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The synthesis and conformational analysis of 13- and 14-membered macrocyclic ethers Clyne, Dean Sutherland 1998

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The Synthesis and Conformational Analysis of 13- and 14-Membered Macro-cyclic Ethers by  DEAN SUTHERLAND CLYNE  B . S c , The University of Lethbridge, 1990  A THESIS SUBMITTED IN PARTIAL F U L F I L L M E N T O F THE REQUIREMENTS FOR THE D E G R E E OF D O C T O R O F PHILOSOPHY in T H E F A C U L T Y O F G R A D U A T E STUDIES (Department of Chemistry)  W e accept this thesis as conforming to the required standard  T H E UNIVERSITY O F BRITISH COLUMBIA January, 1998 © Dean S. Clyne, 1998  In presenting this thesis in partial fulfilment  of the requirements for an advanced  degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department  or by his  or  her  representatives.  It is  understood  that  copying  or  publication of this thesis for financial gain shall not be allowed without my written permission.  Department The University of British Columbia Vancouver, Canada  DE-6 (2/88)  ii  ABSTRACT  As part of an ongoing study of the chemistry of macrocyclic compounds in o laboratory, the 1 4 m e m b e r e d macrocyclic ethers 90, 92, 103, 104, 116, 119, 137, and 154, and the 1 3 m e m b e r e d macrocyclic ethers 168, 171, 179, 180, 190, and 193 with substituents both close to and remote from the oxygen a t o m were synthesized.  strategy for the preparation of these macrocyclic ethers involved either the Baeyer-  Villiger ring expansion of a cyclic ketone, or the macrolactonization of a long chain  hydroxy acid to give a lactone. Ultimately, the ether oxygen of the lactone would  b e c o m e the oxygen of the macrocyclic ether. The lactone was often used to introdu  substituents in the vicinity of the ether oxygen. Once this purpose was served, the carbonyl of the lactone was removed either via a conversion to an intermediate thionolactone obtained b y reaction with Lawessons ' reagent, or reduced directly via boron trifluoride etherate mediated sodium borohydride reaction.  The diastereomeric 1 4 m e m b e r e d ethers 103 and 104, and the 1 3 m e m b e r e d  ethers 179 and 180 were prepared under both radical reduction and hydrogenation  conditions, and the stereoselectivities of these methods were compared. In general the stereoselectivities were low (<18% d. e.). The relative configurations of 103, 104, 179, and 180 were determined through chiral GC analysis.  The unsaturated 1 4 m e m b e r e d ethers 157, 158, 163, and 164 were prepared via  the ruthenium catalyzed metathesis of an acyclic diene ether. The configuration of th double bond in these unsaturated ethers was determined with H homonuclear 1  decoupling N M R experiments. The isomerization of the carbon-carbon double bond  using phenyl disulfide under photolysis conditions was studied. The product ratios o  the metathesis cyclization and the isomerization reactions were compared to value obtained from molecular mechanics calculations.  The conformation of the 13- and 1 4 m e m b e r e d ethers was analyzed using bo N M R spectroscopy and molecular mechanics calculations.  The diamond lattice  Ill  conformations were good starting points in the analysis of the 1 4 m e m b e r e d rings  were not suited to the 1 3 m e m b e r e d rings. The [13333] conformation was found to a good model for the analysis of the odd-sized 1 3 m e m b e r e d rings. Additional  H-DNMR experiments were performed at low temperatures where the conformationa 1  interconversion rates of the macrocyclic ethers were slowed. The D N M R spectra were  interpreted using predicted A8 values from both anisotropy and van der Waals ste compression effects. The results from the analysis of the D N M R spectra and the  molecular mechanics calculations were compared. The calculations often gave one o  t w o preferred low energy conformations with a regular geometry. The alkyl substituen  were found to complicate the conformations of s o m e of the macrocyclic ethers studied  The transition state energies of the individual macrocyclic ethers were  determined from the D N M R spectra to be approximately 8-10 kcal/mol in the case  the 1 4 m e m b e r e d ethers and 6-8 kcal/mol in the case of the 1 3 m e m b e r e d ethers.  1 4 m e m b e r e d ether values were compared to computer calculated values obtained  using a dihedral drive method. The calculated values were in general higher and in range of 10-15 kcal/mol.  V  TABLE OF CONTENTS Abstract  ii  Table of Contents  v  List of Schemes List of Figures  viii x  List of Tables  xiii  Abbreviations  xvi  Acknowledgments  xix  1  2  Introduction  1  1.1.1  Synthesis of Macrocyclic Ethers by Intramolecular O-Alkylation  3  1.1.2  Synthesis of Macrocyclic Ethers by Olefin Metathesis  4  1.1.3  Synthesis of Macrocyclic Ethers from Macrocyclic Lactones  8  1.2.1  Conformational Analysis  20  1.2.2  Nuclear Magnetic Resonance in Conformational Analysis  20  1.2.3  Conformational Analysis of 6-Membered Rings  27  1.2.4  Conformational Analysis of Medium and Large Rings  30  1.2.5  Conformational Analysis of 14-Membered Rings  33  1.2.6  Conformational Analysis of 13-Membered Rings  38  1.2.7  Transition State Theory in Large Rings  40  14-Membered Macrocyclic Ethers  45  2.0.1  Synthesis of 14-Membered Macrocyclic Ethers  46  2.0.2  Conformational Analysis of 14-Membered Macrocyclic Ethers  48  2.1.1  Synthesis of Oxacyclotetradecane (90) and 2-Methyloxacyclotetradecane (92)  50  2.1.2  Conformational Analysis of Oxacyclotetradecane (90)  52  2.1.3  Conformational Analysis of 2-Methyloxacyclotetradecane (92)  64  2.2.1  Synthesis of 2,14-Dimethyloxacyclotetradecanes (103) and (104)  73  vi 2.2.2 Conformational Analysis of (2R*, 14R*)-2,14-Dimethyloxacyclotetradecane (103)  82  2.2.3 Conformational Analysis of (2S*, 14R*)-2,14-Dimethyloxacyclotetradecane(104) 91 2.3.1 Synthesis of 2,2-Dimethyloxacyclotetradecane (116)  100  2.3.2 Conformational Analysis of 2,2-Dimethyloxacyclotetradecane (116) 2.4.1 Synthesis of 3,3-Dimethyloxacyclotetradecane (119)  117  2.4.2 Conformational Analysis of 3,3-Dimethyloxacyclotetradecane (119) 2.5.1 Synthesis of 6,6-Dimethyloxacyclotetradecane (137)  2.6.1 Synthesis of 8,8-Dimethyloxacyclotetradecane (154)  136 146  2.6.2 Conformational Analysis of 8,8-Dimethyloxacyclotetradecane (154) 2.7.1 Conclusion  14-Membered Macrocyclic Unsaturated Ethers  118 128  2.5.2 Conformational Analysis of 6,6-Dimethyloxacyclotetradecane (137)  3  108  154 160  166  3.1.1 Synthesis of (Z/E)-Oxacyclotetradec-5-enes (157) and (158)  167  3.1.2 Cis-Trans Isomerization of (Z/E)-Oxacyclotetradec-5-ene169 (157) and (158)  169  3.2.1 Synthesis of (Z/E)-14-Methyloxacyclotetradec-5-enes (163) and  (164)  172  3.2.2 Cis-Trans Isomerization of (Z/E)-14-Methyloxacyclotetradec-5-enes (163) and (164) 176 3.3.1 Conclusion  4  13-Membered Macrocyclic Ethers  178  180  4.0.1 Synthesis of 13-Membered Macrocyclic Ethers  180  4.0.2 Conformational Analysis of 13-Membered Macrocyclic Ethers 4.1.1 Synthesis of Oxacyclotridecane (168) and 2-Methyloxacyclotridecane(171)  181 185  4.1.2 Conformational Analysis of Oxacyclotridecane (168)  187  4.1.3 Conformational Analysis of 2-Methyloxacyclotridecane (171)  193  4.2.1 Synthesis of 2,13-Dimethyloxacyclotridecanes (179) and (180) 4.2.2 Conformational Analysis of 2,13-Dimethyloxacyclotridecane (179)  199 .. 205  5  4.2.3  Conformational Analysis of 2,13-Dimethyloxacyclotridecane (180)  4.3.1  Synthesis of 2,2-Dimethyloxacyclotridecane (190)  4.3.2  Conformational Analysis of 2,2-Dimethyloxacyclotridecane (190)  4.4.1  Synthesis of 3,3-Dimethyloxacyclotridecane (193)  4.4.2  Conformational Analysis of 3,3-Dimethyloxacyclotridecane (193)  4.5.1  Conclusion  236  4.6.1  General Conclusion  236  Experimental  ..  210 216  ....  220 227  ....  228  239  5.1.1  General  239  5.1.2  Conformational Analysis Methods  242  5.1.3  Chemical Methods  242  References  336  Spectral Appendix  345  LIST OF SCHEMES S c h e m e 1. Synthesis of Laurenan (37)  14  Scheme 2. Conversion of Thionocaprolactone (61) into an Oxacycloheptane63  19  S c h e m e 3. Synthesis of the B C D ring Fragment 67 of Brevetoxin A (1)  1  S c h e m e 4. Synthetic Strategy for the Preparation of Macrocyclic Ethers S c h e m e 5. Synthesis of Oxacyclotetradecane (90) and 2-Methyloxacyclotetradecane (92) 51 S c h e m e 6. Retrosynthetic Analysis of 2,14-Dimethyloxacyclotetradecanes (103) and (104)  47  74  S c h e m e 7. Synthesis of 2-Methylcyclotridecanone (97) via 1-Dibromomethylcyclododecanol (94) 75 S c h e m e 8. Synthesis of 2,14-Dimethyloxacyclotetradecanes (103) and (104) via Thionolactone 1 0 1 77 S c h e m e 9. Synthesis of 2,14-Dimethyloxacyclotetradecanes (103) and (104) via Enol Ether 100  78  S c h e m e 10. Retrosynthetic Analysis of 2,2-Dimethyloxacyclotetradecane (116) ... 101 S c h e m e 11. Synthesis of 2,2-Dimethylcyclotridecanone (106) S c h e m e 12. Retrosynthetic Analysis of 13-Methyl-13-tetradecanolide (114)  102 104  S c h e m e 13. Synthesis of 13-Methyl-13-tetradecanolide (114)  105  S c h e m e 14. Synthesis of 3,3-Dimethyloxacyclotetradecane (119)  118  S c h e m e 15. Retrosynthetic Analysis of 6,6-Dimethyloxacyclotetradecane (137) ... 129 S c h e m e 16. Synthesis of 8-Bromooctanal ethylene acetal (123)  130  S c h e m e 17. Synthesis of Bisalkylated Dithiane 127  131  S c h e m e 18. Synthesis of 9-Methylene-13-hydroxytridecanoic acid (131)  133  S c h e m e 19. Synthesis of 6,6-Dimethyloxacyclotetradecane (137)  135  S c h e m e 20. Retrosynthetic Analysis of 8,8-Dimethyloxacyclotetradecane (154) ... 147 S c h e m e 21. Synthesis of Alkylating Agents 1 4 1 and 142 S c h e m e 22. Synthesis of 7-Methylene-13-hydroxytridecanoic acid (149) S c h e m e 23. Synthesis of 8,8-Dimethyloxacyclotetradecane (154) S c h e m e 24. Synthesis of Oxacyclotetradec-5-enes (163) and (164)  148 151 153 168  ix Scheme 25. Retrosynthetic Analysis of 14-Methyloxacyclotetradec-5-enes  (163) and (164)  172  Scheme 26. Synthesis of 14-Methyloxacyclotetradec-5-enes (163) and (164)  174  Scheme 27. Synthesis of Oxacyclotridecane (168) and 2-Methyloxacyclotridecane(171)  186  Scheme 28. Synthesis of 2-Methyloxacyclotridecane (171) via Hydrogenation Scheme 29. Retrosynthetic Analysis of 2,13-Dimethyloxacyclotridecanes (179) and (180) Scheme 30. Synthesis of 2,13-Dimethyloxacyclotridecanes (179) and (180) via Radical Reduction Scheme 31. Synthesis of 2,13-Dimethyloxacyclotridecanes (179) and (180) via Hydrogenation  187 199 201 202  Scheme 32. Retrosynthetic Analysis of 2,2-Dimethyloxacyclotridecane (190)  216  Scheme 33. Synthesis of Methyl 11-carbomethoxy-12-oxotridecanoate (186)  218  Scheme 34. Synthesis of 2,2-Dimethyloxacyclotridecane (190)  219  Scheme 35. Synthesis of 3,3-Dimethyloxacyclotridecane (193)  228  X  LIST OF FIGURES Figure 1.  Intramolecular Formation of Cyclic Monoethers and Diethers  4  Figure 2.  Mechanism for the Intramolecular Metathesis Cyclization of a Diene  5  Figure 3.  Synthesis of a Brevetoxin A Subunit 11 via Metathesis Cyclization  7  Figure 4.  Synthesis of frans-Fused Oxacycles 15-17 via Metathesis Cyclization ... 7  Figure 5.  Mechanism of the Free Radical Reduction of a Lactone with Trichlorosilane  9  Figure 6.  Competitive Pathways in the Trichlorosilane Reaction of Esters  10  Figure 7.  Reduction of Steroidal Lactones with Sodium Borohydride  11  Figure 8.  Proposed Mechanism of the Reaction of Tebbe Reagent 32 with a Lactone  Figure 9.  12  Comparison of Nucleophilic Attack on Lactones and Thionolactones ... 15  Figure 10. Mechanism of Reaction of Lawesson's Reagent 4 8 with an Ester Figure 11. Regions of Shielding and Deshielding for a Carbon-Carbon Single Bond as the Result of Diamagnetic Anisotropy Figure 12. Possible Orbital Arrangements for y-Anti and y-Gauche Effects in 3,3-Dimethyloxacyclohexane  17 23 27  Figure 13. Shielding of the Axial Proton (H ) in Cyclohexane as the Result of a  Figure 14.  the Diamagnetic Anisotropy of a 3 Carbon-Carbon Bond  29  Differences in 8  30  ae  for C-2 and C-5 Geminal Protons in 1,3-Dioxane  Figure 15. The Lowest Energy Diamond Lattice Conformation of Cyclotetradecane  34  Figure 16. The Corner and Pseudocorner Positions and the Surrounding Dihedral Angles  35  Figure 17. Transannular Hydrogen Interactions in Cyclotetradecane  37  Figure 18. Movement of a Corner Atom by One Position with an Accompanying Change in Sign of the Surrounding Gauche Dihedral Angles  42  Figure 19. Conformation Interconversion Pathways for Cyclotetradecane as the Result of the Single Corner Movement Mechanism  43  Figure 20. Variable Temperature 500 MHz H NMR of Oxacyclotetradecane (90) in C H C I F : C H C I F (4:1)  56  1  2  Figure 21.  2  Single Corner Movement Transition State for Interconversion of the [3434]-1 90-A and the [3344]-1 90-B Conformations of 90  63  xi Figure 22. H NMR Assignments of the C-2 and C-14 Protons of 2-Methyloxacyclotetradecane (92) from COSY and N O E D S Experiments 1  64  Figure 23. N e w m a n Projections of 92 Showing the Geometry of C-2 in the [3434]-1 and [3434]-4 Conformations  66  Figure 24. Variable Temperature 500 MHz H NMR of 2-Methyloxacyclotetradecane(92) in CHCIF:CHCIF (4:1) 1  2  Figure 25.  69  2  Interconversion of Conformations of 92 via Single Corner M o v e m e n t s  73  Figure 26. GC Analysis for 2,14-Dimethyloxacyclotetradecanes (103) and (104) on a Chiral Cyclodex-B Column  80  Figure 27. Variable Temperature 500 MHz H NMR of (2R*,14R*)-2,14-Dimethyloxacyclotetradecane (103) in CHCIF:CHCIF (4:1) 84 1  2  2  Figure 28. Variable Temperature 500 MHz H NMR of (2S*,14R*)-2,14-Dimethyloxacyclotetradecane(104)inCHCIF:CHCIF(4:1) 94 1  2  2  Figure 29. Interconversion of Conformations of 104 via Single Corner Movements  100  Figure 30. Variable Temperature 500 MHz H NMR of 2,2-Dimethyloxacyclotetradecane(116) in CHCIF:CHCIF (4:1) 110 1  2  2  Figure 31. Interconversion of Conformations of 116 via Single Corner Movements  116  Figure 32. Variable Temperature 500 MHz H NMR of 3,3-Dimethyloxacyclotetradecane (119) in CHCIF:CHCIF (4:1) 121 1  2  2  Figure 33. Interconversion of Conformations of 119 via Single Corner M o v e m e n t s  127  Figure 34. Variable Temperature 500 MHz H NMR of 6,6-Dimethyloxacyclotetradecane(137)inCHCIF:CHCIF(4:1) 139 1  2  2  Figure 35. Interconversion of Conformations of 137 through the [3344J-1 Conformation  145  Figure 36. Variable Temperature 500 MHz H NMR of 8,8-Dimethyloxacyclotetradecane (154) in CHCIF:CHCIF (4:1) 156 1  2  2  Figure 37. Interconversion of Conformations of 154 via Single Corner Movements  163  Figure 38. Variable Temperature 500 MHz H NMR of Oxacyclotridecane (154) in CHCIF:CHCIF (4:1) 189 1  2  2  Figure 39. H NMR Assignments of the C-2 and C-13 Protons of 2-Methyloxacyclotridecane (171) from COSY and N O E D S Experiments 1  Figure 40. Variable Temperature 500 MHz H NMR of 2-Methyloxacyclotridecane(171)inCHCIF:CHCIF(4:1)  194  1  2  2  196  xii Figure 41. GC Analysis for 2,13-Dimethyloxacyclotridecanes (179) and (180) on a Chiral Cyclodex-B Column  203  Figure 42. Lowest Energy Conformation of Vinyl Ether 176  205  Figure 43. Variable Temperature 500 M H zH N M R of (2R*,13R*)-2,13-Dimethyloxacyclotridecane (179) in CHCIF:CHCIF (4:1) 207 Figure 44. Variable Temperature 500 M H zH N M R of (2S*,13R*)-2,13-Dimethyloxacyclotridecane(180)inCHCIF:CHCIF(4:1) 212 1  2  2  1  2  2  Figure 45. Variable Temperature 500 M H zH N M R of 2,2-Dimethyloxacyclotridecane (190) in CHCIF:CHCIF (4:1) 222 1  2  2  Figure 46. Variable Temperature 500 M H zH N M R of 3,3-Dimethyloxacyclotridecane (193) in CHCIF:CHCIF (4:1) 231 1  2  2  xiii  LIST OF TABLES Table 1.  Reagents used in the Thionation of Hexadecanolide (54)  16  Table 2.  The Three Lowest Energy Conformations of Cyclotetradecane  36  Table 3.  The Two Lowest Energy Conformations of Cyclotridecane  Table 4.  H and C NMR Assignments for Oxacyclotetradecane (90) in CDCI at R o o m Temperature 1  13  3  Table 5.  van der Waals Radii for S o m eA t o m Groups  Table 6.  Low Energy Conformations of Oxacyclotetradecane (90)  Table 7. Table 8.  H and C NMR Assignments for 2-Methyloxacyclotetradecane (92) in CDCI3 at R o o m Temperature  1  Table 14.  60  65  Experimental and Calculated Coupling Constants for the Low Energy  Table 10.  Table 13.  54  13  Conformations of 92  Table 12.  53  Thermodynamic Values for the Five Lowest Energy Conformations of 90 61  Table 9.  Table 11.  39  67  Low Energy Conformations of 2-Methyloxacyclotetradecane (92)  71  Thermodynamic Values for the Five Lowest Energy Conformations of 92 72 Yield and Selectivity in the Preparation of 2,14-Dimethyloxacyclotetradecanes (103) and (104) 82 H and C NMR Assignments for (2R*,14R*)-2,14-Dimethyloxacyclotetradecane (103) in CDCI3 at R o o m Temperature 1  13  Low Energy Conformations of (2R*, 14R*)-2,14-Dimethyloxacyclotetradecane (103)  83 89  Table 15.  Thermodynamic Values for the Five Lowest Energy Conformations of 103 90  Table 16.  H and C NMR Assignments for (2S*. 14R*)-2,14-Dimethyloxacyclotetradecane (104) in CDCI at R o o m Temperature 1  13  92  3  Table 17.  Thermodynamic Values for the Five Lowest Energy Conformations of 104 97  Table 18.  Low Energy Conformations of (2S*. 14R*)-2,14-Dimethyloxacyclotetradecane (104)  98  Reaction Conditions used in the Attempted Baeyer-ViNiger Oxidation of Ketone 106  103  Table 19.  xiv Table 20. Table 21.  Reaction Conditions used in the Attempted Thionation of Lactone 114 H and C NMR Assignments for 2,2-Dimethyloxacyclotetradecane (116) in CDCI at R o o m Temperature 1  13  3  Table 22.  107  Low Energy Conformations of 2,2-Dimethyloxacyclotetradecane (116)  108 114  Table 23.  Thermodynamic Values for the Five Lowest Energy Conformations of116 115  Table 24.  H and C NMR Assignments for 3,3-Dimethyloxacyclotetradecane (119) in CDCI3 at R o o m Temperature  Table 25.  1  13  Low Energy Conformations of 3,3-Dimethyloxacyclotetradecane (119)  119 125  Table 26.  Thermodynamic Values for the Five Lowest Energy Conformations of 119 ' 126  Table 27.  H and C NMR Assignments for 6,6-Dimethyloxacyclotetradecane (137) in CDCI3 at R o o m Temperature  Table 28.  1  13  Low Energy Conformations of 6,6-Dimethyloxacyclotetradecane (137)  137 143  Table 29.  Thermodynamic Values for the Five Lowest Energy Conformations of 137 144  Table 30.  H and C NMR Assignments for 8,8-Dimethyloxacyclotetradecane (154) in CDCI3 at R o o m Temperature  Table 31.  1  13  Low Energy Conformations of 8,8-Dimethyloxacyclotetradecane (154)  155 160  Table 32.  Thermodynamic Values for the Five Lowest Energy Conformations of 154 161  Table 33.  Experimental and Theoretical Equilibrium Ratios for the Isomerization Reaction of Oxacyclotetradec-5-enes (157) and (158) 171  Table 34.  Experimental and Theoretical Equilibrium Ratios for the Isomerization Reaction of 14-Methyloxacyclotetradec-5-enes (163) and (164) 177  Table 35.  Relative Energies of Conformations of (Z/E)-14-Methyloxacyclotetradec-5-ene (163) and (164) and their Percent Population  178  Table 36.  The Oxygen Substituted [13333] Conformations and their Relative Strain Energies 182  Table 37.  Other Oxygen Substituted 13-Membered Conformations with Low Strain Energy  184  XV  Table 38.  H and C NMR Assignments for Oxacyclotridecane (168) in  1  13  CDCI3 at R o o m Temperature Table 39. Table 40. Table 41. Table 42.  Low Energy Conformations of Oxacyclotridecane (168)  1  13  Thermodynamic Values for the Five Lowest Energy Conformations  Table 43.  Table 45.  192  Thermodynamic Values for the Five Lowest Energy Conformations of 168 193 H and C NMR Assignments for 2-Methyloxacyclotridecane (171) in CDCI3 at R o o m Temperature 195 of 171  Table 44.  188  197  Low Energy Conformations of 2-Methyloxacyclotridecane (171) Yield and Selectivity in the Preparation of 2,13-Dimethyloxacyclotridecanes (179) and (180) H and C NMR Assignments for (2R*,13R*)-2,13-Dimethyloxacyclotridecane (179) in C D C I 3 at R o o m Temperature 1  198 205  13  206  Table 46.  Thermodynamic Values for the Five Lowest Energy Conformations of 179 208  Table 47.  Low Energy Conformations of (2R*, 13R*)-2,13-Dimethyloxacyclotridecane (179)  209  H and C NMR Assignments for (2S*,13R*)-2,13-Dimethyloxacyclotridecane (180) in CDCI3 at R o o m Temperature  .• 210  Table 48.  1  13  Table 49.  Thermodynamic Values for the Five Lowest Energy Conformations of 180 214  Table 50.  Low Energy Conformations of (2S*, 13R*)-2,13-Dimethyloxacyclotetradecane (180)  215  H and C NMR Assignments for 2,2-Dimethyloxacyclotridecane (190) in CDCI3 at R o o m Temperature  220  Table 51. Table 52.  1  13  Thermodynamic Values for the Five Lowest Energy Conformations of 190  Table 53. Table 54.  225  Low Energy Conformations of 2,2-Dimethyloxacyclotridecane (190) H and C NMR Assignments for 3,3-Dimethyloxacyclotridecane  1  13  (193) in CDCI3 at R o o m Temperature Table 55. Table 56.  .. 226  Low Energy Conformations of 3,3-Dimethyloxacyclotridecane (193)  229 .. 235  Thermodynamic Values for the Five Lowest Energy Conformations of 193 236  LIST OF ABBREVIATIONS 2-dimensional acetyl azobis(isobutyronitrile) aqueous boiling point butyl chemical ionization concentrated correlation spectroscopy cyclopentadienyl cyclohexyl change in chemical shift change in chemical shift between a geminal pair of axial and equatorial protons in a cyclohexane system desorption chemical ionization diastereomeric excess dihydropyran 4-dimethylaminopyridine /V,/V-dimethylformamide 1,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone dimethyl sulfoxide dynamic nuclear magnetic resonance activation energy electron ionization ethyl ethyl acetate Gibbs free energy gas chromatography hour  xvii H H M B C H M P A H M Q C  enthalpy heteronuclear multiple bond connectivity spectroscopy hexamethylphosphoramide heteronuclear multiple guantum coherence spectroscopy  H R M S /Pr  high resolution mass spectrum or spectrometry isopropyl  IR  infrared (spectroscopy)  J  coupling constant  kcal  kilocalorie  LAH  lithium aluminum hydride  LDA  lithium diisopropylamide  LRMS  low resolution mass spectrum or spectrometry  LTMP  lithium 2,2,6,6-tetramethylpiperidine  M  parent mass {mass spectra) or molar, moles per Litre (concentration)  M A B R m C P B A M e  bis(4-bromo-2,6-di-te/t-butylphenoxide) mefa-chloroperbenzoic acid methyl  m p  melting point  m/z  mass-to-charge ratio  n  normal  NBS  /V-bromosuccinimide  H NMR  1  C NMR  nuclear magnetic resonance (proton)  13  nuclear magnetic resonance (carbon)  N O E  nuclear Overhauser effect  p PCC Ph  para pyridinium chlorochromate phenyl  p p m  parts per million  PPTS  pyridinium para-toluenesulfonate  pyr  pyridine  R f  retention factor or ratio-to-front  rt  r o o m temperature  S  entropy  T  coalescence temperature  Tf  triflate  tert  tertiary  TFAA  trifluroacetic acid  THF  tetrahydrofuran  TLC  thin-layer chromatography  T T M S H  tris(trimethylsilyl)silane  Ts or p-Ts  tosyl or para-toluenesulfonyl  U H P  urea hydrogen peroxide  v / v  volume per volume  c  xix  ACKNOWLEDGMENTS Firstly, I would like to thank Professor Larry Weiler, my  Ph.D.  research  supervisor, for his guidance, encouragmenent, insight and patience. I am privileged to have been a m e m b e r of the Weiler lab. I thank the staff of the NMR  Laboratory (Liane and Marietta), Mass Spectrometry  Laboratory, Microanalysis Laboratory (Mr. Peter Borda), and Rak)  Glass Shop (Mr. Steve  for their assistance. My thanks to Dr. Nick Burlinson and Mr. Ray Syvitski for their  helpful discussions and suggestions regarding various aspects of NMR  spectroscopy. I  thank also Professor T h o m a s M o n e y for reading this thesis prior to its submission. The assistance and efforts of Mr. Mardy Leibovitch (now and  Mr. Matthew Netherton with the  photolysis reactions and  Dr. Mardy Leibovitch) chiral GC analysis  performed during the course of this research are gratefully acknowledged. Special thanks to Dr. Michael Ivery (How  are things...), Dr. Anurag Sharadendu  (Where are we going for lunch?), and Dr. Michael W o n g (A special thank ewe),  for their  helpful suggestions and advice both scientific and otherwise.  I thank Vivienne for her seemingly endless display of patience during the writing of this thesis. I can not thank you enough for giving me the time and space necessary to complete this task. Believe.  "There are those that break and bend I'm the other kind, I'm the other kind"  S. Earle  D dedicate tAis ifiesis to myfamily 7  UAanA youfor your fooe, support, and encouragement over  years.  1  CHAPTER 1 INTRODUCTION The  p h e n o m e n o n k n o w n as red tide is the result of vast blooms of unicellular  algae. The  n a m e is derived from the  colour of certain blooms which contain the  carotenoid pigment peridinin, however the term is used in a broader sense to describe blooms of other colours as well as colourless ones. One  such algae is Gymnodinium  breve Davis which produce very potent neurotoxins of which the  brevetoxins are  a  prominent subclass. These algae are responsible for major environmental, economic and  health problems each year. The  massive fish kills, and  catastrophic consequences of red tide include  mollusk poisoning. H u m a n s can also be affected, as the result  of seafood consumption during outbreaks of red tide.  One  of the earliest recorded incidents of red tide poisoning involved Captain  George Vancouver in 1793  w h e n he and  his crew suffered poisoning after consuming  seafood in a coastal area of British Columbia. On the east coast of the United States 2 1 ,  in 1987  and  1988,  a total of 740  Atlantic coast from New  bottlenose dolphins were found washed up along the  Jersey to Florida, also the  victims of red  tide poisoning. 2  Biologically, brevetoxins bind to sodium channels in cell membranes, and thereby keep the channels open and cell. The the  allow for continuous, and  damaging sodium ion influx into the  s y m p t o m s of brevetoxin poisoning in h u m a n s include: tingling sensations in  m o u t h and digits, disruption of coordination (ataxia), hot-cold reversal  temperature sensation, dilated pupils, brachyrdia, diarrhea, and  of  respiratory problems. 2  Poisoning with these s y m p t o m s is c o m m o n l y k n o w n as neurotoxic shellfish poisoning (NSP), or paralytic shellfish poisoning (PSP).  Cultures of the  dinoflagellate Gymnodinium breve Davis (Ptychodiscus  brevis  Davis) were extracted to give samples of several brevetoxins including brevetoxin A (1), the m o s t potent ichthyotoxin of this family. Analysis of this toxin culminated in solving of its X-ray crystal structure in 1986  by Shimizu and  the  coworkers. Extensive 3  2 N M R analysis has also been performed on brevetoxin A (1) by Nakanishi and coworkers.'  5 4  0  The polyether structure of these toxins was unprecedented. Brevetoxin A (1) contains a total of 10 rings, ranging in size from 5- to 9-members. A total of  22 stereogenic centers, and three carbon-carbon double bonds are also present. T  complex architecture of this molecule is composed of a single carbon chain in a lad like array of trans fused cyclic ethers. As a consequence of the n u m b e r of 8-  9 m e m b e r e d cyclic ethers which are present, brevetoxin A (1) represents a formidab synthetic target since these m e d i u m sized cyclic ethers are notoriously difficult to  construct. A total synthesis has not yet been achieved, but the campaigns which h  been waged towards the synthesis of brevetoxin A have resulted in the developmen n e w reactions and synthetic strategies for the preparation of cyclic ethers.  An u m b e r of synthetic methods have been developed for the preparation of  cyclic ethers. These can be grouped into t w o general strategies with the first of th  involving an intramolecular cyclization to form the cyclic ether. The second strategy  3 involves the modification of an existing ring, such as a lactone, to give the cyclic ether. Large ring lactones are  readily available via a n u m b e r of hydroxy acid cyclization  methods. Thus, lactones can be viewed as precursors to macrocyclic ethers, since the difficult issue of ring closure has already been solved in these systems. The problem of cyclic ether synthesis is thereby reduced to that of converting a lactone into the desired cyclic ether.  1.1.1 Synthesis of Macrocyclic Ethers by Intramolecular O-Alkylation  The  intramolecular cyclization at the  ether oxygen is a difficult reaction to  perform successfully in large rings. A study of the cyclization of a series of b r o m o alcohols using a variety of base and solvent combinations in our laboratory by Kelly in 1991 met  with limited success in the production of the desired 1 4 m e m b e r e d  macrocyclic ethers.  6  In a study of the kinetics of cyclic ether formation, it was coworkers that the rate of the cyclization reaction was formed ring (Figure 1). The 7  reactivity was  shown by llluminati and  dependant on the size of the  noted to drop off significantly by a factor  greater than 10 as the ring size increased from 6- to 9-membered. A levelling of the 4  rate was observed for further increases in the ring size, with similar values obtained for ring sizes 11-16. A comparison of the rates of monoether 4 and diether 5 formation in general, showed the diether formation rates to be higher. This was  attributed to a  reduction of transannular interactions as a result of the substitution of the methylene groups for oxygen, and is consistent with Dales ' view that 1,4- and 1,5-CH-O interactions are favoured over the corresponding CH-HC interactions. 8  4  a  0  "  75%  (v/v)  ag. EtOH^  0  ^Nc^-J  X(CH)Br 2n  2 X = CH,n = 5-16  j X =  2  3X=0 Figure 1.  A^^  5  X  =  CH  2  °  Intramolecular formation of cyclic monoethers and diethers (from ref.  7).  In such an intramolecular cyclization, an activation at one end of the hydrocarbon chain, similar to the  methods n o wc o m m o n l y used to afford lactone  cyclizations might be successful. One such m e t h o d involves the formation of a trichloroacetimidate intermediate. This chemistry has  been applied to the introduction  of benzyl ether protecting groups. 9  1.1.2  Synthesis of Macrocyclic Ethers by Olefin Metathesis  An alternative to cyclization at the  ether oxygen involves cyclization at s o m e  point in the hydrocarbon chain via a carbon-carbon bond forming process. The metathesis reaction which takes a pair of alkenes and couples t h e m in an intramolecular sense in the The  presence of a catalyst is suited for such a cyclization.  1 0  reaction is believed to proceed through a metallocyclobutane intermediate formed  by reaction of one  of the  alkenes with the  catalyst (Figure 2).  undergoes elimination of ethylene to form a new  This intermediate  metal carbene which further reacts to  form a fused metallocyclobutane intermediate. Elimination of a metal carbene fragment **  A A  results in the formation of a carbon-carbon double bond in the newly formed ring.  5  Figure 2.  Mechanism for the intramolecular metathesis cyclization of a diene.  The first reports of the metathesis reaction for the preparation of macrocyclic c o m p o u n d s used tungsten chloride as the metal catalyst with tetramethyltin as a cocatalyst. Dehydroexaltolide (7) was obtained from diene ester 6 as a mixture of Zand E isomers in 65% yield.  1 2  Hydrogenation of lactone 7 gave exaltolide, the  macrocyclic m u s k component of the angelica root.  6  7  6  Other catalyst systems have been employed in metathesis reactions including: W C I e / C p z T i M e z and WOCIVCpaTiMez, Re07/AI03, and CHRe0. However, all 1 5  1 4 1 3 ,  2  1 6  3  2  3  of these catalyst systems in general have a low tolerance for the presence of o  functional groups in the metathesis precursors, and the yield of the metathesis produ can be low. In recent years, m o r e complex organometallic catalysts have been introduced m o s t notably the m o l y b d e n u m neophylidene complex 8 developed b y Schrock and coworkers. 7 1  The development and application of the m o l y b d e n u m  neophylidene complex 8 was largely responsible for the recent advances of olefin metathesis as a synthetically useful carbon-carbon bond forming reaction.  However,  owing to the difficulty of preparing 8, and also the sensitivity of this catalyst to ox water, and polar functional groups, another generation of catalysts with ruthenium the core of the organometallic complex has been developed by Grubbs and  coworkers. This organometallic ruthenium alkylidene complex 9 is easier to prepare, 8 1  essentially air stable as a solid, and still catalytically active without rigorous oxygen a  water exclusion from the reaction system. As a result of the compatibility of these catalysts with a range of functional groups, a variety of heteroatom containing c o m p o u n d s have been prepared using olefin metathesis including: ethers, crown 1 1  ethers, lactones, ketones, amines, lactams, and sulfides. 1 9  2 0  1 6  2 1  N  (CFafeMeCO^JI (CF)MeCO32  Ph  J>le  V-f  2  2 3  P | C y 3  C  k  Ru=^  K  c l  ^  P  h  C y &  8  As indicated earlier, the marine toxin brevetoxin A (1) contains several m e d i u m  sized cyclic ethers. An approach to s o m e m e d i u m sized cyclic ether subunits was  recently reported b y Clark and Kettle using the olefin metathesis reaction to perform cyclization.  2 4  The diene 10 was reacted with the Schrock catalyst 8 to give the  9-membered cyclic ether 1 1 in 86% yield (Figure 3).  This chemistry has also been  7  used to prepare 8 m e m b e r e d cyclic ethers. These cyclic allyl ethers can functionalized by allylic oxidation and rings E and  F of brevetoxin A.  be further  isomerization to give systems corresponding to  Alternatively, hydroboration, or isomerization followed  by hydroboration could provide m e d i u m ring ethers corresponding to the B and  G rings  of brevetoxin A.  p-MeOC H4 6  Figure 3.  The  Synthesis of a brevetoxin A subunit 11 via metathesis cyclization (from ref. 24). metathesis cyclization has also been applied to the synthesis of other trans-  fused oxacycles 15-17 of different ring sizes. These challenging synthetic targets 2 5  possess interesting biological activity. The the  metathesis cyclization of dienes 12-14 with  ruthenium catalyst 9 proceeded to give the  fused bicyclic ethers in good to  excellent yield with control of the stereochemistry (Figure 4).  12 n = 1 13 n = 2 14 n = 3  Figure 4.  15 n = 1 16 n = 2 17 n = 3  Synthesis of frans-fused oxacycles 15-17 via metathesis cyclization (from ref. 25).  8 1.1.3  Synthesis of Macrocyclic Ethers from Macrocyclic Lactones  As an alternative to the acyclic approaches used in the preparation of macrocyclic ethers mentioned above, a n u m b e r of approaches in which a macrocyclic  precursor is converted into the corresponding ether have also been developed. These methods involve the modification of an existing ring, generally a lactone to give the macrocyclic ether. Often the lactones are accessible via the cyclization of a hydroxy acid precursor. A n u m b e r of methods have been developed for the  cyclization of  macrocyclic lactone precursors."  2 63 0  Tsuragi and coworkers have prepared both acyclic and cyclic ethers from aliphatic esters or lactones via a reduction with trichlorosilane under free radical conditions.  3 1 3 , 2  Ring opened side products as the  result of ionic intermediates are  minimized by this free radical process. This reaction can be initiated with either y or uv radiation or with the photoinduced decomposition of di-te/f-butyl peroxide. This chemistry has been applied to the  reduction of small ring y, 5, and s lactones,  3 2  heptanolide and 3,3,8,8-oVheptanolide as well as to the bicyclic lactones 18 and 3 3  19.  34  Kinetic studies have shown the reduction to proceed via a free radical mechanism with the addition of trichlorosilane to the carbonyl group of the ester or lactone 20 followed by further attack of the silane onto the resulting acetal-type intermediate to give the ether 21 (Figure 5).  19  9  SiCI  3  HSiCI  3  (SiCI)0 3 2  SiCI  HSiCI  3  3  Figure 5.  Mechanism of the free radical reduction of a lactone with trichlorosilane.  A side reaction of the trichlorosilane reduction is the deoxygenation of the est 22 to give the hydrocarbon 25.  35  The reaction of the acetates of a variety of alcoh  showed that for primary R' groups, the reduction to the desired ether 24 occurred exclusively (Figure 6, A), while for tertiary R' groups, the deoxygenation product 25  dominated (Figure 6, B). W h e n R' w a s secondary, a mixture of both reduction an  deoxygenation products were obtained. Thus the proportion of the intermediate radica  23 which underwent deoxygenation and yielded hydrocarbon products was related to the stability of the intermediate alkyl radical.  10 H  OSiCI  3  R -  R -  -OR  3  R -  0  sicb -OR'  ? '  (A)  H  SiCIH - H SiC  -OR  24  3  R — i — O R '  22  23  \  OSiCI  3  R—1=0 +  •R'  SiCIH 3  RH '  (B)  25  Competitive pathways in the trichlorosilane reaction of esters.  Figure 6.  Pettit and coworkers have s h o w n that a lactone can also be directly reduced to give cyclic ethers using a mixture of sodium borohydride and boron trifluoride etherate. The reducing agent in these reactions was presumed to be diborane formed 3 6  in situ. The reduction of lactone 27 under these reaction conditions gave 44% cyclic ether 29, and 42%  of diol 31,  36  of the  while the reduction of the unsubstituted lactone  26 gave only diol 30, and none of cyclic ether 28 (Figure 7). In contrast to the silane reduction described above, the presence of alkyl branching adjacent to the ether oxygen here, results in an increase of the yield of the ether product.  3 7  11  28, R = H 29, R=CH  30, R = H 31,R=CH  3  3  Figure 7. Reduction of steroidal lactones with sodium borohydride (from ref. 36).  Alkyl substituents can be introduced adjacent to the oxygen of a cyclic ether  reaction of a lactone with the organotitanium reagent 32 developed b y Tebbe an  coworkers. The reactive species is thought to be a titanium carbene which reacts w 8 3  the carbon-oxygen double bond of the lactone to form intermediate 33 with a f m e m b e r e d ring (Figure 8 ) .  3 9  Elimination of a titanium-oxygen species gives the product  34, a cyclic ether with an exocyclic methylene.  12  H C 5  5  / v Me  n  Ti=CH H C/  7 1 Al H C Cf Me / S  5  2  N  5  5  32  .  34 Figure 8.  0-K)n  33  Proposed mechanism of the reaction of 7ebbe reagent 32 with a lactone (from ref. 39).  7he exocyclic olefin can be subsequently reduced to give an a-methyl group, or further modified to give other alkyl substituents. For example a hydroboration-oxidation sequence was used in recent syntheses of the marine natural products isolaurepan (35),  lauthisan (36),  laurenan (37),  and obtusan (38),  s o m e 7-9 m e m b e r e d  cyclic ethers corresponding to unsaturated non-terpenoid metabolites of the alga  Laurencia.  