation is outlined in Scheme 2.23.  The amine reacts with the ketone in 2.99 to form an imine (2.100).  Under acidic conditions, the carbonyl of the ester is protonated, making it susceptible to nucleophilic attack by the nitrogen atom of the imine.  Methanol is eliminated and removed from the reaction, resulting in the formation of iminium ion intermediate 2.101.  Removal of a proton forms the enamide 2.87.  Enamide 2.87 was isolated as a 15:1 mixture of double bond isomers, with only the major isomer shown.  The mixture of isomers was ultimately inconsequential to the following reaction. Chapter 2:  The Total Synthesis of (+)-Fawcettidine   66  O 2.99 OCH3 O H N O Ph 2.87 10 mol% PtCl2 PhCH3, 80 oC 3 g, 75% N O Ph 2.86 Ph NH2 AcOH, PhCH3 3 g, 99%  Scheme 2.22:  Synthesis of 2.86 using a platinum(II)-catalyzed cycloisomerization  The key platinum(II)-catalyzed annulation reaction was tested on substrate 2.87.  Enamide 2.87 underwent smooth conversion to tricycle 2.86 by treatment with 10 mol% of platinum(II) chloride in toluene at 80 oC.  Formation of the product (2.86) was verified by the appearance of a 1-proton doublet at a chemical shift of 5.02 ppm in the 1H NMR spectrum which is attributed to the vinyl proton of the enamide.  Diagnostic signals corresponding to the exocyclic olefin were also observed as two 1-proton singlets at chemical shifts of 4.92 ppm and 4.72 ppm.  O 2.99 OCH3 O N O Ph 2.101 H2N Ph AcOH N 2.100 OCH3 OPh H -MeOH H Base N O Ph 2.87  Scheme 2.23:  Proposed mechanism for the condensation reaction leading to enamide 2.87  The mechanism of the platinum(II)-catalyzed annulation reaction is shown in Scheme 2.24. The electrophilic metal first coordinates to form the activated platinum-alkyne π-complex (2.102).  The nucleophilic enamide functional group then attacks the alkyne in a 5-exo-dig mode of cyclization to form tricycle 2.103.  Protodemetallation and reformation of the enamide give compound 2.86.  The platinum(II)-catalyzed annulation was successful in installing the quaternary stereocenter, the C13-C14 double bond (fawcettidine numbering), as well as the exocyclic alkene.   Chapter 2:  The Total Synthesis of (+)-Fawcettidine   67 N O Ph 2.102 PtCl2 N O Ph 2.103 PtCl2 N O Ph 2.86 + H+  Scheme 2.24:  Postulated mechanism of the key platinum(II)-catalyzed cycloisomerization step  The disubstituted alkene was utilized immediately in an attempt to oxidize the adjacent carbon atom (Scheme 2.25).  If successful, the allylic oxidation would place the ketone at the correct position on the 5-membered ring for elaboration to (+)-fawcettidine (2.5).  The double bond of the enamide functional group was left intact to observe any potential interference in the allylic oxidation reaction.  Tricycle 2.86 was treated with an aqueous solution of tert-butyl hydroperoxide and 50 mol% of selenium dioxide to give alcohol 2.104 in 52% yield as a 1:1 mixture of diastereomers.  The alcohol 2.104 was then further oxidized using manganese(IV) oxide to provide enone 2.105 in 77% yield.  N O Ph 2.86 tBuOOH 50 mol% SeO2 CH2Cl2 52% N O Ph 2.104 OH MnO2 CH2Cl2 77% N O Ph 2.105 O  Scheme 2.25:  Allylic oxidation adjacent to the exocyclic olefin  Enone 2.105 was isolated as a white solid.  Recrystallization of the solid from dichloromethane and hexanes gave X-ray quality crystals.  The solid state molecular structure of 2.105 is shown in Figure 2.5.  The X-ray structure confirms that the enone was formed in the desired position, that the C7 and C15 substituents are trans to one another, and that the quaternary carbon center was formed with the desired configuration.  A C13-C14 bond length of 1.334(3) Å indicates that the double bond of the enamide remains.  Chapter 2:  The Total Synthesis of (+)-Fawcettidine   68  Figure 2.5:  ORTEP representation of the solid state structure of enone 2.105  The yield of the allylic oxidation was moderate at best.  The low yield was potentially due to interference by the trisubstituted olefin, although there was no experimental evidence to support this claim.  Nonetheless, it was decided that the double bond of the enamide would be removed to facilitate both the allylic oxidation and further operations following Route A.  The removal of the enamide double bond was not as straightforward as initially anticipated.  A variety of reduction conditions were tested, the results of which are summarized in Table 2.1.  Treatment of enamide 2.86 with triethylsilane and trifluoroacetic acid did not have any affect, and all of the starting material was recovered (entry 1).  Sodium cyanoborohydride with acid (entry 2) or without acid but at reflux (entry 3) did not provide any product.  Reaction of enamide 2.86 with 5 mol% of silver triflate and triethylsilane gave 15% (60% based on recovered starting material) isolated yield of the desired product 2.106 (entry 4).  In an attempt to increase the yield, the amount of silver triflate was increased to 20 mol% and the reaction temperature was increased from 45 oC to 80 oC (entry 5).  Increasing the catalyst load and the reaction temperature had no benefit and 92% of the starting material 2.86 was recovered.  Next, a stronger reducing agent was tested (entries 6-9).  Enamide 2.86 was treated with sodium borohydride and acetic acid in methanol as a solvent.  Even after refluxing for 12 hours, no reaction was observed (entry 6).  The same reaction conditions were tested again, but the methanol was removed and acetic acid was used as a solvent.  After 12 hours at 85 oC, 14% (46% based on recovered starting material) of the desired product 2.106 was isolated (entry 7). When the reaction was repeated using trifluoroacetic acid – a much stronger acid – as a solvent, Chapter 2:  The Total Synthesis of (+)-Fawcettidine   69 all of the starting material reacted to give one product in 84% yield (entry 8).  The product formed unfortunately was solely tricycle 2.106X, where the exocyclic alkene had isomerized into the ring.  Finally, enamide 2.86 was tested under the same conditions as entry 7, but at room temperature.  The desired product 2.106 was isolated in 87% yield after a reaction time of 4 hours (entry 9).  The configuration at C13 was not determined.   Table 2.1:  Attempted reduction of enamide 2.86 to amide 2.106 N O Ph 2.86 N O Ph 2.106 conditions N O Ph 2.106X entry conditions result a,b,c  ratio (2.106:2.106X) 1 Et3SiH, TFA, CH2Cl2, 0 oC→rt, 12 h NR (100% RSM) - 2 NaHBCN3, 2 M HCl-EtOH, MeOH, rt, 12 h NR (88% RSM) - 3 NaHBCN3, MeOH, reflux, 20 h NR (100% RSM) - 4 5 mol% AgOTf, Et3SiH, CH2Cl2, 45 oC, 12 h 15% (60% BRSM) 1:0 5 20 mol% AgOTf, Et3SiH, PhCH3, 80 oC, 20 h trace (92% RSM) - 6 NaBH4, AcOH, MeOH, reflux, 12 h NR (94% RSM) - 7 NaBH4, AcOH, 85 oC, 12 h 14% (46% BRSM) 1:0 8 NaBH4, TFA, 85 oC, 3 h 84% 0:1 9 NaBH4, TFA, rt, 4 h 87% 1:0 aReported yields are isolated yields.  bNR = no reaction; RSM = recovered starting material; BRSM = based on recovered starting material. cReported yields are the maximum of single experiments.    With reduced compound 2.106 in hand, the allylic oxidation was repeated (Scheme 2.26). Amide 2.106 was first reacted with tert-butyl hydroperoxide and 50 mol% of selenium dioxide, followed by reaction with manganese(IV) oxide.  Enone 2.85 was isolated in 54% after the two steps.  The overall yield of the allylic oxidation increased, but not significantly.  Other methods of allylic oxidation were therefore explored.  Chapter 2:  The Total Synthesis of (+)-Fawcettidine   70 N O Ph 2.106 N O Ph 2.85 O 1) tBuOOH,     50 mol% SeO2, CH2Cl2 2) MnO2, CH2Cl2 54 % (2 steps)  Scheme 2.26:  First test allylic oxidation reaction of substrate 2.106  First, variations using selenium dioxide were examined (Table 2.6.2).  The conditions described in Scheme 2.26 were repeated, but 2 equivalents of water were added and the reaction mixture was stirred for 68 hours at reflux.  Manganese(IV) oxide was again used to form the enone (entry 2).  Longer reaction time and higher temperature did not increase the yield, and the product was isolated in 37% yield (41% based on recovered starting material).  Changing the solvent from dichloromethane to 1,2-dichloroethane produced enone 2.85 in 47% yield (entry 3). Following a literature procedure, amide 2.106 was reacted with one equivalent of selenium dioxide in 1,4-dioxane at 85 oC (entry 4).80  After complete oxidation using manganese(IV) oxide, 70% of enone 2.85 was isolated.   Table 2.2:  Optimization of the allylic oxidation of compound 2.106 N O Ph 2.106 N O Ph 2.85 conditions O  entry conditions yield 2.85 (%) a,b,c  1 1) 50 mol% SeO2, tBuOOH, CH2Cl2, reflux, 12 h 2) MnO2, CH2Cl2, rt, 12 h 54% (2 steps) 2 1) 50 mol% SeO2, tBuOOH, H2O, CH2Cl2, reflux, 68 h 2) MnO2, CH2Cl2, rt, 24 h 37% (41% BRSM) 3 1) 50 mol% SeO2, tBuOOH, H2O, ClCH2CH2Cl, reflux, 1 h 47% 4 1) SeO2, 1,4-dioxane, 85 oC, 1.5 h 2) MnO2, CH2Cl2, rt, 24 h 70% 5 CrO3, 3,5-dimethylpyrazole, CH2Cl2, reflux, 5.5 h trace 6 CrO3, pyridine, CH2Cl2, rt, 2 days trace (71% RSM) 7 1 mol% Rh2(cap)4, tBuOOH, K2CO3, CH2Cl2, rt, 4 h 37% (41% BRSM) aReported yields are isolated yields.  bRSM = recovered starting material; BRSM = based on recovered starting material. cReported yields are the maximum of single experiments. Chapter 2:  The Total Synthesis of (+)-Fawcettidine   71  Chromium based allylic oxidations were also tested.  Amide 2.106 was reacted with Corey’s chromium trichloride-3,5-dimethylpyrazole reagent to give only a trace amount of product (entry 5).81  The chromium trichloride-pyridine complex of Sarett also gave little product (entry 6).82, 83  Treatment of amide 2.106 with 1 mol% of dirhodium(II) caprolactamate in the presence of tert-butyl hydroperoxide and base gave 37% (41% based on recovered starting material) of product 2.85 (entry 7).84  The chromium and rhodium based oxidation systems have been exceptionally effective for allylic oxidation reactions in the literature.  In this case it is possible that significant steric interference exists between compound 2.106 and the metal oxidants, impeding efficient allylic oxidation.  Despite the overall disappointing results, the conditions described in entry 4 improved the yield of the allylic oxidation by close to 20% compared to the original oxidation conditions tested.  N O Ph 2.106 a) SeO2     1,4-dioxane b) MnO2, CH2Cl2 70% N O Ph 2.85 O H3CO OCH3 O O NaH THF 72% N O Ph O H3CO OCH3 O O 2.107 N O Ph H3CO O 2.108 O O OCH3 OHO OH TsOH.H2O PhH 94% N O Ph 2.109 OCH3 O O NaCl, DMSO H2O H H H  Scheme 2.27:  Synthesis of diester 2.108 and an attempted Krapcho reaction  As mentioned, the purpose of the exocyclic alkene is to facilitate formation of the final 7- membered ring within (+)-fawcettidine (2.5).  Functionalization was anticipated to be easily installed by taking advantage of the conjugate addition acceptor properties of enone functional group in 2.85 (Scheme 2.27).  Enone 2.85 was reacted with dimethyl malonate and sodium hydride to form diester 2.107 in 72% as one diastereomer.  To avoid future functional group compatibility issues involving the ketone, it was protected as a ketal (2.108).  Subsequent Krapcho decarboxylation of ketal 2.108 resulted in its deprotection (2.109), rendering the previous protection strategy unnecessary.67-69  Chapter 2:  The Total Synthesis of (+)-Fawcettidine   72  Alternatively, the Krapcho decarboxylation was performed first, affording methyl ester 2.109 in 70% yield from diester 2.107 (Scheme 2.28).  The ketone was then protected as the ketal (2.110) followed by global reduction using lithium aluminum hydride to produce alcohol 2.111 in 59% yield over two steps.  N O Ph O H3CO OCH3 O O 2.107 NaCl, DMSO H2O N O Ph 2.109 OCH3 O O 70% HO OH TsOH.H2O PhH N O Ph 2.110 OCH3 O O O LiAlH4 THF NPh 2.111 OH O O H H H H 59% (2 steps) Scheme 2.28:  Synthesis of amine 2.111  At this stage the attempted closure of the 7-membered ring took place.  Ring closure was envisaged to occur by SN2 displacement of an appropriate leaving group by the nitrogen atom. An iodine atom was recognized as an appropriate leaving group (2.112).  Following the procedure for an Appel reaction, alcohol 2.111 was treated with triphenylphosphine and iodine (Scheme 2.29).41, 42  The resulting product appeared to be a 1:1 mixture of compounds by 1H NMR spectroscopy, but its identity could not be confirmed.  NPh 2.111 OH O O NPh 2.112 I O O PPh3, I2 imidazole CH2Cl2 1:1 mixture?? H H  Scheme 2.29:  Attempted Appel reaction of alcohol 2.111  The Appel reaction was the final experiment performed for Route A.  Routes A and B were carried out simultaneously, and focus shifted to Route B as the better candidate for successful completion of (+)-fawcettidine (2.5).  Route A was ultimately successful in achieving a late stage intermediate (2.111).  Four steps would complete the synthesis of (+)-fawcettidine (2.5) following Route A, discounting any unforeseeable issues (Scheme 2.30).  Conversion of the primary alcohol (2.111) to an iodine atom (or other appropriate leaving group) would give iodide Chapter 2:  The Total Synthesis of (+)-Fawcettidine   73 2.112.  Removal of the benzyl protecting group would close the 7-membered ring by nucleophilic displacement of the iodine atom (2.113).  Reintroduction of the enamine was expected to occur using the oxidant potassium ferricyanide,85 affording compound 2.114. Conversion of the ketal to the ketone under standard acidic conditions would yield (+)- fawcettidine (2.5).  NPh 2.112 I O O H2 10 % Pd/C MeOH N O O 2.113 N O O 2.114 N O ≡ H3C H N H H (+)-fawcettidine (2.5) O K3Fe(CN)6 NaHCO3 1 M HCl THF H H H H  Scheme 2.30:  Planned steps for the completion of (+)-fawcettidine via Route A   2.7   Synthetic Studies: Route B  At the outset of Route B, a major question was the identity of a thiol protecting group that would be compatible with the platinum(II)-catalyzed annulation.  A thiocarbamate protecting group was selected for the following reasons: a) it could be synthesized from a readily available mercaptoamine (2.115) and incorporated into the molecule during the condensation procedure, b) the electron-withdrawing nature of the thiocarbamate could reduce interference of the sulfur atom with the platinum(II) catalyst, and c) it could be easily hydrolyzed in base to free a thiolate anion.   The protecting group was synthesized following literature procedures (Scheme 2.31).86 Mercaptoethylamine hydrochloride was selectively protected with di-tert-butyl-dicarbonate to give thiol 2.116, followed by treatment with ethyl isocyanate to form thiocarbamate 2.117 in 89% over two steps.  The tert-butyl carbamate protecting group was removed using trifluoroacetic acid to afford amine salt 2.118.  The amine salt was utilized directly in the condensation reaction. Chapter 2:  The Total Synthesis of (+)-Fawcettidine   74 H2N SH .HCl BocHN SH BocHN S H N O 2.115 2.116 2.117 Boc2O, NEt3 CH2Cl2 N C O Et NEt3, CH2Cl2 89% (2 steps) H3N S H N O F3C O O 2.118100% CH2Cl2 TFA  Scheme 2.31:  Synthesis of amine salt 2.118  The application of the thiocarbamate protecting group to the total synthesis of (+)- fawcettidine (2.5) was first investigated using model studies in an effort to conserve chiral starting material.  Racemic ketoester 2.119 was contributed by fellow Dake group member Tyler Harrison for this purpose.  Ketoester 2.119 condensed with amine salt 2.118 to form enamide 2.120 in 82% yield (Scheme 2.32).  Next, the compatibility of the thiocarbamate protecting group under platinum(II)-catalysis was investigated.  I was delighted to find that enamide 2.120 underwent smooth cyclization to form tricycle 2.121 in 68% yield.  Allylic oxidation of tricycle 2.121 using a two-step procedure gave enone 2.122 in 32% yield (42% based on recovered starting material).  Optimization of the allylic oxidation was not performed on the model compound 2.121 due to a minimal amount of material available, although enough remained to test the thiocarbamate deprotection procedure.  Enone 2.122 was treated with 1M sodium hydroxide.  The base successfully released the thiolate anion which added directly into the enone accepter, establishing the desired configuration at C4 and closing the final ring of the model compound (2.123).  O 2.119 OCH3 O 2.118, AcOH 82% N O SEtHN O 2.120 5 mol% PtCl2 PhCH3, 90 oC 68% N O SEtHN O 2.121 PhCH3 1) tBuOOH,     50 mol% SeO2     CH2Cl2 2) MnO2, CH2Cl2 32% (2 steps) 42% BRSM N O SEtHN O 2.122 O N O S O 1 M NaOH MeOH 82% ≡ O N H H 2.123 O S H  Chapter 2:  The Total Synthesis of (+)-Fawcettidine   75 Scheme 2.32:  Model study of base induced cyclization to form sulfide 2.123  The solid state molecular structure of sulfide 2.123 is shown in Figure 2.6.  The structure confirms the identity of the compound and the relative stereochemistry between the quaternary carbon center, C4, and C7.  The model study was concluded with successful isolation of sulfide 2.123 since all the material had been consumed.  The results using the thiocarbamate functional group were exciting overall, and it was decided that the synthesis following Route B should be tested using the chiral starting material (2.99).   Figure 2.6:  ORTEP representation of the solid state molecular structure of model compound 2.123  Identical procedures used in the model study were performed commencing with ketoester 2.99.  Chiral ketoester 2.99 was condensed with amine salt 2.118 to form enamide 2.124 in 70% yield on a 4 gram scale (Scheme 2.33).  The subsequent platinum(II)-catalyzed cycloisomerization of enamide 2.124 afforded tricycle 2.125 in excellent yield.  Product formation was verified by the appearance of two 1-proton singlets at chemical shifts of 4.87 ppm and 4.63 ppm in the 1H NMR spectrum, attributable to the protons of the exocyclic alkene.  O 2.99 OCH3 O H 2.118, AcOH 4 g, 70% N O SEtHN O 2.124 10 mol% PtCl2 PhCH3, 90 oC 3 g, 87% N O SEtHN O 2.125 PhCH3  Scheme 2.33:  Synthesis of 2.125 using a platinum(II)-catalyzed cycloisomerization  Allylic oxidation of chiral enamide 2.125 using the two-step procedure (50 mol% of selenium dioxide and tert-butyl hydroperoxide, followed by manganese(IV) oxide) gave enone Chapter 2:  The Total Synthesis of (+)-Fawcettidine   76 2.126 in 23% yield (33% yield based on recovered starting material) (Scheme 2.34). Optimization of the oxidation was deemed necessary for completion of the synthesis.  N O SEtHN O 2.125 N O SEtHN O 2.126 O 1) tBuOOH,     50 mol% SeO2, CH2Cl2 2) MnO2, CH2Cl2 23% (2 steps) 33% BRSM Scheme 2.34:  First allylic oxidation of substrate 2.125  The results of the optimization studies on the oxidation of enamide 2.125 are summarized in Table 2.7.1.  The original conditions are displayed in entry 1.  The addition of 2 equivalents of water to the reaction mixture seemed to increase the yield of product (2.126) slightly (entry 2). The same reagent combination in 1,2-dichloroethane as a solvent did not increase the yield of product isolated (entry 3).  Treatment of enamide 2.125 with 1 equivalent of selenium dioxide in 1,4-dioxane at 85 oC gave enone 2.126 in 54% after 1.5 hours (entry 4).80  Oxidation using 1 mol% of dirhodium caprolactamate, tert-butyl hydroperoxide, and base gave a complex mixture of unidentifiable products (entry 5).   Table 2.3:  Optimization of the allylic oxidation of compound 2.125 N O SEtHN O 2.125 N O SEtHN O 2.126 O conditions  entry conditions yield 2.126 (%) a,b,c  1 1) 50 mol% SeO2, tBuOOH, CH2Cl2, reflux, 2 days 2) MnO2, CH2Cl2, rt, 18 h 23% (2steps; 33% BRSM) 2 1) 50 mol% SeO2, tBuOOH, H2O, CH2Cl2, reflux, 36 h 2) MnO2, CH2Cl2, rt, 32 h 35% (42% BRSM) 3 1) 50 mol% SeO2, tBuOOH, H2O, ClCH2CH2Cl, reflux, 1 h 19% 4 1) SeO2, 1,4-dioxane, 85 oC, 1.5 h 54% 5 1 mol% Rh2(cap)4, tBuOOH, K2CO3, CH2Cl2, rt, 4 h complex mixture aReported yields are isolated yields.  bBRSM = based on recovered starting material. cReported yields are the maximum of single experiments.  Chapter 2:  The Total Synthesis of (+)-Fawcettidine   77   The choice of allylic oxidation conditions tested was largely based on the results of the oxidation of compound 2.106, summarized in Table 2.6.2, Section 2.6.  Comparing the results for each, the optimal conditions for the allyic oxidation in both cases is 1 equivalent of selenium dioxide in 1,4-dioxane at 85 oC.  With the optimized conditions for the formation of enone 2.126 in hand, synthesis towards (+)-fawcettidine continued.   The thiocarbamate protecting group was next removed using 1M sodium hydroxide (Scheme 2.35).  An interesting problem arose at this time: it was discovered that treatment of chiral enone 2.126 with aqueous base led to a small amount of product (2.127), and a large amount of a dimer (2.128) (Scheme 2.35, eq 1).  The dimer was formed via disulfide linkage between the molecules.  The dimerization was likely not observed during the model studies due to the deprotection being performed on such small scale: 0.018 grams (model study) versus 0.1 grams or more (this study).  Disulfide formation is an oxidation reaction that can be caused by atmospheric oxygen, so removal of oxygen from the reaction mixture should eliminate this problem.  To that end, the aqueous solution of 1M sodium hydroxide was sparged with argon prior to use to remove all oxygen, and the reaction was carried out under an atmosphere of nitrogen.  Treatment of enone 2.126 with oxygen-free 1M sodium hydroxide formed tetracycle 2.127 in 76% yield, as evidenced by the disappearance of two 1-proton singlets at chemical shifts of 6.11 ppm and 5.20 ppm in the 1H NMR spectrum which corresponded to the protons on the exocyclic alkene (Scheme 2.35, eq 2).  N O SEtHN O 2.126 O 1 M NaOH 76% N 2.127 O S O ≡ H3C H O N H H O S H N O SEtHN O 2.126 O 1 M NaOH N O S O N O S 2.128 O (sparged) (1) (2) N 2.127 O S O H  Scheme 2.35:  Undesired dimer formation and a solution to the problem Chapter 2:  The Total Synthesis of (+)-Fawcettidine   78  Although compound 2.127 is tetracyclic, the last ring must be contracted with the simultaneous expulsion of a sulfur atom, to form the all-carbon 7-membered ring present in (+)- fawcettidine (2.5).  The focus therefore shifted towards the proposed Ramberg-Bäcklund reaction.71-74  The requisite sulfone (2.130) was prepared in two steps (Scheme 2.36).  First, the ketone (2.127) was protected as the ketal (2.129) by treatment with ethylene glycol and pyridinium para-toluenesulfonate.  Oxidation of the sulfide (2.129) with meta-chloroperbenzoic acid afforded sulfone 2.130 in excellent yield.  Sulfone 2.130 was next tested for reactivity using conditions reported by Ramberg and Bäcklund.  All attempts to carry out the Ramberg-Bäcklund reaction by the Meyers’ procedure failed.  However, the one-step procedure reported by Chan turned out to be successful (Scheme 2.36).87  Treatment of sulfone 2.130 with dibromodifluoromethane in a tert-butyl alcohol/dichloromethane solvent mixture and in the presence of potassium hydroxide adsorbed onto alumina enabled the isolation of alkene 2.131 in 46% yield.  H3C H N H H 2.129 O S O O mCPBA CH2Cl2 98% H3C H N H H 2.130 O S O O O O CBr2F2 KOH.alumina tBuOH, CH2Cl2 46% H3C H N H H 2.131 O O O H3C H O N H H 2.127 O S HO OH PPTs, PhH 87%  Scheme 2.36:  Synthesis of compound 2.131 using a Ramberg-Bäcklund reaction  The mechanism of the Ramberg-Bäcklund reaction is outlined in Scheme 2.37.  The acidic proton adjacent to the sulfone functional group in 2.130 is first deprotonated by the hydroxide base, followed by quenching with an electrophilic bromine atom from dibromodifluoromethane to give bromide 2.133.  Protons to the other side of the sulfone are also acidic, and one is deprotonated with excess base.  The anion can then attack the carbon three atoms away and extrude the bromide ion, forming episulfone 2.134.  Cheletropic extrusion of sulfur dioxide gives alkene 2.131.  There are two points about the mechanism as illustrated in Scheme 2.37: a) both sets of protons adjacent to the sulfone in 2.130 are acidic, so the depicted site of deprotonation Chapter 2:  The Total Synthesis of (+)-Fawcettidine   79 was chosen arbitrarily, and b) the formation of the episulfone and extrusion of sulfur dioxide is drawn as a stepwise procedure, but is likely a concerted mechanism.  A mechanism involving a diradical anion species has also been suggested.72, 74, 88  N O S O O O O H N O S O O O O C Br Br F F N O S O O O O Br N O O O N O O O S O O - SO2 KOH KOH OH 2.130 2.132 2.133 2.134 2.131 ≡ H3C H N H H O O O H H H H H  Scheme 2.37:  Mechanism of the Ramberg-Bäcklund reaction  Interestingly, crystals of alkene 2.131 were amenable to X-ray diffraction and a solid state structure was obtained (Figure 2.7).  The bond lengths of 1.325(3) Å and 1.328(4) Å between C13-C14 and C2-C3 (fawcettidine numbering), respectively, indicate C-C double bond character.  The correct configuration at C4 is also confirmed by the solid state molecular structure.   Figure 2.7:  ORTEP representation of the solid state molecular structure of olefin 2.131  The success of the Ramberg-Bäcklund reaction provided compound 2.131, a molecule containing all the skeletal carbon atoms with the correct configuration of (+)-fawcettidine (2.5). Only a series of functional group manipulations was required to complete the synthesis.  First, Chapter 2:  The Total Synthesis of (+)-Fawcettidine   80 the C2-C3 double bond had to be removed (Scheme 2.38).  This was accomplished by heterogeneous hydrogenation using a palladium on carbon catalyst in an ethanol/THF solvent mixture, giving compound 2.135 in 57% yield.  Enamide 2.135 was reduced to enamine 2.136 using lithium aluminum hydride, and the ketal was removed using a solution of aqueous 1M hydrochloric acid in THF to afford (+)-fawcettidine (2.5).  H3C H N H H 2.131 O O H2, Pd/C EtOH/THF 57% O H3C H N H H 2.135 O O 71% O LiAlH4 THF H3C H N H H 2.136 O O H3C H N H H (+)-fawcettidine (2.5) O 1 M HCl THF 60% Scheme 2.38:  Completion of the total synthesis of (+)-fawcettidine  As the structure elucidation of (+)-fawcettidine was defined by its synthesis from other members of the Lycopodium alkaloid family, high-field NMR spectroscopic data are not available for comparison.  It was therefore compared to recently isolated, hydroxylated derivatives of (+)-fawcettidine (Figure 2.8).89  Key spectroscopic data include the 1H NMR signal attributed to the enamine (5.69 ppm in 2.5) which is consistent with that in 8α,11α- dihydrofawcettidine (5.65 ppm).  The IR stretching frequency of the cyclopentane carbonyl is also consistent (1741 cm-1 versus 1740 cm-1).  The signals in the 13C NMR spectra attributed to C13, C14, and C5 correspond well with the (+)-fawcettidine relative (2.137).  Chapter 2:  The Total Synthesis of (+)-Fawcettidine   81 H3C H O N H H H3C H O N H H OH HO H H δ 5.69 ppm, d, J = 5.2 Hz δ 5.65 ppm, d, J = 3.2 Hz νmax C=O: 1741 cm-1 νmax C=O: 1731 cm-1 H3C H O N H H H3C H O N H H OH HO (+)-fawcettidine (2.5) 8α, 11α-dihydroxyfawcettidine (2.137) δ 128.1 ppm δ 128.2 ppm δ 147.0 ppm δ 143.0 ppmδ 219.9 ppm δ 217.4 ppm  Figure 2.8:  Comparison of NMR and IR data of (+)-fawcettidine (2.5) and structurally related 8α,11α- dihydrofawcettidine (2.137)  Unfortunately, the optical rotation data obtained (in ethanol) for synthetic 2.5 is at odds with that reported in the original isolation literature.30  The measured optical rotation of synthetic 2.5 was found to be +61o (c = 0.25, EtOH), whereas the measured literature value was +161o (c = 0.6, EtOH).  However, the optical rotation of synthetic 2.5 in chloroform (+92o (c = 0.41, CHCl3)) compares well with that reported for synthetic (+)-fawcettimine (2.3) (+89 o (c = 0.55, MeOH)).41   2.8   Conclusion  The first reported total synthesis of (+)-fawcettidine (2.5) was carried out in 16 steps from chiral pool starting material (R)-(+)-pulegone (2.56).  An important key feature of the successful synthesis (Route B) was a platinum(II)-catalyzed annulation of a highly functionalized enamide (2.124).  In one step, the annulation reaction placed the double bond of the enamine in the correct position, set the quaternary carbon stereocenter, and provided an exocyclic alkene to facilitate further functionalization.  Another important design feature was the selection of the thiocarbamate protecting group and its placement relative to an enone functional group. Deprotection of the thiocarbamate closed the final ring to form tetracycle 2.127 and ultimately set up the third key step, the Ramberg-Bäcklund reaction.  Chan’s one-pot Ramberg-Bäcklund Chapter 2:  The Total Synthesis of (+)-Fawcettidine   82 conditions successfully contracted the 8-membered ring to the requisite 7-membered ring, extruding sulfur dioxide.   The study of (+)-fawcettidine (2.5) presented in this chapter was also successful in achieving a late stage intermediate (2.111) via Route A.  The key step of the synthesis was also the platinum(II)-catalyzed annulation of enamide 2.87.  If the synthesis following Route A is completed in the future, another feature would be the oxidative reintroduction of the enamine at the culmination of the synthesis.   2.9   Experimental  2.9.1 General Experimental All reactions sensitive to air or moisture were carried out in flame-dried glassware under an atmosphere of nitrogen.  Tetrahydrofuran was distilled from sodium benzophenone ketyl prior to use.  Dichloromethane and triethylamine were distilled from calcium hydride and degassed by sparging with argon prior to use.  Toluene was distilled from sodium and degassed by sparging with argon prior to use.  All commercial reagents or materials were used without purification unless otherwise noted.  Thin layer chromatography (TLC) was performed on DC-Fertigplatten SIL G-25 UV254 pre-coated TLC plates.  Triethylamine washed silica gel was stirred with triethylamine before packing and then sequentially flushing the silica gel with ethyl acetate followed by hexanes.  To dry load crude compounds onto silica gel prior to column chromatography, the compound was dissolved in an appropriate solvent and dry silica gel was added.  The solvent was then removed in vacuo until the silica gel was freely flowing.  Buffered (pH 8) saturated aqueous ammonium chloride was prepared by adding 50 mL of ammonium hydroxide to 950 mL of saturated aqueous ammonium chloride solution.  Melting points were performed using a Mel-Temp II apparatus (Lab devices USA) and are uncorrected.  Proton nuclear magnetic resonance (1H NMR) and carbon nuclear magnetic resonance (13C NMR) spectra were recorded in deuterochloroform unless otherwise noted.  Chemical shifts are recorded in parts per million (ppm) and are referenced to the centerline of deuterochloroform (δ 7.27 ppm 1H NMR; δ 77.0 ppm 13C NMR).  Data was recorded as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = tripet, q = quartet, qt = quintet, m = multiplet, br = Chapter 2:  The Total Synthesis of (+)-Fawcettidine   83 broad).  Coupling constants (J values) are given in Hertz (Hz).  The complexity of the 1H NMR spectrum for mixtures of isomers does not allow for unequivocal assignment of each isomer.  For mixtures of isomers, all of the signals in the 1H NMR associated with the major isomer are assigned.  The isolated signals associated with the minor isomer are assigned.  In the 13C NMR, all of the peaks for the mixture of two isomers are listed if they cannot be distinguished based on intensity of the signal.  For mixtures >8:1, only the signals for the major isomer are listed.  Low resolution ESI mass spectra were recorded on a Bruker Esquire-LC ion trap mass spectrometer equipped with an electrospray ion source.  High resolution EI mass spectra were recorded on a Kratos MS-50 double focusing mass spectrometer.  High resolution ESI mass spectra were recorded on a Waters/Micromass LCT time of flight (TOF) mass spectrometer equipped with an electrospray ion source.  Microanalyses were recorded on a Fisons Instruments Carlo Erbal EA 1108 elemental analyzer.  All mass analyses and microanalyses were performed by the Microanalytical Laboratory at the University of British Columbia.  2.9.2 Synthesis of a Common Ketoester Starting Material O O O 2.56 2.91 Epoxide (2.91) A 2 L 3-neck round-bottomed flask was charged with 99.0 mL of R-(+)-pulegone (2.56) (609 mmol) and 400 mL of methanol.  To the clear solution was added 104 mL of hydrogen peroxide (30 wt. % in H2O, 913 mmol) in 20 mL portions.  The reaction mixture was cooled to 18 oC using a cold water bath.  A solution of 3.83 g of lithium hydroxide monohydrate (91.3 mmol) in 50 mL of water was added dropwise to the reaction mixture.  The reaction mixture was stirred for 5.5 h while the temperature was maintained at 20-25 oC.  The resulting white cloudy suspension was poured into 900 mL of a solution of brine and then extracted four times with dichloromethane.  The combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo to afford a clear liquid.  The crude liquid was purified by distillation under reduced pressure to afford 98.4 g (96 %) of a 2:1 mixture of diastereomers of the title compound 2.91 as a clear liquid, bp = 80-85 oC, 0.5 mmHg (lit. 94-97 oC, 5 mm Hg). IR (neat): 2958, 2873, 1721 cm-1.  1H NMR (400 MHz, CDCl3): δ 2.39-2.29 (m, 3H), 2.00-1.87 (m, 4H), 1.36 (s, 3H), 1.15 (s, 3H), 0.99 (d, J = 6.8 Hz, 3H).  Additional signals associated with Chapter 2:  The Total Synthesis of (+)-Fawcettidine   84 the minor isomer: δ 2.53 (dt, J = 13.1, 3.0 Hz, 1H), 2.13 (dd, J = 13.7, 4.4 Hz, 1H), 2.10 (dd, J = 13.3, 4.1 Hz, 1H), 1.85-1.74 (m, 2H), 1.73-1.66 (m, 2H), 1.36 (s, 3H), 1.14 (s, 3H), 1.01 (d, J = 6.1 Hz, 3H).  13C NMR (100 MHz, CDCl3): δ 207.6, 206.5, 70.3, 70.2, 63.5, 63.3, 51.5, 49.6, 34.1, 33.1, 30.8, 30.3, 30.1, 26.4, 22.1, 20.0, 19.8, 19.7, 19.5, 19.0.  MS (APCI): 169 (M + H)+. 2.91 has been previously prepared, see: Katsuhara, J. J. Org. Chem. 1967, 32, 797-799.  O SPh O O 2.91 2.92 O S O Ph 2.93 (R)-5-methyl-2-(phenylsulfinyl)cyclohexanone (2.93) To a solution of 20.5 g of sodium hydride (855 mmol) in 600 mL of THF was added a solution of 87.4 mL of thiphenol (855 mmol) in 60 mL of THF dropwise.  To the resulting thick, white suspension was added dropwise a solution of 95.9 g of epoxide 2.91 (570 mmol) in 100 mL of THF.  The resulting yellow suspension was heated to reflux and stirred for 19 h.  The reaction mixture was cooled to rt and quenched with a saturated solution of sodium bicarbonate.  The layers were separated and the aqueous layer was extracted twice with diethyl ether.  The combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo to afford a yellow oily solid.  The product was moved onto the next reaction with no further purification.  To a solution containing 90.1 g of crude compound 2.92 (409 mmol) in 700 mL of glacial acetic acid was added 62.9 g of sodium perborate tetrahydrate (409 mmol) in 10 g portions.  In order to avoid over-oxidation to the sulfone, the reaction was monitored by thin layer chromatography after each addition of sodium perborate tetrahydrate.  After the reaction was complete, the mixture was poured into a solution of 1 M HCl and extracted three times with diethyl ether.  To the combined organic fractions was added ice cold water.  To the biphasic solution was carefully added solid sodium bicarbonate until the aqueous layer tested neutral to litmus paper.  The combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo to afford a thick orange oil.  The crude oil was purified by column chromatography on silica gel (1:1→1:3 hexanes:ethyl acetate) to afford 85.1 g (88% over 2 steps) of a 1:1 mixture of diastereomers of the title compound 2.93 as an orange oil. Chapter 2:  The Total Synthesis of (+)-Fawcettidine   85 IR (neat): 2956, 2872, 2238, 1712, 1044 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.68-7.62 (m, 4H), 7.58-7.56 (m, 2H), 7.51-7.47 (m, 4H), 3.68 (dd, J = 10.6, 5.8 Hz, 1H), 3.37-3.31 (m, 1H), 2.53-2.47 (m, 2H), 2.28-2.23 (m, 1H), 2.16-1.91 (m, 8H), 1.84-1.79 (m, 1H), 1.43-1.31 (m, 2H), 1.00 (d, J = 6.1 Hz, 3H), 0.97 (d, J = 6.5 Hz, 3H).  13C NMR (100 MHz, CDCl3): δ 205.5, 205.3, 131.6, 131.1, 129.4, 129.2, 129.1, 126.0, 124.9, 124.7, 73.4, 73.2, 50.5, 50.4, 34.2, 34.1, 32.3, 32.2, 25.2, 23.0, 22.0, 21.6.  MS (APCI): 237 (M + H)+.  O 2.57 O S O Ph 2.93 (R)-5-Methylcyclohex-2-enone (2.57) To a solution of 1.2 g of sulfoxide 2.93 (5.1 mmol) in 50 mL of benzene was added 2.1 mL of pyridine (26 mmol).  A condenser was attached to the round-bottomed flask and the reaction mixture was heated to reflux for 2 h.  The solution was cooled to rt and the solvents were removed by rotary evaporation in vacuo to afford a yellow oil.  The crude oil was purified by column chromatography on silica gel (10:1 hexanes:ethyl acetate) to afford 0.39 g (70 %) of the title compound 2.57 as a light yellow oil. IR (neat): 2958, 1680, 880, 735 cm-1.  1H NMR (400 MHz, CDCl3): δ 6.95 (ddd, J = 10.1, 5.3, 2.4 Hz, 1H), 6.00 (dd, J = 10.0, 2.6 Hz, 1H), 2.47 (dd, J = 15.7, 3.5 Hz, 1H), 2.45-2.38 (m, 1H), 2.25-2.16 (m, 1H), 2.14-2.10 (m, 1H), 2.01 (tt, J = 9.2, 2.6 Hz, 1H), 1.06 (d, J = 6.5 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 201.3, 151.1, 130.6, 47.2, 35.0, 31.1, 22.2.  [α] 20 D = −82 o (c = 0.60, CHCl3). 2.57 has been previously prepared, see: 1) Oppolzer, W.; Petrzilka, M. Helv. Chem. Acta 1978, 61, 2755- 2762.  2) Mutti, S.; Daubié, C.; Decalogne, F.; Fournier, R.; Rossi, P. Tetrahedron Lett. 1996, 37, 3125- 3128.     Chapter 2:  The Total Synthesis of (+)-Fawcettidine   86 O OCH3 OO 2.57 2.94 (R)-Methyl 3-(4-methyl-6-oxocyclohex-1-enyl)propanoate (2.94)  A solution of 2.9 g of enone 2.57 (27 mmol), 3.6 mL of methyl acrylate (40 mmol), and 2.0 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene (13 mmol) in 30 mL of N,N-dimethylformamide was prepared in a 100 mL thick-walled sealable vessel under an atmosphere of nitrogen.  The vessel was sealed and the reaction mixture was heated to 180 oC for 24 h.  The resulting dark red solution was cooled to rt and subsequently washed once with brine and once with water.  The combined aqueous fractions were extracted four times with diethyl ether.  The combined organic fractions were washed four times with brine, dried over sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo to afford an orange oil.  The crude oil was purified by column chromatography on silica gel (10:1→5:1 hexanes:ethyl acetate) to afford 1.7 g (32 %) of the title compound 2.94 as a yellow oil.  O S O Ph O OCH3 O 2.93 2.94 (R)-Methyl 3-(4-methyl-6-oxocyclohex-1-enyl)propanoate (2.94) To a solution of 8.1 g of (R)-5-methyl-2-(phenylsulfinyl)cyclohexanone (2.93) (34 mmol) in 200 mL of DMF at −40 oC was added dropwise 6.2 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene (41 mmol).  The resulting orange solution was stirred at −40 oC for 0.25 h.  Methyl acrylate (3.7 mL, 41 mmol) was added dropwise.  The reaction mixture was stirred for 1 h at −40 oC and then warmed to rt.  The solution was heated to 40 oC for 2 h and then cooled to rt.  The reaction mixture was diluted with water and extracted three times with diethyl ether.  The combined organics were washed five times with brine.  The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford a crude brown oil.  The oil was purified by column chromatography on silica gel (5:1→4:1 hexanes:ethyl acetate) to give 4.2 g (63 %) of the title compound 2.94 as a light yellow oil. IR (neat): 2995, 1739, 1673 cm-1.  1H NMR (400 MHz, CDCl3): δ 6.73-6.71 (m, 1H), 3.63 (s, 3H), 2.49-2.36 (m, 6H), 2.20-1.98 (m, 3H), 1.02 (d, J = 6.5 Hz, 3H).  13C NMR (100 MHz, Chapter 2:  The Total Synthesis of (+)-Fawcettidine   87 CDCl3): δ 200.2, 174.5, 146.5, 138.7, 52.4, 47.5, 35.3, 34.0, 31.5, 26.3, 22.1.  MS (ESI): 219 (M + Na)+.  Anal. Calcd for C11H16O3: C, 67.32; H, 8.22.  Found: C, 67.56; H, 8.29.  [α] 20 D = −39 o (c = 0.63, CHCl3).  HO HO Si(CH3)3 2.95 2.96 4-(Trimethylsilyl)but-3-yn-1-ol (2.96) To a solution of 21.6 mL of 3-butyn-1-ol (2.95) (286 mmol) in 900 mL of THF at –78 °C was added 368 mL of a solution of n-butyllithium (1.55 M in hexanes, 571 mmol) dropwise over a period of 2 h.  The yellow suspension was stirred at –78 °C for 0.5 h before 76.1 mL of chlorotrimethylsilane (599 mmol) was added dropwise over 0.5 h.  The reaction mixture was stirred for an additional hour before being warmed to rt.  To the reaction was added 300 mL of an aqueous 1M HCl solution and the resulting biphasic mixture was stirred at rt for 1 h.  The layers were separated and the aqueous fraction was extracted twice with diethyl ether.  The combined organic fractions were dried over sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo to afford a crude yellow oil.  Purification of the crude material by distillation under reduced pressure afforded 39.4 g (97 %) of the title compound 2.96 as a colorless liquid, bp = 43-46 °C, 0.5 mmHg (lit. 72 °C, 12 mmHg). IR (neat): 3340 (br), 2960, 2175 cm-1.  1H NMR (300 MHz, CDCl3): δ 3.71 (t, J = 6.2 Hz, 2H), 2.48 (t, J = 6.3 Hz, 2H), 1.98 (s, 1H), 0.15 (s, 9H). 2.96 has been previously prepared, see: 1) Davison, E. C.; Forbes, I. T.; Holmes, A. B.; Warner, J. A. Tetrahedron 1996, 52, 11601-11624. 2) Dobbs, A. P.; Jones, K.; Veal, K. T. Tetrahedron 1998, 54, 2149- 2160.  HO TsO Si(CH3)3 Si(CH3)3 Br Si(CH3)3 2.96 2.97 (4-Bromobut-1-ynyl)trimethylsilane (2.97) To a solution of 39.4 g of 2.96 (277 mmol) and 68.7 g of p-toluenesulfonyl chloride (360 mmol) in 300 mL of dichloromethane at 0 °C was added 53.8 mL of pyridine (665 mmol).  The reaction mixture was warmed to rt and stirred for 24 h.  The resulting solution was washed four times with an aqueous 1M HCl solution.  The combined aqueous fractions were extracted three times Chapter 2:  The Total Synthesis of (+)-Fawcettidine   88 with dichloromethane.  The combined organic fractions were dried over sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo to afford a pale yellow oil.  The crude oil was purified by column chromatography on a plug of silica gel (10:1→6:1 hexanes:ethyl acetate) to afford a mixture of toluene-4-sulfonic acid 4-trimethylsilyl-but-3-ynyl ester and p- toluenesulfonyl chloride as a colorless oil.  The material as used in the next reaction without further purification.  To a solution of the crude tosylate in 250 mL of DMF was added 34.2 g of sodium bromide (332 mmol) in one portion.  The resulting suspension was stirred at 65 °C for 4 h.  The reaction mixture was diluted with diethyl ether and washed with water.  The aqueous fraction was extracted once with diethyl ether.  The combined organic fractions were washed five times with brine, dried over sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo to afford a yellow liquid.  The crude liquid was purified by distillation under reduced pressure to give 46.0 g (79 % over 2 steps) of the title compound 2.97 as a colorless liquid, bp = 38-40 °C, 0.5 mmHg (lit. 74-76 °C, 20 mmHg). IR (neat): 2961, 2178 cm-1.  1H NMR (300 MHz, CDCl3): δ 3.42 (t, J = 7.5 Hz, 2H), 2.77 (t, J = 7.5 Hz, 2H), 0.15 (s, 9H). 2.97 has been previously prepared, see: 1) Davison, E. C.; Forbes, I. T.; Holmes, A. B.; Warner, J. A. Tetrahedron 1996, 52, 11601-11624. 2) Dobbs, A. P.; Jones, K.; Veal, K. T. Tetrahedron 1998, 54, 2149- 2160.  O OCH3 O O OCH3 O SiMe3 O OCH3 O SiMe3 2.98 1 : 1 2.94  Methyl 3-((1S,4R,6R)-4-methyl-2-oxo-6-(4-(trimethylsilyl)but-3-ynyl)cyclohexyl)propanoate + Methyl 3-((1R,4R,6R)-4-methyl-2-oxo-6-(4-(trimethylsilyl)but-3- ynyl)cyclohexyl)propanoate (2.98) To a suspension of 5.73 g of magnesium (236 mmol) in 200 mL of THF was added 34.9 g of 4- trimethylsilyl-1-bromo-3-butyne (170 mmol) in one portion.  The reaction mixture was immediately cooled to 0 oC and stirred for 1 h.  The cloudy grey solution was transferred dropwise to a suspension of 34.9 g of copper(I) bromide-dimethyl sulfide complex (170 mmol) Chapter 2:  The Total Synthesis of (+)-Fawcettidine   89 in 400 mL of THF at −78 oC and stirred for 1 h.  To the resulting dark red reaction mixture was added 12.7 mL of chlorotrimethylsilane (99.1 mmol) dropwise.  A solution of 18.5 g of compound 2.94 (94.4 mmol) in 50 mL of THF was added to the red mixture.  The resulting reaction mixture was stirred at −78 oC for 1 h then at −40 oC for 1 h before warming to rt.  The mixture was quenched with basic ammonium chloride solution, diluted with diethyl ether, and the layers were separated.  The organic layer was washed with basic ammonium chloride solution until the aqueous fraction was no longer blue.  The organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo to give a yellow oil.  The crude oil was dissolved in 300 mL of methanol and 3 mL of 3M HCl.  The solution was stirred for 2 h at rt. The solvents were removed in vacuo to yield a crude yellow oil.  The oil was purified by column chromatography on silica gel (10:1→5:1→3:1 hexanes:ethyl acetate) to give 25.6 g (84 %) of a 1:1 mixture of the title compound 2.98 as a pale yellow oil. IR (neat): 2955, 2174, 1740, 1708 cm-1.  1H NMR (400 MHz, CDCl3): δ 3.65 (s, 3H), 2.38-1.87 (m, 1H), 1.71-1.43 (m, 4H), 1.01-0.94 (dd, J = 14.0, 6.1 Hz, 3H), 0.12 (s, 9H).  13C NMR (100 MHz, CDCl3): δ 214.2, 212.5, 174.8, 174.6, 107.2, 107.1, 86.3, 86.2, 55.0, 53.8, 52.5, 52.4, 51.2, 48.1, 40.5, 39.3, 37.3, 35.0, 33.0, 32.8, 32.7, 30.9, 30.5, 26.6, 25.8, 23.2, 22.7, 22.1, 18.6, 18.5, 1.1.  MS (ESI):  345 (M + Na)+.  Anal. Calcd for C18H30O3Si: C, 67.03; H, 9.38.  Found: C, 67.02; H, 9.33.  O OCH3 O SiMe3 O OCH3 O O OCH3 O 2.98 2.99 1 : 1 Methyl 3-((1S,2R,4R)-2-(but-3-ynyl)-4-methyl-6-oxocyclohexyl)propanoate + Methyl 3- ((1R,2R,4R)-2-(but-3-ynyl)-4-methyl-6-oxocyclohexyl)propanoate (2.99) To a solution of 23.7 g of compound 2.98 (73.6 mmol) in 400 mL of THF was added 73.6 mL of tetrabutylammonium fluoride (73.6 mmol, 1M in THF) in 10 mL portions.  The resulting dark red reaction mixture was stirred for 0.10 h at rt before being diluted with diethyl ether.  The solution was washed once with water and once with brine.  The combined aqueous fractions were extracted three times with diethyl ether.  The combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo to give an orange-brown oil.  The crude oil Chapter 2:  The Total Synthesis of (+)-Fawcettidine   90 was purified by column chromatography on silica gel (4:1 hexanes:ethyl acetate) to afford 17.7 g (96 %) of a 1:1 mixture of the title compound 2.99 as a yellow oil. IR (neat): 3288, 2953, 2360, 1738, 1708 cm-1.  1H NMR (400 MHz, CDCl3): δ 3.66 (s, 3H), 2.42- 1.88 (m, 12H), 1.74-1.46 (m, 4H), 1.00 (dd, J = 13.1, 6.1 Hz, 3H).  13C NMR (100 MHz, CDCl3): δ 214.3, 212.5, 174.8, 174.5, 84.4, 84.3, 69.9, 55.0, 53.9, 52.6, 52.5, 51.2, 48.1, 40.3, 39.4, 37.2, 34.9, 32.9, 32.8, 30.9, 30.5, 26.4, 26.1, 23.2, 22.8, 22.2, 17.1, 17.0.  MS (ESI): 273 (M + Na)+.  Anal. Calcd for C15H22O3: C, 71.97; H, 8.86. Found: C, 71.63; H, 8.82.   2.9.3 Route A: Forward Synthesis O OCH3 O N O Ph N O Ph 2.99 2.87 15 : 1 (5R,7R)-1-Benzyl-5-(but-3-ynyl)-7-methyl-3,4,5,6,7,8-hexahydroquinolin-2(1H)-one + (5R,7R)-1-Benzyl-5-(but-3-ynyl)-7-methyl-3,4,4a,5,6,7-hexahydroquinolin-2(1H)-one (2.87) To a solution of 3.1 g of compound 2.99 (12 mmol) in 40 mL of toluene were added 6.7 mL of benzylamine (61 mmol) and 12 mL of glacial acetic acid.  A Dean-Stark apparatus was attached and the reaction mixture was heated to reflux and stirred for 2 h.  The reaction mixture was cooled to rt and diluted with diethyl ether.  The organic layer was washed twice with a saturated solution of sodium bicarbonate.  The combined aqueous layers were extracted once with diethyl ether.  The combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo to give a thick brown oil which solidified when cooled.  The crude compound was purified by column chromatography on triethylamine washed silica gel (3:1 hexanes:ethyl acetate) to afford 3.7 g (99 %) of a 15:1 mixture of the title compound 2.87 as a thick orange oil. IR (neat): 3294, 2927, 2115, 1664, 1496, 1392, 1187, 703, 643 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.29-7.53 (m, 2H), 7.21-7.17 (m, 1H), 7.13-7.11 (m, 2H), 4.87 (s, 2H), 2.61-2.46 (m, 2H), 2.34-2.10 (m, 6H), 1.95 (t, J = 2.6 Hz, 1H), 1.77-1.69 (m, 2H), 1.66-1.60 (m, 1H), 1.51-1.38 (m, 2H), 1.25-1.15 (m, 1H), 1.89 (d, J = 6.5 Hz, 3H).  Additional signals associated with the minor isomer: δ 5.12 (d, J = 15.7 Hz, 1H), 5.01 (d, J = 4.8 Hz, 1H), 4.74 (d, J = 16.1 Hz, 1H), 2.77-2.71 (m, 1H).  13C NMR (100 MHz, CDCl3): δ 171.6, 139.5, 133.0, 129.5, 127.7, 127.1, 119.2, 85.1, 69.8, 44.7, 38.0, 34.9, 34.3, 33.1, 32.6, 25.4, 25.0, 22.5, 17.9.  Additional signals Chapter 2:  The Total Synthesis of (+)-Fawcettidine   91 associated with the minor isomer: δ 170.1, 138.7, 129.4, 127.6, 127.3, 112.9, 85.0, 69.7, 61.3, 47.8, 41.3, 34.0, 33.7, 32.7, 28.8, 26.2, 22.0, 16.9, 15.2.  MS (ESI): 330 (M + Na)+.  Anal. Calcd for C21H25NO: C, 82.04; H, 8.20; N, 4.56. Found: C, 81.56; H, 7.96; N, 4.71.  N O Ph N O Ph 2.87 2.86 (4aS,7aR,9R)-1-Benzyl-9-methyl-5-methylene-3,4,5,6,7,7a,8,9- octahydrocyclopenta[e]quinolin-2(1H)-one (2.86) To a flask containing 2.65 g of compound 2.87 (8.61 mmol) and 0.229 g of platinum(II) chloride (0.861 mmol) was added 30 mL of toluene.  The reaction mixture was heated to 80 oC and stirred for 2 h.  The orange reaction mixture was cooled to rt and filtered through a plug of triethylamine washed silica gel, rinsing with diethyl ether.  The solvents were removed in vacuo to give a bright yellow oil.  The crude oil was purified by column chromatography on triethylamine washed silica gel (4:1 hexanes:ethyl acetate) to afford 2.69 g (75 %) of the title compound 2.86 as a yellow oil. IR (neat): 2925, 2868, 1669, 1636, 1368, 12.01, 699 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.30- 7.16 (m, 5H), 5.39 (d, J = 15.7 Hz, 1H), 5.02 (d, J = 4.8 Hz, 1H), 4.92 (s, 1H), 4.73 (s, 1H), 4.52 (d, J = 15.7 Hz, 1H), 2.70-2.57 (m, 2H), 2.52-2.26 (m, 3H), 2.09-1.95 (m, 2H), 1.89-1.84 (m, 1H), 1.70-1.62 (m, 1H), 1.54-1.48 (m, 1H), 1.41-1.34 (m, 1H), 1.26-1.19 (m, 1H), 0.87 (d, J = 7.0, 3H).  13C NMR (100 MHz, CDCl3): δ 170.2, 154.4, 140.1, 138.9, 129.5, 129.4, 127.7, 113.0, 109.6, 49.6, 48.9, 41.7, 33.6, 30.4, 29.7, 29.6, 29.3, 27.6, 22.4.  MS (ESI): 330 (M + Na)+.  Anal. Calcd for C21H25NO: C, 82.04; H, 8.20; N, 4.56. Found: C, 81.85; H, 8.20; N, 4.74.  [α] 21 D = +127o (c = 1.91, CHCl3).     Chapter 2:  The Total Synthesis of (+)-Fawcettidine   92 N O PhN O Ph OH 2.86 2.104 (1:1)  (4aS,7aS,9R)-1-Benzyl-6-hydroxy-9-methyl-5-methylene-3,4,5,6,7,7a,8,9- octahydrocyclopenta[e]quinolin-2(1H)-one (2.104) To a solution of 0.94 g of compound 2.86 (3.1 mmol) in 10 mL of dichloromethane was added 1.6 mL t-butylhydroperoxide (70 wt % solution in H2O, 12 mmol) in one portion.  To the biphasic reaction mixture was added 0.17 g of selenium dioxide (1.5 mmol) in one portion.  The reaction mixture was stirred at rt for 48 h.  The reaction was stopped by the addition of 6 mL of a saturated solution of sodium bicarbonate and 6 mL of a saturated solution of sodium bisulfite with vigorous stirring for 0.5 h.  The orange suspension was diluted with dichloromethane, water, and the layers were separated.  The aqueous fraction was extracted three times with dichloromethane.  The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo to afford a yellow oil.  The crude oil was purified by column chromatography (4:1→1:1→1:3 hexanes:ethyl acetate) to give 0.52 g (52 %, 59 % BRSM) of the title compound 2.104 as a pale yellow oil. IR (neat): 3398, 2868, 1626, 1496, 1402, 1202, 909, 730 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.31-7.19 (m, 5H), 5.32 (d, J = 15.3 Hz, 1H), 5.22 (d, J = 6.5 Hz, 1H), 5.08-5.04 (m, 1H), 4.93- 4.89 (m, 1H), 4.59-4.51 (m, 2H), 2.71-2.60 (m, 2H), 2.28-2.17 (m, 2H), 2.01-1.74 (m, 3H), 1.40- 1.23 (m, 3H), 0.88 (d, J = 7.4, 3H).  Additional signals associated with other isomer: δ 2.49-2.42 (m, 1H), 1.62-1.55 (m, 1H).  13C NMR (100 MHz, CDCl3): δ 170.6, 170.2, 157.8, 157.7, 140.3, 140.2, 138.7, 138.6, 129.5, 129.4, 127.8, 127.7, 114.3, 113.7, 113.5, 110.1, 75.2, 72.4, 61.4, 49.1, 48.9, 48.3, 47.9, 40.8, 40.0, 39.0, 38.3, 35.0, 33.9, 31.2, 30.9, 30.5, 28.8, 28.3, 22.3, 22.2, 22.0, 15.2.  MS (EI): 323 (M)+.     Chapter 2:  The Total Synthesis of (+)-Fawcettidine   93 N O PhN O Ph OH O 2.104 2.105 (4aS,7aS,9R)-1-Benzyl-9-methyl-5-methylene-3,4,7,7a,8,9- hexahydrocyclopenta[e]quinoline-2,6(1H,5H)-dione (2.105) To a solution of 0.505 g of alcohol 2.104 (1.56 mmol) in 15 mL of dichloromethane was added 1.37 g of manganese dioxide (15.6 mmol) in one portion.  The black suspension was stirred for 30 h at rt and subsequently filtered through Celite®, rinsing with ethyl acetate.  The solvents were removed in vacuo to yield a pale yellow oil.  The crude product was purified by column chromatography on triethylamine washed silica gel (2:3 hexanes:ethyl acetate) to afford 0.387 g (77 %) of the title compound 2.105 as a white solid. IR (neat): 2928, 2869, 1728, 1669, 1636, 1496, 731 cm-1.  1H NMR (400 MHZ, CDCl3): δ 7.31- 7.18 (m, 5H), 6.09 (s, 1H), 5.36 (d, J = 15.7 Hz, 1H), 5.19 (s, 1H), 5.18 (s, 1H), 4.56 (d, J = 15.7 Hz, 1H), 2.78-2.65 (m, 2H), 2.58-2.48 (m, 1H), 2.37-2.28 (m, 2H), 2.07 (d, J = 18.7 Hz, 1H), 1.92-1.88 (m, 2H), 1.41-1.37 (m, 2H), 0.95 (d, J = 7.0 Hz, 3H).  13C NMR (100 MHz, CDCl3): δ 205.8, 169.5, 148.9, 139.3, 138.4, 129.6, 128.0, 127.7, 120.7, 113.7, 49.1, 46.8, 42.8, 36.0, 34.0, 30.5, 29.9, 29.0, 22.3.  MS (EI): 321 (M)+.  [α]21D = +66.1 o (c = 1.53, CHCl3).    N O Ph O    ORTEP representation of the solid state structure of 2.105 ...........................................................................................................................................................   Chapter 2:  The Total Synthesis of (+)-Fawcettidine   94 N O PhN O Ph 2.86 2.106 (4aS,7aR,9R)-1-Benzyl-9-methyl-5-methylene-decahydrocyclopenta[e]quinolin-2(1H)-one (2.106) To a solution of 6.17 g of enamide 2.86 (20.1 mmol) in 60 mL of trifluoroacetic acid at 0 oC was added 1.52 g of sodium borohydride (40.1 mmol) slowly over 1 h.  The reaction mixture was warmed to rt and stirred for 3 h.  The solution was cooled to 0 oC and quenched slowly with a solution of 30 % NaOH until it tested neutral to pH paper.  The aqueous solution was extracted three times with diethyl ether.  The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo to yield a brown oil.  The crude oil was purified on silica gel (1:1 hexanes:ethyl acetate) to afford 5.42 g (87 %) of the title compound 2.106 as a single diastereomer. IR (neat): 2955, 1738, 1642, 704 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.32-7.20 (m, 5H), 5.39 (d, J = 15.7 Hz, 1H), 5.08 (s, 1H), 4.98 (s, 1H), 4.18 (d, J = 15.7, 1H), 3.70 (dd, J = 13.1, 3.9 Hz, 1H), 2.72-2.41 (m, 4H), 2.00-1.82 (m, 5H), 1.66 (dt, J = 12.2, 3.1 Hz, 1H), 1.59 (td, J = 13.1, 6.1 Hz, 1H), 1.30-1.19 (m, 3H), 0.71 (d, J = 7.0 Hz, 3H).  13C (100 MHz, CDCl3): δ 172.9, 150.0, 138.9, 129.5, 128.3, 127.8, 110.8, 56.8, 50.5, 46.1, 43.1, 35.1, 31.3, 31.2, 30.7, 30.4, 28.6, 27.0, 19.1.  MS (ESI): 310 (M + H)+.  [α]22D = −44 o (c = 0.92, CHCl3).  N O PhN O Ph O 2.106 2.85 (4aS,7aS,9R)-1-Benzyl-9-methyl-5-methylene-3,4,7,7a,8,9- hexahydrocyclopenta[e]quinoline-2,6(1H,5H)-dione (2.85) A solution of 0.17 g of amide 2.106 (0.55 mmol) and 0.061 g of selenium dioxide (0.55 mmol) in 7 mL of 1,4-dioxane was heated to 85 oC and stirred for 1.75 h.  The brown solution was cooled to rt and the solvents were removed in vacuo to afford a red-brown residue.  The residue was purified by column chromatography on silica gel (3:1→1:1→0:1 hexanes:ethyl acetate) to afford the crude product as a yellow oil.  The silica gel was flushed with methanol to recover 0.080 g of Chapter 2:  The Total Synthesis of (+)-Fawcettidine   95 the allylic alcohol (0.25 mmol).  To a solution of the allylic alcohol in 4 mL of dichloromethane was added 0.22 g of activated manganese dioxide (2.6 mmol).  The suspension was stirred for 24 h at rt and then filtered through Celite®, rinsing with ethyl acetate and methanol.  The solution was concentrated in vacuo to afford a black film.  The crude film was purified by column chromatography on silica gel (1:1→0:1 hexanes:ethyl acetate) to yield a second portion of the title compound 2.85 as a yellow oil.  A total yield of 0.12 g (70 %) of the title compound 2.85 was obtained. IR (neat): 2958, 2930, 1728, 1636, 1455, 1408, 731, 704 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.35-7.22 (m, 5H), 6.29 (s, 1H), 5.43 (s, 1H), 5.43-5.40 (m, 1H), 4.20 (d, J = 15.3 Hz, 1H), 3.76 (dd, J = 12.6, 3.9 Hz, 1H), 2.71-2.63 (m, 2H), 2.58-2.53 (m, 1H), 2.21-2.15 (m, 1H), 2.04-1.77 (m, 5H), 1.64 (td, J = 12.8, 5.5 Hz, 1H), 1.43 (dt, J = 14.0, 4.9 Hz, 1H), 1.14-1.06 (m, 1H), 0.77 (s, 3H).  13C NMR (100 MHz, CDCl3): δ 206.8, 172.2, 145.8, 138.5, 129.6, 128.3, 128.1, 121.9, 57.3, 48.4, 46.2, 43.1, 37.2, 36.5, 32.0, 31.3, 30.2, 27.6, 19.3.  MS (ESI): 324 (M + H)+.  [α]22D = −109o (c = 2.03, CHCl3).  N O PhN O Ph O H3CO OCH3 O O O 2.85 2.107 Dimethyl 2-(((4aS,7aS,9R)-1-benzyl-9-methyl-2,6-dioxo-dodecahydrocyclopenta[e]quinolin- 5-yl)methyl)malonate (2.107) To a suspension of 0.02 g of sodium hydride (0.7 mmol) in 2 mL of THF was added dropwise 0.1 mL of dimethyl malonate (0.7 mmol).  The resulting solution was stirred for 0.1 h at rt.  A solution of 0.1 g of enone 2.85 (0.3 mmol) in 4 mL of THF was added to the reaction mixture. The resulting yellow solution was heated to 50 oC and stirred for 2 h.  The reaction mixture was cooled to rt, diluted with diethyl ether, washed once with a saturated solution of ammonium chloride and once with brine.  