40  1 3  13  The methylenation of lactone 39 using the Tebbe reagent 32 followed b y ra  chromatographic purification on alumina gave the unstable enol ether 40 (Scheme 1 This enol ether was subjected to hydroboration with oxidative workup to give the  hydroxymethyl c o m p o u n d 41. Very high selectivity for the desired diastereomer w a s  obtained w h e n diisoamylborane w a s used as the hydroborating agent. The hydroxy  methyl group of 41 was oxidized with PCC and chain extended to give alkene  Hydrogenation of the carbon-carbon double bond of 42 gave the C-8 propyl group complete the synthesis of laurenan (37).  4 0  14 Scheme 1. Synthesis of Laurenan (37) (from ref. 40) a  Key: (a)Tebbe reagent 32, THF, toluene, pyridine, -40 ° C to rt; (b) diisoamylbora THF, 0 °C; then H0, NaOH, 0 °C, 59% from 39; (c) PCC, mol. sieve CHCI, rt, 91%; (d) Ph P=CHMe, THF, rt; (e) Pd-C (5%), H, EtOAc, 72% 41.  a  2  2  2  2  3  2  The transformation of a lactone into a thionolactone and subsequent reductio represents another synthetic approach to macrocyclic ethers. The direct nucleophilic attack on the carbonyl of a lactone 43 generally results in ring fission due to the  instability of the initially formed tetrahedral intermediate 44 (Figure 9). However, the analogous tetrahedral intermediate derived from the attack on the carbon of a thionolactone 45, is stable at low temperature and undergoes S-alkylation to give relatively stable intermediate 46. This intermediate can in turn be converted into macrocyclic ether 47. "  4 1 4 3  15  Figure 9. Comparison of nucleophilic attack on lactones and thionolactones.  The process of conversion of a carbonyl into a thionocarbonyl was first carri  out using phosphorous pentasulfide. However, this m e t h o d generally required high 4 4 , 5  temperatures and resulted in low yields due to significant side reactions. More 4 6 4 ,7  recently, a dithiodiphosphetane disulfide such as Lawessons ' reagent 48 which is  prepared by the reaction of phosphorous pentasulfide with anisole, has been s h o w n effect thionation of m o s t simple lactones in good yield.  45,48  The success of this reage  is highly dependent on the nature of the substrate and on the reaction conditions particular strict control of temperature is required in order to obtain optimal yields.  48  To address these synthetic problems, a n u m b e r of other reagents have be introduced including: 49, 50, 51, 52, and 53. 4 9  5 0  5 0  5 1  5 1  A study b y Nicolaou and  coworkers of the reaction of hexadecanolide (54) with the thionation reagents 48-  (Table 1) showed that reagents 49, 52, and 53 gave slightly higher yields of the  16 thionolactone 55 (63-67%) compared to that obtained with Lawessons ' reagent 48 (60%).  51  However, these alternate reagents generate phosphoric acid-type species  with moisture at elevated temperatures over the required long reaction periods, and thus often do not offer an improvement over Lawessons ' reagent 48.  R-P  P-R  v b  S  toluene, A  55  54  Table 1.  Reagents Used in the Thionation of Hexadecanolide (54)  Reagent  48  R  -O~~ 0-°^0- M e 0  Reagent  R  51  MeO—S—  s  49  50  c i  52  53  F  -0- Q -  s _  s  -  Reagents 56 and 57 are structurally similar to 48, but are completely unreactive towards benzophenone under thionation conditions. This result provided a clue that 5 2  intact Lawessons ' reagent 48 was not the active thionating agent.  1 7  Kinetic studies support a reaction mechanism which involves a rapid and symmetrical cleavage of the Lawessons ' reagent "dimer" to give a monomeric 3-coordinate phosphorous (V) species 58 (Figure 10).  4 5 , 5 3  This electrophilic  phosphorous ylide can undergo a subsequent slower reaction involving a nucleophilic  attack b y the carbonyl oxygen of the substrate. The betaine intermediate then can eliminate to give the thionocarbonyl 59.  1 8  A report b y Baxter and Bradshaw in which compounds with electron withdrawi  substituents conjugated to an ester carbonyl failed to react under thionation condition while compounds with conjugated electron donating substituents experienced an  increased rate of reaction supports this mechanism. Moreover, it was found that 4 5  esters containing an ether functionality such as 60 were difficult to thionate. This w  attributed to a competition between the carbonyl oxygen and the m o r e basic et oxygen atoms for the electrophilic phosphorous. 4 5  60  Once formed, the C 1 carbon of a thionolactone such as 61 can be reacte  a variety of nucleophiles to give after S-alkylation with methyl iodide the mixed thiok  62 (Scheme 2). A variety of organometallic reagents were examined by Nicolaou an coworkers, and reagents such as methyl lithium, allyl lithium, and lithium triethylborohydride gave good yields of the desired mixed thioketals. Reductive 5 1  desulfurization of these thioketals using triphenyltin hydride, gave the cyclic ether 51,55  63.  1 9  Scheme 2. Conversion of Thionocaprolactone (61) into an Oxacycloheptane 63 (from ref. 51) a  61  62  63  Key: (a) RLi, THF, -78 °C; then Mel, 75-86%; (b) PhSnH, AIBN, toluene, A, 85%.  a  3  This thionolactone chemistry was used in a recent synthesis of the B C D r  fragment of brevetoxin A (1) (Scheme 3). The tricyclic bislactone 64 was converte  with Lawessons ' reagent 48 into the bisthionolactone 65. This c o m p o u n d was furthe  reacted first with tri(n-butyl)tin lithium followed b y methyl iodide trapping of the resulta  sulfur anion to give the mixed thioketal c o m p o u n d 66. Cleavage of the thiomethy groups gave the tricyclic ether 67.  5 6  Scheme 3. Synthesis of the B C D Ring Fragment 67 of Brevetoxin A (1) (from ref. a  67  66  Key: (a) Lawessons ' reagent 48, 1,1,3,3-tetramethylthiourea, xylenes, 115°C, 3 h 63%; (b) n-BuSnLi, THF, -78 °C; then CHI, -78 °C, 86%; (c) (CuOTf), be pentamethylpiperidine, rt, 45%.  a  3  3  2  20  1.2.1 Conformational Analysis The  shape of organic molecules can  increasing precision and sophistication.  be specified according to three levels of  The first of these levels, constitution,  designates the m a n n e r in which the atoms are joined together with chemical bonds.  The next level, configuration, designates which of several possible ways the atoms of a molecule with a given constitution are spatially connected so that isomeric forms can be obtained. The  final level of sophistication, conformation, designates in which of  several possible ways the atoms of a molecule with a given configuration are arranged in space. Conformational isomers or conformers usually cannot be isolated since their interconversion involves a rotation about single bonds within a molecule. Conformational analysis is the  interpretation or prediction of physical or chemical  properties, and of the relative energies of compounds as determined b y their conformation or conformations.  1.2.2 Nuclear Magnetic Resonance in Conformational Analysis One  of the  m o s t powerful tools for conformational analysis is dynamic N M R  spectroscopy (DNMR). D N M R can be used for the qualitative and quantitative study of conformational changes in organic compounds as a function of changes in temperature. A classical application of D N M R is the study of rotation about the 5 7 8 ,  carbon-nitrogen bond in dimethylformamide (68). At low temperatures the two methyl 5 8  groups give two distinct signals in the H NMR 1  spectrum (slow exchange rate). As  the  temperature is raised the barrier to rotation about the carbon-nitrogen bond which has significant double bond character is overcome and the methyl groups b e c o m e indistinguishable. The signals for the  two  methyl groups broaden (intermediate  exchange rate), and finally m e r g e into one signal (fast exchange rate). The temperature at which the signals are broadest and can not be distinguished from each other is referred to as the coalescence temperature (T). c  21  68  F r o m the temperature dependence of the spectra, rate constants and activatio parameters can be determined. The rate of exchange (kc) at coalescence can be  calculated using either equation 1 or 2, where Av is the separation of the signa hertz measured at a temperature below T. Equation 1 is applied in the case of c  uncoupled nuclei, and equation 2 is applied w h e n the nuclei are coupled to each o and J is the coupling constant in hertz.  k=7c Av/2  V2  (1)  c  (2)  k =JL(AV - 6 J ) 2  2  v  c  2*  The rate of exchange can in turn be used to calculate the free energy of  activation {AG*) for the conformational process using the Eyring equation (3) where: is the ideal gas constant, T is the coalescence temperature, k is the Boltzmann c  B  constant, k is the rate constant, and h is Plancks ' constant. c  AG* = RT In (kT/kh) c  B  c  (3)  c  = R T (23.76 + In (T / k)) c  c  c  Several computer programs have been developed to assist in the analysis o  D N M R data. These programs can be used to analyze the line shape of H N M 5 9  1  spectra collected at various temperatures and calculate the rates for the conformation process at the temperature over which the conformational change occurs. The  activation energy (E) can be determined from Arrhenius plots of log k vs. 1 / T , a a  enthalpy (AH*) and entropy (AS*) of activation can be determined from Eyring plot log ( k / T ) vs. 1 / T .  22 D N M R studies provide information about the coupling constants, the chemical  shifts, the relaxation time, and the line shape changes of the atoms in a compound as a function of temperature. The coupling constants can provide information about the geometry of the compound. For example in cyclic systems, the Karplus equation (4) can be used to determine the dihedral angles of vicinal protons, and hence the torsional angles of the ring itself. Here, A and C are constants, and 0 is the H-C-C-H dihedral angle.  J = A cos9 + C  3  (4)  2  The chemical shift (5) gives information about the shielding of protons in the molecule. For example, the value of 5  ae  which is the difference in chemical shift of a  geminal axial and an equatorial proton for a specific carbon in a molecule. A positive  value indicates that the chemical shift of the axial proton is at higher field (shielded) relative to the equatorial proton. The chemical shift difference of geminal protons in a molecule is determined by a n u m b e r of shielding effects including: diamagnetic anisotropy  (O- N), A  steric compression  (O- T), S  and electric field (a).  6 0  E  Much of the pioneering w o r k in the determination of the anisotropies  (O- N) A  diamagnetic  of bonds was performed by ApSimon and coworkers who derived the  anisotropies of carbon-carbon and carbon-hydrogen bonds through a comparison of the chemical shifts of protons in a series of cycloalkanols. It is the bonds located p to 6 1  the methylene group of interest which are thought to contribute most to this shielding  effect. The bonds a to the geminal pair of protons are symmetrical with respect to both the axial and the equatorial protons and therefore do not have a differential affect on the chemical shift of the geminal protons in a cyclohexane system.  23  The  screening contribution is composed of both an angular term, as well as  an  anisotropy term as calculated by the McConnell expression (5), where the anisotropy (Ax)  or (XL - XT) is composed of terms parallel and perpendicular to the axis of s y m m e t r y  of the atom-hydrogen (X-H)  bond, R is the distance between the proton and the centre  of the induced magnetic dipole of the bond, and y is the angle between the direction of R and the s y m m e t r y axis. This leads to regions of shielding and deshielding about the bond of interest.  Aa =  AY  (1 - 3 cos y) 3 R  (5)  3  For a carbon-carbon single bond, this equation describes a region shaped like a  double cone with areas of deshielding within the cones, and areas of shielding outside of the cones (Figure 11).  Shielding  +AX  Figure 11.  +AX Deshielding  Regions of shielding and deshielding for a carbon-carbon single bond as the result of diamagnetic anisotropy.  W h e n a hydrogen a t o m is held in close proximity to another a t o m in a molecule, at a distance less than the sum  of their van der Waals radii, the chemical shift of the 6 2  24 hydrogen can be shifted downfield as a result of the steric compression effect  (O-ST)-  63  In the study of tricyclic c o m p o u n d s 69-73, a series of half cage compounds related to the  birdcage hydrocarbon, unusually high shielding and deshielding effects were  observed in the N M R spectra.  6 4 , 6 5  The  rigid geometry present in these c o m p o u n d s  results in steric repulsion between the endo hydrogen and chemical shift of the endo hydrogen (H) b  2.40  oxygen groups. The  in 69 which has an exo hydroxyl group was  ppm compared to alcohol 71, which has an endo hydroxyl group, and a chemical  shift of 3.55  ppm for the opposing endo hydrogen (H). b  found to vary with the nature of the  The  size of this effect was  functional group opposite to the sterically  compressed hydrogen. In a series of oxygen substituted compounds 70-73, the magnitude of the chemical shift change varied in the order 0"Na > OH > OMe +  >  OAc.  This chemical shift trend parallels the magnitude of the electron density at the oxygen a t o m in each of these compounds.  69  70 71 72 73  R R R R  = Na+ =H = OMe = OAc  The change in chemical shift for the sterically compressed hydrogen is attributed to the electron cloud of the oxygen functional group repelling the bonding electrons in the C-H bond towards the C-H bond. This polarization of the methylene electron b  a  cloud accounts for the deshielding of the inside hydrogen mentioned above, and shielding of the outside hydrogen atoms (H) as well; 1 . 1 0 ppm a  compared to 0.88  ppm in 71.  in the case of 69,  the  25  The shielding of the proton is caused b y a steric repulsion of the electron c  in the opposing C-H bond, a w a y from the hydrogen nucleus and towards the ca a  nucleus, it follows that the effect should be observed in the C N M R spectrum a 13  result of this charge polarization as well.  66,67  In a study of the bicyclo[3.3.1]nonane  74-76, C-3 and C-7 are in close spatial proximity to each other. In fact, it is 6 8  through space van der Waals interaction of endo groups at C-3 and C-7 which thought to be the main driving force for conformational preferences in these systems. Substituents at C-7 have an influence on the chemical shift of C-3. 6 9 7 , 0  isomers having an endo hydrogen at C-3, the chemical shift of C-7 is approxim  2 1 p p m . For example, the chemical shift of C-7 is 2 1 . 1 p p m in the unsubstitute  and 20.6 p p m in the exo substituted 75. However in 76 with a C-3 endo subst  the chemical shift of C-7 is shifted upfield b y 5 p p m as a result of steric comp  shielding to 15.5 ppm. In all three compounds, the distance between the C-3 and  endo substituents was determined to be less than 2 A.  The polarization of carbon-carbon and carbon-hydrogen bonds b y a dipole o  charge can also influence the shielding and chemical shift of the protons in a mole  The magnitude of this electric field effect (a) is calculated from: the polarizability (P E  the bond of length (L), the size of the charge (q) at a distance (r) and an angle the field gradient to the bond of interest using the Buckingham equation (6).  7 1  = k S q (cos 0) P / (L r) 2  CTE  (6)  26  This shielding effect (a) is greatest for bonds which are parallel to each oth E  and perpendicular to their line of centers, and of a lesser magnitude for gauche bo  or bonds of other skewed geometries. For example, in cyclohexane an axial C-H bo  is affected b y the shielding of t w o parallel y C-H axial bonds and t w o vicinal gau  C-H bonds. While an equatorial C-H bond would experience the lesser polarizatio  shielding effect of four vicinal gauche C-H bonds. The shielding of axial hydrogen atoms has been noted to increase with the n u m b e r of axial C-H bonds in other  saturated hydrocarbons, and in s o m e steroids studied b y Schneider and coworkers a 2 7  The effect of introducing a heteroatom into a cyclohexane results in changes  the C N M R spectrum of the molecule. Deshielding of the carbons a and p to the n e 13  heteroatom are largely the result of the increased electronegativity of the heteroatom relative to that of carbon.  This shift varies approximately linearly with the  electronegativity of the heteroatom. The heteroatom also has a significant affect on 5 7  the chemical shift of the carbon three bonds away. It was first proposed that this e resulted from a shielding of the y-carbon b y the heteroatom via a polarization of electrons through the steric compression mechanism described above. However, 6  results from subsequent studies were not explained b y a steric effect alone.  The  y-effect was found to be of a similar magnitude for a n u m b e r of substituents wh differed widely in their A value and van der Waals radii.  7 6  This indicated that th  y-effect was controlled b y m o r e than simple size considerations, and both steric a  electronic factors were considered. The y-effect was found to depend on both t electronegativity of the heteroatom, and also on the dihedral angle between the heteroatom and the y-carbon.  7 6 , 7 7  A stereoelectronic interaction is likely responsible for the dihedral dependence of the y-effect since the steric relationship between the y-carbon and the n e w  heteroatom orbitals changes with their dihedral angle; The transmission of electronic  information along a molecular chain is associated with the overlap of properly align (parallel) orbitals. This leads to distinct stereoelectronic pathways for arrangements  27 having either an anti or a gauche arrangement between the  heteroatom and the  y-carbon.  The  effect of the heteroatom in a series of 3,3-dimethyl substituted 6 m e m b e r e d  heterocycles on the y-carbon through an anti relationship gave either a slight shielding or a deshielding effect of 1-2 ppm  depending on the nature of the heteroatom and  dihedral angle. The  believed to result from the electronic interaction of  7 7  effect was  the  orbitals antiperiplanar with respect to the bond in the y-anti pathway (Figure 12).  In  comparison, the affect of the heteroatom on a y-carbon in a gauche relationship was larger than the y-anti effect, typically shielding the y-carbon by 4-8 ppm. effect was  The y-gauche  believed to be the result of the interaction of parallel orbitals on adjacent  a t o m s (Figure 12).  y-anti  y-Qauch©  Figure 12. Possible orbital arrangement for y-anti and y-gauche effects in 3,3-dimethyloxacyclohexane. 1.2.3  Conformational Analysis of 6-Membered Rings  The  concepts and  ideas of conformational analysis are now  widely used in the  interpretation of chemical transformations and reaction mechanisms in organic chemistry, and also in the explanation of steric and compounds. The  electronic effects in organic  conformational analysis of cyclohexane and  the m o s t widely studied topics in organic chemistry. In 1890,  it's derivatives is one  of  Sachse first suggested  that cyclohexane existed in two puckered arrangements which later b e c a m e k n o w n as the  chair and  boat conformations. Until that time, the 8 7  prevailing theory depicted  cyclohexane as a regular planar hexagon, rather than a three dimensional structure. In 1925,  Hueckel clearly showed that cyclohexanes were in fact not planar structures with  28  the synthesis of the bicyclic cis and trans isomers of decalin/ However, it was n s  until 1950 w h e n the analysis of reactions of cyclohexanes and steroids, with their  multiple cyclohexane rings, by Barton that the power of cyclohexane conformationa analysis received the recognition it deserved. By viewing cyclohexane as having a three dimensional conformation, Barton was able to explain the results of organic reactions in these systems which had previously puzzled chemists.  8 0  The axial  positions (H) in cyclohexane are m o r e hindered than the equatorial positions (H) d a  e  to transannular interactions, and this leads to the conformational preference of transition states, reaction pathways, and substituents in these systems.  The chair-chair ring interconversion of cyclohexane which converts the ring to i  mirror image via rotation of carbon-carbon single bonds is rapid atrt.This proce interchanges the axial and equatorial substituents, thus making t h e m spectrally  equivalent b y N M R analysis. The rate of this process is dependent on the temperat  of the system. As the temperature is lowered, the interconversion of the axial and  equatorial substituents is slowed. At low temperature a particular conformer with eithe  the axial or the equatorial substituent would predominate. The axial and equatorial  substituents are no longer spectrally equivalent, and accordingly the N M R spectrum becomes m o r e complex.  A D N M R study of cyclohexane gave a value of 10.3 kcal/mol for the free en  of activation (AG*) for ring inversion, with a value of 10.8 kcal/mol obtained for the enthalpy of activation (AH*) for this s a m e process.  8 1  Determination of the vicinal  coupling constants for cyclohexane gave, via the Karplus equation (4), an internal  torsion angle for cyclohexane of 58° which is slightly distorted from 60°, the ang  29 predicted if all the carbons had an ideal tetrahedral geometry. The difference in 2 8  chemical shift at low temperature between a geminal pair of axial and equatorial  protons (5 ) was found to be 0.48 ppm. In cyclohexane, the axial proton lies out 8 3  ae  of the deshielding cone resulting from the diamagnetic anisotropy of the p carbon-  carbon bonds while the equatorial proton lies within the deshielding cone (Figure 13)  Figure 13. Shielding of the axial proton (H) in cyclohexane as the result of the diamagnetic anisotropy of a p carbon-carbon bond. a  The torsional change resulting from replacing a methylene group with a  heteroatom (X) can result in either a flattening or a puckering of the ring. In a stu  the oxygen heterocycle, tetrahydropyran, the larger C-O-C bond angle, and the shor C-0 bond length caused a slight flattening of the chair conformation as compared  cyclohexane. Changes in bond angle in this heterocycle were of less importance th changes to the torsion angles in influencing the magnitude of the free energy of activation of ring inversion (AG ). 4  60  D N M R studies gave a A G of 10.3 kcal/mol for t 4  ring inversion and a chemical shift difference (5 ) for the protons at C-2 of 0.50 p p ae  tetrahydropyran. 4 8  This chemical shift difference is similar to that obtained for  cyclohexane itself, thus suggesting that the diamagnetic anisotropy of the p carbon-  oxygen single bond is similar to that of a carbon-carbon single bond. Results from study of 1,3-dioxanes indicate that the orientation of the carbon-oxygen bond can influence the value of 5 . ae  the axial proton, but 8  ae  85  In this study, 8 for C-2 was positive denoting shielding ae  for C-5 w a s negative, indicative of a deshielding of the  proton at that carbon (Figure 14). The geometry of the C-2 and C-5 protons wit  respect to the carbon-oxygen bonds is approximately the s a m e however the orientatio  30 of the carbon-oxygen bond at C-2  is different from that of C-5  which may  account for  the difference in the shielding observed in this system.  Ha  H  a  Figure 14. Differences in 8 for C-2 and C-5 geminal protons in 1,3-dioxane. ae  To summarize, the introduction of a heteroatom into a ring can result in changes to the N M R spectrum as a result of differences in the electronegativity of the heteroatom relative to the methylene group. The introduce new  lone pairs of the heteroatom can also  electronic interactions, and the magnitude and  anisotropy of the C-X bonds can  affect the NMR  shape as a result of differences in the C-X-C  sign of the diamagnetic  spectrum. Finally, changes in ring  bond angle and C-X  bond length relative  to the carbocycle can also affect the NMR spectrum.  1.2.4  Conformational Analysis of Medium and Large Rings  This section begins with a brief historical account of large ring or macrocyclic compounds. The first macrocyclic compounds were isolated in 1926 investigating the constituents of m u s k oil.  86,87  civetone (77) and  The  by Ruzicka while  structure of the large ring ketones,  muscone (78) were elucidated using chemical methods only, a  process complicated by the scarcity of functional groups in these compounds. research was of twofold importance.  First these musklike compounds were of  commercial value in the fragrance industry, and physical and  This  second, little was  k n o w n about the  chemical properties of large rings compounds leading to a fundamental  interest as well.  31  O 78  Research in the  79  area of macrocyclic chemistry continued through the  Ruzicka and  Prelog and  of m e d i u m and  large ring hydrocarbons, alcohols, ketones, and  8 8 , 8 9  and  9 0  their coworkers who  investigated the  efforts of  chemical properties lactones. The physical  chemical properties of these macrocyclic ring compounds showed an interesting  and unexpected dependency on ring size. relationship between melting point and  For example, it was found that the  ring size did  not  rise monotonically as with  aliphatic acyclic hydrocarbons."  89 0  Pikromycin (79),  the first of the  isolated by Brockmann and  complex macrocycles called the  Henkel in 1950  from an Actinomyces  macrolides, was  culture. M a n y of 9 1  these large ring lactone macrolides possess interesting biological activity and share several characteristic structural features. They contain 12-, lactones of secondary alcohols and  are  or 1 6 m e m b e r e d  composed of an array of hydroxyl and alkyl  substituents characteristically distributed around the the  14-,  also  ring. Attached to one  or m o r e of  secondary hydroxyl groups are sugars, which are often amino sugars. An 9 2  understanding of the conformation of these macrolides is important in rationalization of the  chemical activity and  the  the  structure activity relationships of these  antibiotics. This has been an area of extensive research, and a combination of spectroscopy methods and conformation of this and  X-ray crystallography have been employed to determine the  other macrolides in both solution and  the solid state.  32 Initially, the shape or conformation of the large ring molecules was poorly  understood. In 1961, Dunitz and coworkers reported an X-ray diffraction study of a series of cyclodecane derivatives all of which had crystallized in a similar conformation. This was a surprising result at the time as these large rings were 3 9  thought to be a flexible chain of atoms capable of existing in m a n y conformations.  1963, Dale realized that the solid state conformations of the cyclodecane derivative  closely followed the diamond lattice, an extended tetrahedral array of carbon-carbon bonds having ideal bond lengths, bond angles, and dihedral angles.  9 4 , 9 5  A  conformation which w a s superimposable on the diamond lattice was therefore predicte to possess a m i n i m u m of angle and torsion strain.  From inspection of space-filling molecular models, Dale proposed diamond lattice conformations for all even m e m b e r e d rings ranging in size from 6- to 1 6 m e m b e r e d by maximizing the n u m b e r of anti dihedral angles and avoiding the  eclipsing of bonds. Dale also recognized a tendency for saturated even-membered 9 4  large rings to adopt compact conformations consisting of t w o parallel methylene chain linked by bridges of m i n i m u m length.  9 4  These rectangular conformations were  proposed to be m o r e stable and possess less torsion and angle strain than those w  large hole in the ring interior. In addition, Dale concluded that conformations of o  m e m b e r e d cycloalkanes would not be strain free as they were not superimposable the diamond lattice, and that for even-membered rings between C  6  and C i  4  n o tota  strain free conformations were possible either since the diamond lattice conformations would have intraannular interactions between internally oriented hydrogen atoms.  9 4 9 ,5  The qualitative recognition of low energy diamond lattice conformations was followed by exploratory calculations of strain energies in m e d i u m and large rings. Semi-quantitative calculations of the enthalpies of m e d i u m and large rings were  performed b y Dale using Dreiding models. These models have the correct carbon 9 6  carbon bond lengths and tetrahedral bond angles.  The dihedral angles of the  macrocycles were manually determined, and compared to a butane potential energ  curve in order to determine the dihedral torsion energies. Subsequently, Anet and  33 coworkers have reported the strain energies of m e d i u m and  large rings as determined  with molecular mechanics calculations.  9 7 9 , 8  1.2.5  Conformational Analysis of 14-Membered Rings  From these analyses, the 1 4 m e m b e r e d ring was  predicted to exist largely in a  quadrangular diamond lattice conformation with t w o four-bond sides in the anti configuration joined by two the joints. The  parallel three-bond sides with gauche torsional angles at  1 4 m e m b e r e d ring in this diamond lattice conformation was  large ring in which the transannular interactions were small. conformation also contained minimal torsion and  the first  This preferred  bond angle strain, and therefore was  designated as being "strain-free". In addition to this lowest energy diamond lattice 9 9  conformation of cyclotetradecane, the calculations also suggested the existence of  two  low energy non-diamond lattice conformations. 6 9  To determine all of the  diamond lattice conformations that were theoretically  possible for cyclotetradecane, Saunders used a ring building program. A total of  13  diamond lattice conformations were found, but as expected, m o s t of these possessed severe transannular interactions.  1 0 0  With the  exception of the  diamond lattice conformation, the strain energy of the  one lowest energy  remaining diamond lattice  conformations were calculated to be higher than the t w o non-diamond lattice conformations found earlier.  The energies of these remaining diamond lattice  conformations ranged from 3-12  kcal/mol above the lowest energy conformation. Thus,  a total of 15 possible conformations were found for cyclotetradecane including 13 diamond lattice conformations and two non-diamond lattice conformations.  34  side view  top view  Figure 15. The lowest energy diamond lattice conformation of cyclotetradecane.  The rectangular nature of the lowest energy conformation of cyclotetradecane is  easily recognized from the top view. This shows the conformation to have four ato  located at the "corners" of the rectangle (Figure 15). These corner atoms are flank  on either side b y gauche dihedral angles that are themselves flanked by anti dihe  angles (Figure 16). A corner a t o m is formally defined as an a t o m flanked b y gau  dihedral angles of the s a m e sign with anti dihedral angles surrounding the gauche  torsions. This is the lowest energy arrangement of dihedral angles about a corner atom.  Another type of corner has been recognized b y Dale and coworkers from  X-ray crystal study of 1,4,8,11-tetraoxacyclotetradecane, and by Neeland during the 1 0 1  study of s o m e 1 4 m e m b e r e d lactones. This involves an a t o m with gauche dihedr 1 0 2  angles on either side, further flanked b y anti dihedral angles, but the gauche dihe  angles have opposite sign (i.e. 180°, -60°, 60°, 180°) (Figure 16). This arrangeme  w a s termed a pseudocorner and is higher in energy than the corner arrangemen 1 0 2  described above.  35 Corner Position  o  Ii  180°  180°  180° -60°  L !  O 3 | 5  7  6  k  -60° -60°  -60° 180° o  I,i  Pseudocorner Position 6  7  180°  180°  -60°  O2  !, J  5 6 O^—O—^Oi  7  -o  ft  -60° 60°  60° 180°  Figure 16. The corner (*) and pseudocorner (**) positions and the surrounding dihedral angles. Dale devised a shorthand notation to n a m e the individual conformations of  macrocyclic rings. This system involved a series of numbers within brackets, with each n u m b e r representing the n u m b e r of bonds between two corner atoms. The direction 9 6  around the ring is chosen such that the sequence is started with the smallest n u m b e ro  bonds, followed by the next smallest n u m b e r of bonds and so forth. Using this notation, the strain-free conformation of cyclotetradecane is designated [3434], and the next lowest energy non-diamond lattice conformations as [3344] and [3335] respectively (Table 2).  36 Table 2.  The Three Lowest Energy Conformations of Cyclotetradecane (from ref. 1 0 2 } Strain Energy 3  Conformation  Top View  Side View  (kcal/mol) o—o—o—o [3434]  o  6  i ^ ^ C l ^ i  0.0  o—o—o—o o—o—o—o—o  '  [3344]  1  o  1 . 1  I  1  0—0—0—0  [3335]  a  o  6  •  1  '  \7  2.4  Calculated with the MM2* force field.  This nomenclature was revised to include the n e w type of corner atom, with  n u m b e r of bonds between a corner and a pseudocorner or between t w o pseudocor  atoms denoted with a primed n u m b e r (e.g. 4'). The numbers are ordered around ring beginning with the priority (corner-corner) > (corner-pseudocorner) > (pseudocorner-pseudocorner). 2 0 1  It w a s not possible to n a m e all large ring  conformations according to either Dales ' original scheme or b y the above extension  Thus in s o m e cases alphabetical letters have been assigned arbitrarily to designate  s o m e conformations. For example in the study of the conformations of the macrolid  oleandomycin, Ogura and coworkers designated conformations with the letters A, B ,  37 and D.  In this case, conformation A has been s h o w n to be the s a m e as the  1 0 3 , 1 0 4  conformation of cyclotetradecane.  The [3434] conformation of cyclotetradecane belongs to the C h s y m m e t r y point 2  group. It contains four diastereotopic methylene groups which experience varying degrees of transannular steric interactions (Figure 17). With the exception of the  corner methylenes, all other methylenes have at least one hydrogen a t o m pointed i  the ring, with the endo-hydrogen of the methylene at the centre of the four-bond  having the m o s t severe steric interaction. In contrast, the hydrogen atoms of the cor  methylenes are both directed to the outside of the ring. Accordingly, these position are best able to a c c o m m o d a t e geminal substitution without suffering the severe  transannular interaction which would result from geminal substitution at other location  on the ring. In general, there is a preference for a geminally substituted carbon to 1 0 5  located first at a corner atom, followed next at a pseudocorner atom, and finally non-corner atom.  n u m b e r of transannular interactions  Figure 17. Transannular hydrogen interactions in cyclotetradecane.  That the preferred conformation of cyclotetradecane in the solid state is actual  the [3434] diamond lattice conformation has been experimentally determined with X-ra  crystallographic studies performed b y Groth. This study gave carbon-carbon bond 1 0 6  lengths of 1.53 A for cyclotetradecane, and average bond angles of 114.6° for all  angles with the exception of the middle of the four-bond side which had a bond an 112.3°.  Spectroscopy studies including N M R studies performed by Anet and  coworkers, and by Moller and coworkers as well as IR and R a m a n studies 1 0 7  1 0 8  performed b y Shannon et al. are in agreement with this conformation being the m 109  38 conformer in solution. The conformation of other 1 4 m e m b e r e d macrocycles including: 1,3,8,10-tetraoxacyclotetradecane (80), decane oxime (82)  110  cyclotetradecanone (81),  111  and cyclotetra-  have also been determined by X-ray crystallographic studies.  112  The conformation of the ring was  found to be [3434] in all cases with s o m e disorder in  the location of the carbonyl of the macrocyclic ketone. O  81  82  1.2.6 Conformational Analysis of 13-Membered Rings  In comparison to 1 4 m e m b e r e d rings, little is k n o w n experimentally about the conformation of 1 3 m e m b e r e d rings. This ring size falls on the m e d i u m and  large sized rings. The  diamond lattice has  geometries for even-membered macrocyclic rings, but  borderline between  been used to define idealized odd-membered rings are  not  superimposable on this lattice. As a strain-free diamond lattice geometry is not accessible, the conformations of the o d d m e m b e r e d rings are  predicted to be m o r e  strained as a result of distorted bond lengths, bond angles, and  dihedral angles.  However, bond length distortion can be minimized in either 3- or 5-sided conformational minima. Semi-quantitative calculations on the  conformation of 1 3 m e m b e r e d rings  performed by Dale using molecular models suggested five low energy conformations. 6 9  More accurate values have been reported by Anet and R a w d a h from iterative force fie calculations the results of which also indicate five l o w energy conformations. 8 9  However, the comparative energies and ordering of the minima differ between the  two  calculations. Anet and  the  R a w d a h concluded that the  [13333] conformation was  global m i n i m u m conformation with the [12433] conformation only 1.4 kcal/mol higher in energy (Table 3).  Three triangular conformations were found to have the next lowest  strain energies. The  [346]  1.6 kcal/mol with the [445]  conformation was and  [355]  calculated to have a strain energy of  conformations at 2.9 kcal/mol, and  3.3 kcal/mol  39 higher in energy relative to the [13333] conformation. The conformation set proposed 8 9  by Dale had the [12433] conformation as the global m i n i m u m conformation. A close 6 9  geometric relationship exists between the triangular and the  quinquangular  conformations in that the sign of the torsion angles around the 1 b o n d side of the quinquangular conformations alternate in exactly the s a m e fashion as in the corresponding near anti bonds of the triangular conformation.  1 3  Table 3.  The Two Lowest Energy Conformations of Cyclotridecane (from ref. 98) Strain Energy 3  Top View  Conformation  Side View  (kcal/mol)  o [13333]  \  ?  o  0.0  o  0—0—0—0  0—0—0—0  T [12433]  1  0  1 0  T  1  o  1 . 4  ! 0  i  /  0—0—0 a  Calculated with the MOL-BUILD program.  The conformation of s o m e 1 3 m e m b e r e d compounds have been determined. The  X-ray crystal structures have been reported for three nitrogen containing  compounds 83-85.  