The combined aqueous fractions were extracted once with diethyl ether.  The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo to yield an orange oil.  The crude oil was purified by column chromatography on silica gel (1:1→0:1 hexanes:ethyl acetate) to afford 0.1 g (72 %) of the title compound 2.107 as a white solid, mp:119-123 oC. Chapter 2:  The Total Synthesis of (+)-Fawcettidine   96 IR (film): 2954, 1734, 1646, 1437, 1412, 914, 731 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.30- 7.26 (m, 2H), 7.21-7.12 (m, 3H), 5.45 (d, J = 16.4 Hz, 1H), 4.22 (dd, J = 10.6, 3.9 Hz, 1H), 4.12 (d, J = 16.4 Hz, 1H), 3.95 (dd, J = 13.1, 3.5 Hz, 1H), 3.76 (s, 3H), 3.71 (s, 3H), 2.76-2.67 (m, 2H), 2.63-2.55 (m, 1H), 2.42 (dd, J = 19.3, 7.6 Hz, 1H), 2.18-2.12 (m, 2H), 2.04-1.84 (m, 5H), 1.75-1.67 (m, 2H), 1.41-1.30 (m, 2H), 0.88 (s, 3H).  13C NMR (100 MHz, CDCl3): δ 218.8, 172.3, 170.2, 169.8, 138.9, 128.7, 126.8, 126.3, 54.2, 52.8, 52.7, 49.4, 46.8, 45.9, 44.6, 42.5, 38.5, 34.5, 30.1, 29.8, 28.8, 27.2, 26.1, 18.0.  MS (ESI): 456 (M + H)+.  Anal. Calcd for C26H33NO6: C, 68.55; H, 7.30; N, 3.07.  Found: C, 68.52; H, 7.36; N, 3.33.  [α] 22 D = −131 o (c = 2.09, CHCl3).  N O Ph O N O Ph O H3CO OCH3 O O OCH3 O 2.107 2.109 Methyl 3-((4aS,7aS,9R)-1-benzyl-9-methyl-2,6-dioxo-dodecahydrocyclopenta[e]quinolin-5- yl)propanoate (2.109) To a solution of 0.5 g of diester 2.107 (1 mmol) in 15 mL of dimethyl sulfoxide were added 0.1 g of sodium chloride (2 mmol) and 0.06 mL of water (3 mmol).  The reaction mixture was heated to 160 oC and stirred for 5 h.  The solution was cooled to rt, poured into 40 mL of water, and extracted five times with diethyl ether.  The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo to afford an orange oily solid.  The crude solid was purified by column chromatography on silica gel (1:1→1:2→0:1 hexanes:ethyl acetate) to afford 0.3 g (70 %) of the title compound 2.109 as a yellow oil. IR (neat): 2933, 1736, 1646, 1438, 1412, 730 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.33-7.16 (m, 5H), 5.40 (d, J = 16.1 Hz, 1H), 4.17 (d, J = 16.1 Hz, 1H), 3.97 (dd, J = 13.1, 3.5 Hz, 1H), 3.69 (s, 3H), 2.92-2.56 (m, 5H), 2.47-2.40 (m, 1H), 2.18-2.05 (m, 3H), 1.95-1.87 (m, 2H), 1.79- 1.66 (m, 4H), 1.43-1.39 (m, 2H), 0.90 (d, J = 7.0 Hz, 3H).  13C NMR (100 MHz, CDCl3): 220.3, 175.1, 173.4, 139.8, 129.6, 127.7, 127.3, 55.4, 52.5, 48.8, 46.7, 45.5, 43.5, 39.4, 35.4, 32.4, 31.0, 30.9, 29.9, 28.2, 22.9, 18.8.  MS (ESI): 420 (M + Na)+.  [α]22D = −116 o (c = 1.45, CHCl3).   Chapter 2:  The Total Synthesis of (+)-Fawcettidine   97 N O Ph O H3CO OCH3 O O 2.107 N O Ph H3CO O 2.108 O O OCH3 O  Ketal (2.108) A solution of 0.07 g of compound 2.107 (0.2 mmol), 0.04 mL of ethylene glycol (0.6 mmol), and 6 mg of p-toluenesulfonic acid monohydrate (0.03 mmol) in 10 mL of benzene was heated to reflux using a Dean-Stark apparatus.  The reaction mixture was stirred at reflux for 17.5 h.  The solution was cooled to rt and carefully poured into a saturated solution of sodium bicarbonate. The layers were separated and the aqueous layer was extracted twice with diethyl ether.  The combined organic fractions were washed once with brine.  The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo to afford a clear yellow oil.  The crude oil was purified by column chromatography on silica gel (1:1→1:3 hexanes:ethyl acetate) to afford 0.07 g (94 %) of the title compound 2.108 as a clear oil. IR (film):  2956, 1749, 1733, 1647 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.28-7.24 (m, 2H), 7.18-7.12 (m, 3H), 5.45 (d, J = 16.6 Hz, 1H), 4.15 (d, J = 16.6 Hz, 1H), 4.00-3.84 (m, 4H), 3.74 (s, 3H), 3.73 (d, J = 9.6 Hz, 1H), 3.68 (s, 3H), 3.56 (dd, J = 10.7, 4.1 Hz, 1H), 2.71-2.53 (m, 3H), 2.26-2.18 (m, 1H), 2.10-1.98 (m, 4H), 1.92-1.81 (m, 2H), 1.60-1.43 (m, 4H), 1.17 (dd, J = 14.2, 5.0 Hz, 1H), 0.81 (d, J = 7.0 Hz, 3H).  13C NMR (100 MHz, CDCl3): δ 173.7, 171.2, 170.9, 140.2, 129.5, 127.5, 127.2, 118.2, 65.2, 63.4, 55.2, 53.6, 53.3, 50.4, 47.7, 45.5, 43.8, 42.7, 42.4, 34.2, 31.3 30.0, 29.5, 28.1, 25.6, 19.0.  MS (ESI): 500 (M + H)+, 522 (M + Na)+.  [α]22D = −412 o (c = 0.11, CHCl3).  N O Ph 2.110 N O Ph O OCH3 O 2.109 OCH3 O O O NPh 2.111 OH O O  Alcohol (2.111) A solution of 0.90 g of compound 2.109 (2.3 mmol), 0.51 mL of ethylene glycol (9.1 mmol), and 0.086 g of para-toluenesulfonic acid monohydrate (0.45 mmol) in 40 mL of benzene was heated to reflux using a Dean-Stark apparatus.  The reaction mixture was heated to reflux for 22 h.  The solution was cooled to rt and carefully poured into a saturated solution of sodium bicarbonate Chapter 2:  The Total Synthesis of (+)-Fawcettidine   98 and diluted with diethyl ether.  The layers were separated and the aqueous layer was extracted twice with diethyl ether.  The combined organic fractions were washed once with brine.  The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo to afford ketal 2.110 as a clear yellow oil.  The crude material was used directly in the next reaction with no further purification.  To a suspension of 0.32 g of lithium aluminum hydride (8.5 mmol) in 5 mL of THF was added a solution of 0.75 g of ketal 2.110 (1.7 mmol) in 10 mL of THF.  The suspension was heated to reflux and stirred for 5 h.  The reaction mixture was cooled to rt and quenched by the slow, sequential addition of 0.32 mL of water, 0.32 mL of 15 % NaOH, and then 0.96 mL of water. The solution was stirred at rt for 0.5 h before filtering through a pad of Celite® covered with magnesium sulfate.  The pad was rinsed exhaustively with diethyl ether.  The filtrate was dried over sodium sulfate, filtered, and concentrated in vacuo to afford a clear oil.  The crude oil was purified by column chromatography on silica gel (30:1→20:1→10:1 dichloromethane:methanol) to afford 0.54 g (80 %; 59 % over 2 steps) of the title compound 2.111 as a clear oil. IR (film): 3424 (br), 2953, 2791, 1713, 700 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.29-7.25 (m, 4H), 7.22-7.16 (m, 1H), 4.03 (d, J = 12.8 Hz, 1H), 3.96-3.89 (m, 3H), 3.78-3.67 (m, 3H), 2.87- 2.78 (m, 2H), 2.64-2.56 (m, 2H), 2.39 (dd, J = 12.3, 4.6 Hz, 1H), 2.21-2.16 (m, 1H), 2.09 (br s, 1H), 2.02-1.87 (m, 5H), 1.76-1.58 (m, 7H), 1.40 (d, J = 13.3 Hz, 1H), 1.34-1.32 (m, 1H), 1.26- 1.19 (m, 1H), 1.04 (d, J = 7.3 Hz, 3H).  13C NMR (100 MHz, CDCl3): δ 142.1, 129.6, 129.1, 127.4, 119.4, 65.5, 65.4, 64.4, 63.7, 59.7, 56.4, 47.2, 47.6, 43.3, 42.1, 35.8, 34.9, 33.4, 30.9, 28.1, 24.6, 24.5, 21.0.  MS (ESI): 400 (M + H)+, 422 (M + Na)+.  [α]22D = +51.9 o (c = 3.16, CHCl3).  2.9.4 Route B: Model Studies H2N SH .HCl BocHN SH BocHN S H N O 2.115 2.116 2.117 tert-Butyl 2-(ethylcarbamoylthio)ethylcarbamate (2.117) To a solution of 10.0 g of mercaptoethylamine hydrochloride (2.115) (88.0 mmol) in 200 mL of dichloromethane was added 12.2 mL of triethylamine (88.0 mmol) in one portion.  The reaction mixture was stirred at rt for 0.2 h.  To the solution was added 19.2 g of di-t-butyl dicarbonate (88.0 mmol) in one portion.  The reaction mixture spontaneously heated to reflux and then cooled to rt.  The resulting white suspension was then stirred at rt for 17 h.  The mixture was Chapter 2:  The Total Synthesis of (+)-Fawcettidine   99 washed twice with water.  The combined aqueous fractions were extracted once with dichloromethane.  The combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo to afford sulfide 2.116 a clear oil.  The material was used in the next reaction with no further purification.  To a solution containing approximately 16 g of crude sufide 2.116 (89 mmol) in 200 mL of dichloromethane was added 3.7 mL of triethylamine (26 mmol) in one portion.  To the resulting mixture was added 14 mL of ethyl isocyanate (1.8 × 102 mmol) very slowly.  The reaction mixture was stirred at rt for 12 h.  The solution was then washed five times with brine.  The combined aqueous fractions were extracted once with dichloromethane.  The combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo to afford and off- white solid.  The solid was recrystallized in two crops from dichloromethane and hexanes to give 19 g (89 % over 2 steps) of the title compound 2.117 as white crystals. IR (film): 3324, 2980, 2252, 1701, 1665 cm-1.  1H NMR (400 MHz, CDCl3): δ 5.72 (br s, 1H), 5.04 (br s, 1H), 3.31 (t, J = 6.1 Hz, 4H), 3.00 (t, J = 6.4 Hz, 2H), 1.42 (s, 9H), 1.15 (t, J = 7.3 Hz, 3H).  BocHN S H N O 2.117 H3N S H N O F3C O O 2.118 2-(Ethylcarbamoylthio)ethanaminium 2,2,2-trifluoroacetate (2.118) To a solution of 19.4 g of thiocarbamate 2.117 (78.0 mmol) in 25 mL of dichloromethane was added 18.0 mL of trifluoroacetic acid (234 mmol) in two portions.  The reaction mixture was stirred at rt for 20 h.  The dichlormethane was removed by rotary evaporation in vacuo.  The excess trifluoroacetic acid was removed by rotary evaporation under reduced pressure (0.5 mmHg) to afford a crude white solid.  The crude solid was triterated with hexanes and then dried under vacuum to afford 20.4 g (100 %) of the title compound 2.118 as a white solid. 1H NMR (400 MHz, DMSO): δ 8.20 (br s, 1H), 7.95 (br s, 3H), 3.16-3.09 (m, 2H), 3.02-2.96 (m, 4H), 1.00 (t, J = 7.3 Hz, 3H). 2.117 and 2.118 have been previously prepared, see: Anada, T.; Karinaga, R.; Mizu, M.; Kuomoto, K.; Matsumoto, T.; Numata, M.; Shinkai, S.; Sakurai, K. e-J. Surf. Sci. Nanotechnol. 2005, 3, 195-202.  Chapter 2:  The Total Synthesis of (+)-Fawcettidine   100 O OCH3 O N O S H N O N O S H N O 2.119 2.120 5 : 1 S-2-(5-(But-3-ynyl)-2-oxo-3,4,5,6,7,8-hexahydroquinolin-1(2H)-yl)ethyl ethylcarbamothioate + S-2-(5-(But-3-ynyl)-2-oxo-3,4,4a,5,6,7-hexahydroquinolin-1(2H)- yl)ethyl ethylcarbamothioate (2.120) A solution of 0.08 g of compound 2.119 (0.4 mmol), 0.3 g of ammonium salt 2.118 (1 mmol), and 0.4 mL of acetic acid in 5 mL of toluene was heated to reflux using a Dean-Stark apparatus. The reaction mixture was stirred for 2 h before cooling to rt.  The solution was diluted with diethyl ether and carefully washed twice with a saturated solution of sodium bicarbonate.  The aqueous fractions were then extracted twice with diethyl ether.  The combined organic fractions were dried over sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo to afford a yellow oil.  The crude oil was purified by column chromatography on triethylamine washed silica gel (3:1→1:1 hexanes:ethyl acetate) to afford 0.09 g (82 %) of a 5:1 mixture of the title compound 2.120 as a pale yellow oil. IR (neat): 3292, 2934, 2115, 1646, 1525 cm-1.  1H NMR (400 MHz, CDCl3): δ 5.91 (br s, 1H), 3.82-3.75 (m, 1H), 3.71-3.61 (m, 1H), 3.32-3.30 (m, 2H), 3.02-2.87 (m, 2H), 2.47-2.36 (m, 2H), 2.29-2.10 (m, 6H), 2.06-2.00 (m, 1H), 1.94 (t, J = 2.2 Hz, 1H), 1.88-1.62 (m, 4H), 1.47-1.32 (m, 2H), 1.14 (t, J = 7.0 Hz, 3H).  Additional signals associated with the minor isomer: δ 5.54 (br s, 1H), 4.02-3.95 (m, 1H), 2.63-2.57 (m, 1H).  13C NMR (100 MHz, CDCl3): δ 171.4, 169.8, 167.5, 139.0, 133.5, 119.5, 106.5, 85.2, 69.6, 69.5, 42.3, 41.0, 39.7, 38.0, 37.3, 33.7, 33.3, 32.8, 32.4, 29.0, 27.3, 27.2, 26.7, 25.9, 25.2, 24.7, 21.1, 17.3, 16.9, 15.9.  MS (APCI): 349 (M + H+), 357 (M + Na)+.     Chapter 2:  The Total Synthesis of (+)-Fawcettidine   101 N O S H N O N O S H N O 2.120 2.121 S-2-(5-Methylene-2-oxo-3,4,5,6,7,7a,8,9-octahydrocyclopenta[e]quinolin-1(2H)-yl)ethyl ethylcarbamothioate (2.121) A solution containing 0.087 g of compound 2.120 (0.26 mmol) and 3.5 mg of platinum(II) chloride (0.013 mmol) in 5 mL of toluene was heated to 90 oC and stirred for 6 h.  The reaction mixture was cooled to rt and filtered through a plug of triethylamine washed silica gel.  The filtrate was concentrated by rotary evaporation in vacuo to afford an orange oil.  The crude oil was purified by column chromatography on triethylamine washed silica gel (1:1 hexanes:ethyl acetate) to afford 0.059 g (68 %) of the title compound 2.121 as a clear oil. IR (neat): 3297, 2924, 1630, 1527, 731 cm-1.  1H NMR (400 MHz, CDCl3): δ 6.03 (br s, 1H), 5.55 (br s, 1H), 4.90 (s, 1H), 4.67 (s, 1H), 4.07-4.00 (m, 1H), 3.73-3.65 (m, 1H), 3.32 (qt, J = 6.5 Hz, 2H), 3.07-2.98 (m, 2H), 2.58-2.34 (m, 4H), 2.27-1.97 (m, 3H), 1.85-1.78 (m, 2H), 1.60-1.52 (m, 1H), 1.48-1.40 (m, 2H), 1.37-1.25 (m, 1H), 1.15 (t, J = 7.4 Hz, 3H).  13C NMR (100 MHz, CDCl3): δ 169.9, 167.6, 154.4, 139.7, 109.4, 106.7, 49.5, 46.1, 45.8, 37.3, 30.3, 29.3, 29.1, 27.6, 27.5, 26.8, 25.4, 15.2.  MS (ESI): 357 (M + Na)+.  N O S H N O N O S H N O 2.121 N O S H N O O 2.122 OH  S-2-(5-Methylene-2,6-dioxo-3,4,5,6,7,7a,8,9-octahydrocyclopenta[e]quinolin-1(2H)-yl)ethyl ethylcarbamothioate (2.122) To a solution of 0.06 g of compound 2.121 (0.2 mmol) in 4 mL of dichloromethane was added 0.07 mL of a solution of tert-butyl hydroperoxide (70 wt. % in H2O, 0.5 mmol) in one portion. To the clear solution was added 9 mg of selenium dioxide (0.09 mmol) in one portion.  The reaction mixture was stirred at rt for 24 h.  The mixture was quenched with 2 mL of a saturated solution of sodium bicarbonate and 2 mL of a saturated solution of sodium bisulfite.  The biphasic mixture was stirred vigorously at rt for 0.3 h.  The reaction mixture was diluted with water and dichloromethane and the layers were separated.  The aqueous layer was extracted three Chapter 2:  The Total Synthesis of (+)-Fawcettidine   102 times with dichloromethane.  The combined organic fractions were dried over sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo to afford the crude alcohol as a clear oily film.  The product was moved onto the next reaction with no further purification.  To an open atmosphere solution of 0.06 g of crude alcohol (0.2 mmol) in 7 mL of dichloromethane was added 0.2 g of manganese(IV) oxide (2 mmol) in one portion.  The flask was capped and the resulting black suspension was stirred at rt for 22 h.  The reaction mixture was filtered over Celite®, rinsing exhaustively with ethyl acetate.  The filtrated was concentrated by rotary evaporation in vacuo to afford a clear oil.  The crude oil was purified by column chromatography on triethylamine washed silica gel (2:1→1:1 hexanes:ethyl acetate) to afford 0.02 g (32 % over 2 steps; 42 % BRSM) of the title compound 2.122 as a clear oil. IR (neat): 3299, 2927, 1725, 1667, 1641, 1536, 757 cm-1.  1H NMR (400 MHz, CDCl3): δ 6.13 (s, 1H), 5.74 (br s, 1H), 5.65 (br s, 1H), 5.21 (s, 1H), 4.14-4.06 (m, 1H), 3.71 (ddd, J = 13.5, 10.9, 5.7 Hz, 1H), 3.35 (qt, J = 6.1 Hz, 2H), 3.13-3.01 (m, 2H), 2.75 (dd, J = 18.7, 7.4 Hz, 1H), 2.61-2.55 (m, 1H), 2.47 (dd, J = 12.0, 7.2 Hz, 1H), 2.30-2.25 (m, 2H), 2.21-2.15 (m, 2H), 1.87- 1.83 (m, 2H), 1.69-1.66 (m, 1H), 1.31-1.21 (m, 1H), 1.18 (t, J = 7.4 Hz, 3H).  13C NMR (100 MHz, CDCl3): δ 205.9, 169.2, 167.6, 149.1, 139.1, 120.5, 107.5, 46.7, 46.3, 43.0, 40.5, 37.4, 30.1, 29.8, 27.5, 27.4, 24.8, 15.2.  MS (ESI): 371 (M + Na)+.  N O S H N O O N O S O 2.122 2.123 Sulfide (2.123) To a solution of 0.018 g of enone 2.122 (0.052 mmol) in 5 mL of methanol was added 7 mL of a solution of 1 M NaOH via pipette.  The reaction mixture was stirred vigorously at rt for 0.3 h. The solution was extracted three times with dichloromethane.  The combined organic fractions were dried over sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo to afford a white film.  The film was purified by column chromatography on triethylamine washed silica gel (1:2→1:3 hexanes:ethyl acetate) to afford 0.012 g (82 % ) of the title compound 2.123 as a white solid. Chapter 2:  The Total Synthesis of (+)-Fawcettidine   103 1H NMR (400 MHz, CDCl3): δ 5.49 (q, J = 2.8 Hz, 1H), 4.74-4.67 (m, 1H), 3.34 (d, J = 10.0 Hz, 1H), 3.13 (d, J = 14.4 Hz, 1H), 3.00-2.88 (m, 2H), 2.75-2.69 (m, 3H), 2.61-2.56 (m, 1H), 2.52- 2.49 (m, 1H), 2.39-2.15 (m, 4H), 2.05-1.89 (m, 2H), 1.78-1.73 (m, 1H), 1.33-1.17 (m, 1H).  13C NMR (100 MHz, CDCl3): δ 218.2, 169.8, 139.0, 114.4, 78.2, 61.2, 44.1, 43.8, 42.4, 37.9, 34.8, 33.5, 29.4, 27.4, 23.9.  MS (APCI): 294 (M + H)+.   N O S O    ORTEP representation of the solid state structure of 2.123 ...........................................................................................................................................................   2.9.5 Route B: Forward Synthesis O OCH3 O N O S H N O N O S H N O 2.99 2.124 10 : 1 S-2-((5R,7R)-5-(But-3-ynyl)-7-methyl-2-oxo-3,4,5,6,7,8-hexahydroquinolin-1(2H)-yl)ethyl ethylcarbamothioate + S-2-((5R,7R)-5-(But-3-ynyl)-7-methyl-2-oxo-3,4,5,6,7,8- hexahydroquinolin-1(2H)-yl)ethyl ethylcarbamothioate (2.124) To a solution of 3.97 g of compound 2.99 (15.9 mmol) and 14.6 g of 2- (ethylcarbamoylthio)ethanaminium 2,2,2-trifluoroacetate (2.118) (55.5 mmol) in 40 mL of toluene was added 15.9 mL of acetic acid.  A Deak-Stark apparatus was attached and the reaction mixture was heated to reflux and stirred for 4.5 h.  The reaction mixture was cooled to rt, diluted with diethyl ether, and washed twice with a saturated solution of sodium bicarbonate.  The combined aqueous fractions were extracted once with diethyl ether.  The combined organic Chapter 2:  The Total Synthesis of (+)-Fawcettidine   104 fractions were dried over sodium sulfate, filtered, and concentrated in vacuo to afford a brown oil.  The crude oil was purified by column chromatography on triethylamine washed silica gel (3:1→1:1→0:1 hexanes:ethyl acetate) to afford 3.89 g (70 %) of the title compound 2.124 as a white solid, mp: 94-99 oC. IR (neat): 3290, 2930 2360, 1651, 1525 cm-1.  1H NMR (400 MHz, CDCl3): δ 6.12 (br s, 1H), 3.73-3.66 (m, 2H), 3.29-3.26 (m, 2H), 2.93-2.89 (m, 2H), 2.44-1.99 (m, 8H), 1.94 (t, J = 2.4 Hz, 1H), 1.83-1.65 (m, 3H), 1.53-1.20 (m, 3H), 1.11 (t, J = 7.3 Hz, 3H), 0.99 (m, 3H).  13C NMR (100 MHz, CDCl3): δ 172.1, 167.8, 133.0, 119.5, 85.6, 70.2, 42.6, 38.3, 37.7, 35.1, 34.8, 33.4, 33.1, 29.5, 26.0, 25.3, 22.9, 18.3, 16.3.  Additional signals associated with the minor isomer: δ 170.7, 170.4, 138.8, 129.8, 128.0, 112.9, 85.4, 70.1, 41.7, 35.6, 34.5, 34.0, 29.2, 26.6, 17.5, 15.7. MS (APCI): 349 (M + H)+.  Anal. Calcd for C19H28N2O2S: C, 65.48; H, 8.10; N, 8.04.  Found: C, 65.22; H, 8.10; N, 7.78.  [α]20D = +24 o (c = 0.57, CHCl3).  N O S H N O N O S H N O 2.124 2.125 S-2-((9R)-9-Methyl-5-methylene-2-oxo-3,4,5,6,7,7a,8,9-octahydrocyclopenta[e]quinolin- 1(2H)-yl)ethyl ethylcarbamothioate (2.125) A solution containing 3.33 g of compound 2.124 (9.57 mmol) and 0.255 g of platinum(II) chloride (0.957 mmol) in 35 mL of toluene was heated to 90 oC and stirred for 5 h.  The reaction mixture was then cooled to rt and filtered through a plug of triethylamine washed silica gel.  The filtrate was concentrated by rotary evaporation in vacuo to give a thick brown oil.  The crude oil was purified by column chromatography on triethylamine washed silica gel (3:1→1:1→0:1 hexanes:ethyl acetate) to afford 2.91 g (87 %) of the title compound 2.125 as a yellow foam. IR (neat): 3288, 2955, 2244, 1657, 1631, 1527 cm-1.  1H NMR (400 MHz, CDCl3): δ 6.28 (br s, 1H), 5.45 (d, J = 3.5 Hz, 1H), 4.87 (s, 1H), 4.63 (s, 1H), 4.02-3.95 (m, 1H), 3.74-3.67 (m, 1H), 3.29 (t, J = 5.7 Hz, 2H), 3.00-2.98 (m, 2H), 2.51-2.30 (m, 5H), 2.03-1.95 (m, 2H), 1.79-1.75 (m, 1H), 1.57-1.45 (m, 2H), 1.38-1.33 (m, 1H), 1.22-1.17 (m, 1H), 1.12 (t, J = 7.0, 3H), 0.99 (d, J = 7.0, 3H).  13C NMR (100 MHz, CDCl3): δ 170.1, 167.5, 154.3, 139.0, 112.7, 109.3, 49.3, 45.6, 41.8, 37.3, 33.5, 30.3, 29.7, 29.4, 29.3, 27.6, 27.4, 22.4, 15.9.  MS (APCI): 349 (M + H)+, 371 (M + Na)+.  [α]21D = +92 o (c = 0.99, CHCl3). Chapter 2:  The Total Synthesis of (+)-Fawcettidine   105  N O S H N O N O S H N O O 2.125 2.126 S-2-((9R)-9-Methyl-5-methylene-2,6-dioxo-3,4,5,6,7,7a,8,9-octahydrocyclopenta[e]quinolin- 1(2H)-yl)ethyl ethylcarbamothioate (2.126) A solution of 0.11 g of annulation product 2.125 (0.30 mmol) and 0.034 g of selenium dioxide (0.30 mmol) in 7 mL of 1,4-dioxane was heated to 85 oC and stirred for 1.75 h.  The resulting brown solution was cooled to rt and the solvents were removed in vacuo to give a red-brown residue.  The residue was purified by column chromatography on triethylamine washed silica gel (3:1→1:1→1:2→0:1 hexanes:ethyl acetate) to afford 0.060 g (54 %) of the title compound 2.126 as a pale yellow oil. IR (neat): 3290, 2932, 2360, 1728, 1667, 1636, 1524 cm-1.  1H NMR (400 MHz, CDCl3): δ 6.11 (s, 1H), 5.80 (br s, 1H), 5.66 (d, J = 4.8 Hz, 1H), 5.20 (s, 1H), 4.09-4.02 (m, 1H), 3.78-3.70 (m, 1H), 3.33 (qt, J = 6.1 Hz, 2H), 3.10-3.01 (m, 2H), 2.75 (dd, J = 18.7, 7.4 Hz, 1H), 2.60-2.30 (m, 4H), 2.15 (s, 1H), 1.91-1.79 (m, 2H), 1.44-1.41 (m, 2H), 1.16 (t, J = 7.4 Hz, 3H), 1.00 (d, J = 7.0 Hz, 3H).  13C NMR (100 MHz, CDCl3): δ 205.9, 169.4, 167.4, 149.0, 138.5, 120.6, 113.3, 46.7, 46.0, 42.8, 37.4, 36.1, 34.0, 30.3, 29.8, 29.0, 27.5, 22.3, 15.9.  MS (ESI): 385 (M + Na)+.  [α]20D = +40.6o (c = 1.58, CHCl3).  N O S H N O O N O S O 2.126 2.127 Sulfide (2.127) A solution of 134 mg of enone 2.126 (0.37 mmol) in 20 mL of freshly sparged 1 M NaOH and 5 drops of dry dichloromethane was stirred vigorously for 12 h.  The aqueous solution was extracted five times with dichloromethane.  The combined organic fractions were dried over sodium sulfate, filtered and concentrated in vacuo to afford a clear oil.  The crude oil was purified by column chromatography on triethylamine washed silica gel (1:1→1:2→0:1 Chapter 2:  The Total Synthesis of (+)-Fawcettidine   106 hexanes:ethyl acetate) to yield 82.0 mg (76 %) of sulfide 2.127 as a white solid, mp: 155 oC (dec). IR (film): 2928, 1734, 1636 cm-1.  1H NMR (400 MHz, CDCl3): δ 5.42 (d, J = 4.3 Hz, 1H), 4.71- 4.64 (m, 1H), 3.36 (dt, J = 13.4, 4.6 Hz, 1H), 3.00-2.87 (m, 3H), 2.69 (t, J = 7.3 Hz, 2H), 2.65- 2.58 (m, 3H), 2.51 (d, J = 9.4 Hz, 1H), 2.36 (septet, J = 4.7 Hz, 1H), 2.17 (dd, J = 18.6, 4.3 Hz, 1H), 2.00-1.97 (m, 2H), 1.60-1.51 (m, 2H), 1.11 (d, J = 7.0, 3H).  13C NMR (100 MHz, CDCl3): δ 217.9, 169.9, 139.1, 120.6, 78.2, 61.5, 44.1, 43.5, 38.9, 37.1, 34.5, 33.6, 31.3, 29.6, 28.1, 22.1. MS (APCI): 292 (M + H)+.  [α]21D = +335 o (c = 0.75, CHCl3).  N S O N O S O O O 2.127 2.129 Ketal (2.129) A solution of 0.35 g of sulfide 2.127 (1.2 mmol), 0.30 g of pyridinium p-toluenesulfonate (1.2 mmol), and 0.40 mL of ethylene glycol (7.1 mmol) in 15 mL of benzene was heated to reflux using a Dean-Stark apparatus.  The reaction was refluxed with stirring for 30 h.  It was then cooled to rt, diluted with diethyl ether, and poured into a solution of saturated sodium bicarbonate.  The aqueous layer was separated and subsequently extracted three times with ethyl acetate.  The combined organic fractions were dried over sodium sulfate, filtered, and concentrated to yield a brown oil.  The crude oil was purified by column chromatography on triethylamine washed silica gel (1:1→1:3→0:1 hexanes:ethyl acetate) to afford 0.35 g (87 %, 93 % BRSM) of ketal 2.129 as a pale yellow oil. IR (neat): 2926, 1636 cm -1.  1H NMR (400 MHz, CDCl3): δ 5.24 (d, J = 3.1 Hz, 1H), 4.66 (ddd, J = 13.7, 11.3, 5.9 Hz, 1H), 3.93-3.78 (m, 4H), 3.30 (dd, J = 13.7, 4.6 Hz, 1H), 3.09 (d, J = 14.8 Hz, 1H), 3.05-2.97 (m, 1H), 2.82-2.57 (m, 3H), 2.38-2.32 (m, 1H), 2.23-2.06 (m, 4H), 1.92-1.85 (m, 1H), 1.80-1.57 (m, 3H), 1.41-1.33 (m, 1H), 1.03 (d, J = 7.0 Hz, 3H).  13C NMR (100 MHz, CDCl3): δ 170.4, 140.4, 120.0, 116.6, 65.6, 64.8, 57.8, 44.5, 41.6, 41.2, 40.2, 35.3, 34.4, 34.2, 34.1, 30.3, 27.3, 22.4.  MS (ESI): 358 (M + Na)+.  Anal. Calcd for C18H25NO3S: C, 64.45; H, 7.51; N, 4.18. Found: C, 64.36; H, 7.58; N, 3.99.  [α]21D = + 206 o (c = 0.26, CHCl3).  Chapter 2:  The Total Synthesis of (+)-Fawcettidine   107 N S O O O O ON S O O O 2.129 2.130 Sulfone 2.130 To a solution of 0.014 g of ketal 2.129 (0.042 mmol) in 1.5 mL of dichloromethane at −78 oC was added dropwise a solution of 0.021 g of m-chloroperbenzoic acid (0.12 mmol) in 2.5 mL of dichloromethane.  The white suspension was stirred for 0.25 h at −78 oC, warmed to rt and stirred for a subsequent 2.5 h.  The reaction mixture was diluted with dichloromethane, washed once with a saturated solution of sodium bicarbonate, once with a saturated solution of sodium bisulfite, and once with brine.  The combined aqueous fractions were extracted once with dichloromethane.  The combined organics were dried over sodium sulfate, filtered, and concentrated to afford a white film.  The crude product was purified by column chromatography on triethylamine washed silica gel (1:1→0:1 hexanes:ethyl acetate) to afford 0.015 g (98 %) of sulfone 2.130 as a clear oil. IR (neat): 2931, 1717, 1646 cm-1.  1H NMR (400 MHz, CDCl3): δ 5.41 (d, J = 3.9 Hz, 1H), 5.22 (ddd,  J = 14.6, 12.4, 6.1 Hz, 1H), 4.02-3.80 (m, 5H), 3.46 (d, J = 16.1, 1H), 3.34 (dd, J = 14.4, 5.8 Hz, 1H), 3.20-3.15 (m, 1H), 3.05-2.98 (m, 1H), 2.70-2.61 (m, 2H), 2.51-2.41 (m, 3H), 2.28- 2.11 (m, 2H), 1.75-1.66 (m, 2H), 1.62-1.56 (m, 2H), 1.09 (d, J = 7.0, 3H).  13C NMR (100 MHz, CDCl3): δ 169.8, 139.1, 119.9, 116.4, 65.7, 65.4, 58.3, 53.6, 48.0, 45.3, 41.4, 40.1, 37.0, 35.5, 33.9, 30.4, 28.2, 22.1.  MS (APCI): 368 (M + H)+.  [α]20D = +149 o (c = 1.23, CHCl3).  N O O O N S O O O O O 2.130 2.131 Olefin 2.131 A suspension of 0.031 g of sulfone 2.130 (0.084 mmol) and 0.30 g of alumina-supported potassium hydroxide in 1.75 mL of tert-butyl alcohol and 0.75 mL of dichloromethane was cooled to −15 oC.  To the cold suspension was slowly added 0.1 mL of dibromodifluoromethane (1.1 mmol).  The reaction mixture was stirred at −15 oC for 2.2 h and warmed to rt.  The mixture was filtered over Celite®, rinsing exhaustively with dichloromethane, and concentrated to give a Chapter 2:  The Total Synthesis of (+)-Fawcettidine   108 N O O O yellow oil.  The crude oil was purified by column chromatography on triethylamine washed silica gel (1:0→3:1→1:1→0:1 hexanes:ethyl acetate) to afford 0.012 g (46 %) of olefin 2.131 as a clear film. IR (neat): 2958, 1695, 1661 cm-1.  1H NMR (400 MHz, CDCl3): δ 5.65-5.62 (m, 1H), 5.54 (s, 1H), 5.39-5.35 (m, 1H), 5.04-5.00 (m, 1H), 3.95-3.89 (m, 4H), 3.62 (dd, J = 17.5, 2.0 Hz, 1H), 2.51-2.33 (m, 3H), 2.31-2.14 (m, 3H), 1.95-1.88 (m, 1H), 1.75-1.61 (m, 3H), 1.34 (ddd, J = 13.6, 10.8, 5.2 Hz, 1H), 1.04 (d, J = 7.0, 3H).  13C NMR (100 MHz, CDCl3): δ 174.2, 141.6, 129.1, 127.1, 125.4, 116.5, 65.7, 64.4, 54.4, 51.0, 50.5, 41.1, 39.4, 37.2, 32.2, 31.3, 26.6, 22.3.  MS (APCI): 302 (M + H)+.  [α]21D = +142 o (c = 0.27, CHCl3).           ORTEP representation of the solid state structure of 2.131 ...........................................................................................................................................................  N O O O N O O O 2.131 2.135 Enamide 2.135 The nitrogen atmosphere of a solution of 0.026 g of olefin 2.131 (0.086 mmol) and 9.0 mg of 5 % palladium on carbon (0.0043 mmol) in 3 mL of a 1:1 ethyl acetate:THF mixture was replaced by purging with hydrogen gas.  A full hydrogen balloon was then attached and the reaction mixture was stirred at rt for 12 h.  The black suspension was filtered through Celite®, rinsing exhaustively with methanol.  The solution was then concentrated to give a yellow film.  The Chapter 2:  The Total Synthesis of (+)-Fawcettidine   109 crude film was purified by column chromatography on triethylamine washed silica gel (1:1→1:3→1:5→0:1 hexanes:ethyl acetate) to afford 0.015 g (57 %) of enamide 2.135 as a white solid. IR (film):  2927, 1738, 1688, 1657 cm-1.  1H NMR (400 MHz, CDCl3): δ 5.57 (s, 1H), 4.38 (dt, J = 12.8, 3.0 Hz, 1H), 3.93-3.83 (m, 4H), 2.87 (ddd, J = 13.3, 9.3, 6.4 Hz, 1H), 2.40-2.20 (m, 4H), 2.16-2.09 (m, 1H), 1.95-1.85 (m, 2H), 1.78-1.57 (m, 6H), 1.34-1.25 (m, 2H), 1.05 (d,  J = 7.0 Hz, 3H).  13C NMR (100 MHz, CDCl3): δ 173.1, 143.0, 126.4, 115.8, 64.8, 63.5, 57.5, 49.9, 47.6, 41.5, 37.8, 37.6, 31.5, 31.3, 28.7, 28.3, 25.8, 21.5.  MS (APCI): 304 (M + H)+.  [α]20D = +106 o (c = 0.76, CHCl3).  N O O N O O O 2.135 2.136 Enamide 2.136 To a suspension of 0.018 g of lithium aluminum hydride (0.48 mmol) in 2 mL of THF was added a solution of 0.015 g of enamide 2.135 (0.048 mmol) in 2 mL of THF.  The reaction mixture was heated to reflux and stirred for 8 h.  The grey suspension was cooled to rt, followed by the slow addition of 18 µL of water, 16 µL of 15 % NaOH, then another 54 µL of water.  The biphasic mixture was stirred for 15 minutes at rt after which 0.2 g of magnesium sulfate was added.  After stirring for another 30 minutes at rt, the mixture was filtered through a pad of Celite® and rinsed exhaustively with diethyl ether.  The filtrate was concentrated in vacuo to afford a clear film. The crude product was purified by column chromatography on triethylamine washed silica gel (1:1→1:3→1:5→0:1 hexanes:ethyl acetate) to afford 9.8 mg (71 %) of enamine 2.136 as a clear oil. IR (neat): 2925, 2852, 1656, 1448 cm-1.  1H NMR (400 MHz, CDCl3): δ 5.52 (d,  J = 1.7 Hz, 1H), 3.95-3.87 (m, 4H), 3.09-2.96 (m, 4H), 2.20-2.18 (m, 1H), 1.98-1.84 (m, 4H), 1.78-1.44 (m, 7H), 1.26-1.11 (m, 3H), 0.98 (d, J = 7.0 Hz, 3H).  