Thiolactam 8 3  114  and the substituted 1 3 m e m b e r e d amine 8 4  115  were both found to have crystallized in the low energy [13333] conformation, although s o m e disorder was present in portions of the rings. The nitrogen a t o m and the carbon of the thionocarbonyl of 83 were on the corners of the 1 b o n d side, and the nitrogen a t o m of the amine 84 was also on the corner of the 1 b o n d side. The 1 3 m e m b e r e d rings of the bisamine 85 were also found to have the [13333] conformation with the substituted nitrogen occupying the corner of a 3-bond side of the ring.  1 1 6  40  ^  -J  85  1.2.7  Transition State Theory in Large Rings  The  interconversion of conformers occurs as the result of rotation about single  bonds. A knowledge of the energy of the molecule as a function of changes to  the  molecular geometry is helpful in rationalizing the mechanistic details of such transformations. In cyclic molecules, a n u m b e r of conformational processes have been described b y Anet including: ring inversion, local ring inversion, and ring pseudorotation.  1 7  An example of ring inversion is the change from one  chair form to the alternate  chair form in 6 m e m b e r e d rings. In general, this process involves a change in sign of all the dihedral angles in the ring with the exception of those dihedral angles that are close to 0° or to 180°.  The  magnitude of the dihedral angles, the bond lengths and  internal angles are either unaffected or only slightly changed. The  the  path followed by this  41 inversion process is not specified, and therefore no particular mechanism for the process is implied.  A local ring inversion is a conformational process which occurs in only part the molecule. The conversion of the chair to the boat in a 6-membered ring is  example of this type of process. Changes to the signs of only t w o of the dihe angles occurs while the values of the remaining four dihedral angles change in magnitude, but not sign.  Ring pseudorotation is a conformational process that results in a conformation,  which is superimposable on the original. This n e w conformation m a y differ from th  original conformation b y an apparent rotation about one or m o r e of the molecular ax  Minor changes in the ring skeleton that m a y occur as a result of the pseudorota process are ignored. This process was first used to describe the conformational  properties of cyclopentane. The atoms of this ring apparently rotate around the ring  with each a t o m residing in the flap position of the envelope conformation for a po of the time.  A conformational isomer or conformer is a structure corresponding to a  conformational energy minima. The transition state between these minima is the lowe energy "pass" between the pair of conformational minima. Whether a single step or  sequence of steps are involved in the conformational exchange process is difficult t determine experimentally, but a knowledge of the geometry and s y m m e t r y of the populated conformations can assist in the suggestion of the  interconversion  mechanism. Additional support for the mechanism can be provided b y a comparison with data from qualitative or quantitative calculations of the relative strain energies the conformational minima and the transition states that separate them.  A mechanism for the interconversion of cyclic conformations has been proposed  b y Dale involving the m o v e m e n t of a single corner a t o m within the ring. This proc 1 1 8  can result in the exchange of both ring atoms and ring substituent sites. In a m a similar to that used for the determination of the geometry and strain energies of  42  possible conformational minima described earlier, Dale used molecular models and 9 6  calculated butane dihedral torsion energies to calculate the barriers  between  conformational minima. H e proposed the m o s t favourable transition state to have 1 8  0 torsional angle between the n e w and the old corner atoms which b e c o m e eclip during the conformational interconversion (Figure 18).  The corner a t o m which is flanked b y t w o gauche dihedral angles of the s a sign, can be m o v e d b y one position in the ring with a resultant change in sign  of the gauche dihedral angles about the n e w corner. This process proceeds through transition state with the bond between the n e w and the old corner atoms eclipsed the t w o adjacent bonds have 120° dihedral angles of opposite sign.  1 1 8  Further rotati  of the ring bonds gives a n e w conformation with the old corner a t o m shifted onto  of the conformation, and gauche dihedral angles of opposite sign around the n e w  corner atom. These local or partial conformational changes can occur without major geometric changes occurring elsewhere in the molecule.  1 1 3  Figure 18. M o v e m e n t of a corner a t o m b y one position with an accompanying chan in sign of the surrounding gauche dihedral angles. The transition state structures for such conformational processes can b e designated in a similar fashion to that used b y Dale for conformational minima.  syn eclipsed bond of the transition state is considered to be a one-bond side, and  n u m b e r is written in italics to differentiate the transition state structure from that o conformational minima. In general, n-sided conformations have (n+1)-sided barriers. 1 1 8  43  In cyclotetradecane, the [3434] lowest energy conformation would proceed to th  higher energy [3344] conformation b y passing over the [73343] conformational barrie After several m o r e repetitions of this process, the atoms are rotated around the and complete site exchange of both ring atoms and substituents can occur (Figure Dale calculated this barrier to be 13.8 kcal/mol higher in energy than the [3434]  conformation. There is also the possibility of an alternate pathway proceeding from 1 8  the [3344] conformation over the [73334] barrier to the less stable [3335] intermed  conformation. This barrier was calculated to be 13.0 kcal/mol higher than the [343 conformation. Conformational interconversion over this alternate barrier would lead 1 8  to exchange of carbon atoms only and not of the substituent hydrogen atoms.  1 1 3  Passing through the [3434] conformation in the middle of the first interconversion pathway has the effect of exchanging geminal substituents and after six repetitions,  hydrogen sites are exchanged. These calculated transition state barriers were found 1 3  to be too high because of approximations m a d e in the calculations. For example, A  and coworkers have reported that the transition state barriers for cyclotetradecane a approximately 7.0 kcal/mol based on H and C D N M R studies. 1  1 3  1 0 7  [3335]  Figure 19. Conformation interconversion pathways for cyclotetradecane as the result of the single corner m o v e m e n t mechanism.  44  The conformational minima of the 1 3 m e m b e r e d rings were m o r e complex tha  that of the 1 4 m e m b e r e d rings, and the conformational interconversion processes ar  also thought to be complicated. The interconversion paths for 1 3 m e m b e r e d rings 1 6  have been described as "complex and interwoven". The lowest energy [13333] an 1 3  [12433] conformational minima can interconvert b y passing over the [721333] barrie  However, if these 5-sided conformers first interconvert to their triangular partners, th barrier to interconversion is thought to lie even lower in energy.  1 1 8  The [346]  conformation, which was calculated to have a strain energy of 2.9 kcal/mol, can  interconvert with the [445] conformation that can in turn interconvert over the [74  barrier. This process would lead to complete site exchange in the molecule. Dale ha calculated this conformational barrier at 7.2 kcal/mol.  1 8  However, the barriers  calculated b y Dale have been s h o w n to be too high, so the actual value shoul lower.  Initial C D N M R studies of cyclotridecane gave only a single line at 13  temperatures as low as -135 °C. This indicates a rapid rate of pseudorotation with 9 8  conformational barrier estimated at 6 kcal/mol.  45  CHAPTER 2  RESULTS AND DISCUSSION  Synthesis and Conformational Analysis of 14-Membered Macrocyclic Ethers S o m e conformational analyses of macrocyclic compounds have been reported in the literature, and a few of these were presented in Chapter 1. Large ring monoethers have received little attention with oxacyclooctane the  largest cyclic ether previously  studied. As part of an ongoing study of the chemistry of macrocyclic compounds in 3 3  our laboratory, methods for the synthesis of 1 4 m e m b e r e d unsubstituted cyclic ethers, and  1 4 m e m b e r e d cyclic ethers with alkyl substituents both adjacent to and remote  from the ether oxygen were examined. Once prepared, the conformational properties of these macrocyclic ethers were analyzed using NMR molecular mechanics calculations. The  spectroscopic techniques, and  conformational preferences of these  macrocyclic ethers, the location of the ether oxygen in the conformation, and the effect of alkyl substituents, especially gem-dimethyl substituents on the conformation of these ethers were of key interest. We also hoped to gain an increased understanding of the conformational interconversion processes of these macrocycles and  of the associated  transition state energies.  Replacing a methylene group in a large ring with an oxygen a t o m is believed to have a limited affect on the  ring conformation. However, the  elimination of s o m e  hydrogen atoms as a result of such a substitution can lead to a reduction of the n u m b e r of steric interactions, particularly transannular interactions, in the molecule. The effect of alkyl substitution on the conformation of the ring is also of interest. Whereas an  oxygen a t o m would be expected to be located at a position with the. m o s t severe hydrogen interactions in the  parent hydrocarbon, an  alkyl substituent would be  expected to be found at a position having the fewest hydrogen steric interactions in the parent hydrocarbon. Since each of the four possible diastereotopic ring sites in  the  [3434] conformation of a 1 4 m e m b e r e d ring has at least one hydrogen pointing outside  46 the ring, monosubstitution should be readily accommodated. However, for the case of gem-disubstituted molecules, the  substituted carbon m u s t be at a corner position.  Severe steric interactions would result from its placement elsewhere in the ring.  2.0.1  Synthesis of 14-Membered Macrocyclic Ethers  The  general synthetic strategy for the preparation of the  macrocyclic ethers in  this study involved the ring expansion of a cyclic ketone to a lactone, thereby eliminating the potential problem of forming the macrocycle via a cyclisation reaction. The  endocyclic oxygen of the lactone ultimately b e c a m e the macrocyclic ether oxygen.  This lactone functionality was oxygen. Once this role was  used to introduce substitution in the vicinity of the ether served, the carbonyl was  removed to give the macrocyclic  ether with a procedure developed by Nicolaou and coworkers using 2,4-bis(45  methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide, Lawessons ' reagent 48, give an intermediate thionolactone. This strategy allowed for the  48  to  production of a  variety of macrocyclic ethers as the result of variations in the substitution pattern of the ketone (R and  R) and lactone (R and  1  2  R) from the  4  5  alkylation reactions, and the  nucleophile (R) used in the Nicolaou conversion (Scheme 4). 3  48  47 Scheme 4.  Synthetic Strategy for the Preparation of Macrocyclic Ethers  0  O  R 2  Baeyer Villiger Oxidation  R1,  R2,  R3,  R4  R5 = H or  C H 3  The macrocyclic ethers chosen for this study included the unsubstituted oxacyclotetradecane (90), the monosubstituted 2-methyloxacyclotetradecane (92), the  disubstituted 2,14-dimethyloxacyclotetradecanes 103 and 104.  1 4 m e m b e r e d macrocyclic ethers with a gem-dimethyl group at C-2 C-6 in 137, and C-8  in 154 were studied also.  and  A series of in 116, C-3 in 119,  48  2.0.2  104  116  137  154  119  Conformational Analysis of 14-Membered Macrocyclic Ethers  The  conformations of these macrocyclic ethers were analyzed using both NMR  spectroscopy and of 1- and  2-D  NMR  molecular mechanics calculations. The experiments (H, 1  C,  13  NOE,  data obtained from a series  COSY, H M Q C , HMBC) were used to  assign as m u c h of the spectra as possible. Although the introduction of the oxygen a t o m did offer s o m e dispersion in the chemical shifts of the signals of the atoms close to the  ether oxygen, approximately half of the  methylenes in each molecule were  remote enough from the ether oxygen to experience very little of this dispersion effec Accordingly, the signals of m a n y of the ring methylenes overlapped, and assignment of the macrocyclic ether NMR  spectra was  the complete  not possible, even at high-field  49 (H, 500 MHz). This problem was also encountered in the study of the parent 1  hydrocarbon. Once the chemical shifts and coupling constants of a particular ethe 1 0 7  were determined, any anomalous values indicative of key conformational features could be identified.  A series of D N M R experiments were performed to provide further information  about the conformation of these cyclic ethers. Since the molecules undergo rapid sit  exchange at rt, these D N M R studies were performed at colder temperatures with 13 as an approximate lower temperature limit. This temperature limit was a function  both the melting point of the solvent system, and the solubility of the cyclic ethe  these cold temperatures. Experiments could be performed at temperatures as low a  1 0 0 K on the spectrometer used, however the solvent systems could not be use such low temperatures.  These D N M R studies provided information about the  interconversion of the conformations through the processes of ring inversion, local rin inversion, and pseudorotation, in addition to the thermodynamic barriers for these processes.  As the temperature is lowered in the D N M R studies, the rates of the conformational interconversion processes slow, and the signals of individual protons change as the effects of site exchange slow. The changes in the chemical shift  various protons as a result of the electronegativity of neighbouring atoms, steric effec  from intramolecular van der Waals repulsions, and diamagnetic anisotropic effects from both the type and the orientation of the neighbouring chemical bonds is used to  rationalize the conformation of the molecule both atrtand at the lower temperatu The results of molecular mechanics calculations are used to assist the rationalization  the experimental data in an effort to m o r e fully describe the conformational propert of the compounds studied.  To simplify the comparison of the 1 4 m e m b e r e d macrocyclic ether  conformations, an extension of the Dale nomenclature was developed to designate t position of the ether oxygen a t o m in the conformation. The [3434] conformation cyclotetradecane, contains four diastereotopic ring positions. These are n u m b e r e d  50 starting with position-1 at the middle of a 4-bond side. In the low energy, non-diamond lattice [3344] conformation, the positions were referred to in a similar m a n n e r again beginning with position-1 at the middle of a 4-bond side and continuing around the ring through the adjacent 3-bond side. Using this nomenclature, the [3434] conformation of oxacyclotetradecane (90) with the ether oxygen in the middle of a 4-bond side would be the [3434]-1 conformation.  [3434]  2.1.1  [3344]  Synthesis of Oxacyclotetradecane (90) and 2-Methyloxacyclotetradecane (92)  The first macrocyclic ether in this study, oxacyclotetradecane (90), was prepared via the Baeyer-Villiger oxidation of cyclotridecanone (86) with trifluoroperacetic acid to give 13-tridecanolide (87). The peracid was H0 solution  1 1 9 , 1 2 0  2  2  generated by the addition of either 70%  or solid urea hydrogen peroxide (UHP) to a solution of 1 2 1  trifluoroacetic anhydride (TFAA) in CHCI. The 2  2  giving higher yields of the desired lactone.  1 2 2 , 1 2 3  UHP  m e t h o d was  The UHP  superior usually  reaction was also easier to  perform since the NaHP0 buffer tended to form a difficult to stir paste with the water 2  present in the 70%  4  H0 solution. The 2  2  lactone was  with Lawessons ' reagent 48. The H NMR 1  converted into thionolactone 88  spectrum of the resultant oil showed two-  proton multiplets between 4.46-4.48 ppm and 2.85-2.88 ppm for the C-13 methylene and the C-2 methylene protons of 88 respectively. The C NMR 13  spectrum contained a  signal at 224.66 ppm for the C-1 thionocarbonyl. The H R M S and chemical analysis results were also consistent with the composition of 88.  5 1 The thionolactone 88 was a c o m m o n intermediate in the synthesis of macrocyclic ethers 90 and 92.  Reaction of the thionocarbonyl of 88 with lithium  triethylborohydride and trapping of the resultant thiolate with methyl iodide gave th unstable mixed thioacetal 89.  This material was reduced immediately with  51  tri(/7-butyl)tin hydride to remove the thiomethyl group and give the macrocyclic ether 9  Reaction of 88 with methyllithium and trapping of the resultant thiolate with methyl iodide, produced the mixed thioketal 91.  51  Like 89, this compound was unstab  and was reduced immediately with tri(n-butyl)tin hydride to give the macrocyclic eth 92  Scheme 5.  Synthesis of Oxacyclotetradecane (90) and 2-Methyloxacyclotetradecane (92) a  O  89 R = H 91 R = Me  90 R = H 92 R = Me  Key: (a) UHP, TFAA, NaHP0, CHCI, 0 °C, 96%; (b) Lawessons ' reagent 48, toluene, A, 73%; (c) LiEtBH, THF, -78 °C; then Mel, 91%; (d) MeLi, THF, then Mel, 90%; (e) A7-BuSnH, AIBN, toluene, A, 43% (90) or 63% (92).  a  2  4  3  3  2  2  52 2.1.2  Conformational Analysis of Oxacyclotetradecane (90)  The  H NMR  spectrum of oxacyclotetradecane (90) at rt in CDCI contained a  1  3  four-proton triplet at 3.41 from 1.29-1.43 ppm, signals at 3.41  ppm,  and  a four-proton quintet at 1.57  ppm,  a 16-proton multiplet  a two-proton multiplet from 1 . 2 1 1 . 2 7 ppm.  ppm and 1.57  The low-field  ppm were assigned to the C-2/C-14 and C-3/C-13 protons  based on their proximity to the electronegative ether oxygen. The  results of the H R M S  and chemical analysis were also consistent with the composition of 90. The  C  NMR  13  spectrum of 90 contained seven signals. The  these signals can be found in Table 4. The is undergoing rapid exchange on the NMR  assignments of  simplicity of these spectra indicate that 90 timescale, and that the exchange results in  a conformation with a plane of symmetry. Each carbon resonance corresponded to a pair of methylenes in the 23.19  ppm  that was  this basis. The  macrocyclic ether with the  exception of the  half the height of the other signals, and  location of this carbon was  without a symmetrical carbon partner. The  was  signal at  assigned to C-8  on  opposite to the ether oxygen leaving it signal at 68.58 ppm  was  assigned to  C-2/C-14, the carbons adjacent to the ether oxygen. These carbons were expected to have the lowest field signal as the result of their proximity to the electronegative ether oxygen. The  remaining C 13  and H signals were assigned with the aid of COSY and 1  H M Q C 2 D N M R experiments. The  chemical shift of the signals for the C-6  methylenes were very similar and  the unambiguous assignment of these signals was  not possible. The  rt NMR  and  C-7  spectra of oxacyclotetradecane (90) are consistent with the  [3434]-1 conformation.  [3434]-1  53 Table 4.  H and C N M R Assignments for Oxacyclotetradecane (90) in CDCI at R o o m Temperature  1  13  3  Position  a  H NMR  1  a  C NMR  13  a  3.41  68.58  1 . 5 7  28.59  1 . 4 0  23.42  1 . 3 6  26.34  1 . 3 2  25.15  1 . 3 2  24.37  1 . 2 4  23.19  b  b  The chemical shift values are in p p m referenced to CHCI (H) and CDCI (C). D u e to signal overlap these signals could not be unambiguously assigned. 1  1 3  3  b  3  The chemical shift of the carbons of the macrocycle were expected to decrea as the through-bond distance from the electronegative oxygen a t o m increased.  According to this trend, the small signal of C-8 should have the highest field chem  shift, with chemical shifts of the other carbons progressively decreasing. However, the  chemical shift of C-4 deviates from this trend. The signal for this carbon is at hig field than expected based on this through-bond distance argument. The  high-field  signal for C-4 is explained on the basis of the y-gauche effect, a stereoelectronic e  resulting from interactions between the orbitals of the oxygen and carbon atoms. T effect typically results in a shielding of 4-8 ppm. There is a gauche geometric 7 6  relationship between the ether oxygen and C-4 in the [3434]-1 and [3434]-4 conformations of 90.  The distance between the oxygen a t o m and C-4 is 2.95 A from an M M 2 *  calculation, a distance m u c h less than 3 . 7 2 A, the s u m of the van der Waals rad oxygen and a methylene group (Table 5). The ether oxygen is so close to 6 2  H-4 do e n  the electron density of this hydrogen is pushed towards C-4 and H-4 resulting in e x o  shielding of both C-4 and H-4 in the rt N M R spectra. This shielding effect is o e x o  observed in the r o o m temperature C spectrum and not in the H N M R spectrum of 13  1  54  due in part to the overlap of signals in the H N M R spectrum in the region of th 1  proton signals. Also, since the ring is conformationally mobile at rt, any effects experienced b y the  C-4  methylene protons are averaged between both  H-4  exo  and  H~4endo-  Table 5.  van der Waals Ra f d oir S o m eA t o m Groups 3  van der Waals radii H  1 . 2 0A  0  1 . 5 2A 1 . 7 0A  CH  2  3  F r o m ref. 62.  The low temperature spectra of 90 were obtained in a 4 : 1 mixture of CHC  (Freon21) and CHCIF (Freon 22) as solvent. Using this mixed solvent system the 2  data could be collected over a broader range of temperatures than the m o r e c o m m N M R solvents such as methanol^ and methylene chloride-d that freeze at 175 K 2  178 K respectively. Experiments were performed in the mixed freon solvent at temperatures as low as 135 K . These freons are protio solvents, and the D N M R  experiments were performed without a deuterium signal lock. The magnitude of the freon solvent peaks was quite large relative to the macrocyclic ether signals, but freon signals had chemical shifts of 7 . 5 p p m and 7 . 2 p p m , and were observed H N M R spectra downfield from the macrocyclic ether signals where they did not  1  interfere with the analysis.  A series of l o w temperature H N M R experiments were performed 1  on  oxacyclotetradecane (90) (Figure 20). The H N M R spectrum of 90 at 220 K containe 1  four signals of relative integration 4:4:16:2, similar to thertspectrum with the  multiplicity of the signals lost at the lower temperature. At 200 K the high-field sign  for the C-8 methylene protons was n o longer visible, and at 190 K the signal for t  protons coalesced into the methylene envelope, and was no longer distinct. At 180  the signal for the C-2 protons adjacent to the ether oxygen broadened. S o m e n e w  55 signals were also visible downfield of the methylene envelope at 1 . 8 4p p m and  1 . 6 1 p p m , and upfield of the methylene envelope at 1 . 0 4 p p m and 0.57 ppm. A the C-2 methylene signal continued to broaden, and the signals downfield of the  methylene envelope b e c a m em o r e distinct. At 165 K , the signal for the C-2 methyle split into three signals clustered around 3.4 p p m . The intensities of these partially overlapping signals were approximately equal. The relative integration of the six signals visible in the spectrum collected at 165 K was approximately 4:2:4:11:4:1.  Further cooling to 135 K , the lowest temperature in this series of D N M R experim did not produce significant changes in the line shape of the spectrum of 90.  As the temperature was lowered, the H N M R spectrum of 90 changed as a 1  result of the slowing of both ring-site and ring substituent exchange. T h e  rationalization of these spectral changes began with the protons of C-2 adjacent to  ether oxygen. This signal progressively broadened until at 165 K , it split into three signals with chemical shifts of 3.43, 3 . 4 0 and 3 . 3 8 p p m . The relative intensity of  signals was 1 . 2 : 1 : 1 based on their peak height. As the temperature was lowered,  process leading to ring inversion and averaging of the C-2 proton signals was slow and the signals for  H-2do e n  and H-2 b e c a m e distinct. In the [3434]-1 conformation e x o  H-2 is deshielded by the anisotropy of the C-3/C-4 bond, with a corresponding e x o  shielding of the  H-2 o e n d  proton. The H-2 proton is deshielded b y a van der Waa e n d 0  steric interaction with H-5 leading to a shielding of e n d 0  H-2oe X  Here, these steric an  anisotropic shielding effects are opposed, and are expected to partially cancel.  57  A large vicinal coupling constant was expected between H-2 do and H-3 in the en  P  [3434]-1 conformation while all other coupling constants for the C-2 protons were predicted to be small. It was for this reason that the low-field portion of the multiplet at 3.43 ppm was assigned to the H-2 proton, and the two high-field portions at 3.40 ppm exo  and 3.38 ppm were assigned to the H-2  end0  proton. The presence of several small  coupling constants in the complex pattern, and the broadened line shape at low temperature contribute to the slightly higher intensity of the H-2  exo  portion of the  multiplet.  The line shape of the D N M R spectra of 90 indicated the presence of a single major conformation at low temperature. This conformation was suggested b y a comparison of the predicted line shapes of the signals for the protons adjacent to the ether oxygen in the low energy conformations of 90 using molecular models and M M 2 * calculations.  a  [3434]-4 In the [3434]-4 conformation, the corner C-2 methylene protons, and the C-14 protons are predicted to have different line shapes. The H-2 proton is deshielded as a P  result of the diamagnetic anisotropy of the O/C-14 bond. The H - 2 proton is deshielded a  by the anisotropy of the C-3/C-4 bond. These deshielding effects are predicted to be of a similar magnitude. Thus, only a small AS was predicted for the C-2 protons. The 4 8  H-14  exo  proton is deshielded by the anisotropy of the C-12/C-13 bond between C-12  and C-13, and shielded by a van der Waals steric interaction between H-14 d and en  0  H-11endo- The magnitude of these anisotropy and steric effects is unknown. Since the C-2 and C-14 protons are in different environments, the line shape in the l o w  58 temperature spectra for these methylene protons is predicted to be symmetric, but  complex with m o r e lines than are visible here. Therefore, this conformation was no considered to be a a highly populated conformation of 90.  The low temperature spectra contained a high-field signal at 0.57 p p m of rela integration 1 : 4 in comparison to the signals at 3 . 4 p p m of the protons adjacent ether oxygen. The high-field signal is assigned to H-8 because of the following e x o  rationalization. In the [3434]-1 conformation, the  H-8 do  der Waals steric interactions with the H-5do/H-11  do  e n  e n  e n  proton is deshielded b y va  protons. This leads to a shieldi  of the H-8 proton. N o transannular steric repulsion between e x o  H-8 d e n  0  and the ether  oxygen appears possible based on the MM2* calculated distance between these atom  which is 3 . 1 0 A. The H-8 proton is further shielded b y electric field effects cause e x o  the parallel bonds of the C-6 and C-10 protons. The s u m of these effects causes a  a  upfield shift of the H-8 proton. The signal for H-8 is believed to overlap with t e x o  e n d 0  methylene envelope. There are n o protons in the [3344]-1 conformation that posse  the correct geometry to give this upfield signal since the distorted geometry of th conformation does not allow for an alignment of these shielding effects. Thus, the temperature spectra of 90 are consistent with the presence of a single conformer;  [3434]-1 conformation in which both ring inversion and pseudorotation have slowed.  The C-3/C-13 corner protons could be assigned in the low temperature spec  of 90. The C-3 proton is deshielded b y the diamagnetic anisotropy of the C-4/CP  bond, and b y the O / C 2 bond. These effects reinforce each other to give a larg with a chemical shift of 1 . 8 4p p m for the H-3/H-13 protons and 1 . 6 1 p p m for P  P  H-3/H-13 protons. The upfield signal of the H-3/H-13 protons overlapped that o a  a  a  a  t w o other protons, but insufficient information is available to unambiguously identify these other protons.  T h e signals of the remaining protons overlap between  1 . 0 1 . 5p p m , and can not be unambiguously assigned either.  A molecular mechanics search for the low energy conformations of 90 was  conducted using the Monte Carlo technique and the MM2* force field. The glob  59 m i n i m u m conformation w a s the [3434]-1 conformation 90-A with the  [3344]-1  conformation 90-B calculated to have the next lowest energy, 0.99 kcal/mol highe  These calculations suggested the existence of three other low energy conformations within 2 kcal/mol of the global m i n i m u m conformation (Table 6). Higher energy  conformations were ignored as they were not considered to be significantly populate over the temperature range studied. The relative populations of these conformations  different temperatures were calculated from enthalpy values (AH°) obtained from the  M M 2 * calculations, and entropy values (AS°) considering both s y m m e t r y and mixin  term contributions (Table 7). The entropic s y m m e t r y component takes into account the  principle that conformations with high s y m m e t r y have low entropy as calculated b  equation 7 where R is the ideal gas constant, and a is the s y m m e t r y n u m b e r o conformer in question. The s y m m e t r y of mixing component is applied w h e n the  conformer is chiral. Since both enantiomeric conformations are equally populated, this  increases the entropy value b y a factor of R(ln2) or 1 . 3 8 cal/mol. The results of th  calculations suggest the [3434]-1 conformation of 90 to be the major conformation ov the temperature range studied in agreement with the D N M R data.  ASsvm = R I n a  (7)  60 Table 6.  L o w Energy Conformations of Oxacyclotetradecane (90) Skeleton  Relative Energy (kcal/mol)  90-A  [3434]-1  0.00  90-B  [3344]-1  0.99  90-C  [13343 '] '  1 . 2 3  90-D  [ 3 4 3 4 ] _ 4  1 . 7 4  90-E  [133 ' 43 ' ] '  1 . 9 4  Conformer  a  Strain energies are relative to the global m i n i m u m conformation calculated with t M M 2 * force field.  61 Thermodynamic Values for the Five Lowest Energy Conformations of 90  Table 7.  (kcal/mol)  AS (cal/mol)  Population (%) 298 K 190 K 135 K  b  Conformer Skeleton  a  b  90-A  [3434]-1  0.00  0.00  55.5  80.0  93.2  90-B  [3344]-1  0.99  1 . 3 8  20.7  11.5  4.6  90-C  [13343 '] '  1 . 2 4  1 . 3 8  13.7  6.0  1 . 8  90-D  [ 3 4 3 4 ] _ 4  1 . 7 4  1 . 3 8  5 . 8  1 . 6  0.3  90-E  [343 '4 '] ' -4  1 . 9 5  1 . 3 8  4.2  0.9  0.1  Strain energy values were calculated with the MM2* force field. Entropy values were calculated using both s y m m e t r y and mixing terms.  The energy of the transition states for the interconversion of conformations of 9  can be determined experimentally b y first calculating the rate of exchange for a pair  signals that undergo fast exchange at rt. This rate is equivalent to the chemical sh  difference (Av) of the pair of signals measured at a temperature below coalescence  Once known, the rate can be used to calculate the free energy of activation (AG*) a  coalescence temperature (T) as obtained from the D N M R spectra, using the equation c  in Chapter 1. At low temperature the signals for the C-2 protons were separated at low  temperature b y 20 Hz. This corresponded to a transition state energy of 8 . 5 kcal/m  with a T of 170 K . The signals of the C-3 protons were separated b y 110 Hz c  temperature which corresponded to a transition state energy of 8 . 9 kcal/mol with a T  190 K . The average of these values is 8 . 7 ±0 . 2 kcal/mol. This is similar in magn  to transition state energies calculated for cyclotetradecane through H and C D N M R 1  1 3  studies, (AG* = 7 kcal/mol, T = 1 5 8 K). The similarity of the A G * values between 1 0 7  c  hydrocarbon and the macrocyclic ether supports the postulate that the introduction o  the heteroatom has a limited effect on the conformation of the ring. The barriers to  inversion in cyclohexane and tetrahydropyran have been determined with values o 8 1  4 8  10.3 kcal/mol obtained for both the hydrocarbon and the cyclic ether.  62  Dale has proposed a mechanism for these conformational interconversions that involves the m o v e m e n t of a single corner a t o m in the starting conformation. The transition state has an eclipsed torsional angle between the old-corner a t o m and  adjacent non-corner atom. This adjacent a t o m becomes the corner a t o m in the n e  conformation. The other dihedral angles in the ring undergo a m i n i m u m of change  during this interconversion process. The repetition of this m o v e m e n t at other corner 1 1 3  positions can lead to site exchange of both ring atoms and substituents. This  mechanism is m o r e complicated for 90 than for a hydrocarbon since m o r e possible  transition state structures exist as a result of the ether oxygen atom. Consequently, t  energies of all possible transition states were not determined. The energy of a [733 transition state structure for the interconversion of the [3434]-1 and  [3344]-1  conformations 90-A and 90-B was calculated to be 12.9 kcal/mol using the dihedr  drive method with 10° increments of the appropriate dihedral angles (Figure 21). 1 2 4  This calculated value was larger than the observed AG* value, however, the differen  between the experimental and calculated transition state energy values m a y be due  the inaccuracy of the assumption that the dihedral angles of the 1 b o n d side and  adjacent bonds were exactly 120°, 0°, -120°. Also, minimization of the dihedral angl  in the remainder of the ring m a y have lead to a better agreement of the experim and theoretical values.  63 [73343]  [3434]-1 90-A  Figure 21.  [73343]  [3344]-1 90-B  Single corner m o v e m e n t transition state for interconversion of the [3434]-1, 90-A, and the [3344]-1, 90-B, conformations of 90.  64  2.1.3 Conformational Analysis of 2-Methyloxacyclotetradecane (92) The  H  NMR  1  spectrum of 2-methyloxacyclotetradecane (92) at rt in CDCI  3  contained a one-proton doublet of triplets at 3.61 of quartets at 3.43  ppm,  ppm,  a one-proton doublet of doublet  a one-proton doublet of doublet of doublets at 3.22  22-proton multiplet from 1.10-1.73 ppm,  and a three-proton doublet at 1.09  three low-field signals between 3 and 4 ppm were assigned to the C-2 C-14  ppm, ppm.  The  methine and  the  methylene protons. These three protons were unambiguously assigned with a  H COSY spectrum that showed a correlation between the signals at 3.61  ppm  1  3.22  a  ppm.  These signals were assigned to the C-14  signal at 3.43  ppm  was  assigned to the  C-2  methylene, and  Irradiation of the signal at 3.61  signal, while irradiation at 3.22  H-14  signal at 3.61  ppm,  determined that the 3.22 syn to the methine H-2 assigned to the C-15  and  the  NOE  1  methylene protons.  ppm showed an enhancement of the 3.22  H-14  the remaining  methine proton. A series of H  difference experiments were used to differentiate between the C-14  and  ppm geminal  ppm showed an enhancement of both the geminal  methine H-2  signal at 3.43  ppm signal corresponded to the H-14 proton (Figure 22).  methyl group. The  The  ppm.  Thus, it  was  proton in a conformation  high-field doublet at 1.09  results of the H R M S and  ppm  was  chemical analysis  were also consistent with the composition of 92.  3.43  ppm  H ^CH  92 Figure 22.  The and  H NMR assignments of the C-2 and C-14 protons of 2-methyloxacyclotetradecane (92) from COSY and N O E D S experiments.  1  C  13  NMR  spectrum of 92 contained 14 lines, two of which were at low-field,  were assigned to the  C-2  and  C-14  carbons. The  highest field carbon at  65  19.82 p p m was assigned to the C-15 methyl group. The balance of the C sign 13  were visible around 25 p p m . The assignment of the remaining C and H signals w 13  1  aided with COSY, H M Q C , and H M B C 2 D N M R experiments (Table 8).  Unfortunate  due to the overlap of signals in the H N M R spectrum, and the small A5 between 1  several signals in the C N M R spectrum, not all of the signals could be assigned. 13  Table 8.  H and C N M R Assignments for 2-Methyloxacyclotetradecane (92) in CDCI at R o o m Temperature  1  13  3  Position  H NMR  1  1 3  3 . 4 3  2 3  not  a  73.32  1 . 5 0 , 1 . 3 9  4 1 1  36.42 assigned'  1 2  1 . 5 7 , 1 . 2 3  22.99  13  1.69, 1 . 4 5  29.00  1 4  3.22, 3 . 6 1  65.99  15 a  C NMR  a  1 . 0 9  19.82  The chemical shift values are in p p m referenced to (H C )H a C n Id CD CI;(C). > D u e to signal overlap these signals could not be unambiguously assigned. 1  1 3  3  As in the case of oxacyclotetradecane (90), the chemical shifts of the ring  carbons of 92 were expected to decrease as the through-bond distance from the et  oxygen increased. The chemical shift of C-12 deviated from this trend as a result o y-gauche effect, with an observed upfield chemical shift to 22.99 p p m .  Examination of the coupling constants for the H 2 and H 1 4 protons provide  s o m e information about the preferred conformation of this macrocyclic ether. The H proton had a large and small coupling constant to the adjacent methylene protons  (Table 9). If the C-15 methyl group is exo and the ether oxygen is in the middle  4-bond side, the H 2 proton would b e endo to the ring. In this orientation, both and small coupling constants are predicted between H 2 and the protons at C-3  (Figure 23). In contrast, if the ether oxygen is adjacent to the corner on a 3-bond  66  in the [3434]-4 conformation, the C-15 methyl group occupies a corner position. Sin  a carbon-oxygen bond is shorter than a carbon-carbon bond, a C-15 methyl group p  preferred as the 1,3-interaction between a C-15 methyl group and H-14 is greate a  e x o  than the 1,3-interaction between the C-15 methyl group and H-14. p  e x o  In this  conformation, n o large coupling constants are expected between H 2 and the C-3 protons (Figure 23).  [3434]-1  [3434]-4  H  CH  3  H-2 Proton  Figure 23. N e w m a n projections of 92 showing the geometry of C-2 in the [3434] and [3434]-4 conformations.  The coupling constants for the H 2 and H 1 4 protons in the [3434]-1, [3434  and [3344]-1 conformations of 92 were calculated and compared to the actual va  (Table 9). The calculated coupling constants for H 2 in the [3434]-4 conformation an H-14 in the [3344]-1 conformation with C-14 adjacent to a 4-bond side were in e x o  agreement with the observed values. These conformations were not predicted to be major conformations of 92.  67  [3344]-1  Table 9.  [3344]-1  Experimental and Calculated Coupling Constants (J) for the Low Energy Conformations of 92 Calculated (Hz)  Experimental (Hz)  Boltzmann  Proton  3  Conformation [3434]-1 [3434]-4 [3344]-1  [3344]-1  3 . 1 9.2  3 . 6 8.5  1 . 9 1 1 . 6 1 . 75 . 0  1 . 9 11.5 3 . 1 1 1 . 6  H-14do  3 . 0 1 0 . 6  2.3 1 0 . 7  1 . 7 11.9 2.4 11.9  3 . 1 11.8 1 . 5 1 1 . 8  H-14  4.2 4.2  3 . 0 4.0  2.2 3 . 8  1 . 05 . 6  H 2 e n  e x o  3  1 . 5 4.7  Calculated coupling constants were averaged for a Boltzmann distribution weighted set of conformations. The  low temperature spectra of 92 were collected in a 4:1  (Freon 21) and CHCIF (Freon 22) as solvent (Figure 24). 2  at 220  K was  mixture of CHCIF 2  The H NMR 1  spectrum of 92  similar to that obtained at rt, with s o m e line broadening. At 190  signals broadened, and methyl signal. The was  2 . 43 . 6  a small signal at 0.57  ppm  K the  b e c a m e visible upfield of the  C-15  relative intensity of this upfield signal increased as the temperature  lowered further. At 180  broadest, and at 170  K, the low-field signals of the C-2  and  C-14  protons were  K the line shape of these signals changed with additional smaller  signals visible at the foot of the original signals. This indicated the freezing out unequally populated conformations. Further cooling to 130  of  K, the lowest temperature  68 in this series of D N M R experiments, did not produce further significant changes in line shape of spectra of 92.  The additional small signals present in the low-field portion of the spectra a  3.71, 3.34, and 3 . 0 3 p p m belong to a minor conformation or conformations of 92.  similarity of the chemical shifts of the major signals at low-field over the temperat  range studied suggests that the major conformation is the s a m e at both rt and  temperature. Additional small signals were expected between 1 . 5 and 2 p p m as we  but n o such signals were observed. Presumably, these were concealed b y the sign  of protons in the major conformation also visible in that region. Examination of th  spectra in the region of the C-15 methyl signal at 1 . 0 3 p p m at low temperature, s  other signals at 0.90 and 1 . 1 6 p p m . The integration of the signal at 0.90 p p mw a  relative to the minor signals at 3 . 3 4 and 3 . 0 3 p p m , but whether this upfield signa  be assigned as a C-15 methyl signal of a minor conformer, or to other major conf proton signals is unclear.  69  70 The  high-field signal at 0.57 ppm  in the low temperature spectra of 92, is similar  to that of the high-field signal observed in the (90). H-14  The  D N M R study of oxacyclotetradecane  relative integration of this high-field signal and  the signal at 3.12 ppm  for  of the major conformer is approximately 1:1. In the [3434]-1 conformation of 92,  exo  the C-8 protons are expected to have a geometry similar to that of the C-8 protons in 90. The  H-8endo proton is deshielded by steric interactions with H-5 do and H - 1 1 en  are calculated to be separated from H-8 do by 2.22 A and en  leads to a shielding of H-8 , and exo  0.57 ppm  in the  low  2.22 A respectively.  that  This  results in the upfield shift of this proton signal to  temperature spectra of 92.  [3434]-4 conformation would lead to two spectra. The  end0  In contrast, the  high-field signals in the  geometry of  the  low temperature  [3344]-1 conformation does not have the correct geometry to cause the  large shielding effect of a single proton as observed. Thus, the [3434]-1 conformation is believed to be the major conformation of 92. H-14endo and  H-14  exo  In this conformation, the A5 of  protons can be rationalized as a deshielding of the H-14  exo  the  proton  by the diamagnetic anisotropy of the C-12/C-13 bond.  A molecular mechanics search for the lowest energy conformations of 92  was  conducted using the Monte Carlo technique and the M M 2 * force field. These calculations gave a total of 13 conformations within 2 kcal/mol of the global m i n i m u m conformation, the [3434]-1 conformation 92-A (Table 10). The conformation was  the  [3434]-4 conformation 92-B with the  second lowest energy methyl substituent at a  corner position. The relative populations of these low energy conformations at different temperatures were calculated from relative energy values obtained from the  MM2*  calculations (Table 11). Since macrocyclic ether 92 is a chiral compound, there were no s y m m e t r y contributions to the entropy. The results of these calculations suggest the [3434]-1 conformation of 92 to be the major conformation over the temperature range studied in agreement with the D N M R data.  71 Table 10.  a  L o w Energy Conformations of 2-Methyloxacyclotetradecane (92)  Strain energies are relative to the global m i n i m u m conformation calculated with th MM2* force field.  72  Table 11.  Thermodynamic Values for the Five Lowest Energy Conformations of 92  Conformer  Skeleton  a  Relative Energy (kcal/mol) 3  298 K  Population (%) 170 K  135 K  92-A  [3434]-1  0.00  44.2  63.1  72.8  92-B  [3434J-4  0.55  17.5  12.5  9.5  92-C  [3344]-1  0.57  17.0  11.8  8 . 8  92-D  [3344]-1  0.58  16.7  11.5  8 . 5  92-E  [13343 '] '  1 . 3 5  4.6  1 . 2  0.5  Strain energy values were calculated with the MM2* force field relative to the glo m i n i m u m conformation. The D N M R study indicated unequally populated multiple conformations of 92  were present at low temperature. The MM2* calculations of 92 were in agreement, w  three conformations of approximately equal energy found within 0 . 6 kcal/mol of th  global m i n i m u m conformation. The relative integration of the low-field major and mino  signals was approximately 2 . 8 : 1 at 150 K . This corresponds to a ratio of majonm  conformers of 64:36, and an energy difference of 0 . 3 1 kcal/mol between the major minor conformers of 92 in reasonable agreement with the population and energy difference obtained from the MM2* calculations.  The introduction of the ether oxygen a t o m and the C-15 methyl group lead large n u m b e r of possible transition state structures for the interconversion of the  conformers of 92. Experimentally, these transition state energies were calculated from  the separation of the three major and minor low-field signals measured to be 27  4 1 Hz, and 49 Hz respectively with a coalescence temperature of 180 K . This ga average transition state energy of 8 . 8 ±0.1 kcal/mol.  The [3434]-1 conformation 92-A can interconvert via the Dale single corner  m o v e m e n t mechanism into the low energy [3344]-1 conformations 92-C and 92-D via 1 3  related [73343] transition state structures (Figure 25). The energies of these structures  73  were calculated with the dihedral drive method to be 13.0 1 2 4  kcal/mol and 12.8 kcal/mol  for the interconversion with 92-C and 92-D respectively and involve hydrogen-hydrogen eclipsing. The interconversion of conformation 92-C with conformation 92-B involves a [73343] transition state with an eclipsing interaction between the C-15 methyl group and proton on C-13. The calculated energy of this transition state structure was 9.8 kcal/mol. This structure was  expected to be higher in energy than other [73343]  transition states with hydrogen-hydrogen eclipsing only. The calculated transition state energies were higher than the observed values of 92.  92-D  Figure 25.  [3434]-4  Interconversion of conformations of 92 via single corner movements.  2.2.1 Synthesis of 2,14-Dimethyloxacyclotetradecanes (103) and (104) The diastereomeric pair of 2,14-dimethyloxacyclotetradecanes 103 and 104 were the next macrocyclic ethers prepared using the general synthetic strategy presented earlier. The  additional methyl group would be introduced onto the ketone  74  prior to the Baeyer-ViNiger ring expansion. Once the requisite ketone w a s produced the synthetic path w a s the s a m e as earlier. The cyclic ketone would be expanded  lactone, and the carbonyl r e m o v e d via a thionolactone intermediate (Scheme 6). In  addition an alternate m e t h o dw a s investigated, wherein the second methyl group wo be introduced via the hydrogenation of an exocyclic double bond rather than via nucleophilic attack of a thionolactone.  Scheme 6.  Retrosynthetic Analysis of 2,14-Dimethyloxacyclotetradecanes (103) and (104)  104 (2S*, 14/?*)  1 0 0 X = CH2  97  86  An u m b e r of synthetic m e t h o d s were examined for the preparation of the alkylated ketone, 2-methylcyclotridecanone (97).  The first m e t h o d involved  a  combination ring expansion-alkylation reaction of cyclododecanone (93) (Scheme 7). Ketone 93 w a s reacted with dibromomethane and lithium 2,2,6,6-tetramethylpiperidine (LTMP) to give the 1-dibromomethylcyclododecanol adduct 9 4 .  125  This adduct was  prepared in our laboratory as an intermediate en route to s o m e 1 4 m e m b e r e d  lactams. The dianion of dibromo alcohol 94 w a s generated with n-butyllithium, and 1 2 6  75  reacted with methyl iodide in the presence of H M P A in a modification of the Y a m a procedure to give the ring expanded alkylated product 97. '  126 127  A difficult  recrystallisation from hexane gave the ketone 97 in low yield. The H N M R spectrum 1  97 contained a one-proton doublet of doublet of quartets at 2.60 p p m for the C-2  methine, as well as a three-proton doublet at 1 . 0 1 p p m for the C-14 methyl group  IR spectrum of 97 contained a band at 1703 cm" for the C 1 carbonyl. This spe 1  data indicated that the desired transformation had occurred.  Scheme 7. Synthesis of 2-Methylcyclotridecanone (97) via 1-Dibromomethylcyclododecanol (94) a  93  94  97  Key: (a) CHBr, LTMP, THF, -78 °C, 79%; (b) n-BuLi, Mel, HMPA, THF, -78 °C 10%.  a  2  2  W e also examined a m e t h o d involving the methylaluminum bis(4-bromo-2,6-difert-butylphenoxide) (MABR) mediated alkylation of a trimethylsilyl enol ether to  synthesize 97. This bulky Lewis acid coordinates to the enol ether, and directs t alkylation. Cyclotridecanone (86) was reacted with hexamethyldisilazane, and a  mixture of trimethylsilyl chloride and lithium iodide to give the trimethylsilyl enol ethe 95 and 96 (Scheme 8).  128,129  These diastereomers were separable on silica, and  identified by a comparison of their C N M R spectra. In general, the chemical shift f 13  C-1 of the Z isomer is shifted upfield relative to that of the E isomer. While the  chemical shift for C-13, the allylic carbon, of the Z isomer is generally shifted down  relative to that of the E isomer. Here, the major enol ether 95 was assigned 1 3 0  76 Z configuration based on chemical shifts of 150.17 ppm and 36.11 C-13  ppm for C-1  and  compared to chemical shifts of 151.70 ppm and 29.48 ppm for C-1 and C-13  of  the minor E isomer.  A solution of M A B R was  generated by the addition of trimethylaluminum in  hexanes to a solution of 4-bromo-2,6-di-fe/f-butylphenol in CH CI .  131,132  2  95 and  96 was  2  A mixture of  reacted with an aliquot of this M A B R solution and subsequently  alkylated with methyl triflate to give ketone 97. proceeded in 57%  133  This two-step reaction sequence  overall yield.  The Baeyer-ViNiger oxidation of ketone 97 was performed with trifluoroperacetic acid in the presence of NaHP0 to give 13-tetradecanolide (98). This peracid was 2  4  generated by the addition of either 70%  H0 solution, ' or UHP, 1 1 91 2 0  2  122123  2  to a solution  of trifluoroacetic anhydride in CHCI. The reaction with H0 did not go to completion, 2  and the unreacted ketone was  2  2  2  inseparable from the lactone by chromatography. To  obtain pure lactone it was necessary to derivatize the residual ketone into an oxime by reaction of the mixture of ketone 97 and lactone 18 with hydroxylamine hydrochloride. The lactone 98 and the oxime 99 were easily separated via column chromatography. The  UHP  reaction of 97 did proceed to completion and eliminated the need for this  derivatization step. The  lactone 98 was  reaction with Lawessons ' reagent 48.  converted into the thionolactone 101 by 5155  The C NMR 13  expected 14 lines with a signal at 224.35 ppm The  1  H NMR  5.62  ppm for the C-3  spectrum of 101 contained the  indicative of the C-1 thionocarbonyl.  spectrum contained a one-proton doublet of doublet of quartets at methine and a three-proton doublet at 1.30  ppm for the  C-14  methyl group. The H R M S and chemical analysis results were also consistent with the composition of  thionolactone 101.  The  thionolactone 101 was  reacted with  methyllithium, and trapping of the resultant sulfur anion with methyl iodide gave the unstable mixed thioketal 102.  5155  This material was reacted immediately under radical  conditions with either tri(n-butyl)tin hydride, or tris(trimethylsilyl)silane (TTMSH), to 1 3 4  cleave the thiomethyl group and give the desired macrocyclic ethers 103 and 104.  The  77 four-step reaction sequence proceeded in 13% as the hydride source, and 26%  Scheme 8.  yield from 97 with tri(/?-butyl)tin hydride  yield with T T M S H as the hydride source.  Synthesis of 2,14-Dimethyloxacyclotetradecanes 103 and 104 via Thionolactone 101 a  O  ?™S  O  86  95 (Z) 96 (E)  97  102  Key:  103 {2R*, 14/?*) 104 (2S*, 14/?*)  (a) (TMS)NH, TMSCI, Lil, CHCI; then EtN, 72%; (b) MABR, MeOTf, CHCI, -40 °C, 79%; (c) UHP, TFAA, NaHP0, CHCI, 0 °C, 97%; (d) Lawesson s ' reagent 48, toluene, A, 77%; (e) MeLi, THF, -78 °C; then Mel, 80%; (f) n-BuSnH, AIBN, toluene, A, 21%; (g) TTMSH, AIBN, toluene, A, 43%. 2  2  2  3  2  3  4  2  2  2  2  78  A solution of (|i-chloro)(|i-methylene)bis(cyclopentadienyl)(dimethylaluminum) titanium, Tebbe reagent 32, in toluene was generated by the addition of a solution of 38  trimethylaluminum in toluene to dichlorotitanocene. W h e n stored under nitrogen at 1 3 5  0 °C this solution was stable for several months.  CH 5  / v Me Ti Al  5v  Me  cf  C5H5'  v  32 The lactone 98 was reacted with this solution of Tebbe reagent 32.  38  The  resultant vinyl ether 100 was unstable and was purified by passing the reaction solution directly through a column of basic alumina with petroleum ether as eluant. The vinyl ether 100 was  immediately hydrogenated to give the macrocyclic ethers 103 and 104.  The reaction sequence proceeded in 22%  Scheme 9.  yield for two-steps.  Synthesis of 2,14-Dimethyloxacyclotetradecanes 103 and Ether 100  104 via Enol  a  98  100  Key: (a) Tebbe reagent 32, Et0, 26%.  DMAP, pyridine, THF,  a  103 (2R*, 14/?*) 104 (2S*. 14/?*)  -40 °C, 86%;  (b) Pt0, H, 2  2  2  The macrocyclic ethers 103 and 104 were separable with silica chromatography,  and each gave a single, distinct peak on GC analysis with a DB-210 column. The  79  relative configuration of the C-2  and  C-14  methyl substituents of 103 and  determined through analysis with a chiral Cyclodex-B GC column. The  104  (2R*,  was  14R*)  or  anti isomer of 2,14-dimethyloxacyclotetradecane is a dl pair of enantiomers which would give rise to two peaks under chiral GC conditions. The (2S*,  14R*)  or syn isomer  of the macrocyclic ether is a m e s o c o m p o u n d which would give rise to only a single peak under chiral GC conditions. GC analysis of 103, the first macrocyclic ether eluted on silica, with the Cyclodex-B column resulted in two retention times of 45.5  minutes and 46.4  peaks of equal intensity with  minutes respectively. GC analysis of 104, the  second macrocyclic ether eluted on silica, gave only a single peak with a retention tim of 51.5  minutes (Figure 26).  and C-14 the (2S*.  Thus, 103 was  identified as the diastereomer with the  methyl groups in an anti configuration {2R*, *\4R*) and 104 was  diastereomer with the  C-2  and  C-14  methyl groups in a syn configuration  14R*).  103  identified as  104  C-2  80  1  Figure 26.  GC analysis for 2,14-dimethyloxacyclotetradecanes 103 and 104 on a chiral Cyclodex-B column; (a) (2R*, 14R*)-2,14-dimethyloxacyclotetradecane (103); (b) (2S*, 14R*)-2,14-dimethyloxacyclotetradecane (104); (c) mixture of (2R*, 14R*) and (2S*, 14R*)-2,14-di methyl oxacyclotetradecane (103) and (104).  The two methods used to form the macrocyclic ethers, hydride cleavage of a thiomethyl group, and hydrogenation of a carbon-carbon double bond are intrinsically different with different intermediates formed, and different reagents used in the transformation. Accordingly, a difference in stereoselectivity in the ratio of 103:104 was expected in each of these methods.  The hydride reduction of the mixed thioketal 102 with tri(n-butyl)tin hydride showed a slight selectivity (4% d. e.) for macrocyclic ether 103 (Table 12).  It was  8 1 hoped that the different properties of the silane hydride reagent would offer an improvement in the selectivity of this reduction. Tris(trimethylsilyl)silane is a bulkier reagent with a greater metal-hydrogen bond strength of 79 kcal/mol compared to  74 kcal/mol in the case of the stannane. As well, the metal-hydrogen bond length 1 3 4  ca. 1 . 4 8 A in the case of the silane compared to 1 . 5 3 A for the tin-hydrogen b 1 3 6  These features m a k e the silane a m o r e selective hydride reagent. Unfortunately, only  a modest improvement in the stereoselectivity of the reduction of 102 was observed  (14% d. e.) with the silane as the hydride source (Table 12). Reaction of pure 103  104 with tri(n-butyl)tin hydride under radical conditions showed n o isomerisation to the other macrocyclic ether. Therefore it was assumed that no isomerisation of the macrocyclic ethers occurred in the hydride reduction of the mixed thioketal.  The reduction of the vinyl ether 100 with Adams' catalyst (Pt0) proceeded with 2  only a slight stereoselectivity (2% d. e.) (Table 12). The vinyl ether w a s very  susceptible to hydrolysis and the choice of platinum oxide as the catalyst was import for the success of the reduction.  Palladium on charcoal, another c o m m o n  hydrogenation catalyst, gave lower yields of the desired macrocycles presumably due  to hydrolysis of the starting material during the hydrogenation. Rhodium on alumina also gave lower yields of the macrocyclic ethers.  Molecular modeling calculations with the MM3* force field suggested that the  [3434]-1 conformation is the m o s t stable conformation of 100 with the exocyclic doub bond essentially perpendicular to the plane of the ring. The next lowest energy conformation, 1 . 8 4 kcal/mol higher in energy was a [3344]-1 conformation. It w a s  believed that either the C-14 methyl group flanking the ether oxygen or the macrocy  ring itself would have a directing effect on the hydrogenation. However essentially n o  stereoselectivity was observed in this reduction, hence the exocyclic double bond m u  be blocked to approximately the s a m e degree b y the C-14 methyl group on one and b y the macrocyclic ring on the other.  100 Table 12.  Yield and Selectivity in the Preparation of 2,14-Dimethyloxacyclotetradecanes 103 and 104  Reagent  Starting Material  103:104  b  Total Yield of 103+104 (%)  n-BuSnH, AIBN  102  52:48  21  TTMSH, AIBN  102  57:43  43  100  49:51  26  3  3  Pt0, H 2  3  b  0  d  2  c  d  c  A syringe p u m p was used to slowly add the solution of tri(n-butyl)tin hydride and AIBN in toluene to the reaction solution. The ratio of 103:104 was determined by gas chromatography. The diastereomers 103 and 104 were separated via radial chromatography. The diastereomers 103 and 104 were purified but not separated.  2.2.2 Conformational Analysis of (2A?*,14/?*)-2,14-Dimethyloxacyclotetradecane (103) The H NMR 1  3.65  ppm,  spectrum of 103 at rt in CDCI contained a two-proton sextet at 3  another two-proton sextet at  1.63 ppm,  1.18-1.43 ppm, and a six-proton doublet at 1.08  ppm.  a 20-proton multiplet from The low-field signal at 3.65  was assigned to the protons of C-2/C-14, while the signal at 1.63 two of the four protons of C-3/C-13. The doublet at 1.08 and C-16  ppm  ppm was assigned to  ppm was assigned to the  C-15  methyl groups. The H R M S and chemical analysis data were also consistent  with the composition of 103.  The C 13  NMR  spectrum contained seven lines indicative of either a plane, or a  symmetry-averaged plane of s y m m e t r y in the molecule. Thus, C-2 and C-14 s a m e chemical shift, as did C-3  and  C-13,  and  so forth. The  had  the  low-field signals at  69.02 ppm and 33.64 ppm were assigned to C-2/C-14 and C-3/C-13 on the basis of  83 their through bond distance from the ether oxygen atom. Three carbons in the  molecule including C-8, were assigned to the peak at 25.15 p p m which was higher  the other carbon signals. The assignment of the remaining H and C signals was 1  13  aided b y COSY, H M Q C , and H M B C 2 D N M R experiments (Table 13). The C-4/C-  signal was shifted to higher field by the y-gauche effect as a result of its geom relationship to the ether oxygen atom.  Table 13.  H and C N M R Assignments for (2R*,14R*)-2,14-Dimethyloxacyclotetradecane (103) in CDCI at R o o m Temperature  1  13  3  Position  H NMR  1  2, 1 4  I T J 0.  3, 13 ,  3 . 6 5  a  33.64  4, 1 2  1 . 3 7  23.13  5, 1 1  1 . 4 0  26.57  6, 10  1 . 3 2  25.34  7,9  1 . 3 2  25.15  8  1 . 2 0  25.15  1 . 0 8  19.63  b  b  The chemical shift values are in p p m referenced to CHCI (H) and CDCI (C). D u e to overlap these signals could not be unambiguously assigned. 1  3  b  C NMR  13  69.02  1.63, 1 . 2 5  15, 1 6 a  a  1 3  3  A series of low temperature spectra of 103 were collected in a 4 : 1 mixture  Freon 2 1 and Freon 22 as solvent (Figure 27). The H N M R spectrum of 103 at 2 1  contained four broad signals. As the temperature w a s lowered, the low-field signal  3 . 6 5 p p m broadened with a coalescence temperature of 195 K . At lower temperat  this signal split into t w o signals of unequal intensity indicative of unequally populate  conformations being present. The chemical shift of the major signal, which remained  fairly broad even at low temperature, was 3 . 5 5 p p m . The chemical shift of the m  signal was 3 . 8 7 ppm. The signal at 1 . 8 7 p p m , also broadened as the temperature  lowered, with a coalescence temperature of 195 K . This signal did not split as t  84  temperature was lowered further, however a shoulder on the downfield side of the signal was visible at low temperature.  85  Analysis of the methylene envelope region of the spectra was complicated b  the overlap of multiple signals. The line shape of the methylene envelope did cha as the temperature was lowered. The line shape of the signal for the C-15 and  methyl groups did not undergo significant changes as the temperature was lowered. n e w signal was visible with a chemical shift of 0.82 p p m at higher field than the signal as the temperature was lowered in the D N M R spectra.  To begin the analysis of the D N M R data, conformations of 103 likely to have  energy were sought. Molecular models were used to evaluate s o m e diamond lattic conformations of this macrocyclic ether. diastereotopic methylene groups.  The [3434] conformation has  four  In the unsubstituted 1 4 m e m b e r e d ether, the  [3434]-1 conformation, with the ether oxygen in the middle of a 4-bond side, i  lowest energy conformation. However, in the case of the 2,14-disubstituted ether 103 one of the methyl groups would be endo to the ring, thereby raising the energy  conformation. The [3434]-4 conformation of the unsubstituted 1 4 m e m b e r e d ether is also low in energy, but the methyl groups of 103 would experience a 1,3-diaxial  interaction in the [3434]-4 conformation. There is also a 1,3-diaxial interaction betwee  the methyl groups of 103 in the [3434]-2 conformation. The methyl groups of 103 a both exo to the ring in the [3434]-3 conformation, and furthermore n o 1,3-diaxial  interactions occur between these groups since they are on different sides of the r  Unfortunately, in this conformation the ether oxygen a t o m is located at a corner pos and n o transannular hydrogen interactions are eliminated b y the oxygen w h e n at position.  86  [3344J-1 N o n e of the [3434] conformations of 103 appeared to be low in strain energy, so the search was  widened to include s o m e non-diamond lattice conformations. In  [3344]-1 conformation, one [3434]-1 conformation.  the  of the methyl groups would be endo to the ring as in the  Both the  [3344]-2 and  the  [3344]-4 conformations have  1,3-diaxial interactions between the methyl groups, and  are therefore not expected to  be low in energy. There are no unfavourable steric interactions between the methyl  groups in the [3344]-3 conformation, but the oxygen a t o m is at a corner position which is k n o w n to b e high in energy. Thus, a priori the conformations of 103 was  identity of the  low energy  unclear. It is likely that the low energy conformations are  similar to s o m e of these, where the steric repulsions of the methyl groups have been reduced by small distortions to the appropriate dihedral angles. Alternatively, the energy conformations may  low  be other non-diamond lattice conformations. In either case,  the identity of low energy conformation of 103 was  not predicted.  87  A regular, low energy conformation of 103 could not be identified Therefore the  D N M R data was analyzed with attention to quantifying the ratio of major and m conformations present, rather than specifically trying to identify the low energy  conformations. The signal for the H 2 and H 1 4 methine protons adjacent to the eth oxygen of 103 broadened, and gave t w o signals of unequal intensity at low temperature. The unequal intensity of the signals eliminated the possibility of the  presence of only one conformation at low temperature. Only one major signal wa observed in the low-field portion of the D N M R spectra at 3.55 ppm, hence the conformation of 103 has a small A5 value between the H 2 and H-14 protons.  T  methine protons of the minor conformation of 103 could have a large A5 with a signa 3.87 p p m , and another signal overlapped with the major conformation signal at  3 . 5 5p p m representing the H 2 and H 1 4 protons. Alternatively, the A5 of the min  conformation could also be small, and these protons are represented b y only the p  at 3 . 8 7 p p m .N o shoulder was visible on the major signal at 3 . 5 5 p p m to suppo  minor conformation, large A5 value argument, and therefore the minor conformation  likely has a small A8 value. The relative intensities of the major and minor downfie  signals was 5.2:1. This corresponded to an 84:16 ratio of conformers with an ene difference of 0.46 kcal/mol.  Signals for the minor conformation were also expected in other regions of th  spectra, a shoulder was visible at 2.08 p p m , on the downfield side of the signal fo  of the protons p to the ether oxygen. The chemical shift of this major signal drifte  downfield to 1.99 p p m as the temperature was reduced. N o obvious signals for th  C-15 and C-16 methyl groups of the minor conformations were identified in the 1 region of the spectrum.  A molecular mechanics search for the low energy conformations of 103 w a s performed with the Monte Carlo technique and the MM2* force field. The global  m i n i m u m conformation was a non-diamond lattice [13343 '] ' conformation 103-A, with another [13343 '] ' conformation 103-B calculated to have a similar energy, only  88  0.02 kcal/mol higher (Table 14). These calculations suggested the existence of ten  other low energy conformations within 1 kcal/mol of the global m i n i m u m conformati  The results of the calculations were in good agreement with the D N M R data with respect to the energy difference between the major and minor conformations.  The  relative populations of these conformations at different temperatures were calculated from relative energy values obtained from the MM2* calculations (Table 15).  89 Table 14.  L o w Energy Conformations of (2R*,14R*)-2,14-Dimethyloxa decane (103) Skeleton  Relative Energy (kcal/mol)  103-A  [13343 '] '  0.00  103-B  [13343 '] '  0.02  103-C  [3434]-1  0.41  103-D  [13343 '] '  0.43  103-E  [124313 '] '  0.45  Conformer  o  a  Strain energies are relative to the global m i n i m u m conformation calculated with t MM2* force field.  90 Table 15.  Conformer  Thermodynamic Values for the Five Lowest Energy Conformations of 103 Relative Energy (kcal/mol)  Skeleton  298  K .  0.00  29.3  34.4  38.9  103-B  [13343 '] '  0.02  28.3  32.6  36.2  103-C  [3434]-1  0.41  14.6  11.6  8 . 9  103-D  [13343 '] '  0.43  14.2  11.0  8.3  103-E  [124313 '] '  0.45  13.7  10.4  7 . 7  lowest energy conformation calculated with the  D N M R data w a s reexamined with consideration of the  conformations 103-A through 103-E. For deshielded by the  103-A through 103-D the exo  carbon-carbon bond (3 to it, and  Waals steric interactions between the  carbon-carbon bond 3 to it, and  endo methyl group and  deshielded by van  with other transannular endo protons. The value that is small. Thus, the a n d / o r 103-B as the  sum  calculated  methine proton  shielded by transannular van  endo protons. In contrast, the endo methine proton was the  135  [13343 '] '  The  der  K  103-A  Strain energy values relative to the MM2* force field.  was  Population (%) 170 K  3  other transannular  shielded by the anisotropy of der  Waals steric interactions  of these effects leads to a predicted A5  D N M R data are  consistent with conformation 103-A  major conformation, with 103-C and/or 103-D as the minor  conformation  The  energies of the transition states for the  interconversion of conformations of  103 were determined from the rate of exchange between a pair of signals averaged at rt in the D N M R spectra. Once known, this rate of exchange was free energy of activation (AG*) with the also obtained from the  coalescence temperature (T) c  D N M R spectra, and  temperature, the signal for the  H-2  and  H-14  the  of the signals  equations in Chapter 1.  protons split into two  intensity. These signals are separated by 162  Hz with a T of 195 c  transition state energy of 9.0 kcal/mol. Unfortunately, it was corner m o v e m e n t pathways for the  used to determine the  interconversion of the  At low  signals of unequal K corresponding to a  not possible to find single calculated conformations of  91 103, and  the  transition state energies could not  be  estimated by  the computer  modelling methods described earlier.  2.2.3 Conformational Analysis of (2S*,14/?*)-2,14-Dimethyloxacyclotetradecane (104) The H NMR  spectrum of 104 at rt contained a two-proton doublet of doublet of  1  quartets at 3.54 doublet at 1.10 and  the  ppm, ppm.  a 22-proton multiplet between 1 . 1 8 1 . 4 9 ppm, The  downfield signal was  high-field doublet was  and  a six-proton  assigned to the protons of C-2/C-14,  assigned to the  C-15 and  C-16 methyl groups  (Table 16).  The  C NMR  13  spectrum contained eight signals for this 15-carbon molecule,  indicative of a plane of s y m m e t r y or a symmetry-averaged plane of s y m m e t r y at rt. Thus, C-2 The  and  C-14  had the s a m e chemical shift, as did C-3  low-field signals at 71.11  ppm  and  36.10  ppm  and  C-13,  and  so forth.  were assigned to C-2/C-14 and  C-3/C-13 on the basis of their through-bond distance to the ether oxygen. The signal for C-4 was  shifted upfield to 22.95 ppm  by a y-gauche effect caused by the geometric  relationship of this carbon to the ether oxygen. The was  assigned to the methyl groups. The  highest field signal at 21.18  signal at 24.86 ppm  the height of the other C signals and was  assigned to C-8.  1 3  across the ring from the ether oxygen atom, and  was  does not have a symmetrical carbon  assignment of the remaining H and C signals was  H M Q C , and  H M B C 2 D N M R experiments (Table 16).  consistent with the composition of 104.  approximately half  This carbon is located  partner. The  1  ppm  1 3  The  assisted with COSY,  H R M S data was also  92 Table 16.  H and C N M R Assignments for (2S*,14R*)-2,14-Dimethyloxacyclotetradecane (104) in CDCI at R o o m Temperature  1  1 3  3  Position  H NMR  1  2, 1 4  a  71.11  1 . 4 6  36.10  1.30  22.95  1.30 b  26.41  1.30  26.17  1 . 3 8  25.55  1 . 2 0  24.86  1 . 1 0  21.18  b  b  15, 1 6 a  b  The chemical shift values are in p p m referenced to CHCI (H) and CDCI (C). D u e to overlap these signals could not be unambiguously assigned. 1  3  b  a  3 . 5 4  b  8  C NMR  1 3  1 3  3  A series of low temperature spectra of 104 were obtained in a 4 : 1 mixture  Freon 21 and Freon 22 as solvent (Figure 28). The H N M R spectrum of 104 at 2 1  contained three signals. This spectrum was similar to the rt spectrum, with m u c h of signal multiplicity lost. As the temperature was lowered, the downfield signal at  3 . 7 4p p m broadened (T = 185 K) to form at low temperature, a pair of sharp s c  3 . 8 2 p p m and 4.03 ppm. At low temperature, a small signal emerged downfield  methylene envelope at 1 . 8 0 p p m . The signal for the methyl groups also broadene  and split into t w o closely spaced signals at 1 . 1 3 p p m and 1 . 0 9 p p m (T = 165 c  high-field in the low temperature spectra, signals at 1 . 0 0 and 0.76 p p m were vis  with a relative intensity approximately equal to that of the 1 . 8 0 p p m signal downfie the methylene envelope. N o significant line shape changes occurred upon further  cooling to 145 K the lowest temperature of this D N M R study. The series of H D N 1  spectra indicate the slowing of a conformational process as the temperature is lower  that results in a loss of molecular symmetry. Individual signals were obtained at lo temperature for the C-15 and C-16 methyl groups as well as for the H 2 and  methine protons. The sharpness of these signals suggests the presence of only on conformation at low temperature.  93 The highly symmetric 1 4 m e m b e r e d [3434] diamond lattice conformation has four diastereotopic methylene groups with different numbers of transannular steric  interactions. The [3434]-1 conformation with the ether oxygen a t o m of 104 located  the middle of a 4-bond side, results in a 1,3-diaxial interaction between the syn me  groups. This severe steric interaction raises the energy of the [3434]-1 and [3344]  conformations, and these are not considered further. The oxygen a t o m in the [3434  conformation with the ether oxygen a t o m located on a 3-bond side adjacent to a c  a t o m leads to relief of the second largest n u m b e r of transannular interactions. In th  conformation, one of the methyl groups is on the corner atom, and is therefore poi  outside the ring. Secondly, and of greater importance, this corner methyl group is  pointed a w a y from the other methyl group on the side of the ring, thus avoiding 1,3-diaxial interaction. The D N M R spectra of 104 were analyzed in terms of the [3434]-4 conformation.  [3434]-4  94  180 K  150 K  145 K  4.0  3.5  3.0  2.5  2.0  1.5  1 .0  ppm  Figure 28. Variable temperature 500 M H zH N M R of (2S*,14R*)-2,14-dimethyloxacyclotetradecane (104) in CHCIF:CHCIF (4:1). 1  2  2  95  In the [3434J-4 conformation, the corner H-2 proton is shielded b y the a  anisotropy of the O / C 1 4 bond. The H-14do proton points to the inside of the ring, e n  is shielded b y the anisotropy of the C-12/C-13 bond, but is deshielded b y van Waals steric interactions with H-3 do and H-11 o that are calculated to be 2.17 A e n  e n d  2 . 2 1 A a w a y from H-14 o. Electric field effects play only a small role here with e n d  slightly shielded as the result of a pair of vicinal gauche carbon-hydrogen bonds. T H-14ndo e  proton is shielded to a lesser degree b y a single vicinal gauche carbon-  hydrogen bond. Thus, the H-14d proton is predicted to be m o r e deshielded, and e n  0  assigned to the signal at 4.03 p p m in the low temperature spectra. The other sign 3 . 8 2 p p m was assigned to the corner H-2 proton. a  In the rt H N M R spectrum of 104, the signals due to the H 3 and H 1 3 p 1  to the ether oxygen overlap with the signals of the methylene envelope. The n e signal visible downfield of the methylene envelope in the low temperature spectra  1 0 4 had a relative integration of 1 : 1 in comparison to each of the sharp dow signals of H-2 and H-14 . In the [3434J-4 conformation, the H-3 do proton is a  e n d 0  e n  deshielded b y the anisotropy of both the O / C 2 and C-2/C-16 bonds. The H-3  e  proton is also deshielded b y a van der Waals steric interaction with H-14 that e n d 0  calculated to be 2.17 A away. The H-13 proton is deshielded by the anisotropy o p  O / C 1 4 and C-11/C-12 bonds. The corner H-13 protons do not experience any transannular van der Waals steric interactions since they point to the outside of  ring. The signals of the other p-protons, H-3 and H-13 are shifted upfield b y the e x o  a  shielding effects. As a result, the downfield signal at 1 . 8 0 p p m is assigned to the deshielded of these p-protons, namely the H-3  e n d 0  proton.  The signal of the C-15 and C-16 methyl groups split into t w o signals of  approximately equal intensity at low temperature. The protons of both the C-15 me  group and the C-16 methyl group are deshielded to approximately the s a m e exten  the surrounding bonds. However, the C-15 methyl group is also shielded as a resul a van der Waals steric repulsion between the H-14 proton and the H-11 e n d 0  e n d 0  an  96 H-3 do protons. The corner C-16 methyl group does not experience such an effect. en  Thus, the low temperature methyl signal at 1.09 ppm is assigned to the C-15 methyl group, and the lower field signal at 1.13 ppm is assigned to the C-16 methyl group.  The high-field signal at 0.76 ppm in the low temperature spectra had a relative integration of 1:1 in comparison to the downfield H-2 and H-14 d proton signals. The a  en  0  H-4endo and H-11 do protons are deshielded in the [3434]-4 conformation as a result of en  van der Waals steric interactions with other endo protons on the ring. This results in the shielding of the H-4  exo  and H-11xo protons. Specifically, the H-4 o proton is e  end  deshielded by van der Waals steric interactions with the H-7 d and H-11 o protons en  0  end  that are calculated to be 2.19 A and 2.23 A from H-4 do. The H-11 do proton is en  en  deshielded by van der Waals steric repulsions with the H-8  end0  and H-14 do protons that en  are calculated to be 2.15 A and 2.21 A a w a y from H-11 do- The magnitude of the van en  der Waals shielding effect has been found to be proportional to the electronegativity of the sterically opposing group. The van der Waals steric interaction between H-4 do 6 4  en  and the electronegative ether oxygen, calculated to be 2.63 A apart, further shields the H-4  exo  proton. Therefore, on the basis of these arguments, the high-field signal at  0.76 ppm is assigned to H-4 . The signal at 1.00 ppm on the high-field shoulder of the exo  methyl signals of 104 is assigned to the H-11  exo  proton.  