13C NMR (100 MHz, CDCl3): δ 148.6, 129.0, 117.3, 65.6, 64.4, 60.8, 56.3, 53.0, 46.8, 43.1, 40.5, 38.9, 33.3, 33.0, 30.0, 27.0, 25.2, 22.6.  MS (APCI): 290 (M + H)+.  [α]20D = +91 o (c = 0.95, CHCl3).  Chapter 2:  The Total Synthesis of (+)-Fawcettidine   110 NN O O O 2.136 2.5 (+)-Fawcettidine (2.5) To a solution of 5.0 mg of enamine 2.136 (0.018 mmol) in 0.5 mL of THF at 0 oC was added 0.05 mL of 1 M HCl.  The solution was stirred at rt for 17 h.  The reaction mixture was neutralized with 0.05 mL of 1 M NaOH and then extracted twice with ethyl acetate.  The combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo to give a pale yellow oil.  The crude oil was purified by column chromatography on triethylamine washed silica gel (1:1→1:3→0:1 hexanes:ethyl acetate) to afford 3.0 mg (60 %) of (+)- fawcettidine (2.5) as a clear oil. IR (neat): 2925, 2853, 1741, 1663 cm-1.  1H NMR (400 MHz, CDCl3): δ 5.69 (d, J = 5.2 Hz, 1H), 3.14-2.98 (m, 4H), 2.74 (ddd, J = 16.6, 7.4, 1.3 Hz, 1H), 2.34-2.24 (m, 2H), 2.20-2.05 (m, 3H), 1.99-1.93 (m, 1H), 1.91-1.83 (m, 1H), 1.79-1.59 (m, 3H), 1.41-1.34 (m, 2H), 1.28-1.21 (m, 2H), 1.05 (d, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 219.9, 147.0, 128.2, 61.4, 57.2, 53.0, 47.1, 45.1, 40.2, 38.3, 35.1, 32.4, 30.2, 28.7, 24.8, 21.8. MS (APCI): 246 (M + H)+.  [α]21D = +92o (c = 0.41, CHCl3), [α] 19 D = +61 o (c = 0.25, EtOH).               Chapter 2:  The Total Synthesis of (+)-Fawcettidine   111 2.10  References 1. Cordell, G. A.; Quinn-Beattie, M. L.; Farnsworth, N. R. Phytother. Res. 2001, 15, 183-205. 2. Kornienko, A.; Evidente, A. Chem. Rev. 2008, 108, 1982-2014. 3. Hanessian, S. Pure Appl. Chem. 2009, 81, 1085-1091. 4. Ma, X.; Gang, D. R. Nat. Prod. Rep. 2004, 21, 752-772. 5. Kobayashi, J. i.; Kubota, T. Nat. Prod. Rep. 2009, 26, 936-962. 6. Jin, Z. Nat. Prod. 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Soc. 1998, 120, 5128-5129. 20. Dugas, H.; Hazenberg, M. E.; Valenta, Z.; Wiesner, K. Tetrahedron Lett. 1967, 8, 4931- 4936. 21. Wiesner, K.; Musil, V.; Wesner, K. J. Tetrahedron Lett. 1968, 9, 5643-5646. 22. Wiesner, K.; Poon, L. Tetrahedron Lett. 1967, 8, 4937-4940. 23. Liu, J.-S.; Zhu, Y.-L.; Yu, C.-M.; Zhou, Y.-Z.; Han, Y.-Y.; Wu, F.-W.; Qi, B.-F. Can. J. Chem. 1986, 64, 837-839. 24. Conroy, H. Tetrahedron Lett. 1960, 1, 34-37. 25. Castillo, M.; Gupta, R. N.; MacLean, D. B.; Spenser, I. D. Can. J. Chem. 1970, 48, 1893- 1903. Chapter 2:  The Total Synthesis of (+)-Fawcettidine   112 26. Castillo, M.; Gupta, R. N.; Ho, Y. K.; MacLean, D. B.; Spenser, I. D. Can. J. Chem. 1970, 48, 2911-2918. 27. Hemscheidt, T.; Spenser, I. D. J. Am. Chem. Soc. 1993, 115, 3020-3021. 28. Hemscheidt, T.; Spenser, I. D. J. Am. Chem. Soc. 1996, 118, 1799-1800. 29. Burnell, R. H. J. Chem. Soc. 1959,  3091-3093. 30. Burnell, R. H.; Chin, C. G.; Mootoo, B. S.; Taylor, D. R. Can. J. Chem. 1963, 41, 3091- 3094. 31. Ishii, H.; Yasui, B.; Nishino, R.-I.; Harayama, T.; Inubushi, Y. Chem. Pharm. Bull. 1970, 18, 1880-1888. 32. Inubushi, Y.; Ishii, H.; Harayama, T.; Burnell, R. H.; Ayer, W. A.; Altenkirk, B. Tetrahedron Lett. 1967, 8, 1069-1072. 33. Ishii, H.; Yasui, B.; Harayama, T.; Inubushi, Y. Tetrahedron Lett. 1966, 7, 6215-6219. 34. Mehta, G.; Sreenivasa Reddy, M.; Radhakrishnan, R.; Manjula, M. V.; Viswamitra, M. A. Tetrahedron Lett. 1991, 32, 6219-6222. 35. Harayama, T.; Takatani, M.; Inubushi, Y. Tetrahedron Lett. 1979, 20, 4307-4310. 36. Heathcock, C. H.; Blumenkopf, T. A.; Smith, K. M. J. Org. Chem. 1989, 54, 1548-1562. 37. Clark, R. D.; Heathcock, C. H. J. Org. Chem. 1973, 38, 3658-3658. 38. Hosomi, A.; Sakurai, H. Tetrahedron Lett. 1976, 17, 1295-1298. 39. Arndt, F.; Eistert, B. Ber. Dtsch. Chem. Ges. 1935, 68, 200-208. 40. Meier, H.; Zeller, K.-P. Angew. Chem., Int. Ed. Engl. 1975, 14, 32-43. 41. Linghu, X.; Kennedy-Smith, J. J.; Toste, F. D. Angew. Chem., Int. Ed. 2007, 46, 7671-7673. 42. Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801-811. 43. Sha, C.-K.; Tsong-Shin, J.; Deh-Chi, W. Tetrahedron Lett. 1990, 31, 3745-3748. 44. Sha, C.-K.; Chiu, R.-T.; Yang, C.-F.; Yao, N.-T.; Tseng, W.-H.; Liao, F.-L.; Wang, S.-L. J. Am. Chem. Soc. 1997, 119, 4130-4135. 45. Sha, C.-K.; Santhosh, K. C.; Lih, S.-H. J. Org. Chem. 1998, 63, 2699-2704. 46. Sha, C.-K.; Lee, F.-K.; Chang, C.-J. J. Am. Chem. Soc. 1999, 121, 9875-9876. 47. Sha, C.-K.; Liao, H.-W.; Cheng, P.-C.; Yen, S.-C. J. Org. Chem. 2003, 68, 8704-8707. 48. Jiang, C.-H.; Bhattacharyya, A.; Sha, C.-K. Org. Lett. 2007, 9, 3241-3243. 49. Liu, K.-M.; Chau, C.-M.; Sha, C.-K. Chem. Commun. 2008,  91-93. 50. Caine, D.; Procter, K.; Cassell, R. A. J. Org. Chem. 1984, 49, 2647-2648. 51. Harayama, T.; Takatani, M.; Inubushi, Y. Chem. Pharm. Bull. 1980, 28, 2394-2402. 52. Kozaka, T.; Miyakoshi, N.; Mukai, C. J. Org. Chem. 2007, 72, 10147-10154. Chapter 2:  The Total Synthesis of (+)-Fawcettidine   113 53. Otsuka, Y.; Inagaki, F.; Mukai, C. J. Org. Chem. 2010, 75, 3420-3426. 54. Pauson, P. L.; Khand, I. U. Ann. N. Y. Acad. Sci. 1977, 295, 2-14. 55. Blanco-Urgoiti, J.; Añorbe, L.; Pérez-Serrano, L.; Domínguez, G.; Pérez-Castells, J. Chem. Soc. Rev. 2004, 33, 32-42. 56. Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380-2383. 57. Mitsunobu, O. Synthesis 1981,  1-28. 58. Swamy, K. C. K.; Kumar, N. N. B.; Balaraman, E.; Kumar, K. V. P. P. Chem. Rev. 2009, 109, 2551-2651. 59. Jung, M. E.; Chang, J. J. Org. Lett. 2010, 12, 2962-2965. 60. Jung, M. E.; Ho, D. G. Org. Lett. 2006, 9, 375-378. 61. Romo, D.; Meyers, A. I. Tetrahedron 1991, 47, 9503-9569. 62. Meyers, A. I.; Snyder, L. J. Org. Chem. 1992, 57, 3814-3819. 63. Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1962, 84, 867-868. 64. Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353-1364. 65. Mutti, S.; Daubié, C.; Decalogne, F.; Fournier, R.; Rossi, P. Tetrahedron Lett. 1996, 37, 3125-3128. 66. Kozak, J. A.; Dake, G. R. Angew. Chem., Int. Ed. 2008, 47, 4221-4223. 67. Krapcho, A. P.; Glynn, G. A.; Grenon, B. J. Tetrahedron Lett. 1967, 8, 215-217. 68. Krapcho, A. P.; Jahngen, E. G. E.; Lovey, A. J.; Short, F. W. Tetrahedron Lett. 1974, 15, 1091-1094. 69. Krapcho, A. P.; Weimaster, J. F.; Eldridge, J. M.; Jahngen, E. G. E.; Lovey, A. J.; Stephens, W. P. J. Org. Chem. 1978, 43, 138-147. 70. Harrison, T. J.; Patrick, B. O.; Dake, G. R. Org. Lett. 2006, 9, 367-370. 71. Ramberg, L.; Bäcklund, B. Ark. Chim. Mineral. Geol. 1940, 13A, 1-50. 72. Paquette, L. A. Acc. Chem. Res. 1968, 1, 209-216. 73. Taylor, R. J. K. Chem. Commun. 1999,  217-227. 74. Taylor, R. J. K.; Casy, G. Org. React. 2003, 62, 357-475. 75. Hwu, J. R.; Hakimelahi, G. H.; Chou, C.-T. Tetrahedron Lett. 1992, 33, 6469-6472. 76. Davison, E. C.; Forbes, I. T.; Holmes, A. B.; Warner, J. A. Tetrahedron 1996, 52, 11601- 11624. 77. Allinger, N. L.; Riew, C. K. Tetrahedron Lett. 1966, 7, 1269-1272. 78. Blumenkopf, T. A.; Heathcock, C. H. J. Am. Chem. Soc. 1983, 105, 2354-2358. 79. Duval, O.; Gomès, L. M. Tetrahedron 1990, 46, 1253-1262. Chapter 2:  The Total Synthesis of (+)-Fawcettidine   114 80. Vincent, G.; Williams, R. M. Angew. Chem., Int. Ed. 2007, 46, 1517-1520. 81. Corey, E. J.; Fleet, G. W. J. Tetrahedron Lett. 1973, 14, 4499-4501. 82. Poos, G. I.; Arth, G. E.; Beyler, R. E.; Sarett, L. H. J. Am. Chem. Soc. 1953, 75, 422-429. 83. Ratcliffe, R.; Rodehorst, R. J. Org. Chem.  1970, 35, 4000-4002. 84. Catino, A. J.; Forslund, R. E.; Doyle, M. P. J. Am. Chem. Soc. 2004, 126, 13622-13623. 85. He, F.; Bo, Y.; Altom, J. D.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 6771-6772. 86. Anada, T.; Karinaga, R.; Mizu, M.; Koumoto, K.; Matsumoto, T.; Numata, M.; Shinkai, S.; Sakurai, K. e-J. Surf. Sci. Nanotech. 2005, 3, 195-202. 87. Chan, T.-L.; Fong, S.; Li, Y.; Man, T.-O.; Poon, C.-D. J. Chem. Soc., Chem. Commun. 1994, 1771-1772. 88. Bordwell, F. G.; Williams, J. M.; Hoyt, E. B.; Jarvis, B. B. J. Am. Chem. Soc. 1968, 90, 429- 435. 89. Katakawa, K.; Nozoe, A.; Kogure, N.; Kitajima, M.; Hosokawa, M.; Takayama, H. J. Nat. Prod. 2007, 70, 1024-1028.     115                 Chapter 3: Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel-Crafts Pathway 2                2 Some material in this chapter has been published.  See: Kozak, J. A.; Dodd, J. M.; Harrison, T. J.; Jardine, K. J.; Patrick, B. O.; Dake, G. R. “Enamides and Enesulfonamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel-Crafts Pathway” J. Org. Chem. 2009, 74, 6929-6935. Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   116 3.1 Introduction The Dake group is interested in using enamides, enecarbamates, and enesulfonamides as nucleophiles in transition metal-catalyzed cycloisomerization reactions.  Initial cycloisomerization reactivity was probed using tetrahydropyridine ring systems with an alkyne tethered at the 4-position, as described in the introductory chapter.1  These investigations proved successful in forming structurally complex nitrogen-containing ring systems.  The scope was therefore extended to substrates bearing the tethered alkyne at the 3-position of the tetrahydropyridine, or the β-position of the enesulfonamide.2  Exchange of the proton at the β- position for an alkyl tether generates a quaternary carbon center upon cyclization.   As an example, Dake and coworkers found that enesulfonamide 3.1 reacted with 5 mol% of platinum(II) chloride, resulting in a 5-exo-dig cyclization (Scheme 3.1).  The putative azacarbenium ion was trapped using methanol to give compound 3.2.  Although compound 3.2 was isolable, the resulting 1:1 diastereomeric mixture made characterization difficult. A one-pot procedure was therefore developed to reduce the methoxy functionality to give spirocycle 3.3.  N Ts a) 5 mol% PtCl2 PhCH3, 80 oC 3 h 80% N Ts 2 equiv.CH3OH b) Et3SiH BF3 .OEt2, rt N Ts 3.1 3.3 OCH3 3.2 Scheme 3.1:  Platinum(II)-catalyzed synthesis of quaternary carbon centers2  As discussed in section 1.6, pendent aromatic rings attack electrophilic sites by undergoing a Friedel-Crafts reaction.  Dake and coworkers wanted to harness the electrophilicity of the intermediary azacarbenium ion in a similar manner.  Friedel-Crafts/Pictet-Spengler-type cyclization of an aromatic ring onto the azacarbenium ion would greatly increase the structural complexity of the products formed (i.e., from bicycles to tetracycles).  A series of enesulfonamides with arene-substituted alkynes were synthesized to test this reactivity (Scheme 3.2).2  Enesulfonamide 3.4 with an electron-rich arene ring cycloisomerized to give tetracyclic products 3.4N and 3.4X in 65% yield and a regioisomeric ratio of 19:1.  Enesulfonamide 3.5 bearing an electron-withdrawing arene ring cycloisomerized to give tetracyclic products 3.5N and 3.5X in 67% yield and a ratio of 1:1.  The isomers were not separable by standard Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   117 purification techniques.  Since a substrate containing an electron-donating aromatic group cyclized with high selectivity, the process became synthetically useful.  N Ts 3 R 10 mol% PtCl2 N Ts + N Ts H H 3.4N, R=OCH3 3.5N, R=CF3 R R 3.4X , R=OCH3 3.5X , R=CF3 3.4, R=OCH3 3.5, R=CF3 PhCH3, 110 oC for 3.4, 65% (3.4N:3.4X 19:1) for 3.5, 67% (3.5N:3.5X  1:1)  Scheme 3.2:  Platinum(II)-catalyzed cyclization to form tetracyclic products2  As shown in Scheme 3.2, two products result from the platinum(II)-catalyzed cyclization of enamides 3.4 and 3.5. The regioisomeric products come from either an initial 5-exo-dig cyclization or a 6-endo-dig cyclization (Scheme 3.3).  Enesulfonamide 3.4 first reacts with a platinum(II) salt to form an activated η2 platinum-alkyne π-complex 3.6.  Attack of the nucleophilic enesulfonamide occurs at one of the two carbons of the alkyne.  The nucleophile can attack in a 5-exo-dig mode of cyclization to form intermediate 3.7.  Alternatively, the nucleophile can attack in a 6-endo-dig fashion to form intermediate 3.8.  Both intermediates 3.7 and 3.8 then undergo Friedel-Crafts cyclization and protodemetallation to give either the “5-exo” tetracyclic product 3.4X or the “6-endo” tetracyclic product 3.4N.  3.4 PtCl2 or 3.6 "5-exo" attack "6-endo" attack N Ts OCH3 3 N Ts OCH3 Pt2+ N Pt- Ts OCH3 N Ts H OCH3 3.7 3.4X N Ts Pt- OCH3 N Ts H OCH3 3.8 3.4N PtBr2  Scheme 3.3:  Formation of regioisomeric products Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   118  The suffixes “N” and “X” are used in the numbering system throughout this chapter and are derived as follows: products that results from an initial 6-endo-dig cyclization of the enamide to the alkyne are given the suffix “N”, while products that derive from an intial 5-exo-dig cyclization are giving the suffix “X”.  The majority of transition metal-catalyzed cycloisomerization reactions occur in a 5-exo- dig mode of cyclization, but can depend on the substituents on the alkyne.3, 4  The tandem platinum(II)-catalyzed addition/Friedel-Crafts reaction developed by Dake depends specifically on the nature of the substituents located on the arene ring.  Enesulfonamide 3.4 contains an electron-rich aromatic ring that pushes electron density onto the alkyne in a non-uniform manner (Scheme 3.4).  The carbon closest to the aromatic ring (i.e., the proximal carbon) has a signal in the 13C NMR spectrum with a chemical shift of 87.8 ppm.  The 13C NMR signal of the alkynyl carbon furthest from the aromatic ring (i.e., the distal carbon) has a chemical shift of 80.7 ppm. These chemical shifts reflect the electron density distribution in the alkyne.  The majority of the electron density resides on the distal carbon due to a resonance contribution from the para- methoxy substituent on the arene ring.  When a platinum(II) salt coordinates to the alkyne as in 3.6, it slips along the alkyne to interact more strongly with the carbon that features more electron density (3.9).  The partial positive character is associated with the proximal carbon atom.  The nucleophile attacks at this position, resulting in a 6-endo-dig cyclization to give intermediate 3.8.  N Pt Ts OCH3 3.8 N Ts OCH3 3.4 δ 87.8 ppm δ 80.7 ppm Pt2+ N Ts OCH3 3.6 Pt2+ N Ts 3.9 H3CO Pt2+ δ η2       η1 slippage  Scheme 3.4:  Rationale for observed isomer ratio of product Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   119  An application of the methodology developed by Dake is demonstrated in the core synthesis of the natural product nakadomarin A by Zhai and coworkers (Scheme 3.5).5  Highly functionalized enecarbamate 3.10 with a pendant alkynyl furan moiety was treated with 18 mol% of platinum(II) chloride to give tetracyclic product 3.11 in a 50% yield.  The authors speculate that the poor yield is due to substrate instability at the reaction temperature.  To circumvent this, the substrate was added slowly via syringe pump.  Despite the high catalyst loading and the moderate yield, the authors were successful in applying this methodology to complete the core of the complex natural product nakadomarin A.  N Boc MeO2C N Ts O 3.10 18 mol% PtCl2 PhCH3, 110 oC N Boc MeO2C 3.11 N O Ts H N N O H H nakadomarin A 50%  Scheme 3.5:  Zhai and coworkers: Platinum(II)-catalyzed cycloisomerization towards the total synthesis of nakadomarin A5 A goal of my PhD research was to expand the scope of the tandem platinum(II)-catalyzed addition/Friedel-Crafts reaction described by Scheme 3.2.  The remainder of this chapter will be divided into 3 sections.  The next section will describe the synthesis of the substrates, with the following section describing the reactions of the substrates within the context of cycloisomerization reactions.  The final section will disclose the experimental results for the reactions described in the previous sections.   3.2 Substrate Synthesis Aldehyde 3.16 was synthesized from commercially available 1-hexyne (3.12) in 4 steps (Scheme 3.6).  1-Hexyne (3.12) was homologated by deprotonation of the acetylenic proton and treated with paraformaldehyde to yield propargyl alcohol 3.13.  An acetylenic zipper reaction of alcohol 3.13 with potassium 3-aminopropylamide6-9 (KAPA reagent: potassium hydride + 1,3- diaminopropane) gave 6-heptyn-1-ol (3.14) in 91% yield, as indicated by the appearance of a triplet at 1.94 ppm in the 1H NMR spectrum attributed to the acetylenic proton.  6-Heptyn-1-ol Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   120 (3.14) was oxidized to aldehyde 3.15 in 86% yield using the Moffatt-Swern method.  Following the procedure of Norman and Heathcock,10 aldehyde 3.15 was converted into methyl ester 3.16 in 58% yield.  The enamine of aldehyde 3.15, created by treatment with piperidine under basic conditions, was added to methyl acrylate, a Michael acceptor.  Acidic workup provided methyl ester 3.16.  All reagents and glassware were rigorously dried to ensure the success of the reaction, as water present in the reaction mixture led to a large amount of homocoupling product.  OH 3.12 3.13 OH 3.14 a)  nBuLi,  THF      -78 oC b)  (CH2O)n KH H2N NH2 92% 91% (COCl)2, DMSO NEt3, CH2Cl2 H 3.15 NH 1. K2CO3, 2. a) CH3CN,          methyl acrylate b) HOAc, H2O 58% H O CO2CH3 3.16 O 86% H O homocoupling product  Scheme 3.6:  Synthetic route for the construction of alkyne 3.16  The synthetic route towards the cyclization substrates diverged at this point.  Methyl ester 3.16 was used to synthesize both enamides 3.17 and 3.18 (Scheme 3.7).  Condensation of ester 3.16 with either methylamine (eq 1) or benzylamine (eq 2) and acetic acid in toluene under dehydrating conditions gave enamides 3.17 and 3.18 in excellent yield.  The formation of the product was verified by the disappearance of the signal attributed to the aldehyde proton in the 1H NMR spectrum and the appearance of the enamide signal at 5.76 ppm and 5.81 ppm for 3.17 and 3.18, respectively.  CH3NH2, AcOH PhCH3 92% N CH3 O 3.17 H O CO2CH3 3.16 BnNH2, AcOH PhCH3 90% N Bn O 3.18 H O CO2CH3 3.16 (1) (2)  Scheme 3.7:  Condensation with primary amines to form enamides 3.17 and 3.18 Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   121  With enamides 3.17 and 3.18 in hand, the route again diverged to form the cycloisomerization substrates.  The alkyne functionality of the enamides was coupled with various commercially available and non-commercially available aryl iodides.  The non- commercially available iodides were synthesized according to Scheme 3.8.  4-Iodo-1,2- dimethoxybenzene (4-iodoveratrole, 3.20) was synthesized in 80% yield from 1,2- dimethoxybenzene (veratrole, 3.19) by treatment with silver acetate and iodine (Scheme 3.8, eq 1).  This reaction was successfully performed on a 40 gram scale.  4-Iodophenyl 4- methylbenzenesulfonate (3.22) was synthesized in 78% yield by the treatment of 4-iodophenol (3.21) with para-toluenesulfonyl chloride and triethylamine (Scheme 3.8, eq 2).  2-Iodo-1- methyl-1H-indole 3.25 was synthesized in two steps from indole (3.23) (Scheme 3.8, eq 3).  The nitrogen was first protected as the lithium carboxylate, and the 2-position was deprotonated with tert-butyllithium.  The anion was finally quenched with 1,2-diiodoethane to give 2-iodoindole (3.24).  Product formation was indicated by a 1-proton doublet at 6.74 ppm in the 1H NMR spectrum attributed to the proton at the 3-position of compound 3.24.  Protection of the nitrogen using sodium hydride and methyl iodide gave the product 3.25 in 91% yield.  3-Iodo-1-methyl- 1H-indole (3.27) was also synthesized in 2 steps from indole (3.23) (Scheme 3.8, eq 4).  Indole (3.23) was treated with potassium hydroxide and iodine in N,N-dimethylformamide to give 3- iodoindole 3.26.  This product was unstable and decomposed rapidly; it was therefore treated directly with sodium hydride and methyl iodide to protect the nitrogen, yielding 3.27 in 93% crude yield over 2 steps. Even with the nitrogen protected, iodoindole 3.27 was generally less stable than the 2-substituted version (3.25).  Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   122 OCH3 OCH3 OCH3 OCH3 I 3.19 3.20 AgOAc, I2 CHCl3 80% I OH I OTs 3.21 3.22 TsCl, NEt3 CH2Cl2 78% N H N H I 3.23 3.24 N I 3.25 CH3 a) nBuLi, THF, CO2 b) tBuLi, ICH2CH2I 84% NaH, MeI THF 91% N H N H 3.23 3.26 I N 3.27 I CH3 KOH, I2 DMF NaH, MeI THF 93% crude (2 steps) (1) (2) (3) (4)  Scheme 3.8:  Synthesis of non-commercially available aryl iodides Enamides 3.17 and 3.18 were coupled with aryl iodides and aryl bromides using a Sonogashira coupling reaction (Table 3.1).11  The reactions were run using 5 mol% of bis(triphenylphosphine)palladium(II) chloride and 10  mol% of copper(I) iodide in a dichloromethane-triethylamine solvent mixture, and were typically complete within 1-5 hours. Bromo-substituted coupling partners were not as reactive as iodide-substituted aromatics (entry 9).  The reaction using 2-bromofuran had to be stirred for 24 hours before the reaction was complete.  The reactions generally proceeded with good to excellent yields.  The instability of the 3-iodo-1-methyl-1H-indole (3.27) (entry 12) is likely the reason for the low yield of the reaction.  Product formation was verified by the disappearance of the acetylenic proton at 1.94 ppm in the 1H NMR spectrum for enamides 3.17 and 3.18 and the appearance of signals corresponding to the aromatic substituent employed.  The enamide proton of the Sonogashira coupling products persisted in the 1H NMR spectrum between 5.76 and 5.87 ppm for N-methyl substituted enamides and 5.81 and 5.85 ppm for the N-benzyl substituted enamides.  With the successful installation of the aromatic functionality, the substrates were tested with platinum(II) chloride and platinum(II) bromide for cycloisomerization reactivity. Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   123 Table 3.1: Sonogashira coupling reactions of enamides NO R conditions NEt3, CH2Cl2 NO R Ar  entry substrate R conditions product Ar yield (%) a,b 1 3.18 Bn C6H5-I, 5 mol% (Ph3P)2PdCl2, 10 mol% CuI 3.28  89 2 3.17 CH3 (p-CH3O)C6H4-I, 5 mol% (Ph3P)2PdCl2, 10 mol% CuI 3.29 OCH3 86 3 3.18 Bn (p-CH3O)C6H4-I, 5 mol% (Ph3P)2PdCl2, 10 mol% CuI 3.30 OCH3 59 4 3.17 CH3 (p-Br)C6H4-I, 5 mol% (Ph3P)2PdCl2, 10 mol% CuI 3.31 Br 87 5 3.17 CH3 3.22, 5 mol% (Ph3P)2PdCl2, 10 mol% CuI 3.32 OTs 56 6 3.17 CH3 (p-CF3)C6H4-I, 5 mol% (Ph3P)2PdCl2, 10 mol% CuI 3.33 CF3 91 7 3.17 CH3 3.20, 5 mol% (Ph3P)2PdCl2, 10 mol% CuI 3.34 OCH3 OCH3  69 8 3.18 Bn 3.20, 5 mol% (Ph3P)2PdCl2, 10 mol% CuI 3.35 OCH3 OCH3  92 9c 3.17 CH3 Br-C4H3O, 5 mol% (Ph3P)2PdCl2, 10 mol% CuI 3.36 O  95 10 3.17 CH3 3.24, 5 mol% (Ph3P)2PdCl2, 10 mol% CuI 3.37 H N  67 11 3.17 CH3 3.25, 5 mol% (Ph3P)2PdCl2, 10 mol% CuI 3.38 N CH3  94 12 3.17 CH3 3.27, 5 mol% (Ph3P)2PdCl2, 10 mol% CuI 3.39 N CH3 32 13 3.17 CH3 (o-SCH3)C6H4-I, 5 mol% (Ph3P)2PdCl2, 10 mol% CuI 3.40 SCH3  92 14 3.17 CH3 (o-OCH3)C6H4-I, 5 mol% (Ph3P)2PdCl2, 10 mol% CuI 3.41 OCH3  81 aReported yields are isolated yields. bReported yields are the maximum of single experiments.  c1- bromofuran was synthesized by Dake group member Jennifer Dodd. Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   124 3.3 Reactions of Substrates Platinum(II)-catalysis was tested on all enamide derivatives.  The reactions were run with 10 mol% of platinum catalyst in toluene (0.2 M) in a thick-walled sealable tube at 110 oC (temperature of the oil bath).  The reactions could not be tested for completion by thin layer chromatography, therefore a standard time of 16 hours was imposed for each reaction based on literature precedent.2  The isomeric products of the reaction are not separable by column chromatography, therefore the amount of each isomer is measured based on the integration of key signals in the 1H NMR spectrum.  The signals were compared to previously reported values to confirm the formation of the products.2  Distinguishing signals for the protons of each isomer are presented in Figure 3.1.  The diagnostic signals are those attributed to the vinyl protons HN1 and HX1 and those for the benzylic protons HN2 and HX2.  The vinylic proton HN1 is a 1-proton triplet with a chemical shift varying between 5.87 ppm and 6.16 ppm and a characteristic coupling constant of approximately 3.6 Hz.  The benzylic proton HN2 is a 1-proton singlet of between 4.30 and 4.40 ppm.  The vinylic proton HX1 is shifted downfield relative to vinylic proton HN1.  The vinylic proton HX2 is a singlet between 6.20 and 6.30 ppm.  The structures for products 3.33N and 3.33X were unambiguously characterized by X-ray crystallography.  N CH3 N CH3 HN2 HX2 3.29N, R=OCH3 3.33N, R=CF3 R R 3.29X, R=OCH3 3.33X, R=CF3 O O HN1 HX1 for 3.29N: δ 5.87 t, J = 3.5 Hz for 3.33N: δ 6.16 t, J = 3.7 Hz for 3.29X: δ 6.20 s for 3.33X: δ 6.30 s for 3.29N: δ 4.33 s for 3.33N: δ 4.39 s for 3.29X: δ 4.26 s for 3.33X: δ 4.33 s  Figure 3.1:  Diagnostic signals in sample 1H NMR analysis of 3.29N/3.33X and 3.29N /3.33X The first substrates tested were those with either para-substituted or unsubstituted aromatic rings on the alkyne functional group.  The results are summarized in Table 3.2.  All reactions were treated under the standard platinum(II)-catalysis conditions unless otherwise noted.  The products of reactions carried out under platinum(II) chloride catalysis were generally isolated in good yield (entries 1, 3, 9-12).  Less reactive substrates had to be heated to 130 oC instead of 110 Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   125 oC to complete the reaction in 16 hours (entries 10 and 12).  Reactions involving substrates with an unsubstituted arene ring resulted in ratios modestly favoring the 6-endo product (entries 1 and 2).  When R2 = OCH3, the amount of 6-endo product formed increases (entries 3, 4 and 9). Electron-withdrawing groups on the aromatic ring decrease the reactivity of the substrate and the selectivity of the reaction (entries 10 and 11).  Interestingly, aryl bromide 3.31 underwent cyclization under the reaction conditions, portraying the distinct behavior between platinum(II)- and palladium(0)-catalysis.  Substrates with strongly electron-withdrawing groups also show decreased reactivity and favor the 5-exo isomer in a 1:2 6-endo:5-exo ratio (entry 12).  The product mixture of substrate 3.33 was amenable to X-ray crystallographic analysis and the solid state structure of both isomers 3.33N and 3.33X were obtained.  Table 3.2: Evaluation of substrates having para- or unsubstituted arene rings N R1 3 O R2 N R1 N R1 H R2 R2 O O H PtCl2 (10 mol%) PhCH3 110-130 oC or alternate (see table footnotes)  entry substrate R 1  R 2  products yield (%) a,b  ratio c  1 3.28 Bn H 3.28N:3.28X 77 4:1 2d 3.28 Bn H 3.28N:3.28X 61 1.5:1 3 3.29 CH3 OCH3 3.29N:3.29X 79 7:1 4d 3.29 CH3 OCH3 3.29N:3.29X 88 9:1 5e 3.29 CH3 OCH3 3.29N:3.29X NR nd 6f 3.29 CH3 OCH3 3.29N:3.29X 41 3:1 7g 3.29 CH3 OCH3 3.29N:3.29X dec nd 8h 3.29 CH3 OCH3 3.29N:3.29X 11 nd 9 3.30 Bn OCH3 3.30N:3.30X 79 18:1 10 3.31 CH3 Br 3.31N:3.31X 66 2:1 11 3.32 CH3 OTs 3.32N:3.32X 68 2:1 12 3.33 CH3 CF3 3.33N:3.33X 52 1:2 aReported yields are isolated yields.  NR=no reaction; dec=decomposition. bReported yields are the maximum of single experiments.   cRatio was determined by inspection of 1H NMR spectrum of product mixture.  nd=not determined.  dReaction was carried out using PtBr2 (10 mol%). eReaction was carried out using AuCl, PPh3, and AgSbF6 (5 mol% each) at 60 oC.  fReaction was carried out using PPh3AuCl and AgSbF6 (5 mol% each) at 80 oC.  gReaction was carried out using S-PhosAuCl (3.42) and AgSbF6 (5 mol% each) at 60 oC.  hReaction was carried out using PtCl2 (10 mol%) and S-Phos (15 mol%). Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   126  Alternative catalytic systems were tested.  Platinum(II) bromide was tested to determine if it would increase the yield or the regioselectivity of the cycloisomerization reaction (entries 2 and 4).  While there seemed to be a decrease in yield and regioselectivity when reacted with enamide 3.28 (entry 2), treatment of enamide 3.29 with 10 mol% of platinum(II) bromide resulted in an increase in yield and regioselectivity (entry 4).  These results do not provide meaningful information and are likely due to differences in technique when performing or purifying the reaction.  Treatment of enamide 3.29 with a mixture of AuCl, PPh3, and AgSbF6 (5 mol% each) did not result in any observable cycloisomerization reaction (entry 5).  A cationic gold(I) system (PPh3AuCl and AgSbF6: 5 mol% each) successfully cycloisomerized enamide 3.29 but the yield was poor and the regioselectivity was decreased relative to the platinum(II) catalytic system (entry 6).  Reactions involving 2-dicyclohexylphosphino-2',6'- dimethoxybiphenyl (S-Phos) as a ligand and part of a complex were examined based on successes in coinage metal catalysis from the primary literature.12-16  Enamide 3.29 decomposed when treated with S-PhosAuCl (3.42) and AgSbF6 (5 mol% each; entry 7).  Adding S-Phos to a platinum(II) chloride catalyzed reaction gave only 11% of isolated product.  