A molecular mechanics search for l o w energy conformations of 104 was conducted using the Monte Carlo technique and the M M 2 * force field. The global m i n i m u m conformation was the [3434]-4 conformation 104-A, as predicted, with the [34'3'4']-4 conformation 104-B calculated to have the next lowest energy, 1.21 kcal/mol  higher than the global m i n i m u m (Table 18). F r o m these calculations we found a total o 16 conformations within 2 kcal/mol of the global m i n i m u m . The fifth lowest energy conformation 104-E was the [3434]-1 conformation. This was not predicted to be a low energy conformation due to a steric interaction between the syn methyl groups. However, a distortion of the dihedral angle of one of the methine carbons resulted in a reduction of the 1,3-diaxial interaction between the methyl groups, and lowered the energy of this conformation  97  The relative populations of these conformations at different temperatures were calculated (Table 17). T h e results of these calculations suggest the [3434]-4  conformation of 104 to be the major conformation over the temperature range studie This is in agreement with the D N M R data. Other conformations were thought to  barely populated at the low temperatures studied, also in agreement with the D N M data.  Table 17.  Conformer  a  Thermodynamic Values for the Five Lowest Energy Conformations of 104  Skeleton  Relative Energy (kcal/mol) 3  298 K  Population (%) 180 K  145 K  104-A  [ 3 4 3 4 ] _ 4  0.00  71.0  91.5  96.3  104-B  [343 '4 '] ' -4  1 . 2 1  9 . 1  3 . 1  1 . 4  104-C  [3344]-4  1 . 3 6  7 . 2  2.1  0.9  104-D  [12443 '] '  1 . 3 8  6.9  1 . 9  0 . 8  104-E  [3434]-1  1 . 4 8  5 . 9  1 . 5  0.6  Strain energy values relative to the lowest energy conformation calculated with th MM2* force field.  98 Table 18.  L o w Energy Conformations of (2S*,14R*)-2,14-Dimethyloxacyclotetradecane (104) Skeleton  Relative Energy (kcal/mol)  104-A  [3434]-4  0.00  104-B  [343 '4 '] ' -4  1 . 2 1  104-C  [3344]-4  1 . 3 6  [12443 '] '  1 . 3 8  [3434J-1  1 . 4 8  Conformer  104-E  a  Strain energies are relative to the global m i n i m u m conformation calculated with t MM2* force field.  99 The energy barriers to the interconversion of conformations of 104 were  calculated b y first determining the rate of exchange between a pair of averaged sign  in the D N M R spectra. Once known, this rate of exchange was used to calculate  free energy of activation (AG*) with the coalescence temperature of the signals (T also obtained from the D N M R spectra, using the equations in Chapter 1. At low  temperature the signals for the H-2 and H-14do methine protons were separated b a  e n  1 0 2 Hz. This corresponded to a transition state energy of 8 . 7 kcal/mol with a T o c  K. The signals of the C-15 and C-16 methyl groups were separated b y 22 Hz. corresponded to a transition state energy of 8 . 2 kcal/mol with a T of 165 K . c  average of these values is 8 . 5 ± 0.3 kcal/mol. These transition state energy values approximately that of the unsubstituted macrocycle ether, oxacyclotetradecane (90), 8 . 7 ± 0.2 kcal/mol.  The single corner m o v e m e n t mechanism proposed b y Dale for  the  interconversion of cyclic conformations w a s used to describe the transition states of t  interconversion of low energy conformations of 104. The energies of these transition  state structures were estimated with molecular modeling calculations using the dihedra drive method and the MM2* force field. An incremental step of 10° was used in 1 2 4  calculations. The global m i n i m u m [3434J-4 conformation 104-A can interconvert with the [3344J-4 conformation 104-C through a [73343] transition state (Figure 29).  Th  transition state energy w a s estimated at 12.9 kcal/mol. The [3344]-4 conformation  104-C can also interconvert with the higher energy [3434]-1 conformation 104-E via another [73343] transition state with an estimated energy of 14.7 kcal/mol. The calculated transition state energies were larger than the observed values.  100  [3434]-4  Figure 29.  2.3.1  [3344]-4  [3434]-1  Interconversion of conformations of 104 via single corner movements.  Synthesis of 2,2-Dimethyloxacyclotetradecane (116)  The first approach to the synthesis of macrocyclic ether 116 followed the general synthetic strategy presented earlier.  The synthetic plan was to ring expand a  dialkylated ketone to give a 1 4 m e m b e r e d lactone with the gem-dimethyl substituents already in place adjacent to the ether oxygen. The carbonyl of this lactone would be removed to give the macrocyclic ether 116 (Scheme 10).  101 Scheme 10. Retrosynthetic Analysis of 2,2-Dimethyloxacyclotetradecane (116)  116  The the  115  dialkylated ketone 106 was  monoalkylated ketone 97  trimethylsilyl chloride, and  0  O  106  86  prepared via a two-step sequence starting with  which was reacted with hexamethyldisilazane,  lithium iodide to form the trimethylsilyl enol ether 1 0 5 .  Unfortunately, a mixture of regioisomers was and  114  no separation of these isomers was  128,129  obtained in the enol ether formation step,  attempted. The  M A B R mediated alkylation of  this mixture of trimethylsilyl enol ethers with methyl triflate gave ketone 106, and also (2S*.  13R*)- and  (2R*, 13R*)-dimethylcyclotridecanone (107) and  the alkylation of the regioisomeric trimethylsilyl enol ethers.  1 3 3  (108) resulting from  1 0 2  0  0  107  108  The alkylation products 107 and 108 were identified b y a GC comparison wit  authentic samples. A smaller proportion of the desired thermodynamic enol ether 1 2 6  105 was obtained than expected. Based on GC analysis of the ketones formed in subsequent alkylation step, an approximate ratio of 1 : 1 kinetic to thermodynamic  product was formed. The two-step sequence proceeded in a modest 31% yield due  the formation of significant quantities of 107 and 108 resulting from the isomeric kinet  enol ethers. The C N M R spectrum of 106 contained a signal at 216.09 p p m for t 13  C 1 carbonyl and a signal at 24.62 p p m for the C-2 geminal methyl groups.  The  H N M R spectrum of 106 contained a two-proton multiplet between 2.48-2.51 p p m  1  the C-13 methylene, and a six-proton singlet at 1 . 0 9 p p m for the C-2 gem-dim groups consistent with the structure of 106. Scheme 11. Synthesis of 2,2-Dimethylcyclotridecanone (106)  O  O T M S  O  106  105  97  a  Key: (a) (TMS)NH, TMSCI, Lil, CHCI; then EtN, 94%; (b) MABR, MeOTf, CHC -40 °C, 33%.  a  2  2  2  3  2  103  The Baeyer-ViNiger oxidation of ketone 106 was attempted under a variety  conditions. The reaction of ketone 106 with trifluoroperacetic acid formed in situ fro trifluoroacetic anhydride and U H P (Table 19, Entries 1-3) was unsuccessful even with ten-fold excess of the reagents.  1 2 2 , 1 2 3  p-TsOH (Entry 4) or Li C0 1 3 8  2  139  3  The reaction of m-CPBA in the presence of eith  (Entry 5) also failed to yield any of the desired lacto  114.  O  106  Table 19.  Entry  Reaction Conditions used in the Attempted Baeyer-Vi Niger Oxidation of Ketone 106 Reaction Conditions  equiv. of oxidant  yield  3  1  rtI, UHP, TFAA, NaHP0, CHC  6  0  2  rtI, UHP, TFAA, NaHP0, CHC  10  0  3  A I, UHP, TFAA, NaHP0, CHC  10  0  /77-CPBA, p-TsOH, CHCI  10  0  m-CPBA, LiC0, CHCI  10  0  2  5  4  2  2  4  2  4  3  114  2  4  2  2  2  3  2  2  2  2  2  2  Analysis of the product mixture b y gas chromatography showed only starting material to be present.  The synthesis of the gem-dimethyl lactone 114 did not proceed as outlined  the original synthetic plan. However, the keto acid 112, an intermediate prepared  previously in our laboratory en route to s o m e p-keto lactones, represented an altern  precursor to lactone 114. This keto acid could be reacted to give a tertiary hydr 1 4 0  acid, however it was unclear whether this sterically hindered compound would cycliz  104 to give lactone 114 using standard macrolactonisation techniques (Scheme 12). Once formed the lactone 114 was to be converted into the macrocyclic ether 116.  Scheme 12. Retrosynthetic Analysis of 13-Methyl-13-tetradecanolide (114)  114  113  112  The b r o m o acid 109 was converted into the methyl ester 110 under Fischer esterification conditions. This ester was chain extended by alkylation with the anion of methyl acetoacetate to give diester 111.  141  The diester 111 was decarboxylated under  strongly acidic conditions to give the keto acid 112. The desired gem-dimethyl group was introduced using Grignard chemistry to give the hydroxy acid 113.  The hydroxy  acid 113 was cyclized with the Yamaguchi procedure with triethylamine and 2,4,6-trichlorobenzoyl chloride, and subsequently reacted with a catalytic a m o u n t of D M A P under high dilution conditions to give the gem-dimethyl lactone 114.  28  The five-  step reaction sequence proceeded in 18% yield with the Grignard and cyclisation reactions having the lowest yields of the sequence. The H NMR spectrum of 114 1  105 contained a two-proton multiplet from 2.15-2.17 ppm a six-proton singlet at 1.35  for the C-14  and  spectrum of 114 contained a band at 1727  cm"  signal at 172.14 ppm  ppm  for the C-1  C-15  for the C-2  geminal methyl groups. The  and the C  1  NMR  13  carbonyl. The  methylene, as well as  H R M S and  IR  spectrum contained a  chemical analysis results  were also consistent with the composition of lactone 114.  Scheme 13. Synthesis of 13-Methyl-13-tetradecanolide (114)  114  113  a  112  Key: (a) HS0, CHOH, A , 82%; (b) NaH, CHCOCHCOOCH, THF, DMF, rt; 110, A ; (c) HCI (cone), CHOH, H0, A , 95% (2 steps); (d) CHMgBr, CHCI, 0 °C, 43%; (e) EtN, THF, 2,4,6-trichlorobenzoyl chloride,rt;then DMAP, toluene, A , 54%.  a  2  4  3  3  3  2  2  3  3  2  2  3  With the examined. The reagent 50,  50  lactone 114 in hand, the  conversion into thionolactone 115  reaction of 114 with either Lawessons ' reagent 48,  48  was  the Japanese  or phosphorus pentasulfide in toluene, or the higher boiling xylene  heated at reflux did not produce any  1 4 2 , 1 4 3  of the desired thionolactone 115.  GC  and  TLC  1 0 6  analysis of the reaction mixture in all cases showed n o evidence of the formation o desired thionolactone (Table 20).  50  Decomposition of the starting material w a s noted, presumably via acid hydrolys caused b y acidic species formed from the thionation reagents. The reaction of  Lawesson s ' reagent 48 in xylene heated at reflux with either pyridine or thiourea as  base to counter this hydrolysis was investigated. GC analysis of these reactions again  showed n o formation of the desired thionolactone 115, although the starting materi  w a s still present even after t w o days reaction time (Table 20, Entry 6-7). The reac  of the Lawessons ' reagent 48 w a s apparently blocked b y the sterically demanding C-1 gem-dimethyl substituents adjacent to the lactone functionality of 114.  114  115  107 Table 20. Entry  3 b  c  Reaction Conditions Used in the Attempted Thionation of Lactone 114 Reaction Conditions 3  solvent  yield/%  1  48  toluene  0  2  50  toluene  0  3  PS  toluene  0  4  48  xylene  0  5  50  xylene  0  2  5  b  b  b  b  b  6  48, pyridine (cat.)  xylene  0  7  48, thiourea (cat.)  xylene  0  C  C  These reactions were performed with the solvent heated at reflux. Analysis of the product mixture b y gas chromatography showed that the starting material decomposed and n o product w a s present. Analysis of the product mixture b y gas chromatography showed that only starting material was present. The effort to synthesize the macrocyclic ether 116 was apparently at an  insurmountable barrier. Preparation of the gem-dimethyl lactone 114 had proven to be challenging, but ultimately successful.  However, all attempts to prepare the  thionolactone 115 had failed. In search of additional alternatives, a m o r e detailed  search of the literature uncovered a report of the reduction of a lactone with sod  borohydride in the presence of boron trifluoride etherate to directly give a cyclic ether a steroidal system. The application of this methodology to our system m e t with 3 6  success. The boron trifluoride etherate mediated reaction of sodium borohydride with lactone 114 gave the macrocyclic ether 116 in 51% yield.  114  116  1 0 8 2.3.2 Conformational Analysis of 2,2-Dimethyloxacyclotetradecane (116)  The H NMR  spectrum of 2,2-dimethyloxacyclotetradecane (116) at rt in CDCI  1  3  contained a two-proton triplet at 3.25 ppm, 20-proton multiplet from 1 . 2 3 1 . 4 3 ppm, low-field signal was  and  ppm, a  a six-proton singlet at 1.13  assigned to the protons of C-14,  atom, and the signal at 1.57 assigned to the  a two-proton quintet at 1.57  T h e  adjacent to the ether oxygen  ppm was assigned to the protons of C-13.  C-2 geminal methyl groups. The  ppm.  The singlet was  remaining proton signals were  overlapped in the methylene envelope region.  The the  C spectrum of this c o m p o u n d contained 14 lines. Due  to the overlap of  1 3  signals in theH N M R spectrum, even with H M Q C and H M B C 2 D N M R 1  experiments, only a limited n u m b e r of the carbon signals could be assigned (Table 21). The low-field signal at 73.88 ppm was assigned to the quaternary C-2 carbon, and signal at 37.97 ppm was 58.88 ppm  was  carbons C-15  assigned to the adjacent C-3.  assigned to the  and C-16  The  other low-field signal at  C-14 methylene carbon, and  the  were assigned to the signal at 26.66 ppm.  geminal methyl The H R M S analysis  was also consistent with the composition of 116. Table 21.  H and C NMR Assignments for 2,2-Dimethyloxacyclotetradecane (116) in CDCI at R o o m Temperature  1  1 3  3  Position  H NMR  1  a  2  (1214| 15 J11 c> 16 1 3  I  a  1  4  3^  r  —  1 . 4 6  3 4-10  not  C NMR  13  a  73.88 37.97 assigned  1 5  1 1  1 . 2 7  24.56  1 2  1 . 4 0  24.50  13  1 . 5 7  28.34  1 4  3.25  58.88  15, 16  1 . 1 3  26.66  The chemical shift values are in ppm referenced to CHCI (H) and CDCI (C). Due to signal overlap these signals could not be assigned. 1  3  b  the  1 3  3  109 A series of D N M R experiments were performed with 116 using a 4:1 mixture of Freon 21 and Freon 22 as solvent (Figure 30). The H NMR spectrum of 116 at 220 K 1  contained four signals. This was similar to the rt spectrum, however the signals had broadened at the lower temperature. As the temperature was lowered, the downfield signal at 3.25 ppm for the C-14 protons broadened to form at low temperature a pair of signals at 3.31 and 3.15 ppm (T = 180 K). The signal for the C-13 protons at 1.57 ppm c  also broadened as the temperature was lowered to give at low temperature, signals at 1.69 ppm and 1.50 ppm. The signal for the geminal methyl groups at 1.13 ppm split as the temperature was lowered to give signals at 1.15 ppm and 1.10 ppm (T = 190 K). c  As only one pair of major signals were observed for the geminal methyl groups, only one major conformation was predicted to be present. Also visible in the high-field region of the low temperature spectra were two signals at 0.93 ppm and 0.67 ppm.  [3434]-4  [3434]-2  A gem-dimethyl substituted carbon is always restricted to a corner position in low energy conformations of 1 4 m e m b e r e d rings. If located at another position on the  ring, one of the methyl groups points into the ring, resulting in a severe transannular steric interaction.  1 0 5  In the case of the 1 4 m e m b e r e d macrocyclic ether 116 that  contains the C-2 gem-dimethyl group adjacent to the ether oxygen, this restriction prevents the oxygen from occupying the 1-position in the middle of a 4-bond side in the [3434]-1 conformation. Two possible diamond lattice conformations that have C-2 at a corner position are the [3434]-4 and [3434]-2 conformations. In the unsubstituted ether, the [3434]-4 conformation is the preferred conformation of this pair. The transannular steric interactions eliminated by an oxygen a t o m at this position are greater than in the case of the [3434]-2 conformation. These diamond lattice conformations were both considered as possible major conformations of 116 in the analysis of the D N M R data.  1 1 1 The analysis of the D N M R data begins with the downfield signals of the protons of C-14.  In the [3434]-4 conformation, the H-14do proton is shielded b y the e n  diamagnetic anisotropy of the C-12/C-13 bond. However, van der Waals steric interactions between this proton and the H-11do and H-3do protons results in a e n  e n  deshielding of the H-14 proton. The calculated distances between these protons e n d 0  and the H-14do proton are 2.20 A and 2.17 A respectively. Both of these values are e n  less than the sum of the van der Waals radii for a pair of hydrogens. Conversely, the 6 2  H-14 proton is deshielded by the anisotropy of the neighbouring bond, and shielded e x o  b y the van der Waals interactions. The relative magnitudes of these effects is unknown, but the anisotropy contribution is thought to be larger. The H-14do proton is e n  expected to have two large coupling constants, a vicinal coupling to H-13, and a p  geminal coupling to H-14. In contrast, H-14 would have only the large J e x o  e x o  gem  coupling constant. Thus, the broad signal at 3.15 ppm is assigned to H-14do, and the e n  sharper signal at 3.31 ppm to the H-14 proton based on these chemical shift and e x o  coupling constant arguments.  In the [3434]-2 conformation, C-14 is located at the middle of a 4-bond side of the ring. Here, H-14 is shielded as the result of van der Waals interactions between e x o  the H-14ndo proton, and the H-3 and H-11do protons. The calculated distances e n d 0  e  e n  between H-14 and these other protons are 2.10 A and 2.14 A respectively. e n d 0  T h e  H-14 proton is further shielded b y electric field effects caused b y the parallel e x o  alignment of the carbon-hydrogen bonds between C-14 and H-14, and C-12 and e x o  H-12. The reinforcement of these shielding effects would result in a larger A 5 than p  observed here in the low temperature spectra of 116. conformation, a pair of large coupling constants (J, J  Moreover, in the [3434]-2  3  )  gem  are expected for B O T H the  H-14o and H-14 protons. This predicted lineshape is in poor agreement with that e x o  e n d  observed here in the low temperature spectra. Therefore, this conformation was not considered further as a major conformation in the analysis of the low temperature spectra of 116.  In thertH NMR spectrum of 116, the C-13 protons p to the ether oxgyen, were 1  resolved from the methylene envelope while the protons of C-3 overlapped with the  112 methylene envelope. At low temperature however, two signals were visible at 1.69 ppm and 1.50 ppm which were assigned to protons p to the ether oxygen. In the [3434]-4 conformation, H-3 do is deshielded by the diamagnetic anisotropy of the O/C-2 bond, en  and also by the carbon-carbon bond between C-2 and the p-methyl group. A van der Waals steric interaction with H-14 o further deshields this proton. The H-13 proton is end  a  shielded by the anisotropy of both the C-14/0 bond, and the C-11/C-12 bond. No van der Waals steric interactions are expected for the C-13 corner protons in the [3434]-4 conformation since both are exo to the ring. This combination of effects lead to the assignment of the lower field signal at 1.69 ppm to the H-3 do and H-13 protons. The en  p  higher field signal at 1.50 ppm was assigned to the m o r e shielded H-3 o and H-13 eX  a  protons.  The averaging of the C-2 geminal methyl groups of 116 is slow at l o w temperature, and a pair of signals of approximately equal intensity at 1.15 and 1.10 ppm are visible at low temperature. The presence of this pair of signals indicates that a conformational interconversion that results in exchange of the geminal methyl groups is no longer rapid at the low temperature. The assignment of the signals at 1.15 and 1.10 ppm to the C-2 and C-2 methyl groups is ambiguous at this time. a  P  The signals observed at high-field in the D N M R spectra of 116 are assigned to the H-4 and H-11 o protons. In the [3434]-4 conformation, the H-4 do and H-11 do exo  eX  en  en  protons are deshielded as a result of a series of van der Waals steric interactions. The H-4endo proton is only 2.17 A from H-7 d , and 2.29 A from the H-11 do proton. en  0  en  The  H-11endo proton is located 2.20 A from H-14 , and 2.11 A from H-8 do- These end0  en  deshielding effects result in the shielding of the H-4 and H-11 exo  exo  protons. It is the  distance from the ether oxygen that results in the different chemical shifts of these protons at low temperature. In a study described in Chapter 1, the magnitude of the van der Waals shielding effect was found to be proportional to the electronegativity of the sterically opposing group. The electronegative ether oxygen is calculated to be 6 4  2.60 A from H-4 o, and 3.25 A from H-11 , and hence would m a k e a greater end  end0  contribution to the shielding of the H-4 proton. For these reasons the highest field exo  113 signal at 0.67  ppm is assigned to H-4, and the other high-field signal at 0.93 e x o  ppm to  the H-11exo proton.  A molecular mechanics search for the lowest energy conformations of 116 was conducted using the Monte Carlo technique and the MM3* force field. These calculations gave a total of eight conformations within 2 kcal/mol of the calculated lowest energy conformation which was the [3434]-4 conformation 116-A. The second lowest energy conformation was  the [3434]-2 conformation 116-B. As expected, the  gem-dimethyl group was situated at a corner position in all of the low energy conformations (Table 22).  These two lowest energy conformations were the s a m e as  those predicted by analysis of transannular interactions in 116.  The relative  populations of these conformations at different temperatures were calculated from relative strain energies obtained from the MM3* calculations (Table 23).  These results  suggested that a single conformation, the [3434]-4 conformation 116-A, was the major conformation over the temperature range studied in agreement with the D N M R data.  1 1 4 Table 22.  L o w Energy Conformations of 2,2-Dimethyloxacyclotetradecane (116) Skeleton  Conformer  [3434]-4  0.00  116-B  [3434]-2  0.81  116-C  [13343 '] '  1 . 2 7  116-D  [3344]-4  1 . 2 9  116-E  [3344]-2  1 . 3 1  116-A  o  \  Relative Energy (kcal/mol)  '  Strain energies are relative to the global m i n i m u m conformation calculated with t MM3* force field.  115  Table 23.  Thermodynamic Values for the Five Lowest Energy Conformations of 116  Conformer  Skeleton  3  Relative Energy (kcal/mol) 3  298 K  Population (%) 180 K  145 K  116-A  [3434]-4  0.00  62.8  84.4  91.4  116-B  [3434]-2  0.81  15.9  8.7  5 . 4  116-C  [13343 '] '  1 . 2 7  7.4  2.4  1 . 1  116-D  [3344]-4  1 . 2 9  7.1  2.3  1 . 0  116-E  [3344]-2  1 . 3 1  6.8  2.1  1 . 0  Strain energy values relative to the lowest energy conformation calculated with th MM3* force field.  The energies of the conformational interconversion transition states of 116 were  determined from the rate of exchange between a pair of averaged signals in the D  spectra. Once known, the rate of exchange was used to calculate the free energy  activation (AG ) with the coalescence temperature (T) also obtained from the D N M R 4  c  spectra, using the equations in Chapter 1. At low temperature, the C-14 proton sig were separated b y9 1  Hz. This corresponded to a transition state energy of  8 . 5 kcal/mol with a T of 180 K . The signals of the protons p to the ether oxyge c  separated at low temperature b y 95 Hz. This gave an energy barrier of 9 . 4 kcal/ with a coalescence temperature of 200 K .  The signals of the geminal methyl gr  were separated b y 26 Hz, with a T of 190 K . This corresponded to a transition c  energy of 9 . 4 kcal/mol. The average of these values is 9 . 1 ± 0 . 4 kcal/mol. This v is higher than that obtained for the unsubstituted oxacyclotetradecane (90), 8 . 7 ±0 . 2 kcal/mol.  The single corner m o v e m e n t mechanism proposed b y Dale for  the  interconversion of cyclic conformations such as those proposed here, requires a seri of [73343] transition state structures. The energies of these were estimated with molecular modelling calculations using the dihedral drive method, and the MM3* 1 2 4  force field. An incremental step of 10° of the necessary dihedral angles was used  1 1 6 this calculation. The steric requirements of the gem-dimethyl group d e m a n d that this functional group remain at a corner position in the low energy conformations. Similarly, the transition state structures for the interconversion of the conformations of 116 also have the gem-dimethyl group at a corner position. The  suggested energies of the  [73343] transition state conformations for the interconversion of the global m i n i m u m [ 3 4 3 4 ] _ 4 conformation 116-A with the [3344]-2 and [3344]-4 conformations 116-E and 116-D were calculated at 13.3 kcal/mol and 12.8  kcal/mol (Figure 31).  The energy of  the [73343] transition state conformation involved in the interconversion of the higher energy [3434]-2 conformation 116-B with the [3344]-2 conformation 116-E w a s calculated to be 13.5  kcal/mol. These calculated transition state energies were larger  than the observed values. This may be due to the inaccuracy of the assumption that the dihedral angles of the 1 b o n d side and adjacent bonds were 120°,  0°, and  120°  respectively. Any conformational interconversion involving m o v e m e n t of the geminally  substituted carbon a t o m a w a y from the corner position would also be expected to hav a higher energy.  [3344]-4  Figure 31.  [3434]-2  Interconversion of conformations of 116 via single corner movements.  1 1 7 2.4.1  Synthesis of 3,3-Dimethyloxacyclotetradecane (119)  The  Baeyer Villiger oxidation of cyclotridecanone (86) gave lactone 87. The  gem-dimethyl substituents were introduced via a sequential alkylation with LDA and methyl iodide to give ultimately the H NMR  1  The  spectrum of lactone 118 contained a two-proton multiplet from 4.04-4.07 ppm  for the C-13  methylene and a six-proton singlet at 1.15  groups. The C-1  gem-dimethyl lactone 118 (Scheme 14).  C NMR  13  carbonyl. The  ppm for the C-2  geminal methyl  spectrum contained 14 lines with a signal at 1 7 8 . 2 1 ppm for  H R M S and  the  chemical analysis results were also consistent with the  composition of lactone 118. Formation of a thionolactone with Lawesson s ' reagent 48 is problematic in the case of sterically hindered lactones such as 118. conversion of this lactone to the macrocyclic ether 119 was  144  Hence, the  performed via the direct  reduction with sodium borohydride in the presence of boron trifluoride etherate in heated at reflux to give the reduction did  not  macrocyclic ether 119 in a low  proceed at r o o m temperature. The  proceeded in an overall yield of  8%.  THF  yield of 11%. This 3 6  four-step reaction sequence  118 Scheme 14. Synthesis of 3,3-Dimethyloxacyclotetradecane (119)  1  0  86  87  117  118  119  Key: (a) UHP, TFAA, NaHP0, CHCI, 0 °C, 96%; (b) LDA, THF, -78 °C; then Mel, 84%; (c) LDA, THF, -78 °C; then Mel, 86%; (d) BFEt0, NaBH, THF, rt; then triglyme, A , 11 % .  a  2  4  2  2  3  2  4  2.4.2  Conformational Analysis of 3,3-Dimethyloxacyclotetradecane (119)  The H NMR  spectrum of 3,3-dimethyloxacyclotetradecane (119) at rt in CDCI  1  3  contained a two-proton triplet at 3.38 quintet at 1.55  ppm,  singlet at 0.84  ppm.  ppm,  a two-proton singlet at 3.03  an 18-proton multiplet between 1 . 1 8 1 . 4 2 ppm, The  and  downfield signals were assigned to the  methylenes adjacent to the ether oxygen, the triplet to C-14, (Table 24).  ppm,  The H COSY data was 1  and  C-16  the  the singlet to ppm  to the  C-2 C-13  protons. The  high-field singlet was  groups. The  results of the H R M S and chemical analysis were also consistent with the  structure of 119.  and  a six-proton  protons of  used to assign the signal at 1.55 assigned to the C-15  a 2-proton  geminal methyl  1 1 9  The C spectrum of 119 contained 1 4 lines. The t w o lowest field signals at 13  77.38 and 68.81 p p m were assigned to C-2 and C-14 respectively. The assignmen other C andH signals w a s aided with COSY, H M Q C , and H M B C 2 D N M R 13  1  experiments (Table 24). The signal at 34.09 p p m was assigned to the C-3 quatern  carbon, and the signal at 37.43 p p m to the adjacent C-4 methylene. The chemica of the C-3 geminal methyl groups was 26.12 p p m .  Table 24.  H and C N M R Assignments for 3,3-Dimethyloxacyclotetradecane (119) in CDCI at R o o m Temperature  1  13  3  3  Position  H NMR  1  b  3.03  C NMR  13  b  77.38 34.09  1 . 2 2  37.43  not  15, 1 6 3  b  0  1 . 3 6  22.84  1 . 5 5  28.81  3.38  68.81  0.84  26.12  Arrows s h o wH M B C correlations. The chemical shift values are in p p m referenced to CHCI (H) and CDCI (C). D u e to signal overlap these signals could not be assigned. 1  3  c  assigned  1 3  3  The low temperature H N M R spectra of 119 were obtained in a 4 : 1 mixture 1  Freon 2 1 and Freon 22 as solvent (Figure 32). The spectrum of 119 at 220 K  similar to the rt spectrum however the signals had broadened at the lower temperat  At 200 K , the C-14 methylene signal broadened, and the signal for the C-2 proton  extremely broad. At this s a m e temperature, the signal for the C-13 protons, p to ether oxygen, was unresolved on the low-field shoulder of the methylene envelope,  the C-3 geminal methyl signal had broadened to a significant degree. At 190 K , signals for the C-2 and C-14 protons broadened further, and the signal for the  120 protons downfield from the methylene envelope also was poorly resolved. In the  upfield portion of the spectrum, the C-3 geminal methyl signal split into a pair of equa intense signals at 0.93 ppm and 0.77 ppm.  At lower temperatures, the line shape of the a-proton signals became distinct with a total of seven peaks visible in this region from 2.5 to 3.7 ppm at 140 K, the lowest temperature examined in this D N M R series. This is indicative of multiple conformations being present even at low temperature. Three signals at 1.61, 1.75, and  1.84 ppm were visible in the region where the C-13 proton signals were expected. The  geminal methyl signals were quite broad, with no additional peaks visible in that reg  to indicate the presence of minor conformations. Also, at temperatures below 175 K an unresolved, broad peak at 0.62 ppm on the high-field shoulder of the methyl signals was visible.  The low energy conformations of 119 are predicted to have the C-3 gem-dimethyl substituted carbon at a corner position of the ring. This configuration  allows for the ether oxygen to be located in the middle of a 4-bond side in the [3434 conformation, thereby removing the transannular hydrogen interactions present at that location in the parent hydrocarbon. The ether oxygen can also be located on the  3-bond side in the [3434]-4 conformation where transannular hydrogen interactions are present in cyclotetradecane as well. The non-diamond lattice [3344]-1 conformations of 119 with the gem-dimethyl group at a corner position flanked by either two 4-bond  sides, or a 3- and a 4-bond side were also expected to have low strain energy. Th conformations were considered as likely low-energy conformations in the analysis of the D N M R spectra of 119.  121  122 13  12 13  14 2  14  [3434]-4  [3434]-1  14  [3344]-1  [3344]-1 The peaks. The  downfield portion of the low temperature spectra of 119 contained seven three lowest field peaks were triplet-like with relative heights of 1:2:1.  However the A8 values of these peaks are approximately 50 Hz, and therefore too large to have been the result of vicinal coupling. The downfield peaks of the D N M R spectra therefore m u s t result from a n u m b e r of unequally populated conformations present at the low temperature. The four higher field signals at 3.27, were assigned to the C-2  protons of 119. The  3.12,  2.99,  and 2.65  ppm  downfield pair of signals in this group  are assigned to the major conformation and are m o r e intense than the upfield pair of signals that are  assigned to the  minor conformation, with an approximate relative  intensity of 2.2:1. This corresponds to an energy difference of 0.21 the major and  minor conformations. The  A5 value of the C-2  kcal/mol between  protons in the major  conformation is small, while in the minor conformation it is large. The values for the C-2  protons in the  predicted A5  low energy conformations suggested above were  compared in an effort to identify the major and minor conformations of 119.  In the [3434]-1 conformation, the H-2 proton is deshielded by the anisotropy of e x o  the C-3/C-4 bond, and shielded by the anisotropy of the carbon-carbon bond between C-3 and the C-3  P  methyl group. Also, this proton is shielded by a van der Waals steric  interaction between the H-2do and the H-5do protons that are calculated to be 2.20 e n  e n  A  123 apart. The result of these effects is a predicted small A5 for the C-2 protons in this conformation with the H-2 proton at higher field. In the [3434]-4 conformation, the e x o  H-2 proton is deshielded by the anisotropy of the C-3/C-4 bond, but shielded by the e x o  anisotropy of the carbon-carbon bond between C-3 and the C-3 methyl group. Also, a  this proton is shielded by van der Waals steric interactions between the  proton  H-5 do  H-2ndo-  The combination of these effects is a predicted A8 value that is large for the  e  H-13do p rotons  e n  and the  e n  and  H-2 do  e n  that are calculated to be 2.20A and 2.19 A from  C-2 protons in this conformation with the H-2 proton at higher field. e x o  In the [3344]-1 conformation with the gem-dimethyl substituted corner a t o m  flanked by a pair of 4-bond sides, The H-2 proton is deshielded by the anisotropy of e x o  the C-3/C-4 bond, but shielded by the anisotropy of the carbon-carbon bond between C-3 and the C-3 methyl group. The magnitude of these effects is unequal as a result P  of the distorted geometry of this non-diamond lattice conformation. Also, the H-2  e x o  proton is shielded by a van der Waals steric interaction between the H-2  e n d 0  and H-5 do e n  protons that are calculated to be 2.27 A apart. A large A5 value is predicted for the C-2 protons in this conformation as a result of these effects. In the other [3344J-1  conformation where the substituted corner a t o m is between a 3- and a 4-bond side, th environment of the C-2 protons is similar to that of the C-2 protons in the [3434]-1 conformation, with a small A8 value predicted. In summary, the chemical shift differences between the C-2 protons is small in the [3434]-1 conformation and in the [3344]-1 conformation with the gem-disubstituted  corner a t o m flanked by a 3- and a 4-bond side. These are possible candidates for the major conformation of 119. The A8 value was predicted to be large for the [3434]-4 and  the [3344]-1 conformation where the gem-disubstituted corner a t o m is flanked by a pair of 4-bond sides. These are possible candidates for the minor conformation of 119. A similar analysis was performed for the three signals of the C-14 protons at 3.61, 3.53, and 3.42 ppm. The triplet-like pattern here was the result of the unequally intense overlapping doublets of the major and minor conformations of 119. Although the heights of the peaks at 3.61 and 3.42 ppm are approximately equal, the 3.61 ppm  124  peak is partially overlapped with the middle 3 . 5 3 p p m peak, artificially increasing t  height of this signal. Thus, the t w o signals for the minor conformation are the peak  3.61 and 3.53 p p m , with the major conformation signals at 3.42 p p m and 3 . 5 3 p  The observed A8 values of the C-14 protons in the major and minor conformations 119 are both small. In all cases, a comparison of the shielding effects experienced  the C-14 protons in the four low energy conformations gave small predicted A5 valu  and hence did not assist in determining which conformation might be the major or m one observed.  The signal of the C-3 gem-dimethyl groups of 119 split as the temperature w  lowered to give a pair of signals at 0.93 and 0.77 ppm. Unfortunately, n o signal the methyl groups of the minor conformation could be identified. However, these  signals m a y be hidden b y the major conformation proton signals in this region, and b y the s o m e w h a t broad signals of the major conformation methyl groups. A molecular mechanics search for low energy conformations of 119 was  conducted with the Monte Carlo technique and the MM3* force field. The calculat  global m i n i m u m was the [3434]-1 conformation 119-A with the [3344]-1 conformati 119-B calculated to have the next lowest energy, 0.49 kcal/mol higher. These calculations suggested the existence of five other conformations within 2 kcal/mol the global m i n i m u m conformation (Table 25). Higher energy conformations were ignored since they were not considered to be significantly populated over the temperature range examined.  The relative populations of these low energy  conformations at different temperatures were calculated from the relative energies  obtained from the MM3* calculations (Table 26). The results of these calculations suggest the [3434]-1 conformation 119-A to be the major conformation over the  temperature range studied with the second m o s t populated conformation, the [3344] conformation 119-B, also significantly populated. These assignments are consistent  with the D N M R data and above proposals. The calculated relative energies betwee the major and minor conformations is 0.49 kcal/mol, a value higher than the 0 . 2 1 kcal/mol observed in the D N M R spectra.  125 Table 25.  L o w Energy Conformations of 3,3-Dimethyloxacyclotetradecane (119) Conformer  Skeleton  Relative Energy (kcal/mol)  119-A  [3434]-1  0.00  119-B  [3344]-1  0.49  119-C  [3344]-1  1 . 0 5  119-D  [3434]-4  1 . 2 0  119-E  [13343 '] '  1 . 7 5  Strain energies are relative to the global m i n i m u m conformation calculated with t MM3* force field.  126  Thermodynamic Values for the Five Lowest Energy Conformations of 119  Table 26.  Conformer  3  Skeleton  Relative Energy (kcal/mol) 3  298 K  Population (%) 190 K  140 K  119-A  [3434]-1  0.00  51.8  68.9  80.8  119-B  [3344]-1  0.49  22.5  18.7  13.8  119-C  [3344J-1  1 . 0 5  1 0 . 1  5.3  2.5  119-D  [3434]-4  1 . 2 0  8 . 8  4.3  1 . 9  119-E  [13343 '] '  1 . 7 5  6 . 8  2.8  1 . 1  Strain energy values relative to the lowest energy conformation calculated with th MM3* force field.  The energies of the transition states for the conformational interconversions o  119 were determined from the rate of exchange between a pair of averaged signals  the D N M R spectra. Once known, the rate of exchange was used to calculate the  energy of activation (AG*) with the coalescence temperature (T) also obtained from th c  D N M R spectra, using the equations in Chapter 1 . At low temperature, the C-3 a a  C-3 methyl signals were separated b y 76 Hz. This corresponded to a transition sta P  energy of 9.3 kcal/mol with a T of 195 K . The signals of the C-14 protons we c  separated b y approximately 44 Hz and 52 Hz in the major and minor conforma  respectively. This corresponded to transition state energies of 9.5 and 9 . 4 kcal/m with a T of 195 K . The signals of the C-2 protons were separated b y 72 Hz c  1 7 2 Hz in the major and minor conformations respectively. This corresponded to  transition state energies of 9 . 5 and 9 . 2 kcal/mol with a T of 200 K . The averag c  these transition state energy values is 9 . 4±0 . 1 kcal/mol.  The single corner m o v e m e n t mechanism proposed b y Dale for  the  interconversion of cyclic conformations such as those examined here, requires a seri  of [73343] transition state structures. The energies of these structures were calculate  from molecular modelling calculations using the dihedral drive method, and the MM 1 2 4  force field. An incremental step of 10° to the necessary dihedral angles was used  127 this calculation. The steric requirements of the gem-dimethyl group requires that this functional group be maintained at a corner position in the low energy conformations. Similarly, the transition state structures for the interconversion of the conformations of 119 also m u s t have the gem-dimethyl group located at a corner position. The calculated energies of the [73343] transition state conformations for the interconversion of the global m i n i m u m [3434J-1 conformation 119-A with the [3344]-T conformations 119-B and 119-C are 10.2 kcal/mol and 9.4 kcal/mol (Figure 33). The energy of the [73343] transition state conformations needed to complete the cycle through the [3434]-4 conformation 119-D are calculated to be 9.5 kcal/mol above the global m i n i m u m for conformation 119-B, and 10.5 kcal/mol above the global m i n i m u m from the [3344J-1 conformation 119-C.  These are in good agreement with the observed  transition state energy values.  Figure 33.  [3434]-1  [3344]-1  [3344]-1  [3434]-4  Interconversion of conformations of 119 via single corner movements.  128 2.5.1  Synthesis of 6,6-Dimethyloxacyclotetradecane (137)  The  preparation of the macrocyclic ether 137 required a different approach than  that used to synthesize the macrocyclic ethers presented above. The  introduction of a  gem-dimethyl group at a position remote from the oxygen a t o m of the macrocyclic ether m e a n t that these substituents could not be introduced through the alkylation of  the  intermediate lactone or ketone. Instead, the synthetic strategy involved the preparation  of the molecule from two parts, which were coupled together using a dithiane ring as the central unit of the acyclic molecule (Scheme 15).  This dithiane ring was eventually  converted into the desired gem-dimethyl group. The  macrocycle was  cyclisation of a hydroxy acid, and macrocyclic ether 137.  the  resultant lactone was  formed via  transformed into the  the  130 The symmetric 1,8-octanediol (120) was give the monobrominated alcohol 121.  145  treated with 48%  hydrobromic acid to  This b r o m o alcohol was oxidized under  Swern conditions to give the b r o m o aldehyde 122 which was subsequently protected by reaction with ethylene glycol to give the ethylene acetal 123 (Scheme 16). three-step reaction sequence proceeded in an overall yield of 77%. spectrum of 123 contained a one-proton triplet at 4.78  This  The H N M R 1  ppm for the C-1 methine proton  of the acetal. As well, a pair of multiplets between 3.77-3.92 ppm for the C-1' and  C-2'  methylenes of the acetal were observed. In the IR spectrum, the band at 1711  cm" 1  from the C-1 carbonyl of the penultimate aldehyde 122 was absent.  Scheme 16. Synthesis of 8-bromooctanal ethylene acetal (123)  a  123  122  Key: (a) 48% HBr, CH, A, 92%; (b) (COCI), D M S O , EtN, CHCI, -78 °C, (c) PPTS, HOCHCHOH, CH, A, 93%.  a  6  6  2  2  2  6  3  2  2  90%;  6  A solution of 1,3-propanedithiol and dihydropyran in CHCI was 2  boron trifluoride etherate to give the hydroxy dithiane 125,  146  2  treated with  which was protected as a  tetrahydropyranyl ether to give 126 in a yield of 81 % for two-steps (Scheme 17).  1 4 7  The  131 protected dithiane 126 has been prepared previously in our laboratory. The anion of 1 4 1  126 was generated with n-butyllithium in THF at -20 °C and alkylated with b r o m o acetal 123 to give 127.  146  This reaction, even w h e n performed with an excess of dithiane 126  anion, proceeded in only a modest yield. The H NMR 1  spectrum of 127, a pale yellow  oil, contained one-proton doublet of doublets with chemical shifts of 4.78 4.53 ppm for the C-1  methine of the ethylene acetal and  tetrahydropyranyl ether respectively as 2.73-2.76 ppm for the C-4' spectrum contained two  and C-6'  well as  the C-13  ppm  methine of the  a four-proton multiplet  methylenes of the dithiane ring. The  low-field signals at 104.56 and  and  98.74 ppm  C  13  from NMR  for the acetal  carbons of the acetal and the tetrahydropyranyl protecting groups respectively. The H R M S and chemical analysis results were also consistent with the composition of 127.  Scheme 17. Synthesis of Bisalkylated Dithiane 127  a  S  S  125  b  ^0  .0.  • c  127  126  Key: (a) BFEt0, CHCI, 0 °C, 84%; THF,-20 °C; then 123, 49%.  a  3  2  2  2  (b) DHP,  PPTS, CHCI,rt,96%; 2  2  (c) n-BuLi,  1 3 2 With the dithiane 127 in hand, the next task was  to transform the dithiane ring  into the desired gem-d\methyl group. Difficulties were encountered with the unwante cleavage of the protecting groups w h e n this conversion was compound, and of 127 was  hence the conversion was  1 4 8 , 1 4 9  but  protecting groups was encountered. cleavage involving the investigated.  1 5 0  This was  difficulty with the  first attempted with  To overcome this problem, an alternative  use of mercuric perchlorate with calcium carbonate was  carbonyl of 128 was  using the Tebbe reagent 3 2 . hydroxy aldehyde 130.  dithiane ring  cleavage of the acetal  This reaction proceeded rapidly to give the  acetals intact. The  The  performed in two stages. The  hydrolyzed into the ketone 128 (Scheme 18).  NBS under standard conditions  attempted on the protected  3 8 1 5 1  "  1 5 3  ketone 128 with both  converted into the exo-methylene group of 129 Removal of the acetal protecting groups gave the  147  oxidation of the  aldehyde in the  required chemoselective conditions. Too the primary hydroxyl group. The  presence of the  primary alcohol of 130  powerful an oxidant could have also oxidized  m e t h o d chosen was  a silver oxide oxidation with the  oxidant generated in situ from silver nitrate and sodium hydroxide. This reaction was 1 5 4  performed in the absence of light to minimize the photoreduction of Ag. +  this oxidation step proceeded in only a modest 30% The C-14 the  H NMR  1  C-13 methylenes respectively. The  179.13 ppm  yield to give the hydroxy acid 131  spectrum of this oil contained a two-proton singlet at 4.68  exo-methylene and two-proton triplets at 3.64  for the  C-1  carbonyl of the  contained bands at 3639 cm'  1  and  1712  Unfortunately,  ppm  and 2.32  ppm  ppm  for  the  for the C-2  and  C N M R spectrum contained a signal at  13  carboxylic acid. The cm" 1  IR spectrum of 131  for the carboxylic acid and  the C-9 double bond consistent with the structure 131.  1644  cm" 1  for  133 Scheme 18. Synthesis of 9-Methylene-13-hydroxytridecanoic acid (131)  b  131  130  129  Key: (a) Hg(CI0), CaC0, THF, H0, 80%; (b) Tebbe reagent 32, DMAP, pyr, THF, -40 °C, 53%; (c) PPTS, acetone, H0, A, 90%; (d) AgN0, NaOH, THF, H0, 30%. 38  a  42  3  2  2  3  2  The  Yamaguchi procedure wherein the hydroxy acid is first activated as a mixed  anhydride with triethylamine and 2,4,6-trichlorobenzoyl chloride was hydroxy acid 131.  28  This activated anhydride was cyclized under high dilution  conditions to give the lactone 132 (Scheme 19).  2 8 , 1 5 5  then was  used to cyclize the  The  exocyclic methylene of 132  converted into a cyclopropyl group using diethylzinc and chloroiodomethane  via a procedure similar to that developed by Denmark." This reaction was 1 5 61 5 8  be  superior to the traditional  Simmons-Smith procedure  bis(chloromethyl)zinc reagent is m o r e reactive than the  1 5 9 , 1 6 0  found to  since the  bis(iodomethyl)zinc reagent  134 used in the Simmons-Smith conditions.  1 5 6 , 1 5 7  The cyclopropyl group of 133 was ring  opened under hydrogenolysis conditions with A d a m s catalyst (Pt0 ) in acetic acid to 2  give the gem-dimethyl lactone 1 3 4 .  161  Hydrogenolysis of cyclopropyl rings occurs  preferentially at the least substituted carbon-carbon bond leading to the desired gem-dimethyl product.. The H NMR 1 6 2  1  spectrum of 134 contained a six-proton singlet  at 0.82 ppm for the geminal methyl groups, as well as a two-proton multiplet from 4.10-4.12 ppm for the C-13 methylene group. The  1 3  CN M R contained 14 lines, with  one low-field signal at 173.70 ppm for the C-1 carbonyl. The H R M S data was also consistent with the composition of lactone 134.  The remainder of the synthesis involved the conversion of the lactone into the desired macrocyclic ether. The lactone 134 was reacted with Lawesson s ' reagent 48 to give the thionolactone 1 3 5 .  5 1 5 5  This thionolactone was reduced with  lithium  triethylborohydride and trapped with methyl iodide to give the mixed thioacetal 1 3 6 . This c o m p o u n d was  5 1 5 5  reacted immediately with a solution of tri(n-butyl)tin hydride to  r e m o v e the thiomethyl group of 1 3 6 under radical conditions to give the desired macrocyclic ether 137. This six-step reaction sequence proceeded in an overall yield of 10%.  135 Scheme 19. Synthesis of 6,6-Dimethyloxacyclotetradecane (137)  a  1 3 6  137  Key: (a) EtN, THF, 2,4,6-trichlorobenzoyl chloride, rt; then DMAP, toluene, A, 52%; (b) EtZn, CICHI, CICHCHCI, 0 °C, 85%; (c) Pt0, H, HOAc, 73%; (c) Lawessons ' reagent 48, toluene, A, 47%; (e) LiEtBH, THF, -78 °C; then Mel, 94%; (f) n-BuSnH, AIBN, toluene, A, 67%.  a  3  2  2  2  2  2  3  3  2  136 2.5.2  Conformational Analysis of 6,6-Dimethyloxacyclotetradecane (137)  The H NMR  spectrum of 6,6-dimethyloxacyclotetradecane (137) at rt in CDCI  1  3  contained a two-proton triplet at 3.43 two-proton quintet at 1.60 from 1 . 2 9 1 . 4 2 ppm, singlet at 0.84  ppm.  ppm,  The  were assigned to C-3 ppm  was  a two-proton triplet at 3.42  a two-proton triplet at 1.54  low-field signals at 3.43  and  and  C-14  C-13,  and  respectively. The  3.42  ppm  ppm,  and  C-16  and  a six-proton  were assigned to the  signals at 1.54  and  1.60  geminal methyl groups. The  assignment of these signals was  H M Q C , and H M B C2 D N M R experiments (Table 27).  The  to C-12  ppm  signal at C  13  NMR  aided with COSY,  long-range H- C NMR data 1  integral in distinguishing between the signals in the region of C-2  chemical shifts of the C-2 to C-4 and the C-14  a  a ten-proton multiplet  the methylenes 3 to the ether oxygen. The  assigned to the C-15  spectrum contained 14 lines. The  was  ppm,  a six-proton multiplet between 1 . 1 1 1 . 1 7 ppm,  a-methylene protons of C-2  0.84  ppm,  and  1 3  C-14.  The  portions of this macrocyclic ether  were very similar. H o w e v e r a correlation between one of the carbon atoms adjacent to the quaternary C-6,  and  the protons of one  m a d e these assignments possible. The assigned to C-2 carbon had  and  C-14  of the methylenes y to the ether oxygen  downfield signals at 68.17  adjacent to the ether oxygen atom. The  a chemical shift of 32.39 ppm.  The  H R M S data was  C-6 quaternary  chemical shifts of C-5  carbons that flanked the quaternary carbon were 37.76 and The  and 67.70 ppm were  also consistent with the structure of 137.  and  C-7,  the  38.88 ppm respectively.  1 3 7  Table 27.  H and C N M R Assignments for 6,6-Dimethyloxacyclotetradecane (137) in CDCI at R o o m Temperature  1  13  3  3  Position  68.17  3  1 . 5 4  29.20  4  1 . 3 4  22.48  5  1 . 1 7  37.76 32.39  ~  7  1 . 1 2  38.88  8-11  not  assigned  1 2  1 . 4 0  23.55  13  1 . 6 0  28.74  1 4  3.42  67.70  0.84  29.32  0  Arrows s h o wH M B C correlations. The chemical shift values are in p p m referenced to CHCI (H) and CDCI (C). D u e to signal overlap these signals could not be unambiguously assigned. 1  3  c  b  3.43  15, 1 6  b  13  b  2  6 .  3  C NMR  H NMR  1  1 3  3  The low temperature N M R spectra of 137 were obtained in a 4 : 1 mixture  Freon 2 1 and Freon 22 as solvent (Figure 34). The H N M R spectrum of 137 at 2 1  had already broadened in comparison to the rt spectrum. The signals of the  a-methylenes, C-2 and C-14, at 3 . 4 p p m continued to broaden with a coalesc  temperature of 190 K . Below this temperature, t w o closely spaced signals were vis at 3 . 4 6 and 3 . 4 2 ppm. N o small signals for minor conformations were visible in  region, suggesting the presence of only a single conformation at low temperature. T  p-proton signals between 1 . 5 and 1 . 6 p p m in the rt spectrum coalesced above 2 This w a s the highest temperature of the D N M R series, and the signals for these  protons were already broad. At lower temperatures, signals at 1 . 8 6 ppm, 1 . 5 9 p p  and 1 . 5 2 p p m were visible for these protons. The signal at 0.88 ppm, downfield o  methyl singlet is an impurity. The signal for the C-6 geminal methyl groups at 0.84  1 3 8  did broaden s o m e w h a t as the temperature was lowered, but it remained averaged o the temperature range examined. The remaining signals for other methylene protons  137 were overlapped at rt, and although line shape changes did occur in this region the temperature was lowered, signal overlap prevented a detailed analysis.  The combination of a n u m b e r of factors including, a general preference of  1 4 m e m b e r e d rings for the [3434] diamond lattice conformation over the non-diamon  lattice [3344] conformation, the placement of the ether oxygen at the middle of a 4-  side, and the placement of the gem-dimethyl group at a corner position suggeste  s o m e likely low energy conformations for 137. These included the diamond lattice [3434]-1 and [3434]-4 conformations, and the non-diamond lattice [3344]-1  conformation. In the analysis of the D N M R study of 137, these conformations were considered as candidates for the major conformation of 137.  [3344J-1  139  140  In the [3434]-4 conformation, the ct-methylene protons are n o t in similar  environments. One set occupies a corner position, while the other is on a 3-bond side. The H-2 proton is deshielded by the anisotropy of the C-3/C-4 bond, while the H-2 a  P  proton is deshielded by the anisotropy of the O / C 1 4 bond. These effects are of a similar magnitude, and a small A6 value is predicted. In the case of the C-14 protons, the H-14 proton is deshielded by the anisotropy of the C-12/C-13 bond, but shielded e x o  by van der Waals steric interactions between H-14d and the H-3do and H-11do e n  0  e n  e n  protons that are calculated to be 2.18 A and 2.23 A a w a y from H-14do- These van de e n  Waals steric shielding effects oppose the larger anisotropic effect, and a smaller A5 is expected than for the anisotropic shielding alone. Thus, since the C-2 and C-14 methylene protons occupy different environments in this conformation, the line shape for these protons is predicted to be m o r e complex than observed here.  The non-diamond lattice geometry of the [3344]-1 conformation is distorted and places the C-2 and C-14 protons in slightly different environments. The C-12 dihedral  angle is calculated to be 16° less than in the [3434]-1 conformation. This changes the anisotropic shielding contribution to the chemical shift of the C-14 protons.  T h e  calculated distances between the H-2 and H-5do, and the H-11do and H-14do e n d 0  e n  e n  e n  protons are 2.27 A and 2.29 A. These distances are less than the sum of the van der Waals radii for a pair of hydrogens, and a small van der Waals steric repulsion 2 6  contribution to the A5 of the a-methylene protons is expected. The sum of these effects  could lead to four separate signals for the a-methylene protons. However, depending  on the magnitude of the chemical shift changes caused by the dihedral angle distortion the signals may be partially overlapped.  In the [3434]-1 conformation of 137, the C-2 and C-14 protons adjacent to the ether oxygen are on a 4-bond side. The local environment of these methylenes is essentially equivalent, and any effects experienced by the C-2 protons are also experienced by the C-14 protons. The H-2 proton is deshielded by the anisotropy of e x o  the C-3/C-4 bond, and the H-2do proton is deshielded by a steric interaction with e n  141 H-5ndo, calculated to be 2.22 A away. This van der Waals steric repulsion results e  shielding of H-2x. e  0  The anisotropic shielding effect opposes the van der Waals  shielding effect and the magnitude of the overall shielding is reduced. Thus, the expected A8 for the a-methylene protons in the [3434]-1 conformation is small, in  agreement with the low temperature H N M R spectra, and the [3434]-1 conformation 1  likely to be a major conformation of 137. The downfield portion of the signal at  3 . 4 6 p p mw a s assigned to H-2 and H-14, while the upfield portion at 3 . 4 2 p p m e x o  e x o  assigned to the endo protons.  The p-methylene protons of the [3434]-4 conformation are expected to give  symmetric line shape as the result of anisotropy and van der Waals shielding effe  The H-3do proton is deshielded by the anisotropy of the C-2/0 bond, and deshielde e n  b y a van der Waals steric repulsion with H-14o. The reverse effects are experienc e n d  b y H-3, and a normal A5 value is predicted. The H-13 proton is deshielded b y e x o  p  anisotropy of both the C-11/C-12 bond and the O / C 1 4 bond. N o van der Waals repulsions are expected since these protons occupy a corner position in this  conformation. The anisotropy shielding effects are additive giving a large predicted A5 value for C-13.  Four signals are expected for the p-methylene protons in this  conformation as a result of these effects with the signals of the C-3 protons flanke the signals of the C-13 protons. The lowest field p-methylene proton signal at  1 . 8 6 p p m integrates to two-protons, where a one-proton signal at low-field for the H  proton is expected for this conformation. Therefore, the [3434]-4 conformation is not major conformation of 137.  In the [3434]-1 conformation, the C-3 and C-13 methylenes are both locate corner positions, and similar chemical shifts for each methylene are expected.  T  H-3 proton is deshielded b y the anisotropy of both the C-4/C-5 bond, and the O P  bond. These effects are additive and a large A5 value is predicted. The relative  integration of the p-methylene signals at 1.86, 1.59, and 1.52 p p m compared to th a-methylene signals at 3.4 p p m is approximately 2:1:1:4. The downfield signal is  assigned to H-3 and H-13, and the upfield signals at 1 . 5 9 and 1 . 5 2 p p m are as P  p  142 to H-3 and H-13. The chemical shift difference of the upfield signals at low a  a  temperature is equal to the chemical shift difference of the C-3 and C-13 methylene  protons at rt. It is unclear w h y this chemical shift difference is not also observed in downfield signal. The observed D N M R data is still consistent with the [3434]-1 conformation of 137.  A CD N M R study of 137 was also carried out in a 4 : 1 mixture of Freon 2 1 13  Freon 22 as solvent. O n e signal was observed for the C-6 quaternary carbon throu  the 145-220 K temperature range examined. Only one signal was observed at low  temperatures for each of the C-5 and C-7 carbons adjacent to the quaternary carb  These results are consistent with one conformation being present at low temperature or alternatively a case where one conformation is considerably m o r e populated than  others present. The C-15 and C-16 geminal methyl groups gave one signal at hig  temperature (220 K), a broad signal at 200 K , and t w o signals as the temperature lowered to 145 K . At low temperature these signals are separated b y 50 Hz.  T  result is consistent with a single conformation present at low temperature where th process of ring inversion is slow, and the C-15 and C-16 methyl groups are n o averaged as in the [3434]-1 conformation.  A molecular mechanics search for low energy conformations of 137 w a s conducted with the Monte Carlo technique and the MM3* force field. The global m i n i m u m conformation w a s the [3434]-1 conformation 137-A with the [3434]-4  conformation 137-B calculated to have the next lowest energy, 1.15 kcal/mol higher. These calculations suggested the existence of four other low energy conformations within 2 kcal/mol of the global m i n i m u m conformation (Table 28). Higher energy  conformations were ignored as they were not considered to be significantly populated The relative populations of these conformations at different temperatures were  calculated from relative energies obtained from the MM3* calculations (Table 29). T h results of these calculations suggested the [3434]-1 conformation of 137 to be the  major conformation over the temperature range studied in agreement with the D N M data.  143 Table 28.  L o w Energy Conformations of 6,6-Dimethyloxacyclotetradecane (137) Skeleton  Relative Energy (kcal/mol)  137-A  [3434]-1  0.00  137-B  [3434J-4  1 . 1 5  137-C  [13343 '] '  1 . 4 9  137-D  [3344]-1  1 . 5 3  137-E  [13343 '] '  1 . 6 6  Conformer  o  a  Strain energies are relative to the global m i n i m u m conformation calculated with th MM3* force field.  144 Table 29.  Conformer  Thermodynamic Values for the Five Lowest Energy Conformations of 137  Skeleton  Relative Energy (kcal/mol)  Population (%) 185 K  3  298 K  135 K  137-A  [3434J-1  0.00  73.6  92.0  97.8  137-B  [3434]-4  1.15  10.5  4.0  1.3  137-C  [13343 '] '  1.49  5.9  1.6  0.4  137-D  [3344J-1  1.53  5.6  1.4  0.3  137-E  [13343 ' '1  1.66  4.5  1.0  0.2  Strain energy values relative to the lowest energy conformation calculated with the MM3* force field. The energy of the transition states for the interconversion of conformations of 137 was determined from the D N M R spectra. The signals for the a-methylene protons are separated by 21 Hz with a T of 190 c  K leading to a transition state energy of  9.5 kcal/mol. The signals of the p-methylene protons are also averaged at rt. At low temperature where the exchange rate was lowered, these are found to have chemical shift differences of 134 and 164 Hz. At an estimated T of 230 K, this corresponds to a c  transition state energy of 10.7  kcal/mol. The  C-15  separated by 50 Hz with a T of approximately 200 c  and  C-16  methyl signals are  K in the C 13  D N M R study.  This  corresponds to a transition state energy of 9.7 kcal/mol. The average of these values is 10.0 ±0.5 kcal/mol.  The  single corner m o v e m e n t mechanism proposed by  Dale for  the  interconversion of the low energy [3434]-1, [3434]-4 and [3344]-1 conformations 137-A, 137-B, and 137-D requires [73343] transition state structures. The energies of these were estimated via molecular modelling calculations using the dihedral drive method  1 2 4  and  the MM3* force field. The  energies of the [73343] transition states for  the  interconversion of the [3434]-1 and [3434]-4 conformations 137-A and 137-B with the [3344]-1 (Figure 35).  conformation 137-D were estimated at 10.7 kcal/mol and  10.4 kcal/mol  The 1 b o n d side of the transition state structure was located between the  145 "moving" corner atoms of the interconverting conformers. The conformations with 1 b o n d sides can be interconverted with the 4-sided conformers through the [3344]-1 conformation. These conformations do not interconvert via the single corner m o v e m e n t mechanism, b u t rather via the rotation of dihedral angles on the side of the conformation. The energy of the transition state for the interconversion of the [13343 '] ' conformation 137-E with the [3344]-1 conformation 137-D w a s estimated 10.4 kcal/mol. This value was obtained by driving the C-10  and C-12  at  dihedral angles.  The calculated and observed transition state energies are in good agreement. These  values are both m o r e than 1 kcal/mol higher than the observed transition state energ of oxacyclotetradecane (90). Transition states involving m o v e m e n t of the geminally substituted carbon a w a y from the corner position, as would occur in the pseudorotation of 137, are expected to be higher in energy.  [3434]-1  [1334'3']  Figure 35.  [3344]-1  [3434]-4  Interconversion of conformations of 137 through the [3344]-1 conformation.  146  2.6.1  Synthesis of 8,8-Dimethyloxacyclotetradecane (154)  The synthetic plan for the preparation of the macrocyclic ether 154 was developed according to the s a m e strategy used for the preparation of 6,6-dimethyloxacyclotetradecane (137). Again the molecule was  prepared in two parts  and coupled using a dithiane ring as the central unit (Scheme 20).  In this case, both  the left and right synthetic fragments of 154 were prepared from 1,6-hexanediol (138). The  central dithiane ring was subsequently converted into the  gem-dimethyl group  while the ring of the macrocycle was formed via the cyclisation of a hydroxy acid to give a lactone that would be converted into macrocyclic ether 154.  148 The  diol 1,6-hexanediol (138) was  alkylating agents attached to the  the  c o m m o n starting material for both the  dithiane ring. This diol was  treated with  48%  hydrobromic acid under Dean-Stark conditions to give the monobrominated alcohol 139 (Scheme 21 ).  145  This b r o m o alcohol was  divided into two portions with the first portion  protected as a tetrahydropyranyl ether. This two-step reaction sequence proceeded 1 4 7  in an overall yield of 87%.  The  remaining portion of 139 was  conditions to give the b r o m o aldehyde 1 4 0 .  163,164  The  first oxidized under Swern  aldehyde 140 was  then protected  as the ethylene acetal 141. This three-step reaction sequence proceeded in an overall yield of  62%.  Scheme 21. Synthesis of Alkylating Agents 141 and  142  a  140  Key: (a) 48% HBr, CH, A, 90%; (b) DHP, D M S O , EtN, CHCI, -78 °C, 76%;  a  6  3  6  2  2  141  PPTS, CHCI, rt, 97%; (c) (COCI), (d) PPTS, HOCHCHOH, CH, A, 2  2  2  2  2  6  6  90%.  149 The  bisalkylated dithiane 144 was  (Scheme 22).  prepared via a two-step reaction sequence  The anion of 1,3-dithiane was generated with n-butyllithium and  alkylated with 0.66  equivalents of b r o m o acetal 141 to give the heptane 143.  146  This  monoalkylated product was reacted further with n-butyllithium to generate the anion of 143 which was alkylated with 1.2 equivalents of bromide 142 to give 144.  146  of the dithiane ring gave ketone 145.  150  Hydrolysis  This reaction sequence proceeded in 16%  yield for three-steps with the second alkylation giving the lowest yield. The H 1  spectrum of 145 contained a one-proton triplet at 4.81 acetal, and a one-proton doublet of doublets at 4.54 tetrahydropyranyl ether. The C NMR 13  NMR  ppm for the C-1 methine of the ppm for the C-13  methine of the  spectrum of 145 showed a signal at 211.32 ppm  and the IR spectrum showed a sharp band at 1716  cm" for the C-7 carbonyl. 1  Conversion of the ketone into the gem-dimethyl group was accomplished in twoparts as in the case of 6,6-dimethyloxacyclotetradecane (137). reaction of ketone 145 with Tebbe reagent 32  38  The small scale  proceeded to give, after column  chromatography with basic alumina, alkene 146 in 70% yield.  151,152  Unfortunately,  these reaction conditions gave low yields on the required larger scale. The crude  reaction mixture was filtered directly through basic alumina which quenched the excess Tebbe reagent as well as removed unwanted titanium compounds from the alkene product. This filtration step was  problematic w h e n performed on a large scale.  To  overcome this, the methylenation of the ketone with a Wittig reagent was investigated. The  anion of methyl triphenylphosphonium iodide was generated and  ketone 145 to give the alkene 146 in 66% yield (Scheme 22).  reacted with  This Wittig chemistry  was found to be better suited to the larger reaction scale. The H N M R spectrum of 1  146 contained a two-proton singlet at 4.64 at 1643  ppm and the IR spectrum contained a band  cm" for the carbon-carbon double bond. The 1  H R M S and chemical analysis  results were also consistent with the composition of alkene 146.  Removal of the protecting groups under weakly acidic conditions gave the hydroxy aldehyde 147.  147  The chemoselective oxidation of the aldehyde of 147 was  performed with sodium chlorite to give hydroxy acid 148.  165  This reaction sequence  1 5 0 proceeded in 36% yield for the three-steps beginning with the Wittig reaction.  Th  H N M R spectrum of this colourless oil contained a singlet at 4.65 p p m for the  1  methylene of the double bond as well as a triplet at 2.30 p p m for the C-2 me  adjacent to the acid group of 148. The I R spectrum contained bands at 3637 cm  1712 cm" for the carboxylic acid terminus of the hydrocarbon and at 1644 cm" fo 1  double bond of 148.  1  151 Scheme 22. Synthesis of 7-Methylene-13-hydroxytridecanoic acid (149)  147  a  148  Key: (a) n-BuLi, THF, -20 °C; then 141, 67%; (b) n-BuLi, THF, -20 °C; then 142, (c) Hg(CI0), CaC0, THF, H0, rt, 61%; (d) (CH)PCHI, n-BuLi, THF, 0 °C, 66%; (e) PPTS, acetone, H0, A, 86%; (f) NaCI0, NaHP0, (CH)CCHCH, f-butyl alcohol, H0, rt, 63%.  a  42  3  2  6  2  32  3  2  5  3  2  2  4  152 The cyclisation of the  hydroxy acid 148 was achieved with the Yamaguchi  procedure with the hydroxy acid first activated as a mixed anhydride with 2,4,6-trichlorobenzoyl chloride and then cyclized under high dilution conditions to give 2 8  the  lactone 149 in 42% yield (Scheme 23). The exocyclic methylene of 149 was 2 8  converted into a cyclopropyl group.  1 5 9 , 1 6 0  addition of the  This reaction was sluggish and further  zinc complex precursors was necessary to optimize the  yield. The  cyclopropyl group of 150 was hydrogenolyzed with Adams' catalyst to give the ge/77-dimethyl lactone 151.  161  TheH N M R spectrum of 151 contained a two-proton  multiplet between 4.14-4.16 ppm  1  for the C-13 methylene adjacent to the ether oxygen  as well as a six-proton singlet at 0.81  ppm  for the new  geminal methyl groups.  CN M R spectrum contained 14 lines with a low-field signal at 173.56 ppm  13  carbonyl. The The  IR spectrum contained a band at 1736  cm" 1  The  for the C-1  also for the C-1 carbonyl.  H R M S results were also consistent with the composition of lactone 151.  The lactone 151 was reacted with Lawessons ' reagent 48 to give the thionolactone 152.  51  The thionolactone was further reacted with lithium  triethylborohydride followed by trapping of the resultant sulfur anion with methyl iodide to give the  mixed thioacetal 153.  51  This compound was reacted immediately with a  solution of tri(/7-butyl)tin hydride under radical conditions to reduce the thiomethyl group of 153 to give the macrocyclic ether 154. This reaction sequence proceeded in 2% yield for the  six-steps with the  Simmons-Smith cyclopropanation and  reduction steps having the lowest yields.  the hydride  153 Scheme 23. Synthesis of 8,8-Dimethyloxacyclotetradecane (154)  a  153  154  Key: (a) EtN, THF, 2,4,6-trichlorobenzoyl chloride, rt; then DMAP, toluene, A, 42%; (b) Zn-Cu, CHI, l , Et0, A, 34%; (c) Pt0, H, HOAc, rt, 78%; (d) Lawesso reagent 48, toluene, A, 54%; (e) LiEtBH, THF, -78 °C; then Mel, 98%; (f) /7-BuSnH, AIBN, tol, A, 40%.  a  3  22  2  2  2  3  3  2  154 2.6.2  Conformational Analysis of 8,8-Dimethyloxacyclotetradecane (154)  The H NMR  spectrum of 8,8-dimethyloxacyclotetradecane (154) in CDCI at rt  1  3  contained a four-proton triplet at 3.40 1 . 5 3 1 . 5 8 ppm,  1 . 4 1 1 . 4 7 ppm,  1 . 1 4 1 . 2 4 ppm,  and  and  ppm,  three four-proton multiplets between  1.28-1.35 ppm,  a six-proton singlet at 0.81  an eight-proton multiplet between  ppm.  The  assigned to the protons of C-2/C-14. The  singlet at 0.81  geminal methyl groups of C-8 (Table 30).  The  downfield triplet was ppm  was  H R M S analysis was  assigned to  the  also consistent with  the composition of 154.  The  C  13  NMR  spectrum contains eight lines indicating that either 154 has  a  plane of symmetry, or is undergoing site exchange that is rapid on the NMR timescale. The  downfield signal at 69.27 ppm  29.09 ppm was  was  assigned to the C-8  assigned to C-2/C-14, and  geminal methyl groups. The  assigned to the quaternary C-8 carbon since this signal was  height of the other C 13  signals. The  data from COSY, H M Q C , and was  was  remaining C 13  the  signal at  signal at 32.80 ppm approximately half the  and H signals were assigned with 1  H M B C 2 D N M R experiments. The  signal for C-4/C-12  shifted to higher field than expected based on its through-bond distance from the  ether oxygen. This upfield shift was  caused by a y-gauche effect with the ether oxygen  as a result of the gauche dihedral relationship between C-4 and the ether oxygen atom.  155 Table 30.  H and C N M R Assignments for 8,8-Dimethyloxacyclotetradecane (154) in CDCI at R o o m Temperature  1  13  3  H NMR  Position  12 /  \l4  1 0 j ^ 15  V J  8  1  C NMR  13  a  2, 1 4  3 . 4 0  69.27  3, 13  1 . 5 5  27.31  4, 1 2  1 . 4 4  24.80  5, 1 1  1 . 3 1  27.90  6, 10  1 . 2 0  21.56  1 . 1 8  3 8 . 6 1  7,9 6  a  8  32.80  ~  15, 1 6  29.09  0 . 8 1  The chemical shift values are in p p m referenced to CHCI (H) and CDCI (C). 1  3  1 3  3  A series of D N M R experiments were carried out with 154 using a mixture o  Freon 2 1 and Freon 22 as solvent (Figure 36). The H N M R spectrum of 154 at 2 1  contained six signals similar to the rt spectrum however at the lower temperature,  signals had broadened. At lower temperatures, the downfield signal at 3 . 4 0p p m for  C-2/C-14 protons broadened to form, at intermediate temperatures, a pair of signals  3 . 5 5 and 3 . 2 7 ppm. The upfield signal at 3 . 2 7 p p m broadened as the temperature lowered further. The signal at 1 . 5 5 p p m for the C-3 protons broadened to give temperatures below 185 K a downfield signal at 1 . 8 0p p m , with another signal  presumably concealed b y the signals of the methylene envelope. The C-8 gemina  methyl group signal did not change significantly over the temperature range studied This data is consistent with one major conformation of 154 being present at low temperature.  1 5 6  decane (154) in CHCIF:CHCIF (4:1). 2  2  1 5 7 It is significant that the signal for the C-8 geminal methyls remains averaged even at low temperature while the signal for the methylene protons adjacent to the ether oxygen does not. One possibile explanation is that the major conformation of 154 is symmetric with a C  2  axis running through the C-8 corner atom. This C  2  axis would  interconvert the equivalent C-8 geminal methyl groups. However the protons adjacent to the ether oxygen would be inequivalent since they are in different environments.  The [3434]-1 and [3434]-4 conformations were low energy conformations in the unsubstituted 1 4 m e m b e r e d ether, but these conformations would have transannular steric interactions involving an endo methyl group in the macrocyclic ether 154. The low energy conformations of 154 would have the C-8 gem-dimethyl group at a corner position of the ring. Therefore, the diamond lattice [3434]-3 conformation, and the nondiamond lattice [3344]-2, [3344]-3 and [3344]-6 conformations of 154, where the C-8 gem-dimethyl group is located at a corner position are possible l o w energy conformations of the macrocyclic ether 154. The ether oxygen a t o m is located at a corner position in each of these conformations with the exception of the [3344]-2 conformation.  An oxygen a t o m does not eliminate any transannular hydrogen  interactions w h e n located at a corner position, and in general such conformations are unfavoured. Non-corner oxygen atoms d o however eliminate s o m e transannular  hydrogen interactions, and the [3344]-2 conformation with its non-corner oxygen a t o m is likely to have a low strain energy. The [3344]-2 conformation with a C s y m m e t r y is a likely major conformation for 154.  2  axis of  158  6  3  4  4  5  [3344]-2  [3434]-3  2  2 o [3344]-6  [3344]-3  The two peaks observed in the D N M R spectra of 154 for the protons adjacent to the ether oxygen were of approximately equal intensity. In the [3344]-2 conformation, the C-2 corner protons do not experience any van der Waals steric interactions since both protons are exo to the ring. The H - 2 proton is deshielded by the anisotropy of the a  O/C-14 bond, but shielded by the anisotropy of the C-3/C-4 bond. These opposing effects are of a similar magnitude, and a small A8 value is expected for the C-2 protons. The H-14 ndo proton is deshielded by van der Waals steric interactions with the H-3 do e  en  and H-11endo protons calculated to be 2.08 A and 2.19 A a w a y from H-14 do. en  results in a shielding of the H-14 protons. The  exo  This  proton, and a larger A5 value than that of the C-2  C-2 and C-14 methylene protons are in different environments in the  [3344]-2 conformation, and different lineshapes are predicted for the two methylene groups. The line shape of the C-2 and C-14 protons in this conformation is predicted to be m o r e complex than that observed in the D N M R spectra. The C-2 and C-14 protons are also in different environments in the diamond lattice [3434]-3 conformation with the oxygen a t o m at a corner position. The  line shape is again predicted to be m o r e  complex than that observed here.  