In general, enamide substrates with a para-methoxy substituent on the aromatic ring were more reactive and more selective for the 6-endo isomer than their phenyl and electron- withdrawing aromatic enamide counterparts.  Consequently, a series of veratrole (1,2- dimethoxybenzene) derived substrates were tested.  The results are summarized in Table 3.3.  Enamide 3.34 cycloisomerized smoothly with 10 mol% of platinum(II) chloride to give a 98% yield of products 3.34N and 3.34X in a 10:1 ratio (entry 1).  Reaction of benzyl-protected enamide 3.35 proceeded with a lower yield (78%) but a more synthetically useful product ratio of 20:1 (entry 2).  The major isomer 3.35N was unambiguously characterized by X-ray crystallographic analysis.  Treating enamide 3.35 with 10 mol% of platinum(II) bromide did not offer any advantage (entry 3).     Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   127  Table 3.3: Cyclization of veratrole derivatives N R1 3 O OCH3 N R1 N R1 H OCH3 OCH3 O O H PtCl2 (10 mol%) PhCH3, 110 oC OCH3 OCH3 OCH3 or alternate (see table footnotes) entry substrate R 1  products yield (%) a,b  ratio c  1 3.34 CH3 3.34N:3.34X 98 10:1 2 3.35 Bn 3.35N:3.35X 78 20:1 3d 3.35 Bn 3.35N:3.35X 79 14:1 aReported yields are isolated yields. bReported yields are the maximum of single experiments. cRatio was determined by inspection of 1H NMR spectrum of product mixture.  dReaction was carried out using PtBr2 (10 mol%).    In principle there are four possible products for the cyclization of the veratrole derivatives (Scheme 3.9).  The Freidel-Crafts portion of the reaction has the opportunity to react at either the 2- or 6-position of the aromatic ring.  The 2-position is directly adjacent to one of the methoxy substituents, and therefore is more sterically hindered than the 6-position.  This steric hindrance is likely the reason for two of the four possible isomers not being observed.  NO R OCH3 OCH3 N R1 N R1 H OCH3 OCH3 O O H OCH3 OCH3 N R1 N R1 H OCH3 OCH3 O O H not observed not observed H3CO H3CO 3.34; R=CH3 3.35; R=Bn PtCl2 (10 mol%) PhCH3 110 oC for 3.34, 98% (3.34N:3.34X 10:1) for 3.35, 78% (3.35N:3.35X 20:1) 3.34N; R=CH3 3.35N; R=Bn 3.34X; R=CH3 3.35X; R=Bn  Scheme 3.9:  Regioisomeric products were not observed Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   128  Electron-rich heteroaromatic systems were next tested for reactivity.  The introduction of a heteroatom was desirable in order to increase the complexity of the products derived from the cycloisomerization reactions.  Alkynyl furan substrate 3.36 was synthesized and tested for reactivity under platinum(II) chloride catalysis (Scheme 3.10).  Treatment under standard conditions gave 51% yield of products 3.36N and 3.36X in a 7:1 ratio, again favoring the 6-endo isomer.  The moderate yield of the reaction is possibly due to instability of the starting material, or the decomposition of one of the two products formed under the reaction conditions.  NO CH3 O PtCl2 (10 mol%) PhCH3 110 oC N CH3 N CH3 H O O H O O 3.36 3.36N 3.36X51% (7:1) Scheme 3.10:  Cyclization of furan derivative 3.36 To test the stability of the starting material, enamide 3.36 was heated to 110 oC in toluene in the absence of the catalyst (Scheme 3.11, eq 1).  The starting material 3.36 was recovered in 69% yield.  Loss of starting material could be due to decomposition under the conditions or due to loss during workup and purification.  The control experiment in this case is inconclusive.  To test the stability of the products, two control experiments were performed.  Heating of the products at 110 oC in toluene without catalyst resulted in the recovery of 63% of the products (Scheme 3.11, eq 2).  In a second attempt, 85% of the products were recovered.  Treatment of the products 3.36N and 3.36X under the standard cyclization conditions resulted in recovery of the products in 64% yield (Scheme 3.11, eq 3).  It is therefore possible that the decrease in yield is due to the instability of the products under the reaction conditions, but is not conclusive.  Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   129 NO CH3 O 3.36 110 oC PhCH3 69% recovered starting material N CH3 H O O 3.36N:3.36X 110 oC PhCH3 63% recovered 3.36N and 3.36X 85% recovered 3.36N and 3.36X (2nd attempt) 64% recovered 3.36N and 3.36XN CH3 H O O 3.36N:3.36X PtCl2 (10 mol%) PhCH3 110 oC (1) (2) (3)  Scheme 3.11:  Control experiments  The introduction of an indole moiety in the cyclization reaction could create products that could be structural mimics of indole alkaloids.  Cyclization of the electron-rich N-methyl indole derivative 3.38 under the standard reaction conditions proceeded smoothly to afford 80% of the product 3.38N and 3.38X in a synthetically useful 20:1 ratio (Scheme 3.12).  NO CH3 PtCl2 (10 mol%) PhCH3 110 oC N CH3 N CH3 H O O H 3.38 3.38N 3.38X 80% (20:1) N N CH3 CH3 N CH3  Scheme 3.12:  Cyclization of 2-substituted indole derivative 3.38   3.4 Unsuccessful Cyclization Reactions The cyclization of a number of substrates proceeded smoothly in good yields and often with useful product ratios.  Other substrates tested in this study did not succeed.  These results are summarized in Table 3.4.  While the N-methyl substituted indole derivative 3.38 reacted under the standard reaction conditions in good yield and regioselectivity, the N-H indole showed poor reactivity.  Indole containing enamide 3.37 gave a 1.5:1 mixture of products 3.37N and Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   130 3.37X in 27% yield (entry 1).  Treatment of 3-alkynyl indole 3.39 under the standard reaction conditions resulted in cyclization to the product 3.39N in 59% yield (entry 2).  No minor isomer 3.39X was observable by 1H NMR.  Isomer 3.39N could not be fully characterized due to decomposition of the product.  This is not surprising considering the instability of the 2- iodoindole compared to that of the 3-iodoindole.  This substrate was generally less stable than its 2-substituted counterpart.   Table 3.4:  Unsuccessful platinum(II)-catalyzed cycloisomerization/Friedel-Crafts reactions conditions NO CH3 Ar cycloisomerization products  entry substrate Ar conditions products yield (%) a  (ratio) b  1 3.37 H N  10 mol% PtCl2, PhCH3, 110 oC, 16 h N CH3 N CH3 H O O H 3.37N 3.37X NH NH  27 (1.5:1) 2 3.39 N CH3 10 mol% PtCl2, PhCH3, 110 oC, 16 h N CH3 N CH3 H O O H 3.39N 3.39X N N CH3 CH3  59 (95:5) 3 3.40 SCH3  10 mol% PtCl2, PhCH3, 110 oC, 16 h - NR (55% RSM) 4 3.40 SCH3  20 mol% PtCl2, PhCH3, 130 oC, 16 h - dec 5 3.41 OCH3  10 mol% PtCl2, PhCH3, 110 oC, 16 h - NR 6 3.41 OCH3  10 mol% PtCl2, PhCH3, 130 oC, 16 h - dec aReported yields are isolated yields.  NR=no reaction; RSM=recovered starting material; dec=decomposition.  bRatio was determined by inspection of 1H NMR spectrum of product mixture.  Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   131  One goal of the project was to attempt to control the regioisomeric ratio in favor of the 5- exo isomer.  The cycloisomerizations of substrates with strongly electron-withdrawing substituents on the aromatic ring were shown to favor the 5-exo isomer in a maximum of a 1:2 ratio (Table 3.3.1, entry 12, parent enamide 3.33).  Placing more strongly electron-withdrawing groups around the aromatic functionality will likely improve the isomeric ratio, but it will also potentially decrease the reactivity substantially, and therefore not be synthetically useful.  An alternative pathway to selectively form the 5-exo isomer is shown in Scheme 3.13. By substituting the ortho-position of the aromatic ring with a heteroatom containing functional group (X = heteroatom), the platinum will presumably coordinate to both the alkyne and the heteroatom (3.43).  The platinum will slip to the carbon of the alkyne directly adjacent to the aromatic ring in order to form a stable 5-memebered ring (3.44).  This slippage of the metal will make the carbon further from the arene ring more electropositive, as in 3.44.  The enamide will attack this position resulting in an initial 5-exo cyclization to form intermediate 3.45.  At this stage the Friedel-Crafts reaction will occur, followed by rearomatization and protodemetallation to give the 5-exo isomer product 3.46.  N CH3 O X R Pt (cat.) N CH3 O X R 3.43 LnPt N CH3 O 3.44 X 5-exo NO CH3 R PtLn 3.45 proto- demetallation N X R CH3 O 3.46 PtLn X R  Scheme 3.13:  Selective formation of the 5-exo product using ortho-substituted aromatic rings   The heteroatoms chosen to test this hypothesis were sulfur (ortho-thioether) and an oxygen (ortho-methoxy).  When enamide 3.40 was treated under the standard reaction conditions, no reaction was observed by thin layer chromatography and 55% of the starting material was recovered (entry 3).  Increasing the catalyst loading to 20 mol% of platinum(II) Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   132 chloride in addition to increasing the temperature to 130 oC resulted in decomposition of the starting material to products that were unidentifiable by 1H NMR (entry 4).  Replacing the ortho- thioether with an ortho-methoxy substituent was tested as an alternative.  The results mirrored those of sulfur.  Under standard conditions there was no observable reaction of enamide 3.41 (entry 5).  Increasing the catalyst load and the temperature resulted in decomposition of the starting material into unidentifiable products (entry 6).  N X R CH3 O 3.47 Ln Pt stable 5-membered ring? N CH3 O X R 3.48 LnPt non-productive binding of catalyst  Scheme 3.14:  Possible explanations for failure of cycloisomerization reactions when X = S, O The reason for the inability of platinum to undergo cyclorearrangement reactions with substrates 3.40 and 3.41 is not clear.  One possibility is the 5-membered ring is stable (3.47), and the catalyst is sequestered and unable to turnover to further catalyze the reaction (Scheme 3.14). Another possibility is the heteroatom binds to the metal as in 3.48, sequestering it against further catalytic activity.  Fürstner believes that inhibition of platinum by kinetically stable complexation to heteroatoms is unlikely since the platinum is carbophilic.17  Also, the reaction proceeds smoothly with para-methoxy and veratrole derivatives therefore it is unlikely that the oxygen atom is binding to the platinum.  The difference in reactivity is clearly influenced by the position of the substituents around the aromatic ring.   3.5 Unexpected Formation of an Azocine Derivative Different catalysts were tested for reactivity in the cycloisomerization of enamides and enesulfonamides during the study.  One catalyst system tested was silver hexafluoroantimonate without the presence of a gold catalyst.  Fellow Dake group member Jennifer Dodd found that treatment of enesulfonamide 3.49 with 10 mol% of silver hexafluoroantimonate resulted in an 83% yield of azocine 3.50 (Scheme 3.15).18  This compound was fully characterized by 2D NMR and X-ray crystallography.  Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   133 N Ts N CH3 N Ts N CH3 3.49 3.50 10 mol% AgSbF6 PhCH3, 80 oC 83% Scheme 3.15:  Formation of azocine derivative 3.50 by silver catalysis18 Treatment of enamide 3.29 using the same catalyst under slightly different reaction conditions was attempted (Scheme 3.16).  Enamide 3.29 was treated with 20 mol% of silver hexafluoroantimonate in dichloroethane.  The use of 20 mol% of catalyst was necessary to complete the reaction.  Completion was necessary since the product of the reaction and the starting enamide 3.29 were not separable by column chromatography.  The observed product did not share the same characteristic 1H NMR signals as that of azocine derivative 3.50, or of the tetracyclic products observed under platinum(II)-catalysis.  The only identifiable signals were those of the aromatic ring, the N-methyl substituent, the para-methoxy substituent, and the enamide proton.  All other signals were broad.  NO CH3 3.29 OCH3 20 mol% AgSbF6 ClCH2CH2Cl 80 oC, 18 h 35% product  Scheme 3.16:  Cycloisomerization of enamide 3.29 with silver hexafluoroantimonate as a catalyst If an 8-membered ring were in fact formed, it would likely be conformationally flexible, and coalescence behavior might be observed.  The product was therefore analyzed by variable temperature (low temperature) NMR.  The variable temperature 1H NMR data are shown in Figure 3.2.  The spectrum taken at room temperature (25 oC) is the topmost trace.  As the temperature is decreased, the broad signals separate into a series of signals with fine structure. The spectrum taken at either −40 oC or −50 oC contains all the signals and correct integration for azocine 3.51.  The purpose of this experiment was only to determine the identity of the product formed.  Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   134 25 oC 10 oC 0 oC -10 oC -20 oC -30 oC -40 oC -50 oC  Figure 3.2:  Variable-temperature NMR analysis of azocine 3.51 The azocine product 3.51 was not unambiguously characterized using 1D 1H NMR spectroscopy and was therefore subjected to 13C NMR and 2D NMR spectroscopy (at −40 oC, high resolution mass spectrometry, and IR spectrometry (Figure 3.3).  N O H3C OCH3 1 3 5 7 10 11 18 COSY correlation HMBC correlation H  Figure 3.3:  NMR correlations for azocine product 3.51  Carbon 1 has a signal in the 13C NMR spectrum with a chemical shift of 174.9 ppm; a typical chemical shift of an amide carbonyl.  HMBC analysis of this signal shows correlations to the methyl group attached to the nitrogen, as well as the enamide proton 3-bonds away.  Ipso carbon 11 of the para-anisole substituent also displays a 3-bond correlation to the enamide proton 10.  Due to the symmetry of the 5-membered ring (carbons 4-8), it was difficult to assign those signals unambiguously. N O H3C OCH3 3.51 Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   135  One possible mechanism for the formation of azocine 3.51 is shown in Scheme 3.17.  After coordination by silver a [2+2] cycloaddition could take place to form cyclobutene intermediate 3.52.  Conrotatory 4π electrocyclic ring opening and isomerization of the double bond gives azocine 3.51.  It is possible that the mechanism occurs in a stepwise manner versus a concerted reaction.  NO CH3 OCH3 NO CH3 OCH3 NO H3C OCH3 Ag+ [2+2] 4π electrocyclic ring opening + isomerization 3.29 3.513.52 Scheme 3.17:  Proposed mechanism for the formation of azocine 3.51  Optimization and scope studies of the cycloisomerization of enamides and enesulfonamides under silver catalysis will not be discussed here.  Readers interested in further studies and alternate proposed mechanisms of this reaction are directed to the Masters thesis of fellow Dake group member Jennifer Dodd.18   3.6 Conclusion The platinum(II)-catalyzed cycloisomerization/Friedel-Crafts alkylation of enamides containing an aromatic functional group on the alkyne was effective in generating nitrogen- containing products of high structural complexity.  Substrates with electron-rich aromatic substituents readily reacted with platinum(II) chloride to produce products in good yields and synthetically useful regioisomeric ratios resulting from an initial 6-endo-dig mode of cyclization. Substrates containing electron-withdrawing aromatic systems showed generally reduced reactivity and poor ratios.  Heteroaromatic enamide 3.36 (furan substituted) reacted under the catalytic conditions to give product, albeit in poor yield and moderate selectivity.  Alternatively, heteroaromatic enamide 3.38 (protected 2-substituted indole) reacted in good yield and excellent selectivity.  Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   136 Some heteroaromatic substrates (unprotected indole and 3-substituted indole) were not compatible with the reaction conditions.  This is likely due to instability of the reactants or the products.  Substrates with a heteroatom-containing functional group at the ortho-position of the aromatic ring either did not react or decomposed under forcing reaction conditions. Silver(I)-catalysis of enamide 3.29 showed a new product unlike the tetracycles observed under platinum(II) catalytic conditions.  Variable temperature NMR was used to determine that the structure formed was an azocine derivative (3.51).   3.7 Experimental  3.7.1 General Experimental Please refer to the general experimental section in Chapter 2 for details.  3.7.2 Synthesis of Substrates OH 3.12 3.13 Hept-2-yn-1-ol (3.13) To a solution of 20.0 mL of 1-hexyne (3.12) (174 mmol) in 300 mL of THF at -78 oC was added dropwise 114 mL of a solution of n-butyllithium (1.60 M in hexanes, 183 mmol).  The resulting solution was stirred at −78 oC for 1 h.  To the reaction mixture was added 5.48 g of paraformaldehyde (183 mmol) in small portions over 0.3 h.  The resulting suspension was stirred at −78 oC for 1 h then warmed to rt and stirred for 20 h.  The clear yellow solution was quenched with a saturated solution of ammonium chloride and diluted with diethyl ether.  The layers were separated and the aqueous layer was extracted with diethyl ether.  The combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo to afford a yellow oil.  The crude oil was purified by distillation under reduced pressure to afford 17.9 g (92 %) of hept-2-yn-1-ol (3.13) as a clear oil, bp = 46-49 oC, 0.5 mmHg (lit. 84-86 oC, 0.5 mmHg). Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   137 IR (neat): 3326 (br), 2935, 2226 cm-1.  1H NMR (400 MHz, CDCl3): δ 4.19-4.18 (m, 2H), 2.76 (br s, 1H), 2.16 (tt, J = 7.0, 2.2 Hz, 2H), 1.52-1.28 (m, 4H), 0.86 (t, J = 7.4 Hz, 3H).  13C NMR (100 MHz, CDCl3): δ 87.1, 79.3, 52.0, 31.6, 22.9, 19.3, 14.5. 3.13 has been previously reported, see: 1) Kumar, G. D. K.; Baskaran, S. J. Org.Chem. 2005, 70, 4520- 4523.  2) Li, M.; O’Doherty, G. A. Org. Lett. 2006, 8, 6087-6090.  OH HO 3.143.13 Hept-6-yn-1-ol (3.14) To a flask containing 25.5 g of potassium hydride (637 mmol) was added 350 mL of 1,3- diaminopropane.  The suspension was stirred for 1 h at rt.  To the resulting green suspension was slowly added 17.9 g of hept-2-yn-1-ol (3.13) (159 mmol).  The first ~2 g of the alcohol were added very carefully to avoid excessive frothing.  After the addition of the alcohol, the reaction mixture was heated to 80 oC and stirred for 1.5 h.  The mixture was then cooled to rt and carefully poured over 600 mL of crushed ice.  The slurry was transferred to a separatory funnel and extracted four times with diethyl ether.  The combined organics were washed twice with brine, dried over sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo to afford a yellow oil.  The crude oil was purified by distillation under reduced pressure to afford 16.2 g of hept-6-yn-1-ol (3.14) (91 %) as a clear, colorless oil, bp = 60-65 oC, 0.5 mmHg (lit. 65- 66 oC, 1 mmHg). IR (neat): 3300 (br), 2938, 2117 cm-1.  1H NMR (400 MHz, CDCl3): δ 3.64 (t, J = 6.5 Hz, 2H), 2.20 (td, J = 7.0, 2.6 Hz, 2H), 1.94 (t, J = 2.6 Hz, 1H), 1.62-1.53 (m, 5H), 1.52-1.45 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 85.4, 69.3, 63.7, 33.2, 29.2, 25.9, 19.4. 3.14 has been previously reported, see: 1) Li, M.; O’Doherty, G. A. Org. Lett. 2006, 8, 6087-6090.  2) Gung, B. W.; Gibeau, C.; Jones, A. Tetrahedron: Asymmetry 2005, 16, 3107-3114.  HO 3.14 H 3.15 O  Hept-6-ynal (3.15) To a solution of 4.0 mL of oxalyl chloride (46 mmol) in 100 mL of dichloromethane at −78 oC was added 5.0 mL of dimethyl sulfoxide (70 mmol) dropwise.  The reaction mixture was stirred Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   138 at −78 oC for 0.25 h.  A solution of 3.9 g of hept-6-yn-1-ol (3.14) (35 mmol) in 14 mL of dichloromethane was slowly added to the cold solution.  After stirring at −78 oC for 0.5 h, 24 mL of triethylamine (175 mmol) was added dropwise to the white suspension.  The resulting reaction mixture was warmed to 0 oC and stirred for 1 h.  The reaction mixture was quenched with water and diluted with diethyl ether.  The layers were separated and the aqueous layer was extracted three times with diethyl ether.  The combined organic layers were then washed once with 1 M HCl and once with brine.  The organic layer was dried over sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo to afford a crude yellow oil.  The crude oil was purified by distillation under reduced pressure to afford 3.3 g (86 %) of the title compound 3.15 as a clear, colorless liquid, bp = 35-39 oC, 0.5 mmHg (lit. 78-80 oC, 20 mmHg). 3.15 has been previously prepared, see: Hopf, H.; Krüger, A. Chem.− Eur. J. 2001, 7, 4378-4385.  H O H O CO2CH3 3.15 3.16 Methyl 4-formylnon-8-ynoate (3.16) A 100 mL round-bottomed flask was charged with a stir bar, 2.95 g potassium carbonate (21.3 mmol), and then flame-dried.  The flask was put under an atmosphere of nitrogen and 11.6 mL of freshly distilled piperidine (117 mmol) was added.  The suspension was cooled to 0 oC and 5.87 g of hept-6-ynal (3.15) (53.3 mmol) was added via syringe pump (0.01 mL/min).  The resulting yellow suspension was stirred at 0 oC for 3 h.  The reaction mixture was filtered through oven- dried Celite®, rinsing with anhydrous diethyl ether.  The solution was concentrated to afford a yellow oil.  The crude oil was immediately put under an atmosphere of nitrogen.  55 mL of dry acetonitrile were added via syringe followed by 9.6 mL of freshly distilled methyl acrylate (107 mmol).  The reaction mixture was heated to reflux for 22 h.  The reaction mixture was cooled to rt and 25 mL of water and 5 mL of glacial acetic acid were added.  The flask was opened to the atmosphere and heated to reflux for 16 h.  The solution was then cooled to rt and extracted three times with diethyl ether.  The combined organic fractions were washed once with 1 M HCl, once with a saturated solution of sodium bicarbonate, and once with brine.  The organic fractions were dried over sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo to afford an orange oil.  The crude oil was purified by column chromatography on silica gel (5:1→1:1 hexanes:ethyl acetate) to afford 6.10 g (58 %) of the title compound 3.16 as a yellow oil. Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   139 IR (neat): 3289, 2950, 2117, 1734, 1438 cm-1.  1H NMR (400 MHz, CDCl3): δ 9.57 (d, J = 2.2 Hz, 1H), 3.64 (s, 3H), 2.35-2.30 (m, 3H), 2.19 (td, J = 7.0, 2.6 Hz, 2H), 1.98-1.93 (m, 2H), 1.82- 1.74 (m, 2H), 1.60-1.48 (m, 3H).  13C NMR (100 MHz, CDCl3): δ 204.8, 174.3, 84.5, 70.0, 52.6, 51.5, 32.2, 28.5, 26.5, 24.5, 19.3.  HRMS (ESI) calcd for C11H16O3Na (M + Na) +: 219.0997. Found: 219.1001.  H O CO2CH3 NO CH3 3.16 3.17 1-Methyl-5-(pent-4-ynyl)-3,4-dihydropyridin-2(1H)-one (3.17) To a solution of 1.60 g of alkyne 3.16 (8.17 mmol) and 20.4 mL of methylamine (40.8 mmol, 2.0 M in THF) in 25 mL of toluene was added 8.2 mL of glacial acetic acid.  A Dean-Stark apparatus was attached and the reaction mixture was heated to reflux and stirred for 4 h.  The reaction mixture was cooled to rt, diluted with diethyl ether, and washed twice with a saturated solution of sodium bicarbonate.  The combined aqueous fractions were extracted twice with diethyl ether.  The combined organic fractions were dried over sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo to afford a yellow oil.  The crude oil was purified by column chromatography on triethylamine washed silica gel (6:1→3:1→1:1 hexanes:ethyl acetate) to give 1.33 g (92 %) of the title compound 3.17 as a yellow solid.  The solid was recrystallized from ethanol and hexanes to give an off-yellow solid, mp = 64-66 oC. IR (neat): 3305, 2939, 2117, 1660 cm-1.  1H NMR (400 MHz, CDCl3): δ 5.76 (s, 1H), 2.99 (s, 3H), 2.47-2.43 (m, 2H), 2.21-2.10 (m, 6H), 1.94 (t, J = 2.6 Hz, 1H), 1.64-1.57 (m, 2H).  13C NMR (100 MHz, CDCl3): δ 169.9, 127.0, 119.3, 84.9, 69.8, 34.6, 33.5, 32.0, 27.3, 25.1, 18.8. MS (ESI): 200 (M + Na)+.  Anal. Calcd for C11H15NO: C, 74.54; H, 8.53; N, 7.90.  Found: C, 74.45; H, 8.62; N, 7.71. 3.17 has been previously reported, see: Harrison, T. J.; Patrick, B. O.; Dake, G. R. Org. Lett. 2007, 9, 367-370.   Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   140 H O CO2CH3 NO Bn 3.16 3.18 1-Benzyl-5-(pent-4-ynyl)-3,4-dihydropyridin-2(1H)-one (3.18) To a solution of 1.04 g of alkyne 3.16 (5.32 mmol) and 2.9 mL of benzyl amine (26.6 mmol) in 25 mL of toluene was added 5.3 mL of glacial acetic acid.  A Dean-Stark apparatus was attached and the reaction mixture was heated to reflux with stirring for 1.25 h.  The reaction mixture was cooled to rt, diluted with diethyl ether, and washed twice with a saturated solution of sodium bicarbonate.  The combined aqueous fractions were extracted three times with diethyl ether.  The combined organic fractions were dried over sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo to yield a brown oil.  The crude oil was purified by column chromatography on triethylamine washed silica gel (3:1→1:1 hexanes:ethyl acetate) to afford 1.20 g (90 %) of the title compound 3.18 as a yellow oil. IR (neat): 3294, 2937, 2116, 1667, 705 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.34-7.22 (m, 5H), 5.81 (t, J = 1.3 Hz, 1H), 4.66 (s, 2H), 2.57 (t, J = 8.1 Hz, 2H), 2.26 (t, J = 8.1 Hz, 2H), 2.18-2.09 (m, 4H), 1.94 (t, J = 2.6, 1H), 1.59 (qt, J = 7.3 Hz, 2H).  13C NMR (100 MHz, CDCl3): δ 169.8, 138.3, 129.6, 128.6, 128.4, 125.6, 120.0, 84.9, 69.8, 49.9, 33.6, 32.3, 27.3, 25.1, 18.8.  MS (APCI): 254 (M + H)+.  Anal. Calcd for C17H19NO: C, 80.60; H, 7.56; N, 5.53.  Found: C, 80.63; H, 7.89; N, 5.55.  OCH3 OCH3 OCH3 OCH3 I 3.19 3.20 4-Iodo-1,2-dimethoxybenzene (4-Iodoveratrole) (3.20) A 1 L, 3-necked round-bottomed flask was charged with 65.5 g of silver acetate (393 mmol) and then flame dried under reduced pressure.  The flask was then cooled to rt and put under an atmosphere of nitrogen.  The flask was charged with 50.0 mL of 1,2-dimethoxybenzene (3.19) (393 mmol).  A solution of 99.7 g of iodine (393 mmol) in chloroform was added to the reaction mixture dropwise over a period of 2 h.  The resulting red suspension was stirred at rt for 1.5 h. The reaction mixture was filtered and washed with chloroform.  The filtrate was concentrated by rotary evaporation in vacuo to afford a dark red oil.  To the red oil was added some dichloromethane and the solution was washed three times with a saturated solution of sodium Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   141 thiosulfate.  The combined aqueous fractions were extracted once with dichloromethane.  The combined organic fractions were dried over sodium sulfate, concentrated by rotary evaporation in vacuo to afford a crude brown oil.  The brown oil was purified by distillation under reduced pressure to give 83.4 g (80 %) of the title compound 3.20 as a clear brown oil (bp = 104 oC, 0.5 mmHg) that solidifies in the fridge.  The solid was recrystallized from ethanol to afford white needles, mp = 35-36 oC (lit. 34-35 oC). IR: 2999, 2955, 2837, 1583, 1500, 839, 798 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.22 (dd, J = 8.5, 2.0 Hz, 1H), 7.12 (d, J = 2.2 Hz, 1H), 6.61 (d, J = 8.7 Hz, 1H), 3.85 (s, 3H), 3.84 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 150.9, 150.2, 130.8, 121.4, 114.2, 83.4, 57.1, 56.9. 3.20 has been previously prepared, see: Janssen, D. E.; Wilson, C. V. Org. Synth. 1956, 36, 46-48.  I OH I OTs 3.21 3.22 4-Iodophenyl 4-methylbenzenesulfonate (3.22) To a solution of 3.03 g of 4-iodophenol (3.21) (13.8 mmol) and 3.41 g of p-toluenesulfonyl chloride (17.9 mmol) in 35 mL of dichloromethane was added 5.8 mL of triethylamine (41.3 mmol) dropwise.  The resulting white suspension was stirred at rt for 5.5 h.  The reaction mixture was diluted with dichloromethane and then washed four times with 1M HCl.  The combined aqueous fractions were extracted once with dichloromethane.  The combined organic fractions were washed once with brine, dried over sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo to afford an oil that solidifies under vacuum.  The solid was purified by recrystallization from a mixture of dichloromethane and hexanes and then rinsed with diethyl ether to afford 4.02 g (78 %) of the title compound 3.22 as pink crystals, mp = 94-96 oC (lit. 99 oC). IR (film): 2930, 1478, 876, 656 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.70 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 9.0 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 6.74 (d, J = 9.0 Hz, 2H), 2.45 (s, 3H).  13C NMR (100 MHz, CDCl3): δ 150.5, 146.7, 139.7, 133.1, 130.9, 129.5, 125.5, 92.7, 22.7. 3.22 has been previously prepared, see: 1) Matheson, D.; McCombie, H. J. Chem. Soc. 1931, 1103-1110. 2) Lee, T.-S.; Kim, J.; Bae, J.-Y. Polymer 2004, 45, 5065-5076.  Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   142 N H N H I 3.23 3.24 2-Iodo-1H-indole (3.24) To a solution of 3.17 g of indole (3.23) (27.1 mmol) in 70 mL of THF at −78 oC was added dropwise 17.7 mL of a solution of n-butyllithium (1.61 M in hexanes, 28.4 mmol).  The resulting milky white reaction mixture was stirred at −78 oC for 0.5 h.  The nitrogen atmosphere was replaced with an atmosphere of carbon dioxide using a balloon.  The carbon dioxide gas was bubbled through the reaction mixture for 0.25 h.  The milky solution turned clear.  The solvents were removed under reduced pressure to afford a white solid.  The white solid was dissolved in 60 mL of THF and cooled to −78 oC before the dropwise addition of 20.0 mL of a solution of t- butyllithium (1.42 M in hexanes, 28.4 mmol).  The resulting bright yellow solution was stirred at to −78 oC for 0.7 h.  To the cold reaction mixture was added a solution of 7.64 g of 1,2- diiodoethane (27.1 mmol) in 10 mL of THF.  The mixture was stirred for 0.75 h before being quenched with 2.7 mL of H2O.  The suspension was warmed to rt and poured into 150 mL of a saturated solution of ammonium chloride.  The reaction mixture was diluted with diethyl ether and the layers were separated.  The aqueous layer was extracted twice with diethyl ether.  The combined organic fractions were washed once with brine, dried over sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo to afford a yellow oil.  The crude oil was purified by column chromatography on silica gel (6:1 hexanes:ethyl acetate) to afford 5.53 g (84 %) of the title compound 3.24 as a white solid.  The solid was recrystallized from hexanes and dichloromethane to afford the product 3.24 as shiny white crystals, mp = 78 oC (lit. 98-99 oC). IR (film): 3465, 2978, 2253, 1438, 654 cm-1.  1H NMR (400 MHz, CDCl3): δ 8.07 (br s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 7.3 Hz, 1H), 7.14 (td, J = 7.6, 1.3 Hz, 1H), 7.09 (td, J = 7.6, 1.3 Hz, 1H), 6.74 (d, J = 1.6 Hz, 1H). 3.24 has been previously prepared, see: Bergman, J.; Venemalm, L. J. Org. Chem. 1992, 57, 2495-2497.  N H N I 3.24 3.25 I CH3  2-Iodo-1-methyl-1H-indole (3.25) Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   143 To a solution of 0.34 g of sodium hydride (14 mmol) in 25 mL of THF was slowly added a solution of 2.3 g of 2-iodo-1H-indole (3.24) (9.4 mmol) in 20 mL of THF.  The reaction mixture was stirred at rt for 0.5 h.  To the resulting yellow suspension was added 0.70 mL of methyl iodide (11 mmol) dropwise.  The reaction mixture was stirred at rt for 2 h.  The mixture was quenched with a saturated solution of ammonium chloride and diluted with diethyl ether.  The layers were separated and the organic fraction was washed once with brine.  The combined aqueous fractions were extracted once with diethyl ether.  The combined organic fractions were dried over sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo to afford a yellow oil.  The crude oil was purified by column chromatography on silica gel (10:1 hexanes:ethyl acetate) to afford 2.2 g (91 %) of the title compound 3.25 as an off-white solid. The solid was recrystallized from hexanes and dichloromethane to afford opaque beige crystals, mp = 72-73 oC (lit. 76 oC). IR (film): 3052, 2938, 1456, 744 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.56 (d, J = 8.0 Hz, 1H), 7.34 (dd, J = 8.3, 0.6 Hz, 1H), 7.21-7.17 (m, 1H), 7.13-7.09 (m, 1H), 6.83 (d, J = 0.6 Hz, 1H), 3.78 (s, 3H). 3.25 has been previously prepared, see: Bergman, J.; Venemalm, L. J. Org. Chem. 1992, 57, 2495-2497.  N H N H 3.23 3.26 I N 3.27 I CH3  3-Iodo-1-methyl-1H-indole (3.27) To a solution of 4.00 g of indole (3.23) (34.1 mmol) and 4.79 g of potassium hydroxide (85.4 mmol) in 60 mL of N,N-dimethylformamide was added dropwise a solution of 8.84 g of iodine (34.8 mmol) in 60 mL of N,N-dimethylformamide.  The resulting brown solution was stirred at rt for 3 h.  The reaction mixture was poured into 800 mL of H2O and ice containing 4 mL of ammonium hydroxide and 1 mL of sodium bisulfite.  The resulting pink precipitate was filtered and washed with cold water.  The crude product 3.26 was moved onto the next reaction with no further purification.  To a suspension of 1.64 g of sodium hydride (68.3 mmol) in 60 mL of THF was added a solution of 8.29 g of compound 3.26 (34.1 mmol) in 50 mL of THF dropwise.  The resulting dark green solution was stirred at rt for 0.75 h.  To the reaction mixture was added 2.6 mL of methyl iodide Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   144 (41.0 mmol) in one portion.  The resulting red suspension was stirred at rt for 1 h.  The reaction mixture was quenched with a saturated solution of ammonium chloride and diluted with diethyl ether.  The layers were separated and the organic fraction was washed once with brine.  The combined aqueous fractions were extracted once with diethyl ether.  The combined organic fractions were dried over sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo to afford 8.13 g (93 %) of the title compound 3.27 as a light red oil.  The oil was not purified further due to instability on to heat and silica gel chromatography. IR (neat): 2945, 2252, 1508, 727 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.50 (d, J = 7.8 Hz, 1H), 7.33-7.31 (m, 2H), 7.28-7.24 (m, 1H), 7.14 (s, 1H), 3.80 (s, 3H).  13C NMR (100 MHz, CDCl3): δ 137.8, 133.8, 131.5, 123.7, 122.2, 121.3, 110.5, 55.8, 34.1. 3.27 has been previously prepared, see: Bocchi, V.; Palla, G. Synthesis 1982, 1096-1097.  Representative Procedure for Sonogashira Coupling Reactions NO Bn NO Bn 3.18 3.28 1-Benzyl-5-(5-phenylpent-4-ynyl)-3,4-dihydropyridin-2(1H)-one (3.28) To a flask charged with 27 mg of bis(triphenylphosphine)palladium(II) chloride (0.038 mmol) and 15 mg of copper(I) iodide (0.076 mmol) was added 2 mL of triethylamine.  To the resulting bright yellow mixture was added a solution of 0.19 g of enesulfonamide 3.18 (0.76 mmol) and 0.1 mL of iodobenzene (0.92 mmol) in 2 mL of dichloromethane in one portion.  The flask was rinsed with 1 mL of triethylamine and added to the reaction mixture.  The reaction vessel was wrapped in aluminum foil and stirred at rt for 2 h.  The reaction mixture was filtered through a pipette of triethylamine washed silica gel using ethyl acetate eluent and then concentrated by rotary evaporation in vacuo to afford the a crude orange syrup.  The crude material was purified by column chromatography on triethylamine washed silica gel (3:1→1:1 hexanes:ethyl acetate) to afford 0.22 g (89 %) of the title compound 3.28 as a clear, yellow oil. IR (neat): 3031, 2933, 1668, 1599, 758 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.37-7.24 (m, 10H), 5.85 (t, J = 1.2 Hz, 1H), 4.68 (s, 2H), 2.60 (t, J = 7.8 Hz, 2H), 2.37 (t, J = 7.0, 2H), 2.30 (t, J = 7.8 Hz, 2H), 2.18 (t, J = 7.4 Hz, 2H), 1.69 (qt, J = 7.0, 2H).  13C NMR (100 MHz, CDCl3): δ 169.8, 138.4, 132.5, 129.6, 129.2, 128.7, 128.6, 128.4, 125.5, 124.8, 120.1, 90.5, 82.2, 49.9, 33.8, Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   145 32.3, 27.6, 25.2, 19.8.  HRMS (ESI) calcd for C23H23NONa (M + Na) +: 352.1677. Found: 352.1673.  NO Bn NO Bn 3.18 3.30 OCH3  1-Benzyl-5-(5-(4-methoxyphenyl)pent-4-ynyl)-3,4-dihydropyridin-2(1H)-one (3.30) Enamide 3.18 (0.20 g, 0.80 mmol), bis(triphenylphosphine)palladium(II) chloride (28 mg, 0.040 mmol), copper iodide (15 mg, 0.080 mmol), and 4-iodoanisole (0.22 g, 0.96 mmol) were combined according to the representative procedure for Sonogashira coupling reactions, except that the reaction mixture was stirred for 5 h.  After purification by column chromatography on triethylamine washed silica gel (4:1→1:1→1:3 hexanes:ethyl acetate), 0.17 g (59 %) of the title compound 3.30 was isolated as a clear, yellow oil. IR (neat): 2934, 2836, 1668, 1606, 1510, 834, 705 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.31- 7.24 (m, 7H), 6.82 (d, J = 9.3 Hz, 2H), 5.83 (s, 1H), 4.66 (s, 2H), 3.79 (s, 3H), 2.61-2.55 (m, 2H), 2.36-2.25 (m, 4H), 2.15 (t, J = 7.1 Hz, 2H), 1.66 (qt, J = 7.1 Hz, 2H).  13C NMR (100 MHz, CDCl3): δ 169.8, 160.1, 138.4, 133.8, 129.6, 128.6, 128.4, 125.5, 120.2, 117.0, 114.9, 88.8, 81.9, 56.3, 49.9, 33.8, 32.3, 27.7, 25.2, 19.8.  HRMS (ESI) calcd for C24H25NO2Na (M + Na) +: 382.1783. Found: 382.1775.  NO CH3 OCH3 NO CH3 3.17 3.29 5-(5-(4-Methoxyphenyl)pent-4-ynyl)-1-methyl-3,4-dihydropyridin-2(1H)-one (3.29) Enamide 3.17 (0.10 g, 0.56 mmol), bis(triphenylphosphine)palladium(II) chloride (20 mg, 0.028 mmol), copper iodide (11 mg, 0.056 mmol), and 4-iodoanisole (0.15 g, 0.62 mmol) were combined according to the representative procedure for Sonogashira coupling reactions, except that the reaction mixture was stirred for 5 h.  After purification by column chromatography on triethylamine washed silica gel (4:1→1:1→1:3 hexanes:ethyl acetate), 0.14 g (86 %) of the title compound 3.29 was isolated as a clear, yellow oil. IR (neat): 2936, 1666, 1606, 834 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.34-730 (m, 2H), 6.83- 6.80 (m, 2H), 5.81 (t, J = 1.2 Hz, 1H), 3.79 (s, 3H), 3.02 (s, 3H), 2.51-2.47 (m, 2H), 2.40 (t, J = Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   146 7.0 Hz, 2H), 2.27-2.23 (m, 2H), 2.19 (t, J = 7.4 Hz, 2H), 1.74-1.66 (m, 2H).  13C NMR (100 MHz, CDCl3): δ 170.0, 160.1, 133.8, 126.9, 119.6, 117.0, 114.9, 88.9, 81.9, 56.3, 34.6, 33.8, 32.1, 27.8, 25.2, 19.9.  HRMS (ESI) calcd for C18H21NO2Na (M + Na) +: 306.1470. Found: 306.1464.  NO CH3 NO CH3 3.17 3.31 Br  5-(5-(4-Bromophenyl)pent-4-ynyl)-1-methyl-3,4-dihydropyridin-2(1H)-one (3.31) Enamide 3.17 (0.21 g, 1.2 mmol), bis(triphenylphosphine)palladium(II) chloride (42 mg, 0.060 mmol), copper iodide (23 mg, 0.12 mmol), and 1-bromo-4-iodobenzene (0.41 g, 1.4 mmol) were combined according to the representative procedure for Sonogashira coupling reactions, except that the reaction mixture was stirred for 4 h.  After purification by column chromatography on triethylamine washed silica gel (5:1→3:1→1:1 hexanes:ethyl acetate), 0.35 g (87 %) of the title compound 3.31 was isolated as a yellow oil. IR (neat): 3478, 2936, 1670, 825 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.40 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 8.6 Hz, 2H), 5.79 (s, 1H), 3.01 (s, 3H), 2.50-2.46 (m, 2H), 2.38 (t, J = 7.0 Hz, 2H), 2.26-2.22 (m, 2H), 2.17 (t, J = 7.4 Hz, 2H), 1.73-1.66 (m, 2H).  13C NMR (100 MHz, CDCl3): δ 169.9, 134.0, 132.4, 127.0, 123.8, 122.7, 119.4, 91.8, 81.2, 34.6, 33.8, 32.0, 27.6, 25.2, 19.9. HRMS (ESI) calcd for C17H18NONa 79Br (M + Na)+: 354.0469.  Found: 354.0466.  NO CH3 NO CH3 3.17 3.32 OTs  4-(5-(1-Methyl-6-oxo-1,4,5,6-tetrahydropyridin-3-yl)pent-1-ynyl)phenyl 4- methylbenzenesulfonate (3.32) Enamide 3.17 (0.26 g, 1.5 mmol), bis(triphenylphosphine)palladium(II) chloride (52 mg, 0.075 mmol), copper iodide (28 mg, 0.15 mmol), and 4-iodophenyl 4-methylbenzenesulfonate (3.22) (0.55 g, 1.9 mmol) were combined according to the representative procedure for Sonogashira coupling reactions, except that the reaction mixture was stirred for 3 h.  After purification by column chromatography on triethylamine washed silica gel (5:1→3:1→1:1 hexanes:ethyl acetate), 0.36 g (56 %) of the title compound 3.32 was isolated as an orange oil. Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   147 IR (neat): 2935, 1667, 862 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 7.8 Hz, 2H), 7.30 (d, J = 7.4 Hz, 2H), 7.29 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 8.6 Hz, 2H), 5.80 (s, 1H), 3.01 (s, 3H), 2.51-2.47 (m, 2H), 2.44 (s, 3H), 2.39 (t, J = 6.9 Hz, 2H), 2.26-2.22 (m, 2H), 2.17 (t, J = 7.2 Hz, 2H), 1.73-1.67 (m, 2H).  13C NMR (100 MHz, CDCl3): δ 169.9, 149.8, 146.5, 133.8, 133.2, 130.8, 129.5, 127.0, 123.9, 123.4, 119.4, 91.8, 80.9, 34.6, 33.8, 32.0, 27.6, 25.2, 22.7, 19.8. HRMS (ESI) calcd for C24H25NO4Na 32S (M + Na)+: 446.1402.  Found: 446.1413.  NO CH3 NO CH3 3.17 3.33 CF3  1-Methyl-5-(5-(4-(trifluoromethyl)phenyl)pent-4-ynyl)-3,4-dihydropyridin-2(1H)-one (3.33) Enamide 3.17 (0.35 g, 2.0 mmol), bis(triphenylphosphine)palladium(II) chloride (69 mg, 0.10 mmol), copper iodide (38 mg, 0.20 mmol), and 4-iodobenzotrifluoride (0.4 mL, 2.4 mmol) were combined according to representative procedure for Sonogashira coupling reactions, except that the reaction mixture was stirred for 4 h.  After purification by column chromatography on triethylamine washed silica gel (4:1→2:1→1:1 hexanes:ethyl acetate), 0.58 g (91 %) of the title compound 3.33 was isolated as a yellow oil. IR (neat): 3323, 2937, 1681, 843 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.52-7.44 (m, 4H), 5.79 (s, 1H), 3.00 (s, 3H), 2.49-2.45 (m, 2H), 2.41 (t, J = 7.0 Hz, 2H), 2.25-2.21 (m, 2H), 2.17 (t, J = 7.4 Hz, 2H), 1.74-1.67 (m, 2H).  13C NMR (100 MHz, CDCl3): δ 169.9, 132.7, 130.3 (q, J = 32 Hz), 128.7, 127.1, 126.1 (q, J = 4 Hz), 125.0 (q, J = 271 Hz), 119.3, 93.4, 81.0, 34.6, 33.7, 32.0, 27.5, 25.1, 19.8.  HRMS (ESI) calcd for C18H18NOF3Na (M + Na) +: 344.1238.  Found: 344.1249.  NO CH3 NO CH3 3.17 3.34 OCH3 OCH3  5-(5-(3,4-dimethoxyphenyl)pent-4-ynyl)-1-methyl-3,4-dihydropyridin-2(1H)-one (3.34) Enamide 3.17 (0.10 g, 0.56 mmol), bis(triphenylphosphine)palladium(II) chloride (20 mg, 0.028 mmol), copper iodide (11 mg, 0.056 mmol), and 4-iodoveratrole (0.16 g, 0.62 mmol) were combined according to the representative procedure for Sonogashira coupling reactions, except that the reaction mixture was stirred for 5 h.  After purification by column chromatography on Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   148 triethylamine washed silica gel (4:1→1:1→1:3 hexanes:ethyl acetate), 0.12 g (69 %) of the title compound 3.34 was isolated a clear, yellow oil. IR (neat): 2936, 1667, 854, 810, 763 cm-1.  1H NMR (400 MHz, CDCl3): δ 6.97 (dd, J = 8.1, 2.0 Hz, 1H), 6.89 (d, J = 1.7, 1H), 6.76 (d, J = 8.3, 1H), 5.80 (s, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.01 (s, 3H), 2.50-2.46 (m, 2H), 2.40 (t, J = 7.0, 2H), 2.27-2.23 (m, 2H), 2.18 (t, J = 7.4, 2H), 1.74- 1.67 (m, 2H).  13C NMR (100 MHz, CDCl3): δ 170.0, 150.0, 149.6, 127.0, 125.6, 119.6, 117.0, 115.3, 112.0, 88.8, 82.0, 56.9, 34.6, 33.8, 32.0, 27.8, 25.2, 19.9.  HRMS (ESI) calcd for C19H23NO3Na (M + Na) +: 336.1576. Found: 336.1568.  NO Bn NO Bn 3.18 3.35 OCH3 OCH3  1-Benzyl-5-(5-(3,4-dimethoxyphenyl)pent-4-ynyl)-3,4-dihydropyridin-2(1H)-one (3.35) Enamide 3.18 (0.14 g, 0.57 mmol), bis(triphenylphosphine)palladium(II) chloride (20 mg, 0.029 mmol), copper iodide (11 mg, 0.057 mmol), and 4-iodoveratrole (0.21 g, 0.8 mmol) were combined according to the general procedure for Sonogashira coupling reactions, except that the reaction mixture was stirred for 2.5 h.  After purification by column chromatography on triethylamine washed silica gel (4:1→1:1→1:3 hexanes:ethyl acetate), 0.20 g (92 %) of the title compound 3.35 was isolated as a clear, orange oil. IR (neat): 2936, 1666, 1513, 732 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.34-7.23 (m, 5H), 6.96 (dd, J = 8.4, 1.8 Hz, 1H), 6.88 (d, J = 2.0 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 5.84 (t, J = 1.2 Hz, 1H), 4.67 (s, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 2.59 (t, J = 8.0 Hz, 2H), 2.35 (t, J = 7.0 Hz, 2H), 2.31-2.27 (m, 2H), 2.16 (t, J = 7.4 Hz, 2H), 1.68 (qt, J = 7.4 Hz, 2H).  13C NMR (100 MHz, CDCl3): δ 169.8, 150.0, 149.6, 138.3, 129.6, 128.5, 128.4, 125.6, 125.5, 120.2, 117.1, 115.3, 112.0, 88.8, 82.0, 56.9, 56.8, 49.9, 33.9, 32.3, 27.7, 25.2, 19.8.  HMRS (ESI) calcd for C25H27NO3Na (M + Na) +: 412.1889.  Found: 412.1891.  NO CH3 NO CH3 3.17 3.36 O  5-(5-(Furan-2-yl)pent-4-ynyl)-1-methyl-3,4-dihydropyridin-2(1H)-one (3.36) Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   149 Enamide 3.17 (0.30 g, 1.7 mmol), bis(triphenylphosphine)palladium(II) chloride (59 mg, 0.10 mmol), copper iodide (32 mg, 0.17 mmol), and 2-bromofuran (0.56 g, 88.6 wt %, 3.4 mmol) were combined according to the representative procedure for Sonogashira coupling reactions, except that the reaction mixture was stirred for 24 h.  After purification by column chromatography on triethylamine washed silica gel (4:1→2:1→1:1 hexanes:ethyl acetate), 0.39 g (95 %) of the title compound 3.36 was isolated as an orange oil. IR (neat): 3115, 2933, 2236, 1663, 744 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.33 (d, J = 1.3 Hz, 1H), 6.47 (d, J = 3.1 Hz, 1H), 6.36-6.35 (m, 1H), 5.82 (s, 1H), 3.03 (s, 3H), 2.52-2.48 (m, 2H), 2.45 (t, J = 7.0 Hz, 2H), 2.72-2.23 (m, 2H), 2.19 (t, J = 7.4, 2H), 1.75-1.68 (m, 2H).  13C NMR (100 MHz, CDCl3): δ 170.0, 143.8, 138.4, 127.1, 119.3, 114.8, 111.7, 94.9, 72.6, 34.6, 33.7, 32.0, 27.3, 25.2, 19.9.  HRMS (ESI) calcd for C15H17NO2Na (M + Na) +: 266.1157.  Found: 266.1152.  NO CH3 NO CH3 3.17 3.37 H N  5-(5-(1H-Indol-2-yl)pent-4-ynyl)-1-methyl-3,4-dihydropyridin-2(1H)-one (3.37) Enamide 3.17 (83 mg, 0.047 mmol), bis(triphenylphosphine)palladium(II) chloride (16 mg, 0.023 mmol), copper iodide (9.0 mg, 0.047 mmol), and 2-iodo-1H-indole (3.24) (0.12 g, 0.51 mmol) were combined according to the representative procedure for Sonogashira coupling reactions.  After purification by column chromatography on triethylamine washed silica gel (4:1→2:1→1:1 hexanes:ethyl acetate), 92 mg (67 %) of the title compound 3.37 was isolated as a brown oil. IR (film): 3263, 2936, 2249, 1639, 806 cm-1.  1H NMR (400 MHz, CDCl3): δ 8.75 (br s, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.12 (t, J = 7.0 Hz, 1H), 6.69 (d, J = 1.3 Hz, 1H), 5.82 (s, 1H), 3.06 (s, 3H), 2.56-2.52 (m, 2H), 2.47 (t, J = 7.0 Hz, 2H), 2.26 (t, J = 8.1 Hz, 2H), 2.21 (t, J = 7.6 Hz, 2H), 1.73 (qt, J = 7.3 Hz, 2H).  13C NMR (100 MHz, CDCl3): δ 170.2, 136.9, 128.7, 127.0, 124.0, 121.5, 121.2, 120.4, 119.6, 111.8, 108.5, 93.8, 74.9, 34.7, 33.8, 32.1, 27.5, 25.2, 20.0.  MS (APCI): 293 (M + H)+.  Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   150 NO CH3 NO CH3 3.17 3.38 N CH3  1-Methyl-5-(5-(1-methyl-1H-indol-2-yl)pent-4-ynyl)-3,4-dihydropyridin-2(1H)-one (3.38) Enamide 3.17 (94 mg, 0.53 mmol), bis(triphenylphosphine)palladium(II) chloride (19 mg, 0.026 mmol), copper iodide (10 mg, 0.053 mmol), and 2-iodo-1-methyl-1H-indole (3.25) (0.18 g, 0.69 mmol) were combined according to the general procedure for Sonogashira coupling reactions, except that the reaction mixture was stirred for 1 h.  After purification by column chromatography on triethylamine washed silica gel (4:1→1:1→1:3 hexanes:ethyl acetate), 0.15 g (94 %) of the title compound 3.38 was isolated as a yellow oil. IR (neat): 2936, 1667, 750 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.57 (d, J = 7.8 Hz, 1H), 7.26- 7.23 (m, 2H), 7.13-7.10 (m, 1H), 6.69 (s, 1H), 5.83 (s, 1H), 3.79 (s, 3H), 3.04 (s, 3H), 2.55-2.50 (m, 4H), 2.25 (dt, J = 15.5, 7.7 Hz, 4H), 1.78 (qt, J = 7.4 Hz, 2H).  13C NMR (100 MHz, CDCl3): δ 169.9, 137.9, 128.2, 127.1, 123.6, 121.7, 120.9, 119.3, 110.3, 107.3, 96.7, 74.0, 34.7, 33.8, 32.1, 31.5, 27.7, 25.2, 20.2.  HRMS (ESI) calcd for C20H22N2ONa (M + Na) +: 329.1630.  Found: 329.1638.  NO CH3 NO CH3 3.17 3.39 N CH3  1-Methyl-5-(5-(1-methyl-1H-indol-3-yl)pent-4-ynyl)-3,4-dihydropyridin-2(1H)-one (3.41) Enamide 3.17 (0.21 g, 1.2 mmol), bis(triphenylphosphine)palladium(II) chloride (41 mg, 0.60 mmol), copper(I) iodide (22 mg, 0.12 mmol), and 3-iodo-1-methyl-1H-indole (3.27) (0.5 mL, 2 mmol) were combined according to the representative procedure, except that the reaction mixture was stirred for 22 h.  After purification by column chromatography on triethylamine washed silica gel (4:1→2:1→1:1 hexanes:ethyl acetate), 0.12 g (32 %) of the title compound 3.39 was isolated as an orange oil. IR (film): 2935, 1659, 1541 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.71 (d, J = 7.8 Hz, 1H), 7.31- 7.24 (m, 2H), 7.20-7.17 (m, 2H), 5.83 (s, 1H), 3.75 (s, 3H), 3.03 (s, 3H), 2.52-2.49 (m, 4H), 2.26 (q, J = 8.0 Hz, 4H), 1.79-1.72 (m, 2H).  13C NMR (100 MHz, CDCl3): δ 170.0, 137.1, 132.5, 130.3, 126.9, 123.5, 121.0, 120.9, 119.8, 110.5, 98.5, 91.5, 75.1, 34.6, 33.9, 33.8, 32.1, 28.1, 25.2, 20.2.  HRMS (ESI) calcd for C20H22N2ONa (M + Na) +: 329.1630.  Found: 329.1624. Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   151 NO CH3 NO CH3 3.17 3.40 SCH3  1-Methyl-5-(5-(2-(methylthio)phenyl)pent-4-ynyl)-3,4-dihydropyridin-2(1H)-one (3.40) Enamide 3.17 (0.21 g, 1.2 mmol), bis(triphenylphosphine)palladium(II) chloride (42 mg, 0.060 mmol), copper(I) iodide (23 mg, 0.12 mmol), and 2-iodo thioanisole (0.39 g, 1.6 mmol) were combined according to the representative procedure, except that the reaction mixture was stirred for 1 h.  After purification by column chromatography on triethylamine washed silica gel (5:1→3:1→1:1 hexanes:ethyl acetate), 0.33 g (92 %) of the title compound 3.40 was isolated as a clear, yellow oil. IR (neat): 2924, 1667, 753 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.35 (dd, J = 7.6, 1.4 Hz, 1H), 7.28-7.24 (m, 1H), 7.13-7.11 (m, 1H), 7.06 (td, J = 7.4, 1.2 Hz, 1H), 5.87 (s, 3H), 3.02 (s, 3H), 2.52-2.49 (m, 4H), 2.47 (s, 3H), 2.29-2.25 (m, 4H), 1.78-1.71 (m, 2H).  13C NMR (100 MHz, CDCl3): δ 170.0, 142.2, 133.2, 129.2, 127.1, 125.1, 124.7, 122.8, 119.5, 97.4, 79.8 34.6, 33.6, 32.1, 27.6, 25.2, 20.0, 16.0.  HRMS (ESI) calcd for C18H21NONaS (M + Na) +: 322.1242.  Found: 322.1246.  NO CH3 NO CH3 3.17 3.41 OCH3  5-(5-(2-Methoxyphenyl)pent-4-ynyl)-1-methyl-3,4-dihydropyridin-2(1H)-one (3.41) Enamide 3.17 (0.27 g, 1.5 mmol), bis(triphenylphosphine)palladium(II) chloride (54 mg, 0.076 mmol), copper(I) iodide (29 mg, 0.15 mmol), and 2-iodoanisole (0.3 mL, 2 mmol) were combined according to the representative procedure, except that the reaction mixture was stirred for 1 h.  After purification by column chromatography on triethylamine washed silica gel (3:1→1:1 hexanes:ethyl acetate), 0.35 g (81 %) of the title compound 3.41 was isolated as a clear, yellow oil. IR (neat): 2938, 1668, 755 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.36 (dd, J = 7.5, 1.4 Hz, 1H), 7.27-7.22 (m, 1H), 6.89-6.84 (m, 2H), 5.83 (s, 1H), 3.86 (s, 3H), 3.01 (s, 3H), 2.48 (q, J = 7.1 Hz, 4H), 2.27-2.20 (m, 4H), 1.73 (qt, J = 7.2 Hz, 2H).  13C NMR (100 MHz, CDCl3): δ 169.1, 160.0, 133.7, 129.2, 126.1, 120.6, 118.8, 113.1, 110.7, 93.8, 55.9, 33.7, 32.8, 31.2, 26.8, 24.3, 19.3.  HRMS (ESI) calcd for C18H21NO2Na (M + Na) +: 306.1470.  Found: 306.1466. Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   152 P Au Cy Cy Cl H3CO H3CO P H3CO H3CO Cy Cy 3.42 Gold Complex (3.42) A filtering flask was charged with a solution of 0.18 g of 2-dicyclohexylphosphino-2',6'- dimethoxybiphenyl (S-Phos) (0.43 mmol) in 20 mL of ethanol.  A solution of 72 mg of hydrogen tetrachloro(III)aurate hydrate (0.21 mmol) in 5 mL of ethanol was filtering into the flask, mixing with the solution contained inside.  The solution was concentrated to half volume by rotary evaporation in vacuo to afford a solution containing a white precipitate.  The precipitate was filtered and washed with ethanol.  The white solid was recrystallized from dichloromethane and hexanes to afford 79 mg (58 %) of the title compound 3.42 as clear, colorless crystals, mp 251 oC (dec.). 1H NMR (300 MHz, CDCl3): δ 7.58-7.42 (m, 4H), 7.22-7.18 (m, 2H), 6.66 (d, J = 8.5 Hz, 2H), 3.70 (s, 6H), 2.19-2.09 (m, 2H), 1.97-1.93 (m, 2H), 1.81-1.64 (m, 8H), 1.46-1.40 (m, 2H), 1.36- 1.15 (m, 8H). 31P NMR (161.98 MHz, CDCl3): δ 39.2. 3.42 has been previously prepared, see: Nieto-Oberhuber, C.; López, S.; Echavarren, A. M. J. Am. Chem. Soc. 2005, 127, 6178-6179.  3.7.3 Reactions of Substrates  Representative Procedure for PtCl2 and PtBr2 Catalyzed Cycloisomerization Reactions NO Bn + NO Bn H H PtCl2:        4                  :                   1 PtBr2:      1.5                 :                   1 NO Bn 3.28 3.28N 3.28X  Tetracycles 3.28N and 3.28X  Method A (PtCl2 as a catalyst):  A solution of 41 mg of enesulfonamide 3.28 (0.13 mmol) and 3.3 mg of platinum(II) chloride (0.013 mmol) in 0.5 mL of toluene was stirred in a sealed tube at 110 oC for 16 h.  The reaction mixture was cooled to rt and directly purified by column Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   153 chromatography on triethylamine washed silica gel (3:1 hexanes:ethyl acetate) to afford 32 mg (77 %) of a 4:1 mixture of 3.28N and 3.28X as a white solid, mp: 117-119 oC.  Method B (PtBr2 as a catalyst):  A solution of 58 mg of enesulfonamide 3.28 (0.18 mmol) and 6.2 mg of platinum(II) bromide (0.018 mmol) in 1.2 mL of toluene was stirred in a sealed tube at 110 oC for 16 h.  The reaction mixture was cooled to rt and directly purified by column chromatography on triethylamine washed silica gel (3:1 hexanes:ethyl acetate) to afford 35 mg (61 %) of a 1.5:1 mixture of 3.28N and 3.28X as a white solid. IR (film): 2933, 1649, 756 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.37-7.13 (m, 9H), 5.95 (t, J = 3.7 Hz, 1H), 5.67 (d, J = 14.6 Hz, 1H), 4.39 (s, 1H), 4.37 (d, J = 14.6 Hz, 1H), 2.41-2.33 (m, 1H), 2.30-2.22 (m, 1H), 2.19-2.08 (m, 1H), 2.02-1.93 (m, 2H), 1.77-1.66 (m, 4H), 1.25-1.23 (m, 1H).  Additional signals associated with the minor isomer 3.28X: δ 7.05-7.03 (m, 1H), 6.21 (br s, 1H), 5.98 (d, J = 14.6 Hz, 1H), 4.30 (s, 1H), 3.73 (d, J = 13.9 Hz, 1H), 1.44-1.38 (m, 2H), 0.98- 0.89 (m, 2H).  13C NMR (100 MHz, CDCl3): δ 171.9, 171.2, 153.1, 145.0, 144.1, 141.0, 138.6, 138.4, 135.7, 135.4, 130.0, 129.7, 129.5, 129.1, 128.7, 128.6, 127.9, 127.8, 126.9, 125.4, 124.1, 121.2, 119.3, 70.0, 66.0, 51.6, 51.5, 46.7, 45.9, 35.6, 33.8, 33.0, 31.8, 30.0, 29.7, 25.3, 23.8, 23.5, 19.0.  HRMS (ESI) calcd for C23H23NONa (M + Na) +: 352.1677. Found: 352.1681.  NO CH3 + NO CH3 H H OCH3 OCH3 PtCl2:        7                  :                   1 PtBr2:       9                   :                   1 NO CH3 OCH3 3.29 3.29X3.29N  Tetracycles 3.29N and 3.29X Method A:  Enamide 3.29 (95 mg, 0.33 mmol), platinum(II) chloride (8.7 mg, 0.033 mmol), and 1.3 mL of toluene were combined according to the representative procedure.  After purification by column chromatography on triethylamine washed silica gel (1:1→1:3 hexanes:ethyl acetate), 73 mg (79 %) of a 7:1 mixture of 3.29N and 3.29X was isolated as a yellow foam.  Method B:  Enamide 3.29 (43 mg, 0.15 mmol), platinum(II) bromide (5.3 mg, 0.015 mmol), and 1.0 mL of toluene were combined according to the representative procedure.  After purification Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   154 by column chromatography on triethylamine washed silica gel (1:1→1:3 hexanes:ethyl acetate), 37 mg (88 %) of a 9:1 mixture of 3.29N and 3.29X was isolated as a yellow oil. IR (film): 2936, 1642, 731 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.30 (d, J = 8.3 Hz, 1H), 6.84- 6.83 (m, 1H), 6.82-6.79 (m, 1H), 5.87 (t, J = 3.5 Hz, 1H), 4.33 (s, 1H), 3.80 (s, 3H), 3.36 (s, 3H), 2.40-2.32 (m, 1H), 2.28-2.21 (m, 1H), 2.18-2.07 (m, 2H), 1.88-1.69 (m, 5H), 1.57 (td, J = 13.1, 3.5 Hz, 1H).  Addition signals associated with the minor isomer 3.29X: δ 7.18 (d, J = 8.7 Hz, 1H), 6.96 (d, J = 8.3 Hz,1H), 6.90 (d, J = 9.2 Hz, 1H), 6.20 (s, 1H), 4.26 (s, 1H), 3.83 (s, 2H), 3.80 (s, 3H), 3.24 (s, 3H), 2.78 (s, 2H).  13C NMR (100 MHz, CDCl3): δ 172.1, 171.3, 161.0, 160.5, 150.1, 145.8, 144.0, 133.2, 131.0, 127.8, 122.4, 118.9, 117.4, 115.1, 115.0, 113.0, 112.3, 110.0, 74.0, 70.6, 56.5, 56.3, 46.9, 46.2, 38.0, 32.3, 30.4, 30.3, 25.3, 18.9.  HRMS (ESI) calcd for C18H21NO2Na (M + Na) +: 306.1470. Found: 306.1479.  NO + NO H H OCH3 OCH3 NO Bn OCH3 3.30 3.30X3.30N Bn Bn 18                  :                 1 Tetracycles 3.30N and 3.30X Method A:  Enamide 3.30 (68 mg, 0.19 mmol), platinum(II) chloride (5.0 mg, 0.019 mmol), and 0.5 mL of toluene were combined according to the representative procedure.  After purification by column chromatography on triethylamine washed silica gel (5:1→1:1 hexanes:ethyl acetate), 54 mg (79 %) of an 18:1 mixture of 3.30N and 3.30X was isolated as a white foam. IR (film): 2938, 1642, 732, 648 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.32-7.25 (m, 6H), 6.77 (dd, J = 8.2, 2.0 Hz, 1H), 6.46 (d, J = 1.6 Hz, 1H), 5.78 (t, J = 3.7 Hz, 1H), 5.34 (d, J = 14.5 Hz, 1H), 4.50 (d, J = 14.5 Hz, 1H), 4.39 (s, 1H), 3.68 (s, 3H), 2.39-2.32 (m, 1H), 2.27-2.20 (m, 1H), 2.18-2.11 (m, 1H), 2.05-1.93 (m, 2H), 1.78-1.63 (m, 4H), 1.32-1.25 (m, 1H).  Additional signals associated with the minor isomer 3.30X: δ 6.97 (d, J = 8.2 Hz, 1H), 6.16 (s, 1H), 5.95 (d, J = 14.1 Hz, 1H), 4.26 (s, 1H), 3.82 (s, 3H).  13C NMR (100MHz, CDCl3): δ 173.2, 161.1, 145.7, 144.5, 138.8, 133.7, 129.8, 129.7, 128.7, 122.0, 116.7, 115.8, 108.8, 70.5, 56.5, 52.0, 47.3, 34.4, 33.6, 32.1, 25.2, 19.0.  HRMS (ESI) calcd for C24H25NO2Na (M + Na) +: 382.1783.  Found: 382.1771.  Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   155 N CH3 + N CH3 H H Br Br 2                    :                   1 O ONO CH3 Br 3.31 3.31N 3.31X  Tetracycles 3.31N and 3.31X Method A:  Enamide 3.31 (69 mg, 0.21 mmol), platinum(II) chloride (5.5 mg, 0.021 mmol), and 0.75 mL of toluene were combined according to the representative procedure, except that the reaction mixture was stirred at 130 oC for 16 h. After purification by column chromatography on triethylamine washed silica gel (5:1→1:1 hexanes:ethyl acetate), 46 mg (66 %) of an 2:1 mixture of 3.31N and 3.31X was isolated as a clear, yellow oil IR (film): 3289, 2942, 1667, 730 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.45 (s, 1H), 7.42-7.40 (m, 1H), 7.27-7.23 (m, 1H), 6.02 (t, J = 3.5 Hz, 1H), 4.33 (s, 1H), 3.32 (s, 3H), 2.61-2.30 (m, 2H), 2.28-2.21 (m, 1H), 2.19-2.03 (m, 2H), 1.96-1.65 (m, 4H), 1.63-1.53 (m, 1H).  Additional signals associated with the minor isomer 3.31X: δ 7.34-7.31 (m, 1H), 7.16 (s, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.20 (s, 1H), 4.28 (s, 1H), 3.23 (s, 3H), 1.49-1.43 (m, 1H).  13C NMR (100 MHz, CDCl3): δ 171.8, 171.1, 153.7, 146.2, 143.6, 139.4, 138.1, 134.0, 132.3, 131.7, 128.8, 128.2, 127.9, 122.4, 121.5, 120.7, 118.5, 73.7, 70.1, 46.8, 46.3, 38.4, 38.0, 35.9, 32.0, 31.1, 30.2, 30.1, 29.4, 25.5, 24.0, 23.8, 18.8.  HRMS (ESI) calcd for C17H18NONa 79Br (M + Na)+: 354.0469. Found: 354.0476.  N CH3 + N CH3 H H OTs OTs 2                    :                   1 O ONO CH3 OTs 3.32 3.32N 3.32X  Tetracycles 3.32N and 3.32b Enamide 3.32 (53 mg, 0.13 mmol), platinum(II) chloride (3.3 mg, 0.013 mmol), and 0.6 mL of toluene were combined according to the representative procedure.  After purification by column chromatography on triethylamine washed silica gel (1:1→0:1 hexanes:ethyl acetate), 36 mg (68 %) of an 2:1 mixture of 3.32N and 3.32X was isolated as a clear, colorless oil. Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   156 IR (film): 2937, 1641, 812, 732 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.71 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 7.31 (s, 1H), 6.97 (d, J = 8.6 Hz, 1H), 6.68 (s, 1H), 5.99 (t, J = 3.5 Hz, 1H), 4.24 (s, 1H), 3.11 (s, 3H), 2.47 (s, 3H), 2.34-2.11 (m, 4H), 2.05-1.96 (m, 1H), 1.91-1.81 (m, 1H), 1.74-1.71 (m, 2H), 1.57-1.49 (m, 2H).  Additional signals associated with the minor isomer 3.32X: δ 7.71 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 7.04-7.01 (m, 1H), 6.96-6.94 (m, 1H), 6.37 (s, 1H), 6.19 (s, 1H), 4.15 (s, 1H), 2.93 (s, 3H), 2.45 (s, 3H), 1.42-1.37 (m, 1H).  13C NMR (100 MHz, CDCl3): δ 171.5, 170.7, 153.8, 150.2, 149.9, 146.8, 146.6, 145.5, 143.4, 139.3, 137.6, 134.0, 133.3, 133.2, 130.8, 129.6, 129.5, 127.8, 123.7, 123.0, 122.5, 120.9, 119.9, 118.8, 118.2, 73.6, 70.0, 46.9, 46.1, 38.0, 37.7, 35.8, 32.0, 31.0, 30.1, 29.3, 25.5, 23.9, 23.8, 22.7, 18.7. HRMS (ESI) calcd for C24H26NO4 32S (M + H)+: 424.1583.  Found: 424.1587.  NO CH3 + NO CH3 H H CF3 CF3 PtCl2:        1                 :                   2 PtBr2:       1                  :                  1.6 NO CH3 CF3 3.33 3.33X3.33N  Tetracycles 3.33N and 3.33X Method A:  Enamide 3.35 (43 mg, 0.13 mmol), platinum(II) chloride (3.5 mg, 0.013 mmol), and 0.6 mL of toluene were combined according to the representative procedure, except that the reaction mixture was stirred at 130 oC for 16 h. After purification by column chromatography on triethylamine washed silica gel (1:1 dichloromethane:hexanes→2:3 dichloromethane:diethyl ether→9:1 dichloromethane:methanol), 22 mg (52 %) of a 1:2 mixture of 3.33N and 3.33X was isolated as a white solid.  X-ray quality crystals were obtained from methanol, mp: 145-147 oC.  Method B:  Enamide 3.33 (55 mg, 0.17 mmol), platinum(II) bromide (6.1 mg, 0.017 mmol), and 1.0 mL of toluene were combined according to the representative procedure.  After purification by column chromatography on triethylamine washed silica gel (1:1→0:1 hexanes:ethyl acetate), 25 mg (46 %) of a 1:1.6 mixture of 3.33N and 3.33X was isolated as a yellow crystalline solid. IR (film): 2943, 1631, 733 cm-1.  1H (400 MHz, CDCl3): δ 7.53 (s, 1H), 7.49 (s, 1H), 7.14 (s, 1H), 6.30 (s, 1H), 4.33 (s, 1H), 3.26 (s, 3H), 2.66-2.07 (m, 5H), 2.00-1.46 (m, 5H).  Additional signals associated with the minor isomer 3.33N: δ 7.51 (s, 1H), 7.46 (s, 1H), 7.12 (s, 1H), 6.16 (t, Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   157 N O CH3 CF3 H J = 3.7 Hz, 1H), 4.39 (s, 1H), 3.37 (s, 3H).  13C (100 MHz, CDCl3): δ 170.8, 170.2, 155.3, 143.9, 143.0, 142.7, 137.7, 135.8, 130.2 (q, J = 32 Hz), 129.0 (q, J = 32 Hz), 126.1, 125.6 (q, J = 4 Hz), 125.0 (q, J= 4 Hz), 124.3 (q, J = 271 Hz), 124.2 (q, J = 271 Hz), 121.9, 121.4 (q, J = 4 Hz), 121.0, 120.7 (q, J = 4 Hz), 117.7, 72.9, 69.2, 46.0, 45.6, 37.6, 37.3, 35.0, 31.0, 30.3, 29.2, 29.0, 28.5, 24.7, 23.1, 22.8, 17.9.   HRMS (ESI) calcd for C18H18NOF3Na (M + Na) +: 344.1238. Found: 344.1236.  Anal. Calcd for C18H18F3NO: C, 67.28; H, 5.65; N, 4.36.  Found: C, 67.09; H, 5.65; N, 4.43.    Figure 3.4:  ORTEP representation of the solid state structure of 3.33X ...........................................................................................................................................................    Figure 3.5:  ORTEP representation of the solid state structure of 3.33N ...........................................................................................................................................................  N O CH3 CF3 H Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   158 N CH3 + N CH3 H H OCH3 OCH3 10                      :                      1 O ONO CH3 OCH3 3.34 3.34N 3.34X OCH3 OCH3 OCH3  Tetracycles 3.34N and 3.34X Method A:  Enamide 3.34 (34 mg, 0.11 mmol), platinum(II) chloride (2.8 mg, 0.011 mmol), and 0.5 mL of toluene were combined according to the representative procedure.  After purification by column chromatography on triethylamine washed silica gel (1:1 hexanes:ethyl acetate), 33 mg (98 %) of a 10:1 mixture of 3.34N and 3.34X was isolated as an off-white solid, mp: 132-134 oC. IR (neat): 2964, 1642, 731 cm-1.  1H NMR (400 MHz, CDCl3): δ 6.87 (s, 1H), 6.76 (s, 1H), 5.82 (br s, 1H), 4.33 (s, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.33 (s, 3H), 2.37-2.22 (m, 3H), 2.14-2.03 (m, 2H), 1.90-1.83 (m, 2H), 1.77-1.71 (m, 2H), 1.62-1.52 (m, 1H).  Additional signals associated with the minor isomer 3.34X: δ 6.60 (s, 2H), 6.15 (br s, 1H), 3.25 (s, 3H), 2.80 (s, 2H).  13C NMR (100 MHz, CDCl3): δ 172.6, 150.7, 150.6, 144.8, 136.4, 133.2, 116.9, 107.2, 104.0, 73.8, 57.1, 57.0, 47.0, 37.9, 32.8, 31.3, 30.6, 25.2, 18.9.  HRMS (ESI) calcd for C19H23NO3Na (M + Na)+: 336.1576.  Found: 336.1570.  N Bn + N Bn H H OCH3 OCH3 O ONO Bn OCH3 3.35 3.35N 3.35X OCH3 OCH3 OCH3 PtCl2:       20                   :                     1 PtBr2:       14                  :                      1 Tetracycles 3.35N and 3.35X Method A:  Enamide 3.35 (63 mg, 0.16 mmol), platinum(II) chloride (4.3 mg, 0.016 mmol), and 0.75 mL of toluene were combined according to the representative procedure.  After purification by column chromatography on triethylamine washed silica gel (1:1→1:3 hexanes:ethyl acetate), 49 mg (78 %) of a 20:1 mixture of 3.35N and 3.35X was isolated as a white solid.  X-ray quality crystals were obtained by recrystallization from dichloromethane and hexanes, mp: 147-149 oC. Method B:  Enamide 3.35 (48 mg, 0.12 mmol), platinum(II) bromide (4.4 mg, 0.012 mmol), and 0.75 mL of toluene were combined according to the representative procedure:  After purification Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   159 by column chromatography on triethylamine washed silica gel (1:1→1:3 hexanes:ethyl acetate), 38 mg (79 %) of a 14:1 mixture of 3.35N and 3.35X was isolated as a white solid. IR (film): 2939, 1644, 1497, 731 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.37-7.36 (m, 2H), 7.34- 7.28 (m, 3H), 6.82 (s, 1H), 6.19 (s, 1H), 5.74 (t, J = 3.7 Hz, 1H), 4.99 (d, J = 14.1 Hz, 1H), 4.74 (d, J = 14.5 Hz, 1H), 4.42 (s, 1H), 3.86 (s, 3H), 3.63 (s, 3H), 2.35-2.27 (m, 1H), 2.24-2.23 (m, 1H), 2.22-2.12 (m, 1H), 2.02-1.86 (m, 2H), 1.77-.174 (m, 2H), 1.73-1.64 (m, 2H), 1.39-1.32 (m, 1H).  13C NMR (100 MHz, CDCl3): δ 173.7, 150.8, 150.6, 145.3, 139.2, 136.1, 133.6, 130.0, 129.8, 128.8, 116.1, 106.7, 103.4, 70.9, 57.1, 57.0, 52.4, 47.6, 35.2, 34.7, 32.5, 25.1, 19.1. HRMS (ESI) calcd for C25H27NO3Na (M + Na) +: 412.1889.  Found: 412.1877.  Anal. Calcd for C25H27NO3: C, 77.09; H, 6.99; N, 3.60.  Found: C, 77.03; H, 6.85; N, 3.55.  Figure 3.6:  ORTEP representation of the solid state structure of 3.35N ...........................................................................................................................................................   N CH3 + N CH3 H H 7                    :                   1 O ONO CH3 3.36 3.36N 3.36X O O O  Tetracycles 3.36N and 3.36X Method A:  Enamide 3.36 (40 mg, 0.16 mmol), platinum(II) chloride (4.4 mg, 0.016 mmol), and 0.6 mL of toluene were combined according to the representative procedure. After purification by column chromatography on triethylamine washed silica gel (1:1 hexanes:ethyl acetate), 21 mg (51 %) of a 7:1 mixture of 3.36N and 3.36X was isolated as a yellow oil. N O O O H Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   160 IR (film): 2941, 1638, 729 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.35 (s, 1H), 6.36 (d, J = 1.8 Hz, 1H), 5.62 (t, J = 3.7 Hz, 1H), 4.22 (s, 1H), 3.15 (s, 3H), 2.44-2.32 (m, 2H), 2.30-2.20 (m, 2H), 2.15 (dt, J = 12.2, 3.0 Hz, 1H), 2.05-1.90 (m, 2H), 1.82-1.75 (m, 2H), 1.68-1.58 (m, 1H). Additional signals associated with the minor isomer 3.36X: δ 7.24 (s, 1H), 6.34 (s, 1H), 6.13 (s, 1H), 4.47 (s, 1H), 3.19 (s, 3H), 2.84 (s, 1H).  13C NMR (100 MHz, CDCl3): δ 171.8, 158.8, 147.5, 135.7, 128.7, 114.4, 109.3, 67.6, 50.6, 35.3, 31.4, 30.4, 29.6, 24.3, 18.3.  HRMS (ESI) calcd for C15H17NO2Na (M + Na) +: 266.1157.  Found: 266.1155.  N CH3 + N CH3 H H 20                   :                   1 O ONO CH3 3.38 3.38N 3.38X N N N CH3 CH3 CH3  Tetracycles 3.38N and 3.38X Method A:  Enamide 3.38 (43 mg, 0.14 mmol), platinum(II) chloride (3.7 mg, 0.014 mmol), and 1.2 mL of toluene were combined according to the representative procedure.  After purification by column chromatography on triethylamine washed silica gel (1:1 hexanes:ethyl acetate), 34 mg (80 %) of a 20:1 mixture of 3.38N and 3.38X was isolated as a yellow film. IR (film): 2936, 1640, 731 cm-1.  1H NMR (400 MHz, CDCl3): δ 7.49 (d, J = 7.8 Hz, 1H), 7.27 (s, 1H), 7.23-7.20 (m, 1H), 7.13-7.09 (m, 1H), 5.81 (t, J = 3.9 Hz, 1H), 4.51 (s, 1H), 3.81 (s, 3H), 3.41 (s, 3H), 2.43-2.26 (m, 3H), 2.21-2.12 (m, 3H), 1.90-1.84 (m, 3H), 1.77-1.69 (m, 1H). Additional signals associated with the minor isomer 3.38X: δ 6.25 (s, 1H), 4.27 (s, 1H), 3.86 (s, 3H), 3.45 (s, 3H).  13C NMR (100 MHz, CDCl3): δ 173.1, 144.3, 143.6, 138.8, 123.7, 123.1, 121.4, 121.0, 120.7, 116.4, 110.7, 69.6, 51.5, 37.3, 33.8, 32.9, 31.9, 30.7, 25.0, 18.5.  HRMS (ESI) calcd for C20H22N2ONa (M + Na) +: 329.1630.  Found: 329.1619.    Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   161 NO CH3 OCH3 3.29 N O H3C OCH3 3.51 (Z)-1-(4-Methoxyphenyl)-3-methyl-5,6,8,9-tetrahydro-3H-cyclopenta[d]azocin-4(7H)-one (3.51) A solution of 0.067 g of enamide 3.29 (0.24 mmol) and 0.016 g of silver hexafluoroantimonate(V) (0.047 mmol) in 2 mL of 1,2-dichloroethane was heated to 80 oC and stirred for 18 h.  The reaction mixture was cooled to rt and filtered through a pipette of triethylamine washed silica gel.  The filtrate was concentrated by rotary evaporation in vacuo to afford a brown oil.  The crude oil was dry loaded onto triethylamine washed silica gel and purified by column chromatography (1:1→1:3 hexanes:ethyl acetate) to afford 0.023 g (35 %) of the title compound 3.51 as a clear, colorless oil. IR (neat): 2949, 1652, 1510, 831, 731 cm-1.  1H NMR (400 MHz, CDCl3, 25 oC):δ 7.23 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 6.05 (s, 1H), 3.83 (s, 3H), 3.08 (s, 3H), 2.64 (br s, 2H), 2.43 (br s, 2H), 2.18 (br s, 4H), 1.73 (qt, J = 7.5 Hz, 2H).  1H NMR (400 MHz, CDCl3, −40 oC): δ 7.26 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 6.06 (s, 1H), 3.83 (s, 3H), 3.30-3.22 (m, 1H), 3.08 (s, 3H), 2.70-2.54 (m, 2H), 2.50-2.43 (m, 1H), 2.39-2.24 (m, 2H), 2.17 (dt, J = 11.7, 3.8 Hz, 1H), 2.01-1.98 (m, 1H), 1.77-1.64 (m, 2H).  13C NMR (100 MHz, CDCl3): δ 174.9, 160.2, 142.7, 136.2, 132.6, 131.2, 129.5, 126.6, 114.9, 56.3, 40.8, 39.6, 35.0, 32.3, 29.8, 23.0.  HRMS (ESI) calcd for C18H22NO2 (M + H) +: 284.1651.  Found: 284. 1656.            Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   162  Table 3.5: NMR data for 3.51 NO H3C OCH3 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 1718 Carbon No. 13 C δ (ppm) a Mult. 1 H δ (ppm) (mult., J (Hz) b,c,d,e HMBC Correlations e 1 174.9 Q  H-10, H-18 2 32.3 CH2 H-2a: 3.30-3.22 (m) H-2b: 2.17 (dt, 11.7, 3.8)  3 29.8 CH2 H-3a: 2.70-2.54 (m) H-3b: 2.70-2.54 (m) H-2a, H-2b 4 142.7 Q H-2a, H-2b, H-3a, H-3b, H- 5a, H-5b, H-6a, H-6b, H-7a, H-7b 5 40.8 CH2 H-5a: 2.50-2.42 (m) H-5b: 2.37-2.28 (m) H-6a, H-6b 6 23.0 CH2 H-6a: 1.77-1.64 (m) H-6b: 1.77-1.64 (m) H-5a, H-5b, H-7a 7 39.6 CH2 H-7a: 2.37-2.28 (m) H-7b: 2.00-1.97 (m) H-6a, H-6b 8 131.2 Q H-3a, H-3b, H-5a, H-5b, H- 6a, H-6b, H-7a, H-7b 9 136.2 Q  H-10, H-12, H-14 10 126.6 CH 6.06 (s) H-18 11 132.6 Q  H-10, H-13, H-15 12, 14 129.5 CH H-12,14: 7.26 (d, 8.8) H-13, H-15 13, 15 114.9 CH H-13,15: 6.89 (d, 8.8) H-12, H-14 16 160.2 Q H-12, H-14, H-13, H-15, H- 17 17 6.3 CH3 H-17: 3.84 (s) 18 35.0 CH3 H-18: 3.08 (s) H-10 aRecorded at 100 MHz.  bRecorded at 400 MHz.  cAssignments based on HMQC and COSY data. dMethylene protons are arbitrarily designated H-Xa and H-Xb.  eOnly those correlations which could be unambiguously assigned are recorded.     Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   163   Table 3.6: NMR data for 3.51 NO H3C OCH3 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 1718 Proton No. 1 H δ (ppm) (mult J (Hz)) a,b  COSY Correlation c  H-2a 3.30-3.22 (m) H-2b, H-3a, H-3b H-2b 2.17 (dt, 11.7, 3.8) H-2a, H-3a, H-3b H-3a 2.70-2.54 (m) H-2a, H-2b, H-3b H-3b 2.70-2.54 (m) H-2a, H-2b, H-3a H-5a 2.50-2.42 (m) H-5b, H-6a, H-6b H-5b 2.37-2.28 (m) H-5a, H-6a, H-6b H-6a 1.77-1.64 (m)   H-5a, H-5b, H-7a, H-7b H-6b 1.77-1.64 (m)   H-5a, H-5b, H-7a, H-7b H-7a 2.37-2.28 (m) H-7b, H-6a, H-6b H-7b 2.00-1.97 (m) H-7a, H-6a, H-6b H-10 6.06 (s) H-12, H-14 7.26 (d, 8.8) H-13, H-15 H-13, H-15 6.89 (d, 8.8) H-12, H-14 H-17 3.84 (s) H-18 3.08 (s) a  Recorded at 400 MHz. b Assignements based on HMQC, HMBC, and COSY data. c Only those correlations which could be unambiguously assigned are recorded.         Chapter 3:  Enamides as Nucleophiles: Formation of Complex Ring Systems through a Platinum(II)-Catalyzed Addition/Friedel Crafts Pathway   164 3.8 References 1. Harrison, T. J.; Dake, G. R. Org. Lett. 2004, 6, 5023-5026. 2. Harrison, T. J.; Patrick, B. O.; Dake, G. R. Org. Lett. 2006, 9, 367-370. 3. Lloyd-Jones, G. C. Org. Biomol. Chem. 2003, 1, 215-236. 4. Zhang, L.; Sun, J.; Kozmin, S. A. Adv. Synth. Catal. 2006, 348, 2271-2296. 5. Deng, H.; Yang, X.; Tong, Z.; Li, Z.; Zhai, H. Org. Lett. 2008, 10, 1791-1793. 6. Brown, C. A.; Yamashita, A. J. Am. Chem. Soc. 1975, 97, 891-892. 7. Brown, C. A. J. Chem. Soc., Chem. Commun. 1975,  222-223. 8. Brown, C. A.; Yamashita, A. J. Chem. Soc., Chem. Commun. 1976,  959-960. 9. Brown, C. A.; Negishi, E.-i. J. Chem. Soc., Chem. Commun. 1977,  318-319. 10. Norman, M. H.; Heathcock, C. H. J. Org. Chem. 1988, 53, 3370-3371. 11. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467-4470. 12. Walker, S., D; Barder, T., E; Martinelli, J., R; Buchwald, S., L Angew. Chem., Int. Ed. 2004, 43, 1871-1876. 13. Nieto-Oberhuber, C.; Muñoz, M. P.; López, S.; Jiménez-Núñez, E.; Nevado, C.; Herrero- Gómez, E.; Raducan, M.; Echavarren, A. M. Chem. –Eur. J. 2006, 12, 1677-1693. 14. Herrero-Gómez, E.; Nieto-Oberhuber, C.; López, S.; Benet-Buchholz, J.; Echavarren, A., M. Angew. Chem., Int. Ed. 2006, 45, 5455-5459. 15. Bender, C. F.; Widenhoefer, R. A. Chem. Commun. 2008,  2741-2743. 16. Leyva, A.; Corma, A. J. Org. Chem. 2009, 74, 2067-2074. 17. Fürstner, A. Chem. Soc. Rev. 2009, 38, 3208-3221. 18. Dodd, Jennifer Megan. M. Sc. Thesis, University of British Columbia, 2010.     165                 Chapter 4: Platinum(II) and Gold(I)-Catalyzed Intramolecular Tandem Addition/Friedel-Crafts Reactions between Acyclic Enamides and 1-Arylalkynes                Chapter 4:  Platinum(II) and Gold(I)-Catalyzed Intramolecular Tandem Addition/Friedel-Crafts Reactions between Acyclic Enamides and 1-Arylalkynes   166 4.1   Introduction  The use of enamide derivatives as π-nucleophiles in platinum(II)-catalyzed cycloisomerization reactions was discussed in chapter 3 and proved to be an effective way to generate structurally complex nitrogen-containing tetracycles.1  As an example, enamide 3.34, a substrate that features an electron-rich aromatic ring, cyclized to products 3.34N and 3.34X in high yield and a 6-endo to 5-exo ratio of 10:1 (Scheme 4.1).  Substrates employing electron deficient aromatic ring systems were generally less reactive.  Enamide 3.33 was treated with 10 mol% platinum(II) chloride to give 3.33N and 3.33X in moderate yield and a regioisomeric ratio favoring the 5-exo isomer.  NO CH3 3 R1 10 mol% PtCl2 NO CH3 + NO CH3 H H 3.34N, R,R1=OCH3 3.33N, R=H, R1=CF3 R R1 R R1 R 3.34X , R,R1=OCH3 3.33X, R=H, R1=CF3 3.34, R,R1=OCH3 3.33, R=H, R1=CF3 PhCH3, 110 oC for 3.34, 98% (3.34N:3.34X 10:1) for 3.33, 52% (3.33N:3.33X 1:2)  Scheme 4.1:  Cycloisomerization/Friedel-Crafts addition reactions discussed in Chapter 31  The enamide functional group within the substrates employed in chapter 3 was confined to a 6-membered ring, as illustrated by the red bonds in Scheme 4.2.  It was proposed that a similar platinum(II)-catalyzed transformation could take place using acyclic enamine derivatives.  Will the reactions proceed as predictably as with cyclic enamide substrates?  Will the regiochemistry of the reaction change?  What will be the stereochemical relationship between the two chiral centers (indicated by blue asterisks in Scheme 4.2)?  This study presents initial work in addressing these questions.  N R 3 R1 PtCl2 (cat.) EWG N R H R1 R1 H N + REWG EWG NO R 3 R1 PtCl2 (cat.) + chapter 3 this chapter N R O H R1 R1 N O R H H H * * * *  Scheme 4.2:  Acyclic version of the cycloisomerization of enamides Chapter 4:  Platinum(II) and Gold(I)-Catalyzed Intramolecular Tandem Addition/Friedel-Crafts Reactions between Acyclic Enamides and 1-Arylalkynes   167  Cycloisomerization of acyclic enamides will give tricyclic structures featuring pendent amido functionalities.  The nitrogen atom will not be confined to the ring system and could potentially be exploited to further functionalize the products.  Biologically active compounds that are structurally related to the acyclic cycloisomerization products are shown in Figure 4.1 (common features are shown in red).  Compound 4.1 has application in the agricultural industry as a herbicide.2  Amine 4.2 is capable of controlling pain in mammals.3  Structurally complex indinivir 4.3, or Crixivan®, is currently used as a protease inhibitor as a part of a highly active antiretroviral therapy to treat HIV and AIDS.  The platinum(II)-catalyzed cycloisomerization of acyclic enamides could be utilized to create structural analogs of these or other biologically active compounds of similar structure.  N NH S O H3CO N N 4.1 4.2 N OH O Ph N OH N O NH N indinavir (4.3) H H H H H  Figure 4.1:  Compounds structurally related to products of acyclic enamide cycloisomerization The modular design of the acyclic enamide substrates should access a variety of product analogs (Figure 4.2).  There are three areas of the substrates that could be altered to examine the substrate scope.  First, the aromatic functional group can be easily altered to a variety of electron-donating, electron-withdrawing, or heteroaromatic moieties.  Second, the enamine derivative can be changed to an enamide, an enesulfonamide, or an enecarbamate.  Third, the tether can be changed by increasing or decreasing the length, as well as incorporating heteroatoms or branches if desired.  N Ar EWG R enamine derivative tether aromatic functional group  Figure 4.2:  Opportunities for variation of the substrate set Chapter 4:  Platinum(II) and Gold(I)-Catalyzed Intramolecular Tandem Addition/Friedel-Crafts Reactions between Acyclic Enamides and 1-Arylalkynes   168  The remainder of this chapter is divided into three sections.  The first section describes the synthesis of the substrates that are used in the study. The following section discusses the reactions of these substrates within the context of cycloisomerization and will be followed by a brief discussion of the results.  The final section describes the experimental procedures for the reactions described herein.   4.2   Synthesis of Substrates  Substrate synthesis for this study commenced with the formation of hex-5-yn-1-ol (4.5) and hept-6-yn-1-ol (3.14) (Scheme 4.3).  An acetylenic zipper reaction of commercially available hex-3-yn-1-ol 4.4 with potassium 3-aminopropylamide4-7 (KAPA reagent: potassium hydride + 1,3-diaminopropane) gave hex-5-yn-1-ol (4.5) in 84% yield, as indicated by the appearance of a 1-proton triplet of doublets at 1.93 ppm in the 1H NMR spectrum (Scheme 4.3, eq 1).  Hept-6- yn-1-ol (3.14) was synthesized as described in chapter 3 (Scheme 4.3, eq 2).  Deprotonation of 1- hexyne (3.12) and treatment with paraformaldehyde gave propargyl alcohol 3.13 in 92% yield. The acetylenic zipper reaction was applied to the propargyl alcohol 3.13 to yield hept-6-yn-1-ol (3.14) in 91% yield.  OH 3.12 3.13 HO 3.14 4.54.4 HO HO a)  nBuLi,  THF      -78 oC b)  (CH2O)n KH H2N NH2 KH H2N NH2 84% 92% 91% (1) (2)  Scheme 4.3:  Synthesis of alcohols 4.5 and 3.14  With alkynes 4.5 and 3.14 in hand, the next step was to couple them using Sonogashira technology8 to various aromatic iodides.  All iodides were commercially available except for 4- iodo-1,2-dimethoxybenzene (4-iodoveratrole) (3.20) and 2-iodo-1-methyl-1H-indole (3.25). The synthesis of these compounds was described in detail in chapter 3 (Scheme 3.2.3, eqs 1 and 3). The Sonogashira coupling reactions were performed using 5 mol% of Chapter 4:  Platinum(II) and Gold(I)-Catalyzed Intramolecular Tandem Addition/Friedel-Crafts Reactions between Acyclic Enamides and 1-Arylalkynes   169 bis(triphenylphosphine)palladium(II) chloride and 10 mol% of copper(I) iodide in a dichloromethane-triethylamine solvent mixture.  The results are summarized in Table 4.2.1.  The reactions were generally finished within 1-3 hours and the products were isolated in good to excellent yields.  The coupling of alcohol 3.14 with 1-bromo-3,5-dimethoxybenzene did not proceed as readily as with aryl iodides due to the decreased reactivity of the bromo-substituted coupling partner (entry 5).  The reaction mixture was stirred at room temperature for 15 hours before being heated to 65 oC for a further two hours to complete the reaction.  Product formation was verified by the disappearance of the acetylenic proton signals for alcohols 4.5 and 3.14 in the 1H NMR spectrum and the appearance of signals corresponding to the aromatic functional group installed.  Table 4.1: Sonogashira coupling reactions of alkynols HO n HO n R conditions NEt3, CH2Cl2 entry substrate n R conditions product yield (%) a,b  1 4.5 1 OCH3 (p-CH3O)C6H4-I, 5 mol% (Ph3P)2PdCl2, 10 mol% CuI 4.6 74 2 4.5 1 OCH3 OCH3  (m,p-CH3O)2C6H3-I (3.20), 5 mol% (Ph3P)2PdCl2, 10 mol% CuI 4.7 83 3 3.14 2 OCH3 (p-CH3O)C6H4-I, 5 mol% (Ph3P)2PdCl2, 10 mol% CuI 4.8 83 4 3.14 2 OCH3 OCH3  (m,p-CH3O)2C6H3-I (3.20), 5 mol% (Ph3P)2PdCl2, 10 mol% CuI 4.9 83  5  3.14 2 OCH3 OCH3 (m,m-CH3O)2C6H3-Br, 5 mol% (Ph3P)2PdCl2, 10 mol% CuI 4.10 70c 6 3.14 2 N CH3  2-iodo-1-methyl-1H-indole (3.25), 5 mol% (Ph3P)2PdCl2, 10 mol% CuI 4.11 83 7 3.14 2 CF3 (p-CF3)C6H4-I, 5 mol% (Ph3P)2PdCl2, 10 mol% CuI 4.12 94 8 3.14 2 NO2 (p-NO2)C6H4-I, 5 mol% (Ph3P)2PdCl2, 10 mol% CuI 4.13 88 aReported yields are isolated yields. bReported yields are the maximum of single experiments  cRequires heating to 65 oC for 2 h. Chapter 4:  Platinum(II) and Gold(I)-Catalyzed Intramolecular Tandem Addition/Friedel-Crafts Reactions between Acyclic Enamides and 1-Arylalkynes   170 Once the aromatic functional groups were successfully installed on the alkyne, the alcohol portion of the substrates was oxidized to the aldehyde using the Moffatt-Swern method (Table 4.2.2).  Moffatt-Swern oxidations were run using 1 equivalent of the alcohol, 1.3 equivalents of oxalyl chloride, 2 equivalents of dimethyl sulfoxide, and 5 equivalents of triethylamine in a solution of dichloromethane, and were stirred between 1 and 2.5 hours.  The products were consistently isolated in high yield.  Product formation was verified by the disappearance of the signal associated with the alcohol functionality and the appearance of a signal consistent with an aldehyde proton in the 1H NMR spectrum.  The aldehyde proton of the products had a diagnostic chemical shift of between 9.77 ppm and 9.83 ppm.  The multiplicity of the signal was not consistent and varied between a singlet and a triplet with a small coupling constant of 1.4-1.7 Hz.    Table 4.2:Moffatt-Swern oxidation reactions HO n H n ROR (COCl)2, DMSO NEt3, CH2Cl2 -78 oC to 0 oC entry substrate n R product yield (%) a,b  1 4.5 1 H 4.14 69 2 4.6 1 OCH3 4.15 80 3 4.7 1 OCH3 OCH3  4.16 88 4 3.14 2 H 3.15 86 5 4.8 2 OCH3 4.17 86 6 4.9 2 OCH3 OCH3  4.18 87 7 4.10 2 OCH3 OCH3 4.19 84 8 4.12 2 CF3 4.20 84 9 4.13 2 NO2 4.21 84 aReported yields are isolated yields. bReported yields are the maximum of single experiments Chapter 4:  Platinum(II) and Gold(I)-Catalyzed Intramolecular Tandem Addition/Friedel-Crafts Reactions between Acyclic Enamides and 1-Arylalkynes   171  Moffatt-Swern oxidation of alcohol 4.11 formed the expected aldehyde 4.22 in a dismal yield of 5%, exemplifying the need for an alternative oxidation method.  Oxidation using Dess- Martin periodinane was tested due to its ease of operation and tolerability of air and moisture (Scheme 4.4).  Alcohol 4.11 was reacted with 1.2 equivalents of Dess-Martin periodinane in dichloromethane at room temperature to afford the desired aldehyde 4.22 in 67% yield. Although the reaction was not as high yielding as the Moffatt-Swern oxidations, the yield was synthetically useful and the product was carried on to the next step.  H O N CH3HO N CH3 rt, CH2Cl2 67%4.11 4.22 O I O OAc OAc AcO  Scheme 4.4:  Oxidation of alcohol 4.22  With a series of aldehydes in hand, the next step was to form the enamide functional group that is crucial to the platinum(II)-catalyzed cycloisomerization reactions.  The aldehydes were condensed with either 2-pyrrolidinone or δ-valerolactam to form the desired enamides (Table 4.2.3).  The condensations were performed with 1 equivalent of aldehyde, between 2-5 equivalents of lactam, and acetic acid in toluene as a solvent.  The reaction mixtures were heated to reflux and water was removed throughout the reaction by a Dean-Stark trap.  The reactions were continued until starting material was not observed by thin layer chromatography.  In some instances the starting material appeared to be consumed yet a small portion was recovered in the final purification step (entries 3 and 6).  The yields of the process varied but were generally high. The formation of the enamides was verified by the appearance of two diagnostic signals in the 1H NMR spectra.  The signal corresponding to the vinylic proton adjacent to the nitrogen atom (α- enamide proton) appeared as a 1-proton doublet with a chemical shift between 7.31 ppm and 6.90 ppm.  The coupling constant of the doublet was consistently between 14.3 Hz and 14.7 Hz, a characteristic of a proton in an E-olefin.  The β-enamide proton signal appeared in the 1H NMR spectrum as a 1-proton doublet of triplets with a chemical shift between 4.86 ppm and 5.04 ppm. The values of the coupling constants of these signals were between 14.3 and 14.6 Hz and between 7.0 and 7.2 Hz, also characteristic of an E-double bond. Chapter 4:  Platinum(II) and Gold(I)-Catalyzed Intramolecular Tandem Addition/Friedel-Crafts Reactions between Acyclic Enamides and 1-Arylalkynes   172  Table 4.3:Condensation of amides and aldehydes to form enamides H n RO lactam, HOAc N n RO m toluene, reflux  entry substrate R lactam n m product yield (%) a,b  1 3.15 H 2-pyrrolidinone 2 1 4.23 100 2 3.15 H δ-valerolactam 2 2 4.24 78 3 4.15 OCH3 2-pyrrolidinone 1 1 4.25 67 (75)c 4 4.16 OCH3 OCH3  2-pyrrolidinone 1 1 4.26 74 5 4.17 OCH3 2-pyrrolidinone 2 1 4.27 81 6 4.18 OCH3 OCH3  2-pyrrolidinone 2 1 4.28 65 (73)c 7 4.19 OCH3 OCH3 2-pyrrolidinone 2 1 4.29 91 8 4.22 N CH3  2-pyrrolidinone 2 1 4.30 96 9 4.20 CF3 2-pyrrolidinone 2 1 4.31 92 10 4.21 NO2 2-pyrrolidinone 2 1 4.32 100 aReported yields are isolated yields. bReported yields are the maximum of single experiments  cYield (in parentheses) based on recovered starting material.   