In the symmetric [3344]-3 and [3344]-6 conformations, the geometry of the C-2 and C-14 protons is similar in each conformation. The  H-2 o proton of the [3344]-3 eX  159 conformation is deshielded by the anisotropy of the O / C 1 4 bond, but shielded by a van der Waals steric interaction between H-2 o and H-13do which are calculated to be e n d  2.12  A apart. The  predicted A5 value for the  e n  H-2do and e n  H-2 protons in this e x o  conformation is small. The H-2 proton in the [3344]-6 conformation experiences both e x o  of these effects, but is further shielded by a van der Waals steric interaction between H-2 o and H-5 o calculated to be 2.18 e n d  e n d  A apart. The A8 between H-2do and H-2 in e n  e x o  this latter conformation is predicted to be larger than that of the [3344]-3 conformation. The A5 value for the C-2 and C-14  protons averaged over both these conformations is  consistent with the observed low temperature spectra.  A molecular mechanics search for low  energy conformations of 154 w a s  conducted with the Monte Carlo technique, and m i n i m u m conformation was (Table 31).  The  the MM3* force field. The global  found to be the non-diamond lattice conformation 154-A  second lowest energy conformation 154-B, was  lattice, but symmetric and 0.41  also non-diamond  kcal/mol higher in energy. The C-8 gem-dimethyl group  is at a corner position in all of the low energy conformations found. The first diamond lattice conformation found was  154-E. This was a [3434]-3 conformation with a corner  C-8 gem-dimethyl group, and the ether oxygen at the opposite corner position. Higher energy conformations were not  considered to be significantly populated over the  temperature range studied. The relative populations of these conformations at different temperatures were calculated from enthalpy values (AH ) and entropy values (AS°) with 0  both s y m m e t r y and mixing contributions (Table 32).  These calculations suggest the  global m i n i m u m non-diamond lattice conformation 154-A is the major conformation over the temperature range examined.  1 6 0 Table 31.  L o w Energy Conformations of 8,8-Dimethyloxacyclotetradecane (154) Skeleton  Relative Energy (kcal/mol)  154-A  [22334]  0.00  154-B  [22244]  0.41  154-C  [3344]-2  0.68  154-D  [3344]-6  1 . 6 1  Conformer  a  Strain energies are relative to the global m i n i m u m conformation calculated with t MM3* force field.  161  Table 32.  Thermodynamic Values for the Five Lowest Energy Conformations of 154  Conformer  Skeleton  Relative Energy (kcal/mol)  AS (cal/mol)  154-A  [22334]  0.00  1 . 3 8  61.0  74.2  81.0  154-B  [22244]  0.41  0.00  15.3  12.6  10.3  154-C  [3344]-2  0.68  1 . 3 8  19.5  12.4  8.4  154-D  [3344]-6  1 . 6 1  0.00  2.0  0.5  0.2  154-E  [3434]-3  1 . 9 7  1 . 3 8  2.2  0.4  0.1  3  b  Population (%) 298 K 190 K 150 K  Strain energy values are relative to the global m i n i m u m conformation calculated with the MM3* force field. Entropy values were calculated with both s y m m e t r y and mixing terms.  3  b  The  D N M R data was  reexamined with the non-diamond lattice conformations  154-A and 154-B in mind. Conformation 154-B has a C axis through the C-8 corner 2  position, and one signal was expected for the geminal methyl groups. No transannular van der Waals shielding effects are experienced by the C-2 and C-14  protons in these  two conformations since they are all exo to the ring. The H-2 and H-14 protons are P  a  both deshielded by the anisotropy of the p-carbon-carbon bond in conformation 154-A, while the H-2  P  and H-14 protons are deshielded in conformation 154-B. The predicted p  A 5 value between these protons in conformation 154-A and  conformation 154-B is  consistent with that observed in the D N M R spectra here. Overall, the D N M R data is consistent either with conformation 154-B, or with conformation 154-A where a local inversion to conformation 154-B still occurs at low temperature.  The  transition state energies for the interconversion of conformations of the  macrocyclic ether 154 were calculated by first determining the rate of exchange between a pair of averaged signals in the D N M R spectra. The rate of exchange was used to calculate the free energy of activation ( A G * ) with the coalescence temperature (T) also obtained from the D N M R spectra, and the equations in Chapter 1. c  temperature, the C-2 proton signals of 154 are separated by 139 Hz. This  At low  \  1 6 2 corresponded to a transition state energy of 8.8 kcal/mol at the coalescence temperature of 190 K. This was the only averaged set of signals in the D N M R spectra of 154 from which a rate of exchange could be determined.  The single corner m o v e m e n t mechanism proposed b y Dale for  the  interconversion of large ring conformations such as the [3344]-2 154-C, [3344]-6 154-D, and  [3434]-3 154-E conformations involve [73343] transition state structures  with a 1 b o n d side between the moving corner atoms (Figure 37).  The  energies of  these transition states were calculated via molecular modelling calculations using the dihedral drive method and the MM3* force field. The necessary dihedral angles were 1 2 4  incremented by 10° during these calculations. The energies of the [73343] transition state structures involved in the interconversion of the diamond lattice [3434J-3 conformation 154-E with the non-diamond lattice [3344]-2 and [3344]-6 conformations 154-C and 154-D were estimated at 13.4  kcal/mol and 14.2  kcal/mol respectively. The  low energy, non-diamond lattice conformations 154-A and 154-B can interconvert via the single corner m o v e m e n t mechanism as well (Figure 37). The energy of the transition state structure was estimated at 10.8 kcal/mol using the dihedral drive method. These conformations are not interconvertable with the other low energy conformations 154-C through 154-E via this s a m e mechanism. This latter transition state energy was  in good agreement with the value derived from the D N M R data,  whereas the transition state barriers of the interconversion through the diamond lattice conformation 154-E were higher. The  observed transition state energy is in better  agreement with that of the interconversion of the non-diamond lattice conformations of 154, in support of the presence of these conformations.  163 C  2  [3344]-2  Figure 37.  2.7.1  [3434]-3  [3344]-6  Interconversion of conformations of 154 via single corner movements.  Conclusion  The  syntheses of the 1 4 m e m b e r e d macrocyclic ethers 90, 92, 103, and 104  were carried out via the Baeyer-Vi Niger ring expansion of the ketones 86 and 97 to give intermediate lactones 87 and 98. Further reaction of these lactones under thionation conditions and subsequent radical reduction gave the macrocyclic ethers. The diastereomeric ethers 103 and  104 were prepared under both hydrogenation and  radical reduction conditions with low selectivity observed under both conditions. configuration of the methyl substituents in 103 and 104 were determined by chiral GC analysis.  The  164  The Baeyer-Vi Niger ring expansion of ketone 106 did not proceed. The required lactone 114 was instead prepared via the cyclisation of hydroxy acid 113 with the  Yamaguchi reagent. The thionation of this lactone also failed, and a direct reduction  the lactone with sodium borohydride in the presence of boron trifluoride etherate w employed to give macrocyclic ether 116.  The macrocyclic ether 119 was prepared via the reduction of lactone 118. However, even under refluxing conditions, the boron trifluoride mediated sodium borohydride reduction of this lactone proceeded in low yield.  Macrocyclic ethers 137 and 154 were prepared from hydroxy acid intermediates  131 and 148. The cyclisation of these intermediates with the Yamaguchi reagent gav  lactones 132 and 149. Further reaction of these lactones under thionation conditions and subsequent radical reduction gave the desired macrocyclic ethers.  The conformation of these 1 4 m e m b e r e d ethers was analyzed with data from H-DNMR experiments. The low-temperature chemical shift difference of protons with 1  signals that were averaged at rt, were generally in agreement with predictions based anisotropy and van der Waals shielding effects in the low energy conformations.  Although m a n y different possible conformations for these large ring compounds exist  only a few conformations were found to be appreciably populated at r o o m temperat  and below. The conformations were consistent with the substituents generally located exo to the ring, with geminal substituted carbon atoms occupying corner positions exclusively. These results were consistent with the molecular mechanics calculations.  In general, the diamond lattice [3434] conformation was preferred with the oxygen a  at either the 1-position or the 4-position. Thus the introduction of the oxygen a t o m  these macrocyclic ethers did not have a significant effect on the conformation of ring.  The transition state energies for the conformational interconversion were  determined from the H D N M R experiments to be in the range of 8 . 5 to 9 . 6 kca 1  165 The interconversion barriers of the gem-dimethyl substituted macrocyclic ethers 116,  119, and 137 were found to be higher than those of the other macrocyclic ethers studied. The calculated single corner m o v e m e n t transition state energies of the  macrocyclic ethers were between 1 0 and 15 kcal/mol and higher than the obser values. Both of these values were larger than those previously obtained for the hydrocarbon cyclotetradecane.  1 6 6  CHAPTER 3  Synthesis and Isomerization of Unsaturated 14-Membered Macrocyclic Ethers Macrocyclic compounds are c o m m o n l y formed via the modification of an existing ring, or through the cyclization of an acyclic precursor. Both of these methods were used to good advantage during the  study of a series of 1 4 m e m b e r e d macrocyclic  ethers, the results of which were discussed in Chapter 2. A cyclization m e t h o d that is currently receiving m u c h attention in the literature is the olefin metathesis cyclization of an acyclic diene. This reaction uses an organometallic catalyst to give a cyclic c o m p o u n d with a carbon-carbon double bond in the  ring at the  location of the ring  closure. An organometallic catalyst s h o w n to be quite useful for this chemistry is the 1 0  ruthenium alkylidene 9 prepared by Grubbs and coworkers.  1 8 1 , 6 6  PCy  3  X= CH2,  COO,  CON,  NH, 0, S  The metathesis cyclization is a general reaction for the  formation of cyclic  compounds with a variety of ring sizes. The m e t h o d is compatible with a range of other  functional groups which allows for the formation of not only cyclic hydrocarbons, but also heterocyclic compounds containing oxygen, sulfur, and 1 1 1 ,9  The product of the  cyclization contains a new  1 6 7  nitrogen atoms. 2 1 , 2 2  synthetic handle, the newly formed  carbon-carbon double bond, that can be further modified to introduce additional substituents into the cyclic system. To evaluate this reaction, the synthesis of s o m e 1 4 m e m b e r e d macrocyclic ethers was undertaken. The target ethers contained different alkyl substitution and also different configurations of the carbon-carbon double  1 6 7 b o n d as a result of the metathesis cyclization. W h a t the preferred configuration of the  double bond would be in each case, as well as, w h a t affect if any the C-2 methyl group would have on the cyclization were questions of interest.  157 (Z) R = H,  158(E) R = H,  3.1.1  163 (Z)  R = CH 164(E) R = CH 3  3  Synthesis of Oxacyclotetradec-5-enes (157) and (158)  The macrocyclic alkenes 157 and 158 were prepared using the metathesis reaction to form the macrocyclic ring. This required as the cyclization precursor an  acyclic diene ether which was produced via the O-alkylation of a primary alcohol. T h e anion of 9-decenol (155) was generated with potassium hydride and reacted with 5-bromo-1-pentene in the presence of D M P U to give the acyclic diene ether 156. This diene was cyclized under metathesis conditions with the Grubbs catalyst 9 .  1 6 6  Solutions of the diene 156 and the metathesis catalyst 9, both in toluene, were slowly  combined under high dilution conditions using a syringe p u m p . This two-step reactio sequence proceeded to give the macrocyclic ethers 157 and 158 in a ratio of 59:41 with an overall yield of 35% (Scheme 24). The macrocyclic ethers 157 and 158 had slightly different R values on silica, as well as different retention times on a DB-210 GC f  column. This allowed for the separation of the isomeric products.  168 Scheme 24. Synthesis of Oxacyclotetradec-5-enes (157) and (158)  a  155  156  157 (Z) 158(E)  Key: (a) KH, THF, 0 °C; then 5-bromo-1-pentene, DMPU, 84%; 9, toluene, 42%.  a  (b) Grubbs catalyst  166  The 5.51  H  1  NMR  spectrum of 157 contained one-proton signals at 5.26  and  ppm for the C-5 and C-6 methine protons of the double bond. Signals were also  present at 3.41  and 3.38  ppm for the protons of the C-2 and C-14  to the ether oxygen. The C  NMR  13  spectrum contained 13 lines with the C-5 and  methine carbon signals at 129.59 and 130.87 ppm, carbons at 68.81  and 68.69 ppm.  methylenes adjacent C-6  and the C-2 and C-14 methylene  Unfortunately the C-2 and C-14  signals could not be  unambiguously assigned even with an H M Q C experiment due to the similarity of their chemical shifts. The IR spectrum of 157 contained a w e a k band at 1649 carbon-carbon stretch of the double bond. In addition, the  cm" for the 1  H R M S and chemical  analysis results were consistent with the composition of ether 157.  The H NMR 1  spectrum of ether 158 contained overlapping signals for the  and C-6 methine protons of the double bond at 5.39  and 5.34  signals for the C-2  chemical shifts of 3.37  and  C-14  methylene protons had  3.48  ppm respectively. The C NMR  and  C-6  13  131.80 ppm.  methylene carbon signals had chemical shifts of 67.01 The  ppm respectively. The and  spectrum of 158 contained 13 lines with the  methine carbon signals at 1 3 0 . 6 1 and  C-5  The  C-2  and  C-5 C-14  and 69.54 ppm respectively.  H R M S and chemical analysis data were also consistent with the composition of  ether 158. A band for the carbon-carbon stretch of the double bond was not visible In the IR spectrum of 158.  In order for a molecular vibration to give rise to an  IR  169 absorption, the molecular motion m u s t result in a change of the dipole m o m e n t of  the  molecule. The change in dipole m o m e n t for the stretching of the carbon-carbon double bond of 158 is either very small or zero, and spectrum at ca. 1600  hence no band is visible in the IR  cm" for the carbon-carbon double bond stretch. 1  In order to determine whether the major isomer of oxacyclotetradec-5-ene had the E or the Z configuration, a series of H homonuclear decoupling NMR experiments 1  were performed. The  coupling constant for olefinic protons of a trans double bond (E)  are typically in the range of 12-18  Hz, while olefinic protons of a cis double bond (Z)  typically have a smaller coupling constant in the H NMR  1  decoupling experiments, it was  range of 6-12  determined that the  major isomer 157 had a coupling constant of 10.7 Hz and assigned the Z configuration. determined to have the  Hz.  1 6 8  From the  olefinic protons of  the  was correspondingly  The double bond of the minor isomer 158 was  E configuration based on a coupling constant of 15.2  between the olefinic protons. Additional H NOE 1  showed an enhancement of the signal of one  Hz  difference experiments on isomer 157 olefinic proton upon irradiation of  the  other olefinic proton thus confirming the cis configuration of the double bond of 158. The trans isomer would not have been expected to s h o w such an enhancement.  Once the configuration of the double bond in 157 and above IR results were clear. The  158 was  determined, the  IR spectrum of 157 contained a w e a k absorption for  the carbon-carbon stretch of the double bond. Typically, the corresponding absorption in the trans isomer is weaker. In the case of the trans isomer 158 this absorption is 1 6 9  not visible in the IR spectrum at all.  3.1.2 Cis-Trans Isomerization of (Z/£)-Oxacyclotetradec-5-ene (157) and (158) Once prepared, the cis-trans isomerization of the carbon-carbon double bond in 157 and 158 was  examined. This reaction is expected to give an equilibrium mixture of  the isomers that is dependent on the relative energies of the low energy conformations of each isomer. Isomerization of carbon-carbon double bonds can be performed with a variety of reagents including: tri(n-butyl)tin hydride, tris(trimethylsilyl)silane, 1 7 0  1 7 1 1 , 7 2  170 iodine, nitrous acid, and phenyl disulfide. 1 7 3  1 7 4  1 7 5 , 1 7 6  Of these possible reagents, the  reaction of phenyl disulfide under photolysis conditions, to generate benzene thiyl radicals, was the m e t h o d chosen. This m e t h o d is less likely to produce positional  isomers, a problem c o m m o n l y encountered with the isomerization of non-conjugated alkenes such as 157 and 158 using iodine or acid reagents.  1 7 5  A solution of ether 157 and phenyl disulfide immersed in a 0.0014 M KCr0 2  solution was photolysed with an Hanovia 4 5 0 W m e d i u m pressure mercury lamp.  combination of pyrex glass and the chromate solution gave an irradiation w i n d o w fr  290-340 nm. W h e n photolysed, the ether 157 gave a mixture of ethers 157 and 1 1 7 7  (GC ratio, 41:59). Using equation 8, this corresponded to an energy difference of  0.22 kcal/mol at 25 ° C (Table 33, Entry 1). W h e n reacted under similar conditio ether 158 also gave a mixture of ethers 157 and 158 (GC ratio, 39:61) which corresponded to an energy difference of 0.26 kcal/mol (Table 33, Entry 2). AG° = - RTInK  (8)  These experimental results were compared to values obtained from molecular  mechanics calculations using the MM3* force field. The global m i n i m u m conformation of the cis alkene 157 w a s a distorted [3434] conformation with an energy of  15.74 kcal/mol. The next conformation was 1 . 0 8 kcal/mol higher in energy. The glo m i n i m u m conformation for the trans isomer 158 w a s a non-diamond conformation with an energy of 15.51 kcal/mol.  lattice  The second lowest energy  conformation of 158 was 0.92 kcal/mol higher in energy. Using these calculated  enthalpy values as an estimation of the relative energies of 157 and 158 (AS = 0) energy difference of 0.23 kcal/mol corresponded to a 40:60 Boltzmann distribution  ethers 157 and 158 at 25 ° C (Table 33, Entry 3). This was in good agreement wit experimental data.  171 Table 33.  Experimental and Theoretical Equilibrium Ratios for the Isomerization Reaction of Oxacyclotetradec-5-enes (157) and (158)  Entry  a  b  c  Ratio 157:158 a  AG° (kcal/mol) b  1  157 (Z)  41:59  0.22  2  158(E)  39:61  0.26  3  MM3*  40:60  0.23  c  The equilibrium ratio of 157:158 was determined by analysis with a DB-210 GC column. AG values were calculated using equation 8 at 25 °C. Calculated relative strain energies were taken as an approximation of AG. 0  0  It is interesting to note, that the trans isomer 158 was the favoured isomer in the isomerization and hence lower in energy. However, cis isomer 157 was the major isomer produced in the metathesis cyclization. This indicates that even though the metathesis reaction is believed to proceed via a series equilibrium processes (Chapter 1),  11  it does not necessarily yield an equilibrium ratio of products. The  metathesis reaction is believed to proceed through a metallocyclobutane intermediate (Chapter 1). The trans isomer of this intermediate is in principle lower in energy and predicted to lead to the trans isomer of the product. However, the results of molecular mechanics calculations showed the lowest energy conformation of the trans isomer 158 is distorted in order to accommodate the carbon-carbon double bond. This deviation from the diamond lattice conformations for the trans alkene 158 could result in a preference for the cis isomer. Therefore, it may be the conformation of the rest of the ring that determines the course of this reaction giving the cis metallocyclobutane intermediate as the preferred intermediate, and 157 as the major isomer with the cis configuration of the double bond although the selectivity was not very high (18% d. e.). The observed selectivity difference between the metathesis products and the  isomerization products could also result from a solvent effect caused by the difference in polarity between toluene (metathesis solvent) and cyclohexane (isomerization solvent).  172 3.2.1  Synthesis of 14-Methyloxacyclotetradec-5-enes (163) and (164)  The  alkenes 163 and  164 were also prepared using the metathesis reaction to  generate the ring of the macrocyclic ether. The contained a methyl group adjacent to the prepared via the O-alkylation of the  required acyclic diene precursor 162  ether oxygen at C-7.  This diene was  secondary alcohol 161 (Scheme 25). The  preparation of the methylated cyclic c o m p o u n d s was  of two-fold interest. Firstly, the  effect of the methyl group on the metathesis cyclization compared to the cyclization of the unsubstituted diene 156 was  of interest. Secondly, this methyl group would aid  the subsequent determination of the stereoselectivity of any  in  reactions performed on  these macrocyclic ethers. These reactions could include the hydroboration and epoxidation of the carbon-carbon double bond of the macrocyclic ether in a study to determine the degree of conformational control of these reactions in these large ring systems.  Scheme 25.  Retrosynthetic Analysis of 14-Methyloxacyclotetradec-5-enes (163)  and  (164)  163(Z) 164 (E)  162  The secondary alcohol 161 was the  161  required synthetic intermediate to the  acyclic diene 162. Reaction of 9-decenol (155) with Jones' reagent gave the carboxylic acid 1 5 9 .  178,179  Reaction of acid 159 with an excess of methyllithium followed b y  173 trimethylsilyl chloride gave the methyl ketone 160.  180  The addition of trimethylsilyl  chloride minimizes the formation of the undesired tertiary alcohol side-product.  Reduction of ketone 160 with lithium aluminum hydride gave the desired secondary  alcohol 161. The anion of 161 was generated with potassium hydride and reacted w  5 b r o m o 1 -pentene to give the metathesis precursor, diene ether 162. The C N M R o 1 3  162 contained 1 6 lines with four lines between 100 and 140 p p m for the four ole  carbons. The H N M R spectrum contained a doublet at 1 . 0 9 p p m for the C-7 me 1  group. This four-step reaction sequence proceeded in an overall yield of 49%. addition of a solution of the Grubbs catalyst 9  1 6 6  Slow  in CHCI to a solution of diene 2  2  under high dilution conditions gave a mixture of the cis and trans isomers of 163 164 in 63% yield (Scheme 26).  1 7 4 Scheme 26. Synthesis of 14-Methyloxacyclotetradec-5-enes (163) and (164)  a  163 (Z) 164 ( £ )  Key: (a) Jones' reagent, acetone, 94%; (b) MeLi, THF, 0 °C; then TMSCI, 72%; (c) LAH, Et0, 0 °C, 96%; (d) KH, DMF, 0 °C; then 5-bromopentene, 76%; (e) Grubbs catalyst 9, CHCI, rt, 63%.  a  2  1 6 6  2  2  The R values for 163 and 164 on silica were very similar making separation f  the isomers only possible under very precise rotary chromatographic conditions.  Analysis of macrocyclic ethers 163 and 164 with a DB-210 or OV-101 GC column u a variety of conditions did not resolve the double bond isomers and gave only a peak for the isomeriq mixture. The macrocyclic ethers 163 and 164 were finally  175  resolved w h e n analyzed with a chiral p D e x 360 GC column (Supelco). This analy  showed that the cyclization reaction proceeded to give 163 and 164 in a 43:57 ratio  should also be noted that under these GC conditions, each isomer gave rise to  distinct pair of peaks due to each double bond isomer itself being composed of a p enantiomers.  TheH N M R spectrum of 163 contained one-proton signals at 5 . 4 6 and 1  5 . 2 6p p m for the C-5 and C-6 methine protons of the carbon-carbon double bond. visible was a three-proton doublet with a chemical shift of 1 . 0 9 p p m for the C-15  group. The C-2 methine and the C-14 methylene protons were resolved and ha chemical shifts of 3.41, 3 . 5 9 and 3 . 2 3 p p m respectively. The C N M R spectrum of 13  contained 1 4 lines with the olefinic carbons C-5 and C-6 having chemical shifts o  130.80 and 129.88 p p m respectively. The C-14 methine carbon and the C-2 meth  carbon adjacent to the ether oxygen had chemical shifts of 73.35 and 66.24 p p m . H R M S and chemical analysis data was also consistent with the composition of 163.  The H N M R spectrum of 164 contained overlapping one-proton signals at 5 . 3 4 1  and 5 . 3 7 p p m for the C-5 and C-6 methine protons of the carbon-carbon double  Also visible was a three-proton doublet with a chemical shift of 1 . 1 1 p p m for the  methyl group. The C-14 methine and the C-2 methylene protons were resolved w  chemical shifts of 3.48, 3 . 4 1 and 3 . 3 4 p p m respectively. The C N M R spectrum of 13  contained 1 4 lines with the olefinic carbons C-5 and C-6 having chemical shifts o  131.87 and 130.77 ppm. The unambiguous assignment of these olefinic signals w a  not possible due to the overlap of the olefinic proton signals in the H M Q C experim  The C-14 methine carbon and the C-2 methylene carbon adjacent to the ether ox had chemical shifts of 73.71 and 65.29 p p m respectively.  The carbon-carbon double bond of the major isomer produced in the metathe  cyclization had the trans geometry as in 164. This was determined through a series  H homonuclear decoupling experiments which showed the coupling constant between  1  the olefinic protons to be 15.2 Hz. The double bond of the minor isomer 163 w  176 determined to have the Z configuration (c/ s ') based on a coupling constant of 10.2  Hz  between the olefinic protons.  164 (E)  163 (Z)  3.2.2  Cis-Trans and (164)  Isomerization of ( 2 7 £ ) - 1 4 - M e t h y l o x a c y c l o t e t r a d e c - 5 - e n e s  Treatment of the alkenes 163 and conditions was 163 and  164 with phenyl disulfide under photolysis  the m e t h o d chosen to study alkene isomerization. A solution of ether  phenyl disulfide was  photolysed with a Hanovia 4 5 0 W m e d i u m pressure  mercury lamp through pyrex glass and  a 0.0014 M KCr0 solution resulting in an 2  irradiation w i n d o w from 290-340 nm. The 1 7 7  and 164 (GC  (163)  4  ether 163 gave a mixture of ethers 163  ratio, 29:71). This corresponded to an energy difference of 0.53 kcal/mol  at 25 °C (Table 34, Entry 1).  W h e n reacted under similar conditions, ether 164 gave  the s a m e mixture of ethers 163 and 164 (GC  ratio, 29:71) (Table 34, Entry 2).  These experimental results were compared to values obtained from molecular mechanics calculations using the MM3* force field. The of  the  21.67  cis alkene 163 is kcal/mol. The  global m i n i m u m conformation  a distorted [3434] conformation with an  next conformation is 0.25  kcal/mol higher in energy. The global  m i n i m u m conformation of 164, the trans isomer, was energy of 20.69 kcal/mol. The  energy of  the [34'3'4'] conformation with an  second conformation of 164 is 0.89  kcal/mol higher in  energy. Using these calculated relative energies of 163 and 164, the energy difference of 0.98 25 °C  kcal/mol corresponded to a 16:84 (Table 34,  Entry 3).  The  equilibrium ratio of ethers 163 and  agreement between the  calculated and  164 at the  1 7 7 experimentally derived data was not as good as in the case of the unsubstituted ethers 157 and 158. Although the calculations did suggest that the trans isomer was  in fact  lower in energy than the cis isomer 163, the calculated energy difference was greater than observed. Table 34.  Experimental and Theoretical Equilibrium Ratios for the Isomerization Reaction of 2-Methyloxacyclotetradec-10-enes (163) and (164)  Entry  a  b  c  Ratio 163:164  a  AG° (kcal/mol) b  1  163 (Z)  29:71  0.53  2  164(E)  29:71  0.53  3  MM3*  16:84  0.98 c  The equilibrium ratio of 163:164 was determined by analysis with a (3-DEX 360 chiral GC column (Supelco). AG° values were calculated using equation 8 at 25 °C. Calculated relative strain energies were taken as an approximation of AG. 0  Since the theoretical and experimental equilibrium ratios for the isomerization reaction of ethers 163 and 164 were not in close agreement, a m o r e detailed calculation involving several of the lowest energy conformations of the ethers together as an ensemble was performed (Table 35). the  This was in contrast to merely comparing  energies of the global m i n i m u m conformations of each isomer.  Using the  Boltzmann distribution expression and equation (9) to weight the contributions of the individual conformations a weighted enthalpy value of 21.06 E isomer, and a weighted enthalpy value of 21.99  kcal/mol for 163 the Z isomer was  obtained. This corresponded to an estimated AG of 0.93 0  ratio of 17:83  (Z:E) for ethers 163 and  kcal/mol for 164 the  kcal/mol and an equilibrium  164. This m o r e detailed calculation gave a  similar equilibrium ratio to that obtained from the simple comparison of the lowest energy conformations of 163 and 164. Thus, either the calculated enthalpy values are over estimated, or the AS term for the isomerization is relevant, and cannot be ignored (AS*0). AH = SniAHi  (9)  178 Table 35.  Relative Energies of Conformations of (Z/E)-14-Methyloxacyclotetradec-5enes (163) and (164) and their Percent Population  ——=  Ether 163  Conformation  Relative Energy 3  (kcal/mol)  3  ' c  (Z)  Ether 164(E)  Population'  Relative Energy Population' c  (kcal/mol)  (%)  (%)  1  0.00  44  0.00  51  2  0.25  29  0.46  23  3  0.85  11  0.89  11  4  0.88  10  0.98  10  5  1.15  6  1.38  5  Estimated from relative energies at 25 °C calculated for 163 field. Calculated with equation 8. Estimated from relative energies at 25 °C calculated for 164 field. Like the  unsubstituted diene 156,  the  group in the  as the  MM3* force  with the  MM3* force  metathesis cyclization of diene 162,  not produce an equilibrium ratio of the ether products. The the cis isomer 157  with the  major product, whereas the  major isomer in the metathesis cyclization. The  unsubstituted diene gave  introduction of the  diene cyclization precursor resulted in the  did  C-2 methyl  trans isomer 164  being the  trans isomer is in general the preferred  product in these macrocyclization reactions.  1 9 , 1 8 1  The  C-2  methyl group is several  carbons removed from the reacting carbon-carbon double bonds and influence of this stereocenter on the transition state of the reaction was  accordingly the not expected to  be large. However, this C-2 methyl group m u s t play a role in the conformation of 1 8 2  transition state and  influence the selectivity of ethers 163  and  164  in the metathesis  cyclization.  3.3.1  Conclusion The  unsaturated 1 4 m e m b e r e d macrocyclic ethers 157,  prepared via  the  ruthenium catalyzed metathesis reaction.  158,  163,  macrocyclic ethers 163  and  164  164 were  These cyclizations  proceeded with low stereoselectivity giving macrocyclic ethers 157 59:41, and  and  in a ratio of 43:57. The  and  158  in a ratio of  geometry of  the  the  179  carbon-carbon double bond in these macrocycles was determined by H homonuclear 1  decoupling N M R experiments. The double bond was isomerized with phenyl disulfide  under photolysis conditions to give in the case of ethers 157 and 158, a 40:60 mixt  of isomers. This corresponded to an energy difference of 0.23 kcal/mol in excellen agreement with the value calculated from the energies of the global m i n i m u m conformations of both 157 and 158. The isomerization of ethers 163 and 164 gave  29:71 mixture of isomers. This corresponded to an energy difference of 0.53 kcal/m in reasonable agreement with 0.98 kcal/mol, the molecular mechanics calculated energy difference between the global m i n i m u m conformations of 163 and 164.  180  CHAPTER 4  Synthesis and Conformational Analysis of 13-Membered Macrocyclic Ethers The synthetic strategy for the  preparation of the  13-membered macrocyclic  ethers in this study was the s a m e as that employed in the preparation of the 1 4 m e m b e r e d macrocyclic ethers (Chapter 2).  The  1 3 m e m b e r e d macrocyclic ether  precursors are less expensive than those used in the preparation of the 1 4 m e m b e r e d analogues. Therefore, the chemistry of these smaller-ring analogues was not only for the synthetic and  of interest  conformational data that could be collected from these  odd-numbered large ring systems, but  also as a t ' esting ground' for the chemical  reactions used here. M a n y of the synthetic problems were resolved in the study of the  13- m e m b e r e d ring systems prior to their application to the 1 4 m e m b e r e d ring systems. This allowed for conservation of the m o r e expensive 1 4 m e m b e r e d macrocyclic ether precursors. For example, the cost of cyclododecanone (93) a c o m m o n starting material for  m a n y of the 1 3 m e m b e r e d macrocyclic ethers is $0.23/gram compared to 3 8 1  $125/gram for cyclotridecanone (86) used in the preparation of several of the 4 8 1  14- m e m b e r e d macrocyclic ethers.  4.0.1 Synthesis of 13-Membered Macrocyclic Ethers The synthetic strategy involved the ring expansion of a cyclic ketone to a lactone, thereby eliminating the potential problem of attempting to form the macrocycle via a cyclization reaction. The ether oxygen of the lactone would ultimately b e c o m e the oxygen of the macrocyclic ether. This lactone functionality was  also used to introduce  substituents in the region of the ether oxygen. Once this role was was  served, the carbonyl  removed to give the macrocyclic ether with a procedure developed by Nicolaou  and coworkers using Lawesson s ' reagent 48 to give an intermediate thionolactone. 5  48  This strategy allowed for a range of macrocyclic ethers to be produced as the result of variations in the substitution pattern of the intermediate ketone and  lactone resulting  from alkylation reactions, and the nucleophile used in the Nicolaou conversion.  181 The 13-membered macrocyclic ethers prepared in this study included the unsubstituted oxacyclotridecane (168), the monosubstituted 2-methyloxacyclotridecane (171), and the disubstituted 2,13-dimethyloxacyclotridecanes 179 and 180. The 1 3 m e m b e r e d macrocyclic ethers with a gem-dimethyl group at C-2 as in 190, and at C-3 as in 193 were also prepared.  168  180  171  179  190  193  4.0.2 Conformational Analysis of 13-Membered Macrocyclic Ethers The conformations of o d d m e m b e r e d rings such as the  1 3 m e m b e r e d cyclic  ethers are not superimposable on the diamond lattice. The strain energy of the distorted conformations of cyclotridecane were s h o w n to be lowest for either 3- or  5-sided conformations. The replacement of a ring carbon a t o m with an oxygen a t o m 8 9  should not influence the conformation of the ring since no n e w angular strain is introduced. However, since s o m e hydrogen atoms are eliminated by this substitution, the n u m b e r of transannular hydrogen interactions can be reduced. The introduction of  the ether oxygen atom, and of alkyl substituents further increases the possible n u m b e r of conformations of these 1 3 m e m b e r e d rings. For example, in the case of the unsubstituted oxacyclotridecane (168), the introduction of the  oxygen a t o m gives  13 possible [13333] conformations, 13 possible [12433] conformations, 13 possible [346]  conformations, and so forth.  1 8 2  A molecular mechanics search for low energy conformations of cyclotridecane  with the MM3* force field found a total of seven conformations within 2 kcal/mol o  global minimum, [13333] conformation. The [13333] conformation is unsymmetric, and all of the ring carbon positions are unique. The strain energies of the [13333]  conformations of the unsubstituted 1 3 m e m b e r e d ether resulting from the systematic substitution of oxygen for each carbon a t o m were calculated with the MM3* force (Table 36). S o m e of these conformations were higher in strain energy, and need  be considered in detail. For example, the conformations with the oxygen a t o m a  corner position were all found to have high strain energies. Substitution of an oxyg  a t o m for C-2, C-11, or C-12 (Table 36 numbering) gave the lowest energy [133 conformations for this 1 3 m e m b e r e d ring.  Table 36. The Oxygen Substituted [13333] Conformations and Their Relative Strain Energies  1  Relative Energy (kcal/mol)  1  2.68  2  0.00  3  3 . 1 5  4  4.76  3  1 3  ^ ^ ^ J ^ ^  5  1 . 3 1  A  V  6  1 . 8 7  v  /  7  4.18  8  1 . 5 8  9  1 . 6 0  1 0  3 . 7 5  1 1  0.79  1 2  0.76  13  3 . 1 8  1 1 l  H  9  3  Oxygen Position  7  5  Strain energies are relative to the lowest energy [13333] conformation calculate with the MM3* force field.  183 To simplify the comparison of the 1 3 m e m b e r e d ether conformations, an  extension of the Dale nomenclature was developed to designate the position of t  ether oxygen a t o m in the conformation. The 13 positions of the [13333] conformat are numbered starting with the 1-position at a 1 b o n d corner and increasing in a  clockwise fashion as s h o w n in Table 36. Using this nomenclature, the low energ  [13333] conformation with the ether oxygen at the 2-position would be the [1333 conformation.  Similar calculations were performed with the other low energy conformations o  cyclotridecane. The strain energy of the conformations resulting from the systematic  substitution of each carbon with an oxygen a t o m was also calculated. This explorat  gave three other 1 3 m e m b e r e d ether conformations likely to have low strain energ  These are the [12334], [12433], and [13324] conformations with oxygen substitution indicated in Table 37. These calculations gave the [12334] conformation of a  1 3 m e m b e r e d cyclic ether the lowest strain energy and it was comparable to the low  energy [13333] conformation found above. This set of six conformations was used a  starting point in the conformational analysis of the 1 3 m e m b e r e d macrocyclic ether examined in this study.  1 8 4 Table 37.  Other Oxygen Substituted 13-Membered Conformations with L o w Strain Energy Conformer  a  Skeleton  Relative Energy (kcal/mol)  [12334]  0.01  [13324]  0.60  [12433]  1 . 0 0  Strain energies are relative to the lowest energy, oxygen substituted [13333] conformation calculated with the MM3* force field.  The transition state interconversions of 1 3 m e m b e r e d rings are m o r e complex than those of the 1 4 m e m b e r e d rings.  Both single corner movements,  and  interconversions between 5- and 3-sided conformations are believed to occur, with interconversions over the latter pathway thought to be lower in energy. Therefore, 1 1 8  this study the transition state energies for the interconversion of the 1 3 m e m b e r e d  ethers were not calculated b y driving the dihedral angles of corner atoms in low en conformations.  