Although there was success using the synthetic route described above, not all substrates were amenable to the Moffatt-Swern oxidation or condensation conditions.  For example, one desired substrate was an enamide that contained an aromatic ring functionalized with an o- carboxylate ester.  Alcohol 3.14 underwent smooth Sonogashira coupling with methyl 2- iodobenzoate to form alcohol 4.33 in good yield (Scheme 4.5).  When alcohol 4.33 was reacted Chapter 4:  Platinum(II) and Gold(I)-Catalyzed Intramolecular Tandem Addition/Friedel-Crafts Reactions between Acyclic Enamides and 1-Arylalkynes   173 under Moffatt-Swern oxidation conditions, an undesired oxidation product was formed that could not be characterized by 1H NMR spectroscopy.  The same result was found using Dess-Martin perodinane.  To circumvent this problem, the enamide was installed prior to incorporation of the aromatic functional group.  Modification of the route in this manner would make it more divergent, greatly reducing the number of synthetic operations to form the substrates.  Originally, I had misgivings about the compatibility between the enamides and the Sonogashira coupling conditions.  Tests with the substrate containing the ortho-ester functional group revealed that these concerns were unfounded, and a new set of substrates was formed using this approach.  3.14 5 mol % (Ph3P)2PdCl2 10 mol % CuI NEt3, CH2Cl2 83% HO I O OCH3 HO OCH3O Moffatt-Swern oxidation or Dess-Martin oxidation undesired product 4.33  Scheme 4.5:  Attempted oxidation of alcohol 4.33  Two non-commercially available iodides were synthesized (Scheme 4.6).  5-Iodobenzo- 1,3-dioxole (4.35) was formed from commercially available 3,4-methylenedioxyaniline (4.34) following a variation of the Sandmeyer protocol9 (Scheme 4.6, eq 1).  para-Toluenesulfonyl protected 2-iodoindole 4.37 was furnished in 2 steps (Scheme 4.6, eq 2).  Indole (3.23) was first treated with base and para-toluenesulfonyl chloride to protect the nitrogen atom.  Treatment of protected indole 4.36 with tert-butyllithium in ether, followed by quenching with iodine gave the desired 2-iodoindole (4.37) in acceptable yield.  4.34 4.35 O OI O OH2N a) H2SO4, NaNO2 b) KI 22% 4.363.23 N Ts N H N Ts I 4.37 KH TsCl 79% a) tBuLi, Et2O, -78 oC b) I2 69% (1) (2)  Scheme 4.6:  Synthesis of non-commercially available iodides 4.35 and 4.37 Chapter 4:  Platinum(II) and Gold(I)-Catalyzed Intramolecular Tandem Addition/Friedel-Crafts Reactions between Acyclic Enamides and 1-Arylalkynes   174  The synthesized iodides 4.35 and 4.37 and other commercially available iodides and bromides were reacted with either enamide 4.23 or enamide 4.24 to furnish a series of substrates suitable for cycloisomerization testing (Table 4.2.4).  As seen previously, the bromo-substituted aromatic ring was less reactive and had to be heated to 60 oC for 22 hours before the reaction was complete (entry 3).  Exposing enamides 4.23 and 4.24 to Sonogashira coupling conditions did not display any compatibility issues and the resulting substrates were isolated in overall good yields.   Table 4.4: Sonogashira coupling reactions of enamides conditions N O m NEt3, CH2Cl2 N O m R  entry substrate m R conditions product yield (%) a,b 1 4.23 1  C6H5-I, 5 mol% (Ph3P)2PdCl2, 10 mol% CuI 4.38 85 2 4.23 1 O O  4.35, 5 mol% (Ph3P)2PdCl2, 10 mol% CuI 4.39 91 3 4.23 1 OCH3 OCH3 OCH3 (o,m,p-CH3O)3C6H2-Br, 5 mol% (Ph3P)2PdCl2, 10 mol% CuI 4.40 68c 4 4.23 1 O OCH3  (o-C(O)OCH3)C6H4-I, 5 mol% (Ph3P)2PdCl2, 10 mol% CuI 4.41 55 5 4.23 1 N Ts  4.37, 5 mol% (Ph3P)2PdCl2, 10 mol% CuI 4.42 65 6 4.24 2 OCH3 (p-CH3O)C6H4-I, 5 mol% (Ph3P)2PdCl2, 10 mol% CuI 4.43 85 7 4.24 2 OCH3 OCH3 (m,p-CH3O)2C6H3-I, 5 mol% (Ph3P)2PdCl2, 10 mol% CuI 4.44 90 aReported yields are isolated yields. bReported yields are the maximum of single experiments  cRequires heating to 60 oC for 22 h.   Chapter 4:  Platinum(II) and Gold(I)-Catalyzed Intramolecular Tandem Addition/Friedel-Crafts Reactions between Acyclic Enamides and 1-Arylalkynes   175 The set of substrates presented in Tables 4.2.3 and 4.2.4 were ready to be tested for cycloisomerization reactivity with platinum(II) chloride.  Despite successful condensation of different lactams with aldehydes, it could not be extended to other nitrogen containing functionality.  For example, attempted condensation of aldehyde 4.16 with N-methyl-p- toluenesulfonamide resulted in the recovery of the starting material, or unidentifiable decomposition products under more forcing reaction conditions.  As a result, an alternative method to install the enamine functional group derivative was necessary in order to increase the substrate scope from simple enamides to enecarbamates and enesulfonamides.  The chosen method to synthesize the enamine derivatives was a copper(I)-catalyzed cross coupling reaction between an amide, sulfonamide, or carbamate, and a vinyl iodide.10  A number of vinyl iodides were prepared, starting with 4.45 and 4.46 (Scheme 4.7).  With aldehydes 4.15 and 4.16 already prepared, the best method to install the vinyl iodide with E-geometry around the double bond was the Takai reaction11.  Aldehyde 4.15 was therefore treated with chromium(II) chloride and iodoform to give a mixture of E- and Z-vinyl iodides (represented as 4.45) in 59% yield and a 3:1 mixture favoring the E-isomer (Scheme 4.7, eq 1).  Veratrole derivative 4.16 was treated under the same conditions to give a mixture of iodides (represented as 4.46) in a 68% yield (based on recovered starting material) and a 4:1 mixture favoring the E-isomer (Scheme 4.7, eq 2).  Diagnostic signals in the 1H NMR spectrum indicative of the E-isomer are a 1-proton doublet at approximately 6.07 ppm with a coupling constant of 14.3 Hz, attributable to the proton adjacent to the iodine atom.  A 1-proton doublet of triplets with a chemical shift of approximately 6.54 ppm and coupling constants of 14.3 Hz and 7.2 Hz is attributable to the internal proton of the olefin.  Chapter 4:  Platinum(II) and Gold(I)-Catalyzed Intramolecular Tandem Addition/Friedel-Crafts Reactions between Acyclic Enamides and 1-Arylalkynes   176 H OCH3 O OCH3 I OCH3 I CrCl2, CHI3 THF, 0 oC to rt 4.15 4.45 59% (3:1) H OCH3 O OCH3 I OCH3 I CrCl2, CHI3 THF, 0 oC to rt 4.16 4.46 62%; 68% BRSM (4:1) OCH3 OCH3 OCH3 (1) (2)  Scheme 4.7:  Takai olefination of aldehydes 4.15 and 4.16 As mentioned in section 4.1, the atoms in the tether can also be varied.  All previous substrates featured all carbon tethers.  The incorporation of heteroatoms into the tether was explored next.  To begin, a vinyl iodide that also contained a portion of the molecule that could be displaced in an SN2 fashion was synthesized (Scheme 4.8).  Following the procedure of Negishi12, vinyl iodide 4.48 was synthesized from propargyl alcohol (4.47) in 32% yield by treatment with diisobutylaluminum hydride and zirconocene dichloride, followed by quenching with iodine.  The alcohol was then displaced using triphenylphosphine, bromine, and triethylamine13 to give the desired vinyl iodide 4.49.  Although each of these two steps is low yielding, the reactions were successful in providing sufficient amounts of material to be used in subsequent reactions.  4.47 OH I H H OH 4.48 I H H Br 4.49 a)  iBu2AlH, Cp2ZrCl2 0 oC to rt b)  I2, THF, -78 oC PPh3, Br2, NEt3 CH2Cl2, 0 oC 32% 52% Scheme 4.8:  Synthesis of vinyl iodide 4.49  The first heteratom-containing tether that was synthesized incorporated an oxygen atom (Scheme 4.9).  Propargyl alcohol (4.47) was subjected to a Sonogashira coupling reaction with 4- iodoveratrole (3.20).  The Sonogashira conditions employed were identical to those reported for the synthesis of other substrates (Tables 4.2.1 and 4.2.4).  Propargyl alcohol 4.50 was formed in excellent yield.  At this stage, vinyl iodide 4.49 was reacted with propargyl alcohol 4.50 under basic conditions to form vinyl iodide 4.51 in 58% yield (based on recovered starting material). Chapter 4:  Platinum(II) and Gold(I)-Catalyzed Intramolecular Tandem Addition/Friedel-Crafts Reactions between Acyclic Enamides and 1-Arylalkynes   177  OH H3CO H3CO OH 4.47 4.50 5 mol % (Ph3P)2PdCl2 10 mol % CuI NEt3, CH2Cl2 4-iodoveratrole (3.20) 86% NaOH, Bu4NHSO4 H2O,  0 oC I O OCH3 OCH34.51 4.49 55%; 58% BRSM  Scheme 4.9:  Synthesis of iodide 4.51  In addition to heteroatoms, other substitution on the tether could also make a difference in the reactivity of the substrate under cycloisomerization conditions.  To this end, a substrate containing a geminal diester on the all carbon tether was synthesized according to Scheme 4.10. Diethyl malonate (4.52) was first alkylated with propargyl bromide to give diester 4.53 in 82% yield.  Diester 4.53 was treated with 4-iodoveratrole (3.20) under Sonogashira coupling conditions to give diester 4.54 in 55% yield.  Compound 4.54 was deprotonated with sodium hydride and alkylated with vinyl iodide 4.49 to form iodide 4.55 in 82% yield.  a) NaH, THF, rt b) Br EtO OEt O O I OCH3 OCH3 OEtO EtO O 4.54 4.55 4.53 EtO OEt O O EtO OEt O O 4.52 82% 5 mol% (Ph3P)2PdCl2 10 mol% CuI NEt3, CH2Cl2 4-iodoveratrole (3.20) 55% OCH3 OCH3 a) NaH, THF b) 4.49, THF 82%  Scheme 4.10:  Synthesis of iodide 4.55  The substitution of a carbon atom with a nitrogen atom in the tether was also investigated. The requisite nitrogen-containing iodide precursor (4.59) was synthesized in three steps (Scheme 4.11).  Alkylation of benzylamine (4.56) with propargyl bromide proceeded in near quantitative yield to form amine 4.57.  Sonogashira coupling of amine 4.57 with 4-iodoveratrole (3.20) gave amine 4.58 in 69% yield.  Amine 4.58 was then treated with vinyl iodide 4.49 and base to install the iodide functionality, giving compound 4.59 in 58% yield and an isomeric mixture of 10:1 in favor of the E-isomer. Chapter 4:  Platinum(II) and Gold(I)-Catalyzed Intramolecular Tandem Addition/Friedel-Crafts Reactions between Acyclic Enamides and 1-Arylalkynes   178  4.56 4.57 NH2 N H N H OCH3 OCH34.58 I N OCH3 OCH3 N OCH3 OCH3 I Br neat 98% 5 mol% (Ph3P)2PdCl2 10 mol% CuI NEt3, CH2Cl2 4-iodoveratrole (3.20) 69% K2CO3, 4.49, 58% (10:1) MeCN, 75 oC 4.59  Scheme 4.11:  Synthesis of iodide 4.59 With a large amount of substrates disposed to form E-enamides, a Z-vinyl iodide was synthesized for the sake of comparison.  Stork-Wittig homologation14 of aldehyde 4.16 resulted in a 5:1 mixture of products (represented as 4.60) favoring the Z-vinyl iodide (Scheme 4.12).  O H OCH3 OCH3 NaHMDS [Ph3PCH2I] +I- THF, -78 oC 74% 4.16 OCH3 OCH3 I OCH3 OCH3 4.60 I (5:1) Scheme 4.12:  Synthesis of Z-iodide 4.60  With the series of vinyl iodides in hand, they were tested for reactivity under the copper(I)- catalyzed coupling conditions.10  The results are summarized in Table 4.2.5.  The reactions were run using 1 equivalent of iodide, 1.2 equivalents of the desired nitrogen-containing fragment, 10- 20 mol% of copper(I) iodide, 15-30 mol% of N,N-dimethylglycine hydrochloride, and 2 equivalents of cesium carbonate in 1,4-dioxane as a solvent.  The reactions were shielded from light and stirred at 80 oC until complete or until no further change was observable by thin layer chromatography.     Chapter 4:  Platinum(II) and Gold(I)-Catalyzed Intramolecular Tandem Addition/Friedel-Crafts Reactions between Acyclic Enamides and 1-Arylalkynes   179 Table 4.5: Copper-catalyzed formation of enamides and enesulfonamides N X 1,4-dioxane, 80 oC I X R1 R R1 OCH3 R1 OCH3 Cs2CO3 X mol% CuI X mol% N,N-DMG H N R R1  entry substrate x R 1  H N R R1 mol % N,N-DMG a  mol % CuI product yield (%) b,c  1 4.46 CH2 OCH3 O NH O  15 30 4.61 88d 2 4.45 CH2 H O NH O Bn 10 20 4.62 70 3 4.46 CH2 OCH3 O NH O Bn 20 30 4.63 76 4 4.45 CH2 H N Ts H3C H  10 20 4.64 58 5 4.46 CH2 OCH3 N Ts H3C H  20 30 4.65 96 6 4.51 O OCH3 NH O  15 30 4.66 82 7 4.55 C(C(O)CH2CH3)2 OCH3 NH O  20 30 4.67 79 8 4.59 NBn OCH3 NH O  15 30 4.68 65 9 4.46 CH2 OCH3 NH O  15 30 4.69 71 10 4.46 CH2 OCH3 N NH  15 30 4.70 46 (91)e a N,N-DMG = N,N-Dimethylglycine hydrochloride.  bReported yields are isolated yields. cReported yields are the maximum of single experiments  dProduct was isolated as an 8:1 mixture of E:Z isomers.  eYield (in parentheses) based on recovered starting material.  Chapter 4:  Platinum(II) and Gold(I)-Catalyzed Intramolecular Tandem Addition/Friedel-Crafts Reactions between Acyclic Enamides and 1-Arylalkynes   180 Carbamates reacted smoothly under the reaction conditions to furnish substrates 4.61, 4.62, and 4.63 in good yield (entries 1-3).  Sulfonamides were also reactive: iodide 4.45 reacted with N-methyl-p-toluenesulfonamide to form enyne 4.64 in moderate yield (entry 4).  When the amount of copper catalyst and amino acid promoter were increased, the yield increased dramatically (entry 5).  2-Pyrrolidinone was coupled with substrates containing an altered tether in moderate to good yields (entries 6-8).  Substrates containing an aromatic heterocycle for the enamide portion of the molecule were also synthesized.  Copper(I)-catalyzed coupling of iodide 4.46 with 2-hydroxypyridine gave product 4.69 in 71% yield (entry 9).  Reaction of 4.46 with imidazole was not as reactive although the substrate was formed in moderate yield with the recovery of a large amount of starting material (entry 10).  Synthesis of the Z-enamide was attempted using the same copper(I)-catalyzed conditions employed for the formation of the E-enamides (Scheme 4.13).  OCH3 OCH3 I 4.60 (5:1 cis:trans) OCH3 OCH34.63 N O O Ph O NH O Ph 20 mol% CuI 30 mol% N,N-dimethylgycine hydrochloride Cs2CO3 dioxane, 80 oC 12% (31% BRSM) Scheme 4.13:  Attempted synthesis of a Z-enamide derivative  Vinyl iodide 4.60 was treated under the standard conditions for the copper(I)-catalyzed cross coupling with a carbamate10,  giving the E-isomer 4.63 in low yield.  A mixture of Z/E vinyl iodides 4.60 were recovered, although the mixture was enriched in the Z-isomer as most of the E-vinyl iodide was converted to product (4.63).  The steric strain present in the Z-substrate was too demanding for product formation to occur under the reaction conditions (Figure 4.3).   Chapter 4:  Platinum(II) and Gold(I)-Catalyzed Intramolecular Tandem Addition/Friedel-Crafts Reactions between Acyclic Enamides and 1-Arylalkynes   181 OCH3 OCH3 N O Ph HO  Figure 4.3:  Steric interaction impedes formation of Z-enecarbamate  An attempt to force the Z-isomer to react was made by performing the reaction with 1 equivalent of copper(I) iodide as well as 1 equivalent of N,N-dimethylglycine hydrochloride, reagents that were previously used sub-stoichiometrically.  The mixture of Z- and E-iodides 4.60 was reacted under the conditions shown to give an unexpected result (Scheme 4.14).  After treatment with stoichiometric amounts of reagents, products 4.71 and 4.72 were isolated. Presumably the iodine atom was eliminated in an E2 manner to form dialkyne 4.71.  Then, under the cross-coupling conditions, this dialkyne was coupled with remaining iodide (4.60) to give cross-coupled product 4.72.  OCH3 OCH3 I 4.60 (5:1 cis:trans) O NH O Ph CuI N,N-dimethylgycine  hydrochloride Cs2CO3 dioxane, 80 oC OCH3 OCH3 OCH3 OCH3 OCH3 OCH34.71 4.72  Scheme 4.14:  Unexpected results when attempting to for a Z-enamide derivative The Evans’ auxiliary derived enecarbamate was obviously too sterically encumbering to form the Z-enecarbamate.  Synthesis of a Z-enecarbamate was attempted again using the smaller 2-oxazolidinone and a vinyl-iodide enriched in the Z-isomer (4.60) (Scheme 4.15).  The reaction again failed to produce any useful amount of Z-enecarbamate.  Treatment under the reaction conditions show resulted in the formation of 4.71, 4.72, and 27% of enecarbamate 4.73 as a 3:1 Z:E mixture.  Chapter 4:  Platinum(II) and Gold(I)-Catalyzed Intramolecular Tandem Addition/Friedel-Crafts Reactions between Acyclic Enamides and 1-Arylalkynes   182 OCH3 OCH3 I 4.60 (12:1 cis:trans) O NH O 20% CuI 30% N,N-dimethylgycine  hydrochloride Cs2CO3 dioxane, 80 oC OCH3 OCH34.73 N O O 27% (3:1 cis:trans) 4.71 4.72  Scheme 4.15:  Attempted formation of Z-enecarbamate 4.73 The amount of Z-enecarbamate formed was not synthetically useful for investigation in cycloisomerization reactions.   Overall, 25 substrates were synthesized to be tested for reactivity in the platinum(II)- catalyzed cycloisomerization reactions.    4.3   Reactions of Substrates  Unlike the cycloisomerization of cyclic enamides described in chapter 3, cycloisomerization of acyclic enamides was proposed to form tricycles featuring a pendant amido-functional group and that lack a quaternary center.  The initial investigation into the cyclorearrangement of acyclic enamides was to determine the level of reactivity of the substrates and the regio- and stereochemical outcome of the products.  Chapter 4:  Platinum(II) and Gold(I)-Catalyzed Intramolecular Tandem Addition/Friedel-Crafts Reactions between Acyclic Enamides and 1-Arylalkynes   183 4.25, n=2; x=1; R1=H; R2=OCH3; R 3=H 4.26, n=2; x=1; R1=OCH3; R 2=OCH3; R 3=H 4.38, n=3; x=1; R1=H; R2=H; R3=H 4.27, n=3; x=1; R1=H; R2=OCH3; R 3=H 4.28, n=3; x=1; R1=OCH3; R 2=OCH3; R 3=H 4.29, n=3; x=1; R1=OCH3; R 2=H; R3=OCH3 4.39, n=3; x=1; R1,R2= -OCH2O -; R3=H 4.40, n=3; x=1; R1=OCH3; R 2=OCH3; R 3=OCH3 4.31, n=3; x=1; R1=H; R2=CF3; R 3=H 4.32, n=3; x=1; R1=H; R2=NO2; R 3=H 4.43, n=3; x=2; R1=H; R2=OCH3; R 3=H 4.44, n=3; x=2; R1=OCH3; R 2=OCH3; R 3=H N O R1 R3 R2 n x 4.64, R1=H; R2=OCH3 4.65, R1=OCH3; R 2=OCH3 N R2 3 Ts CH3 R1 4.61 N O O OCH3 3 OCH3 4.45, R=H 4.46, R=OCH3 N O O OCH3 3 R Ph 4.66, X=O 4.67, X= -C(C(O)OCH2CH3)2 4.68, X=NBn N X OCH3 OCH3 O N O N R 3 4.30, R=CH3 4.42, R=Ts N OCH3 3 OCH3 O OCH3 3 OCH3 N N N O O OCH3 4.41 4.69 4.70 3  Figure 4.4:  Substrates used in this study  The substrates tested in this study are shown in Figure 4.4.  The standard reaction conditions for investigating the cycloisomerization of acyclic substrates do not differ from the cyclic derivatives.  Each reaction was run with 10 mol% of platinum(II) chloride in toluene at 110 oC for 16 hours in a thick-walled, sealable reaction tube.  These conditions were first employed in the investigation of the cycloisomerization of enamide 4.28 (Scheme 4.16).  The reaction resulted in the formation of two products, 4.28A and 4.28C in 67% yield and an 8:1 regioisomeric ratio.  10 mol% PtCl2 toluene, 110 oC,  16 h 67% N O 4.28 OCH3 OCH3 3 OCH3 OCH3 NO 4.28A OCH3 OCH3 NO H 4.28C(8:1) Scheme 4.16:  Initial test cycloisomerization of enamide 4.28 Chapter 4:  Platinum(II) and Gold(I)-Catalyzed Intramolecular Tandem Addition/Friedel-Crafts Reactions between Acyclic Enamides and 1-Arylalkynes   184 The major product (4.28A) was characterized by 1D 1H and 13C NMR and 2D spectroscopy (Scheme 4.17).  The 1H NMR spectrum of 4.28A did not show a signal attributable to a vinyl proton as would be expected of the 6-endo product, but rather it displayed a sharp singlet with a chemical shift of 5.58 ppm.  The multiplicity of the signal and the COSY data indicated that there were no adjacent protons.  In addition, the 13C NMR chemical shift of carbon 1 is significantly upfield (59.3 ppm) from a typical sp2 carbon atom (105-145 ppm), suggesting that it is sp3 hybridized.  The 1D NMR data along with the COSY and HMBC correlations are indicative of the proposed product (see Experimental Section 4.7.3, Tables 4.7.3.1 and 4.7.3.2). Finally, the mass spectrum of the product was 314 m/z, indicating that a cycloisomerization occurred and no new atoms were incorporated into the product.  COSY correlation HMBC correlation OCH3 OCH3 N O H1 9 12 17 15 H H H3 H H product formed OCH3 OCH3 N O expected product Figure 4.5:  2D NMR COSY and HMBC correlations for tricycle 4.28A The major product 4.28A is the result of a 6-endo mode of cyclization followed by alkene migration to the more substituted position under the reaction conditions.  The minor product 4.28C is the result of the less favored 5-exo cyclization pathway (isolated as a single diastereomer).  Support for in situ alkene migration comes from the following experiments. Enamide 4.28 was subjected to the platinum(II) catalyst at a lower reaction temperature (80 oC) in a test-tube reaction flask. The reaction was monitored by thin layer chromatography until it appeared complete.  Products 4.28B and 4.28C were isolated in 72% yield as a 5:1 mixture of isomers (Scheme 4.17).  Interestingly, the resulting products did not match those of the reaction run under standard conditions.  Under the lower temperature and decreased reaction time, the double bond did not isomerize into the more substituted position.  Instead, a 1:1 diastereomeric mixture (represented as 4.28B) was isolated along with 4.28C.  Chapter 4:  Platinum(II) and Gold(I)-Catalyzed Intramolecular Tandem Addition/Friedel-Crafts Reactions between Acyclic Enamides and 1-Arylalkynes   185 N O OCH3 OCH3 NO 4.28 4.28B 10 mol% PtCl2 toluene, 80 oC,  5.5 h 72% OCH3 OCH3 3 OCH3 OCH3 NO H 4.28C H (5:1) Scheme 4.17:  Cycloisomerization of enamide 4.28 at lower temperature and decreased reaction time  Resubjecting 4.28B to the standard reaction conditions (10 mol% platinum(II) chloride at 110 oC) converted the diastereomeric mixture to the previously observed cyclization product (4.28A) in 65% yield (Scheme 4.18, eq 1).  The isolated yield of 4.28A suggests that both diastereomers (4.28B) isomerize.  Alternate methods to isomerize the double bond were also tested.  Heating the mixture with DBU in solvent gave no reaction.  Treating the mixture of diastereomers 4.28B with 10 mol % of rhodium(III) chloride trihydrate at 100 oC in ethanol in a sealed tube resulted in alkene isomerization to give product 4.28A in 74% yield (Scheme 4.18, eq 2).  The rhodium(III)-catalyzed reaction provides a pathway to convert 1:1 diastereomeric mixtures into one compound, thereby facilitating the characterization of the products.  OCH3 OCH3 NO 4.28B 10 mol% PtCl2 toluene, 110 oC,  16 h 65% (1:1) OCH3 OCH3 NO 4.28A OCH3 OCH3 NO 4.28B 10 mol% RhCl3 .3H2O EtOH, 100 oC,  15 h 74% (1:1) OCH3 OCH3 NO 4.28A (1) (2)  Scheme 4.18:  Investigation of alkene isomerization  Further optimization studies led to the investigation of a gold(I) system as a potential catalyst.  Enamide 4.28 was treated with 5 mol% of triphenylphosphine gold(I) chloride ([PPh3AuCl]) and 5 mol% of silver hexafluoroantimonate in dichloroethane at 80 oC to give products 4.28A and 4.28C in 86% yield and a 13:1 regioisomeric ratio after only 1 hour (Scheme 4.19).  These initial results suggested that gold(I)-catalysis was superior to platinum(II)-catalysis Chapter 4:  Platinum(II) and Gold(I)-Catalyzed Intramolecular Tandem Addition/Friedel-Crafts Reactions between Acyclic Enamides and 1-Arylalkynes   186 for the cyclorearrangement of acyclic enamide substrates.  It was decided that all substrates would be tested using platinum(II)- and gold(I)-catalysis.  5 mol% AgSbF6 5 mol% [Ph3PAuCl] DCE, 80 oC, 1 h 86% N O 4.28 OCH3 OCH3 3 OCH3 OCH3 NO 4.28A OCH3 OCH3 NO H 4.28C(13:1)  Scheme 4.19:  Initial cycloisomerization study using gold catalysis  A series of control experiments were performed on substrate 4.28.  Heating enamide 4.28 in toluene to 110 oC in the absence of a catalyst resulted in no reaction.  The starting material was reisolated in 93% yield.  Adding calcium hydride to a standard platinum(II)-catalyzed reaction did not have any effect.  Treatment of enamide 4.28 with 20% HCl in toluene at 110 oC led to decomposition of the starting material.  Treatment with Lewis acid borontrifluoride etherate in toluene at 110 oC also led to decomposition of the starting material.  Enamide 4.29 containing a symmetrically substituted arene ring was tested next.  An unexpected product distribution was observed upon initial investigation (Table 4.3.1).  Enamide 4.29 was first tested under the standard platinum(II) chloride reaction conditions.  Examination of the reaction by thin layer chromatography after 16 hours showed two new products and complete consumption of the starting material.  One product was isolated in 47% yield and the second product was isolated in 35% yield.  Analysis by 1H NMR spectroscopy revealed that the product formed in 47% yield was a 16:1 mixture of 6-endo and 5-exo regioisomers (4.29B and 4.29C).  The product formed in 35% yield corresponds to 4.29D, a substituted naphthalene derivative.        Chapter 4:  Platinum(II) and Gold(I)-Catalyzed Intramolecular Tandem Addition/Friedel-Crafts Reactions between Acyclic Enamides and 1-Arylalkynes   187 Table 4.6: Investigation of product ratio of enamide 4.29 OCH3 NO OCH3H NO H OCH3 OCH3 N O 4.29 OCH3 3 OCH3 OCH3 OCH3 conditions 4.29B 4.29C 4.29D entry conditions yield (%) a,b  of 4.29B and 4.29C ratio (4.29B:4.29C) c  yield (%) a  of 4.29D 1 10 mol% PtCl2, PhCH3, 110 oC, 16 h 47 16:1 35 2 10 mol% PtCl2, PhCH3, 110 oC, 0.25 h 74 2:1 14 3 10 mol% PtCl2, PhCH3, 80 oC, 2 h 88 1:1 2 4 5 mol% [Ph3PAuCl], 5 mol% AgSbF6, ClCH2CH2Cl, rt, 8.5 h 87 2:1 4 aReported yields are isolated yields. bReported yields are the maximum of single experiments  cRatio is based on integration of the 1H NMR signals.   Unexpectedly, the olefin in the 6-endo product (4.29B) did not isomerize.  In an attempt to understand the product distribution, the reaction was tested at different temperatures, with different reaction times, and using gold(I)-catalysis.  First, the reaction was run under the standard reaction conditions in a test-tube reaction flask in order to monitor the reaction (entry 2).  After a reaction time of only 15 minutes, products 4.29B and 4.29C were formed in 74% yield, in a 2:1 ratio, each as a single diastereomer.  The byproduct 4.29D was formed in a 14% yield.  It was hypothesized that under prolonged reaction conditions, the 5-exo product was decomposing to form the byproduct 4.29D.  To further test this, enamide 4.29 was treated with 10 mol% platinum(II) chloride at 80 oC (entry 3).  The reaction appeared to be complete after 2 hours.  The products 4.29B and 4.29C were this time formed in an excellent yield of 88% and a ratio of 1:1.  The byproduct was formed in only 2% yield, suggesting that under a lower temperature, the 5-exo product does not decompose to the substituted naphthalene product 4.29D as fast as at higher temperature.  For completeness, enamide 4.29 was treated with 5 mol% of triphenylphosphine gold(I) chloride and 5 mol% of silver hexafluoroantimonate (entry 4).  The reaction occurred at room temperature, albeit for a longer time.  Products 4.29B and 4.29C were isolated in 87% and a ratio of 2:1.  Byproduct 4.29D was isolated in 4% yield. Chapter 4:  Platinum(II) and Gold(I)-Catalyzed Intramolecular Tandem Addition/Friedel-Crafts Reactions between Acyclic Enamides and 1-Arylalkynes   188  OCH3 NO 4.29B 10 mol% RhCl3 .3H2O EtOH, 100 oC,  16 h 53% OCH3 NO 4.29A OCH3 OCH3 OCH3 OCH3 4.29D 31% H (5:1) Scheme 4.20:  Treatment of cyclization products 4.29B and 4.29C with RhCl3·3H2O  The double bond of the isomeric mixture of compounds 4.29B and 4.29C was isomerized into the more substituted position to facilitate characterization.  A 5:1 mixture of compounds 4.29B and 4.29C was treated with 10 mol% of rhodium(III) chloride trihydrate to give 53% of double bond migration product 4.29A and 31% of naphthalene derivative 4.29D (Scheme 4.20).   NO OCH3 OCH3 1 5 6 Pt2+ 4.74 NO -Pt OCH3 OCH3 4.75 OCH3 OCH3 H NO B N O Pt- OCH3 OCH3 4.76 NO H OCH3 OCH3 C "5-exo" attack "6-endo" attack OCH3 OCH3 D OCH3 OCH3 NO A Friedel-Crafts process alkene  isomerization elimination  Scheme 4.21:  Formation of regioisomeric products The products mixtures resulting from the cycloisomerization of acyclic enamides are more complicated than those from cycloisomerization of cyclic enamides (Scheme 4.21). Coordination by the electrophilic platinum salt catalyst forms the activated η2 platinum-alkyne π-complex 4.74.  Attack of the enamide nucleophile now takes place at one of the two activated carbons of the alkyne.  Attack in a 5-exo-dig fashion will form a new five-membered ring, giving Chapter 4:  Platinum(II) and Gold(I)-Catalyzed Intramolecular Tandem Addition/Friedel-Crafts Reactions between Acyclic Enamides and 1-Arylalkynes   189 intermediary azacarbenium ion 4.75.  Attack in a 6-endo-dig fashion will form a new 6- membered ring, giving intermediate 4.76.  Both intermediates 4.75 and 4.76 then undergo Friedel-Crafts reaction and protodemetallation to give either the “5-exo” tricyclic product C or the “6-endo” tricyclic product B.  After the cycloisomerization event, the 5-exo product (C) can eliminate to give a substituted naphthalene derivative (D).  The initial product resulting from 6- endo closure can undergo an alkene isomerization to fo