185 4.1.1  Synthesis of Oxacyclotridecane (168) and 2-Methyloxacyclotridecane (171)  The first 1 3 m e m b e r e d macrocyclic ether in this study, oxacyclotridecane (168), was  prepared via  the  Baeyer-Villiger oxidation of  cyclododecanone (93) with  trifluoroperacetic acid to give 12-dodecanolide (165). The the addition of solid UHP lactone 165 was  peracid was  generated by  to a solution of trifluoroacetic anhydride in CHCI.  The  1 2 1  2  2  converted into thionolactone 166 with Lawesson s ' reagent 48.  two-step sequence proceeded in 83%  yield. The H NMR 1  51  This  spectrum of the resultant oil  showed two-proton signals at 4.51  ppm  and 2.87  protons of 166 respectively. The  NMR  spectrum contained a signal at 225.20 ppm  C  13  ppm for the C-3  and  C-13 methylene  for the C-1 thionocarbonyl, consistent with the structure of 166.  The  thionolactone 166 was  macrocyclic ethers 168 and triethylborohydride and  a c o m m o n intermediate in the  synthesis of  the  171. Reaction of the thionocarbonyl of 166 with lithium  trapping of the resultant sulfur anion with methyl iodide gave  the unstable mixed thioacetal 167,  51  which was  reduced immediately with tri(A7-butyl)tin  hydride to give the macrocyclic ether 168. The two-step reaction sequence proceeded in 52%  yield (Scheme 27).  Reaction of 166 with methyllithium and trapping of the resultant sulfur anion with methyl iodide, produced the unstable and  was  mixed thioketal 169.  51  Like 167, this c o m p o u n d was  reduced immediately under radical conditions with tri(n-butyl)tin  hydride and AIBN to give the macrocyclic ether 171 in an overall yield of 30% two-steps.  for  the  1 8 6 Scheme 27. Synthesis of Oxacyclotridecane (168) and 2-Methyloxacyclotridecane (171)  a  167 R = H 169 R = Me  168 R = H 171 R = Me  Key: (a) UHP, TFAA, NaHP0, CHCI, 0 °C, 90%; (b) Lawessons ' reagent 48, toluene, A, 92%; (c) LiEtBH, THF, -78 °C; then Mel, 95%; (d) MeLi, THF, then Mel, 97%; (e) n-BuSnH, AIBN, toluene, A, 55% (168) or 31% (171).  a  2  4  2  2  3  3  The lactone 165 was also reacted with Tebbe reagent 3 2 170.  38  to give the vinyl eth  This material was unstable and w a s purified b y passing the reaction solutio  directly through a column of basic alumina with petroleum ether as eluant. The vi  ether 170 was immediately hydrogenated to give the macrocyclic ether 171. The two step reaction sequence proceeded in 57% yield.  187 Scheme 28. Synthesis of 2-Methyloxacyclotridecane (171) via Hydrogenation 3  171  170  165  Key: (a) Tebbe reagent 32 , DMAP, pyridine, THF, (b) Pt0, H, Et0, 85%.  a  2  2  -40 °C, 67%;  2  4.1.2 Conformational Analysis of Oxacyclotridecane (168) The H N M R spectrum of 168 at rt in CDCI contained a four-proton triplet at 1  3  3.42 p p m , a four-proton quintet at 1.54 p p m , a four-proton multiplet between 1 . 4 1 1 . 4 6 ppm,  and a 12-proton multiplet between 1 . 3 0 1 . 3 8 ppm.  The downfield  signal was assigned to the protons on C-2/C-13 adjacent to the ether oxygen (Table 38).  The  signal at 1.54 ppm  was  assigned to the protons on C-3/C-12.  The  chemical shifts of the remaining signals were very similar and could not be unambiguously assigned. The  C NMR  13  the conformation of 168 either has  spectrum contained six signals indicating that  a plane of symmetry, or site exchange processes  that are rapid at rt. The downfield signals at 70.33 and 28.54 ppm were assigned to the C-2/C-13 and  C-3/C-12 methylene carbons. The  were also consistent with the composition of 168.  H R M S and  chemical analysis data  1 8 8 Table 38. H and C N M R Assignments for Oxacyclotridecane (168) in CDCI at R o o m Temperature 1  13  3  H NMR  Position [11  /  a  1  a  a  13]  °>»  2, 13  3 . 4 2  70.33  3, 1 2  1 . 5 4  28.54  4-11  not  assigned  1 5  The chemical shift values are in p p m referenced to CHCI (H) and CDCI (C). D u e to signal overlap these signals could not be unambiguously assigned. 1  3  b  C NMR  13  1 3  3  The low temperature N M R spectra of 168 were obtained in a 4 : 1 mixture  Freon 2 1 and Freon 22 as solvent (Figure 38). The H N M R spectrum of 168 at 2 1  was essentially the s a m e as the rt spectrum, but with broader signals. The sign  continued to broaden as the temperature w a s lowered. At 148 K , the signal for  C-2/C-13 protons split into t w o signals of approximate equal intensity. At temperature  d o w n to 130 K , these signals were resolved with chemical shifts of 3 . 6 1 and 3 . 2  At 125 K , the lowest temperature reached in this D N M R experiment, the upfield s  at 3 . 2 3p p m broadened again. The sample froze before the coalescence temperatu of this second process could be determined.  The broadness of the signals in the D N M R study of 168, is consistent with presence of multiple conformations, even at low temperatures. The signals are insufficiently resolved to determine the ratio of the individual conformations present.  The substitution of an oxygen a t o m into low energy conformations of cyclotridecan  suggested that the [13333], [12334], and [13324] conformations of 168 were likely  have low strain energy. These were the first conformations considered in the analys of the D N M R spectra of this macrocyclic ether.  190  [13333]-2  [12334]  [13324]  The signal for the C-2 and C-13 protons adjacent to the ether oxygen split into two signals as the temperature was lowered. In the [13333]-2 conformation, the H-2  e x o  proton is deshielded by the anisotropy of the C-3/C-4 bond, and the H-13 proton is a  deshielded by the anisotropy of the C-11/C-12 bond. N o van der Waals steric interactions are predicted for the C-13 protons since both are pointing to the outside of the ring. The closest transannular hydrogen to the H-2do proton is H-5do calculated e n  e n  to be 2.32 A away. This distance is only slightly less than the sum of the van der  Waals radii for a pair of protons, and at best a small contribution from this effect is expected. The A 5 value is predicted to be similar in magnitude for both the C-2 and C-13 protons, with a large value expected.  In the [12334] and [13324] conformations, the A 5 value for the C-2 and C-13 protons is predicted to be of a similar magnitude to that of the [13333]-2 conformation. In each case, one of the H-2 protons, and one of the H-13 protons is deshielded by the anisotropy of a neighbouring carbon-carbon bond.  N o van der Waals steric  interactions are expected here, as a result of the distorted geometry of the 1 3 m e m b e r e d ring. The D N M R spectra of 168 are consistent with each of these conformations, and the likely low energy conformations cannot be narrowed any further. For the case of the [13333]-2 conformation, the downfield signal at 3.61 ppm in the low temperature H NMR spectrum could be assigned to the H-2 and H-13 1  e x o  a  protons, and the upfield signal at 3.23 ppm could be assigned to the H-2do and H-13 e n  protons.  p  1 9 1 A molecular mechanics search for low energy conformations of 168 w a s performed with the Monte Carlo technique and the MM2* force field. The global  m i n i m u m conformation was the non-diamond lattice [13333]-2 conformation 168-A as  suggested above. The second conformation 168-B was 0.15 kcal/mol higher in energ A total of six conformations were found within 2 kcal/mol of the global m i n i m u m .  relative populations of these conformations at different temperatures were calculated  from the relative energies obtained from the MM2* calculations (Table 39). The resu  of the calculations suggest that conformations 168-A and 168-B are both significantly  populated over the temperature range studied. This is in agreement with the results  the D N M R study which first were consistent with both of these conformations, a second indicated m o r e than one conformation to be present at low temperatures.  1 9 2 Table 39.  a  L o w Energy Conformations of Oxacyclotridecane (168)  Strain energies are relative to the global m i n i m u m conformation calculated with th MM2* force field.  193 Table 40.  Thermodynamic Values for the Five Lowest Energy Conformations of 168  Conformer  Relative Energy (kcal/mol)  Skeleton  Population (%) 220 K  3  298  K  125  K  168-A  [13333]-2  0.00  35.6  41.2  55.4  168-B  [12334]  0.15  27.5  29.1  30.0  168-C  [346]  0.46  16.4  14.4  8.7  168-D  [13324]  0.64  12.0  9.5  4.2  168-E  [1323 '4 ']  0.86  8.3  5.8  1 . 7  Strain energies are relative to the lowest energy conformation calculated with the M M 2 * force field.  3  The energies of the transition states involved in the interconversion of conformations of the macrocyclic ether 168 were determined from the rate of exchange between a pair of averaged signals in the D N M R spectra. Once known, the rate of exchange was used to calculate the free energy of activation (AG*) with the coalescence temperature (T) also obtained from the D N M R spectra, and the equations c  in Chapter 1. 190 Hz.  At low temperature, the C-2  proton signals of 168 were separated by  This corresponded to a transition state energy of 6.8 kcal/mol with the  coalescence temperature of 150  K.  This was  of a similar magnitude to a preliminary  value of 6.0 kcal/mol obtained for the parent hydrocarbon, cyclotridecane.  9 8  4.1.3 Conformational Analysis of 2-Methyloxacyclotridecane (171) The H N M R spectrum of 171 contained a one-proton doublet of doublet of 1  doublets at 3.67 ppm,  a one-proton doublet of doublet of quartets at 3.36  one-proton doublet of doublet of doublets at 3.23 1.17-1.65 ppm,  and  a three-proton doublet at 1.09  between 3 and 4 ppm were assigned to the C-2  ppm, ppm.  a 20-proton multiplet between The  three low-field signals  methine and C-13  methylene protons.  A H COSY spectrum showed a correlation between the signals at 3.23 1  thus these were assigned to the C-13 assigned to the  methylene protons. The  C-2 methine proton. The  ppm, a  and 3.67  ppm;  remaining signal was  C-13 protons of 171 were assigned b y  1 9 4 comparing  t h e m to  the H 1  2-methyloxacyclotetradecane (92).  N M R data  of  the  1 4 m e m b e r e d ether,  In 92, the C-14 proton syn to the C-2 methine  proton had the higher field chemical shift of the C-14 pair of protons. O n this basis  signal at 3.23 p p m in the H N M R of 171 was assigned to the H 1 3 proton syn t 1  and the signal at 3 . 6 7 p p m was assigned to the H 1 3 proton syn to the C-14 group (Figure 39).  82  Figure 39. H N M R assignments of the C-2 and C-13 protons of 2-methyloxacyclotridecane (171). 1  The C N M R spectrum of 171 contained 13 lines. T w o of these signals were 13  low-field, and were assigned to the C-2 and C-13 carbons adjacent to the ether ox  The highest field carbon at 20.20 p p m was assigned to the C-14 methyl group.  remaining C signals occurred around 25 p p m . The assignment of these signals was 13  aided with data from COSY and H M Q C 2 D N M R experiments (Table 41). The resu  of the H R M S and chemical analysis were also consistent with the composition of 17  1 9 5 Table"41.  H and C N M R Assignments for 2-Methyloxacyclofridecane (171) in CDCI at R o o m Temperature  1  13  3  Position  rii i3|  H NMR  1  a  2  3 . 3 6  3  1 . 3 9  4-11  not  C NMR  13  a  75.32  1 2  I  *J r 1  11  6  1 2  1.61, 1 . 4 8  29.27  13  3.67, 3.23  67.64  1 . 0 9  20.20  The chemical shift values are in p p m referenced to CHCI (H) and CDCI (C). D u e to signal overlap these signals could not be unambiguously assigned. 1  3  b  assigned  3  1 4 a  u D  1 3  3  The low temperature spectra of 171 were obtained in a 4 : 1 mixture of Freon and Freon 22 as solvent (Figure 40). The spectrum at 220 K was similar to  obtained at rt with broader signals at the lower temperature. Further broadening of t signals accompanied b y small changes in the chemical shifts of the signals w a s  observed as the temperture w a s lowered. N o other significant changes were observe  in the spectra at temperatures d o w n to 1 5 4 K , the lowest temperature in this D  experiment. Insufficient data w a s available to unambiguosuly identify the low energy  conformations of 171. The H N M R signals of 171 continue to be averaged as a res 1  of conformational interconversion processes which remain rapid on the N M R timescale even at 1 5 4 K .  1 9 6  220 K  200 K  1 6 8 K  1 6 2 K  1 5 6 K  1 5 4 K ~i—i—i—r  n—i—i—r  3.5  3.0  2.5  2.0  1.5  1.0  ppm  Figure 40. Variable temperature 500 M H zH N M R of 2-methyloxacyclotridecane (171) in CHCIF:CHCIF (4:1). 1  2  2  197 A molecular mechanics search for low energy conformations of 171 w a s performed with the  Monte Carlo technique and  m i n i m u m conformation was  the  MM2* force field. The global  the non-diamond lattice [13333]-2 conformation 171-A, with  171-B, a [13324] conformation, calculated to be 0.20 kcal/mol higher in energy (Table 43). found.  A total of 14 conformations within 1 kcal/mol of the  global m i n i m u m were  The relative populations of the l o w energy conformations at different  temperatures were calculated from relative energies obtained from the calculations (Table 42).  The  MM2*  results of these calculations s h o w several conformations  of 171 to be significantly populated even at low temperature.  Table 42.  Thermodynamic Values for the Five Lowest Energy Conformations of 171  Conformer  Skeleton  Relative Energy (kcal/mol) 3  298  K  Population (%) 200 K  154  K  171-A  [13333]-2  0.00  30.8  36.6  41.9  171-B  [13324]  0.20  21.8  21.9  21.6  171-C  [13333J-2  0.26  20.0  19.2  18.2  171-D  [13333J-2  0.36  16.7  14.7  12.9  171-E  [13324]  0.63  10.7  7.6  5 . 4  Strain energies are M M 2 * force field. The  NMR  relative to the  lowest energy conformation calculated with the  sample of 171 froze before the  slowing of the  signals in the spectrum of 171 could be observed in the transition state energies for the  exchange rate of  any  D N M R experiment. Thus, the  interconversion of conformations of this macrocyclic  ether could not be determined. These energy values are presumably less than 6.8 kcal/mol, the value observed for oxacyclotridecane (168).  1 9 8 Table 43.  L o w Energy Conformations of 2-Methyloxacyclotridecane (171) Skeleton  Conformer  a  Relative Energy (kcal/mol)  171-A  [13333]-2  0.00  171-B  [13324]  0.20  171-C  [13333]-2  0.26  171-D  [13333]-2  0.36  171-E  [13324]  0.63  Strain energies are relative to the global m i n i m u m conformation calculated with t MM2* force field.  199 4.2.1  Synthesis of 2,13-Dimethyloxacyclotridecanes (179) and (180)  The  next 1 3 m e m b e r e d macrocyclic ethers examined were the diastereomeric  pair of 2,13-dimethyloxacyclotridecanes, 179 and  180.  The  C-2 methyl group was  introduced adjacent to the ketone prior to the Baeyer-Villiger ring expansion. Once the desired ketone was ketone was  produced, the synthetic path was  the s a m e as earlier. The cyclic  expanded to a lactone, and the carbonyl was  intermediate (Scheme 29). introduced via  the  Another m e t h o d where the  removed via a thionolactone second methyl group was  hydrogenation of an exocyclic double bond rather than via the  nucleophilic attack of a thionolactone was  also investigated.  Scheme 29. Retrosynthetic Analysis of 2,13-Dimethyloxacyclotridecanes (179) and (180)  179 (2R*, 13/?*) 180 ( 2 S M 3 / ? * )  177X = S 176X = CH2  174  93  A m e t h o d involving the methylaluminum bis(4-bromo-2,6-di-terf-butylphenoxide) (MABR) mediated alkylation of a trimethylsilyl enol ether was prepare the intermediate ketone 174.  employed in order to  Cyclododecanone (93) was reacted with  hexamethyldisilazane, and a mixture of trimethylsilyl chloride and  lithium iodide to give  200 the trimethylsilyl enol ethers 172 and analysis (Scheme 30).  128,129  173 in a 48:52 ratio as determined from GC  Another m e t h o d involving reaction of ketone 93 with  triethylamine and trimethylsilyl chloride gave lower yields of the enol ethers.  These  diastereomers were separable on silica, and were identified by a comparison of their C N M R spectra. In general, the chemical shift for C-1  13  of the Z isomer is upfield  relative to that of the E isomer. While, the chemical shift for C-12,  the allylic carbon, of  the Z isomer is generally downfield relative to that of the E isomer. Here, enol ether 1 3 0  172 was  assigned the Z configuration based on chemical shifts of 149.76 ppm and  36.44 ppm for C-1 and C-12 for C-1 and C-12  compared to chemical shifts of 151.87 ppm and 28.42 ppm  of 173, the E isomer.  A solution of M A B R was generated by the addition of trimethylaluminum in hexanes to a solution of 4-bromo-2,6-di-te/?-butylphenol in CH CI .  131,132  2  enol ethers 172 and  2  A mixture of  173 was reacted with an aliquot of this M A B R solution and  subsequently alkylated with methyl triflate to give ketone 174. coordinated to the enol ether and  133  The bulky Lewis acid  directed the alkylation with methyl triflate. The  BaeyerA/illiger oxidation of ketone 174 was performed with trifluoroperacetic acid in the presence of NaHP0 to give 12-tridecanolide (175). This peracid was 2  4  the addition of UHP  122,123  lactone 175 was reagent 48.  51 5 5  5.61  generated by  to a solution of trifluoroacetic anhydride in CHCI. 2  2  The  converted into the thionolactone 177 by reaction with Lawessons ' TheH N M R spectrum of 177 contained a one-proton signal at 1  ppm for the C-3 methine, as well as a three-proton doublet at 1.27 ppm for  C-14 methyl group. The  the  CN M R spectrum of 177 contained 13 lines with the C-1  13  thionocarbonyl signal at 224.35 ppm, consistent with the structure of 177.  Subsequent reaction of thionolactone 177 with methyllithium and trapping of the resultant sulfur anion with methyl iodide gave the unstable mixed thioketal 178.  51,55  This material was reduced immediately under radical conditions with either tri(/7-butyl)tin hydride or tris(trimethylsilyl)silane (TTMSH) to give the desired 1 3 4  macrocyclic ethers 179 and 180. The four-step reaction sequence proceeded in 13%  201 yield from 174 with tri(/7-butyl)tin hydride as the hydride source, and  23%  yield with  T T M S H as the hydride source.  Scheme 30. Synthesis of 2,13-Dimethyloxacyclotridecanes (179) and (180) via Radical Reduction 3  93  172 (Z) 173 (£)  174  175  177  178  179 (2R*, 13fl*) 180 (2S*, 13/?*)  Key: (a) (TMS)NH, TMSCI, Lil, CHCI; then EtN, 92%; (b) MABR, MeOTf, CHCI, -40 °C, 71%; (c) UHP, TFAA, NaHP0, CHCI, 0 °C, 92%; (d) Lawesson s ' reagent 48, toluene, A, 75%; (e) MeLi, THF, -78 °C; then Mel, 71%; (f) n-BuSnH, AIBN, toluene, A, 26%; (g) TTMSH, AIBN, toluene, A, 46%.  a  2  2  2  3  2  3  4  2  2  2  2  202 The  lactone 175 was  also reacted with Tebbe reagent 32  ether 176. This material was  38  to give the vinyl  unstable, however it could be purified by passing the  reaction solution directly through a column of basic alumina with petroleum ether as eluant. The  vinyl ether 176 was  immediately hydrogenated to give the macrocyclic  ethers 179 and 180. This two-step reaction sequence proceeded in 36% yield.  Scheme 31. Synthesis of 2,13-Dimethyloxacyclotridecanes (179) Hydrogenation  and  (180)  via  3  175  176  Key: (a) Tebbe reagent 32 , DMAP, pyridine, THF, Et0, 52%.  3  179 (2R*, 13/?*) 180 (2S*, 13/?*)  -40 °C, 70%;  (b) Pt0, H, 2  2  2  The  relative configuration of the C-2 and C-13  methyl substituents of 179 and  180 was determined through their analysis with a chiral Cyclodex-B GC column. The macrocyclic ethers 179 and 180 were separable with silica chromatography and each gave a single, distinct peak on GC analysis with a DB-210 column. The (2R*,13R*) or anti isomer of 2,13-dimethyloxacyclotridecane is a dl pair of enantiomers which would give rise to two peaks under chiral GC conditions. The (2S*,13R*) or syn isomer of the  macrocyclic ether is a m e s o c o m p o u n d which would give rise to only a single peak under chiral GC conditions. GC analysis of 179, the first macrocyclic ether eluted on silica, with the  Cyclodex-B column resulted in two  retention times of 45.2  minutes and 46.0  peaks of equal intensity with  minutes respectively. GC analysis of 180, the  second macrocyclic ether eluted on silica, gave only a single peak with a retention tim of 48.5  minutes (Figure 41).  and C-13  Thus, 179 was identified as the diastereomer with the  methyl groups in an anti configuration (2R*,13R*) and 180 was  C-2  identified as  203 the diastereomer with the C-2 and C-13 methyl groups in a syn configuration (2S*,13R*).  180  179  II  Figure41. GC analysis of 2,13-dimethyloxacyclotridecanes (179) and (180) on a chiral Cyclodex-B column; (a) (2R*,13R*)-2,13-dimethyloxacyclotridecane (179) ; (b) (2S*,13R*)-2,13-dimethyloxacyclotridecane (180); (c) mixture of (2R*,13R*) and (2S*,13R*)-2,13-dimethyloxacyclotridecane (179) and (180) .  204  The t w o methods used to form the macrocyclic ethers, hydride reduction of  thiomethyl group, and hydrogenation of a carbon-carbon double bond are intrinsical  different with different intermediates and different reagents used in the transformation  Accordingly, a difference in stereoselectivity in the ratio of 179:180 was expected fo each of these methods.  The hydride reduction of the mixed thioketal 178 with tri(n-butyl)tin hydride  showed n o selectivity for either macrocyclic ether 179 or 180 (Table 44). It was hope  that the different properties of the silane hydride reagent would offer an improvement the stereoselectivity of this reduction. The tris(trimethylsilyl)silane is a bulkier reagent with a greater metal-hydrogen bond strength and a shorter metal-hydrogen bond length.  These features m a k e the silane a m o r e selective hydride  reagent.  Unfortunately, only a very small stereoselectivity for macrocyclic ether 179 was observed (8% d. e.) with the silane as the hydride source (Table 44). Reactions performed with pure 2,14-dimethyloxacyclotetradecanes (103) and (104) the analogous  1 4 m e m b e r e d compounds with tri(n-butyl)tin hydride under radical conditions showed  n o evidence of isomerization to the other macrocyclic ether. Therefore it was assume  here that n o isomerization of the macrocyclic ethers occurred in the hydride reduct of the 1 3 m e m b e r e d ring system either.  The reduction of the vinyl ether 176 with Adams' catalyst (Pt0) proceeded wi 2  low stereoselectivity (18% d. e.) (Table 44). The choice of platinum oxide as the  catalyst was important for the success of the reduction. Palladium on charcoal, an rhodium on alumina, other c o m m o n hydrogenation catalysts, gave lower yields of desired macrocycles in the hydrogenation reaction.  Molecular modeling calculations with the MM3* force field suggested that the [13333] conformation is the m o s t stable conformation of vinyl ether 176 with the  exocyclic double bond in an orientation essentially perpendicular to the plane of th  ring (Figure 42). The next lowest energy conformation was 0.22 kcal/mol higher in  205 energy and  also a [13333] conformation. The  local conformation in the region of the  double bond is similar in both of these conformations. It was methyl group flanking the ether oxygen or the  believed that either the  macrocyclic ring itself would have a  directing effect on the hydrogenation. Modest stereoselectivity for 180 was  observed in  this reduction, hence the exocyclic double bond m u s t be blocked by the macrocyclic ring on one face, and by a slightly lesser degree by the methyl group on the other face.  Figure 42. Lowest energy conformation of vinyl ether 176.  Table 44.  Yield and Selectivity in the Preparation of 2,13-Dimethyloxacyclotridecanes (179) and (180)  Reagent  Starting Material  (%)  50:50  26  TTMSH, AIBN  178  54:46  46  176  41:59  26  2  c  Total Yield of 179+180  178  Pt0, H  b  3  n-BuSnH, AIBN 3  a  179180  2  b  b  c  The ratio of 179:180 was determined by gas chromatography. The diastereomers 179 and 180 were purified but not separated. The diastereomers 179 and 180 were separated via radial chromatography.  4.2.2 Conformational Analysis of (2/?*,13R*)-2,13-Dimethyloxacyclotridecane (179) The H NMR 1  3.69  ppm,  spectrum of 179 at rt in CDCI contained a two-proton sextet at 3  a 20-proton multiplet between 1 . 1 6 1 . 5 8 ppm,  and  a six-proton doublet at  206  1 . 0 8 ppm. The low-field signal at 3 . 6 9p p m was assigned to the protons of C-2/C  and the doublet at 1 . 0 8p p m was assigned to the C-14 and C 15 methyl groups.  The C N M R spectrum at rt contained seven lines indicative of a either a pla 13  of symmetry, or a rapid site exchange process leading to s y m m e t r y in this molec  Thus, C-2 and C-13 had the s a m e chemical shift as did C-3 and C-12, and s  The low-field signals at 69.11 and 34.82 p p m were assigned to C-2/C-13 and C-3/  The signal at 19.56 p p m was assigned to the C-14 and C-15 methyl groups (Tab The H R M S data was also consistent with the composition of 179.  Table 45. H and C N M R Assignments for (2R*,13R*)-2,13-Dimethyloxacyclotridecane (179) in CDCI at R o o m Temperature 1  13  3  Position  1 I a  H NMR  1  a  C NMR  13  a  2, 13  3 . 6 9  69.11  3, 1 2  1 . 4 9 1 . 5 7  34.82  4-11  not  assigned'  14, 15  1 . 0 8  19.56  The chemical shift values are in p p m referenced to CHCI (H) and CDCI (C). D u e to signal overlap these signals could not be unambiguously assigned. 1  3  b  1 3  3  The low temperature spectra of 179 were obtained in a 4 : 1 mixture of Freon and Freon 22 as solvent (Figure 43). The spectrum of 179 at 220 K was similar obtained at rt with broadening of the signals at the lower temperature. Further broadening of the signals accompanied b y small changes in the chemical shifts of  signals was observed as the temperature was lowered. N o other significant change  were observed in the spectra at temperatures d o w n to 150 K , the lowest temperatu  this D N M R experiment. Insufficient data was available to unambiguosuly identify the  low energy conformations of 179. The H N M R signals of 179 continue to be average 1  as a result of conformational interconversion processes which remain rapid on the N timescale, even at 150 K .  207  220 K  190 K  180 K  170 K  165 K  150 K  3.5  ~7—I—I—r  3.0  ~i  2.5  2.0  i  i  1  r  1.5  1.0  0.5  i  i  r  ppm  Figure 43. Variable temperature 500 M H zHN M R of (2R*,13R*)-2,13-dimethyloxacyclotridecane (179) in CHCIF:CHCIF (4:1). 1  2  2  208 A molecular mechanics search for low  energy conformations of 179 w a s  performed with the Monte Carlo technique and global m i n i m u m conformation was The  the MM2* force field (Table 47).  T h e  a non-diamond lattice [12334 '] ' conformation 179-A.  second conformation 179-B was  0.24  kcal/mol higher in energy. A total of seven  conformations were found within 1 kcal/mol of the  global m i n i m u m . The  relative  populations of these conformations at different temperatures were calculated from the relative energies obtained from the MM2* calculations (Table 46). calculations suggest that conformations 179-A, 179-B and  The  results of these  179-C are each significantly  populated over the temperature range studied.  Table 46.  Thermodynamic Values for the Five Lowest Energy Conformations of 179  Conformer  3  Relative Energy (kcal/mol)  Skeleton  3  298  K  Population (%) 220 K  150  K  179-A  [12334 '] '  0.00  34.8  40.7  51.0  179-B  [12334]  0.24  23.3  23.5  22.9  179-C  [12343 '] '  0.38  18.3  17.0  14.1  179-D  [13333]-2  0.57  13.2  10.9  7.4  179-E  [13234]  0.72  10.4  7.9  4.6  Strain energies are MM2* force field. The  NMR  relative to the  lowest energy conformation calculated with the  sample of 179 froze before the slowing of the  exchange rate of  any  signals in the spectrum of 179 could be observed in the D N M R experiment. Thus, the transition state energies for the ether could not be determined.  interconversion of conformations of this macrocyclic  209 Table 47.  L o w Energy Conformations of (2R*,13R*)-2,13-Dimethyloxacyclotridecane (179)  Skeleton  Relative Energy (kcal/mol)  179-A  [12334 '] '  0.00  179-B  [12334]  0.24  179-C  [12343 '] '  0.38  179-D  [13333]-2  0.57  179-E  [13234]  0.72  Conformer  a  Strain energies are relative to the global m i n i m u m conformation calculated with t MM2* force field.  210  4.2.3 Conformational Analysis of (2S*,13/?*)-2 13-Dimethyloxacyclotridecane (180) >  The  H NMR  spectrum of 180 contained a two-proton doublet of doublet of  1  quartets at 3.43  ppm,  a 20-proton multiplet between 1 . 2 3 1 . 4 8 ppm,  doublet at 1.10  ppm.  The  low-field signal at 3.43  C-2/C-13, and  the doublet at 1.10  ppm  was  ppm was  and  a six-proton  assigned to the protons of  assigned to the C-14  and  C-15 methyl  groups (Table 48).  The  C  13  NMR  spectrum at rt contained seven lines indicative of a either a plane  of symmetry, or a rapid site exchange process leading to s y m m e t r y in this molecule. Thus, C-2  and  C-13  had the s a m e chemical shift as did C-3  and  C-12,  and  so forth.  The low-field signals at 74.23 and 37.67 ppm were assigned to C-2/C-13 and C-3/C-12. The signal at 22.31 The  H R M S and  ppm was  assigned to the C-14  and C-15  methyl groups (Table 48).  chemical analysis data were also consistent with the composition of  180. Table 48.  H and C NMR Assignments for (2S*,13R*)-2,13-Dimethyloxacyclotridecane (180) in CDCI at R o o m Temperature  1  13  3  Position  J  [  a  CL  rr  a  4-11 14,  not 15  37.67 assigned"  1.10  22.31  The chemical shift values are in ppm referenced to CHCI (H) and CDCI (C). Due to signal overlap these signals could not be unambiguously assigned. 1  1 3  3  b  The and  a  74.23 b  3, 12  1 5  C NMR  13  3.43  2, 13  ^ 21  H NMR  1  3  low temperature spectra of 180 were obtained in a 4:1 mixture of Freon 21  Freon 22 as solvent (Figure 44).  The  spectrum at 220  K was  similar to that  obtained at rt with the signals broadened at the lower temperature. The a-protons was  extremely broad at 210  signal for  the  K, and split into a pair of equally intense signals  211 with chemical shifts of 3.64 and C-12  and 3.28  ppm at low temperature. The signal for the  C-3  protons p to the ether oxygen also changed as the temperature was lowered.  At temperatures below 210  K, a signal of equally intensity to either the H-2  protons became visible at 1.85 signal for the  C-14  and  C-15  ppm and was  or  H-13  assigned to one of the p-protons. The  methyl groups broadened as the  temperature was  lowered, but even at 150 K, the lowest temperature in this D N M R experiment, only one signal was observed for these protons. Also visible in the low temperature spectra was a signal at higher field than the signal of the methyl groups; at 0.96  ppm.  The intensity  of this upfield signal was equal to one proton.  The  sharpness of the  low temperature signals in the  D N M R study of 180  suggests the presence of a single conformation at low temperature. The substitution of an oxygen a t o m into low energy conformations of cyclotridecane suggested that the [13333] conformations with the oxygen a t o m located at the 2-, 5-, 11-, and 12-positidn (page 182,  Table 36 numbering) were likely to have low strain energy. The ring  skeletons of the [12334] and [13324] conformations (page 184,  Table 37) were also  considered. In each of these six conformations, one of the methyl groups is at a corner position, and  is thus pointing a w a y from the other methyl group thereby avoiding a  1,3-diaxial interaction between the C-14  [13333]  and C-15  [12334]  methyl groups.  [13324]  212  I—i—i—i—i—|—i—i—i—i—|—i—i—i—i—|—i—i—i—i—|—i—i—i—i  3.5  Figure 44.  3.0  2.5  2.0  |  i  i  i  i  1.5  |  i  1.0  i  i  i  |  i  220  K  210  K  205  K  200  K  180  K  150  K  i  ppm  Variable temperature 500 M H zH N M R of (2S*,13R*)-2,13-dimethyloxacyclotridecane (180) in CHCIF:CHCIF (4:1). 1  2  2  213 The  observed A8 value for the H-2  and  H-13  protons in the low temperature  spectra of 180 is of an intermediate value. In the [13333]-5 conformation of 180, the H-13  proton is deshielded by the anisotropy of the C-11/C-12 bond, while the  H-2  proton is shielded by the anisotropy of the C-3/C-4 bond and by a van der Waals steric interaction between H-2 and H-12do. These protons were calculated to be only 2.27 e n  A  apart. The A5 for these protons in this conformation is predicted to be large. A large A5 value is also predicted between the  H-2  and  H-13  protons in the [13333]  conformation with the oxygen a t o m at the 11-position.  In the [13333]-2 conformation, the H-2 proton is shielded by the anisotropy of the C-3/C-4 bond and also by a van der Waals steric interaction with the H-5d proton e n  calculated to be 2.27 and H-13  0  A away. An intermediate A5 value is predicted between the  H-2  protons in this conformation. Similarily, intermediate A6 values are predicted  for the a-protons in the [13333]-12 conformation, and also in the [13324] conformation. The A5 value for the H-2 and H-13  protons in the case of the [12334] conformation is  predicted to be small.  [13333]-2  The  [13333]-12  observed chemical shift difference of the H-2  [13324]  and  H-13  protons in the  D N M R spectra of 180 is consistent with the value predicted for the above three conformations. The p-proton signals in the D N M R spectra were examined in terms of these conformations. The  D N M R spectra s h o w one  of the p-protons of 180 to be  deshielded relative to the others. Unfortunately, in each of these three conformations, one  of the p-protons is predicted to be deshielded relative to the others. In  the  214 [13333]-2 conformation, the C-4/C-5 and the O/C-2 shielded and  H-3 proton is deshielded by the a  bonds. The  anisotropy of both the  three remaining p-protons are predicted to be m o r e  give signals at higher field. Thus, the data for the p-protons did not allow  the likely low-energy conformation of 180 to be narrowed further.  A molecular mechanics search for the conducted with the  low  Monte Carlo technique and  m i n i m u m conformation was  energy conformations of 180 the  was  MM2* force field. The global  the [13333]-2 conformation 180-A (Table 50).  The second  conformation found w a s 180-B, 1 . 5 5 kcal/mol higher in energy. A total of six conformations were found within 2 kcal/mol of the  global m i n i m u m . The  relative  populations of the low energy conformations at different temperatures were calculated from relative energies obtained from the MM2* calculations (Table 49).  The  results of  these calculations suggest that conformation 180-A is the major conformation over the temperature range studied. This is in agreement with the  results of the  D N M R study  where the results were consistent with conformation 180-A.  Table 49.  Conformer  Thermodynamic Values for the Five Lowest Energy Conformations of 180  Skeleton  Relative Energy (kcal/mol) 3  298  K  Population (%) 210 K  150  K  180-A  [13333]-2  0.00  82.5  94.1  98.8  180-B  [13333]-5  1 . 5 5  6.0  2.3  0.5  180-C  [12343 '] '  1 . 7 2  4.5  1 . 5  0.3  180-D  [13324]  1 . 8 6  3.6  1 . 1  0.2  180-E  [12433]  1 . 8 9  3 . 4  1 . 0  0.2  Strain energies are MM2* force field.  relative to the  lowest energy conformation calculated with the  215 Table 50.  L o w Energy Conformations of (2S*,13R*)-2,13-Dimethyloxacyclotridecane (180)  Skeleton  Conformer  180-A  [13333]-2  Relative Energy (kcal/mol)  0.00  180-B  [13333]-5  1 . 5 5  180-C  [12343 '] '  1 . 7 2  180-D  [13324]  1 . 8 6  180-E  [12433]  1 . 8 9  Strain energies are relative to the global m i n i m u m conformation calculated with t M M 2 * force field.  216 The energies of the transition states involved in the interconversion of conformations of the macrocyclic ether 180 were determined from the rate of exchange between a pair of averaged signals in the D N M R spectra. Once known, the rate of exchange was used to calculate the free energy of activation (AG*) with the coalescence temperature (T) c  in Chapter 1.  also obtained from the D N M R spectra and the equations  At low temperature, the  separated by 175 Hz.  signals for the  H-2 and  H-13 protons were  This corresponded to a transition state energy of 9.7 kcal/mol at  a coalescence temperature of 210  K.  The  transition state energy for this macrocyclic  ether is significantly larger than the 6.8 kcal/mol obtained for the unsubstituted oxacyclotridecane (168). The  methyl substituents in 180 m u s t prevent conformations of  this macrocyclic ether from interconverting via lower energy pathways.  4.3.1  Synthesis of 2,2-Dimethyloxacyclotridecane  The  (190)  synthesis of macrocyclic ether 190 followed the general synthetic strategy  presented earlier. The  synthetic plan was  to ring expand a dialkylated ketone to give a  1 3 m e m b e r e d lactone with the gem-dimethyl substituents already in place adjacent to the  ether oxygen. The carbonyl of this lactone would be removed to give the  macrocyclic ether 190 (Scheme 32).  Scheme 32. Retrosynthetic Analysis of 2,2-Dimethyloxacyclotridecane (190)  O  190  189  181  Unfortunately, difficulties were encountered with both the  dialkylation of the  ketone and the Baeyer-Vi Niger oxidation of the ketone to the proposed lactone 189, and this synthetic route was  abandoned. Earlier, it was  s h o w n that the cyclization of  the  217 tertiary hydroxy acid 113 gave the C-13 the  grem-dimethyl lactone 114 in the preparation of  1 4 m e m b e r e d macrocyclic ether 116, the  1 4 m e m b e r e d analogue to ether 190.  This synthetic route in which the desired ring was reaction rather than through the  expansion of an  formed as the result of a cyclization existing ring was  viewed as  a  promising alternative synthetic path.  113  The  114  preparation of the  116  desired tertiary hydroxy acid, the  acyclic precursor to  lactone 189, began with the reaction of 1,10-decanediol (182) with 48% hydrobromic acid to give the b r o m o alcohol 183 (Scheme 33). Oxidation of this alcohol with the 1 4 5  Jones' reagent gave the b r o m o acid 1 8 4 . Fischer esterification conditions gave the  178,179  Reaction of the b r o m o acid 184 under  methyl ester 185.  This ester was chain  extended by alkylation with the anion of methyl acetoacetate to give diester 186. four-step reaction sequence proceeded in an overall yield of 72%.  The  H  The  141  NMR  1  spectrum of 186 contained three singlets for the three methyl groups, the ester methyl groups had  chemical shifts of 3.70  methyl group was  2.19  ppm.  and  3.60  ppm,  while the chemical shift of the  Three carbonyl signals were visible in the  spectrum of 186 at 203.18, 174.19 and  170.13 ppm  for the C-12  C  NMR  13  ketone and  C-13  the  two  ester carbonyls respectively. This spectral data as well as the H R M S and the chemical analysis results were all consistent with the structure of 186.  218 Scheme 33. Synthesis of Methyl 11-carbomethoxy-12-oxotridecanoate (186)  185  a  186  Key: (a) 48% HBr, CH, A, 73%; (b) Jones' reagent, acetone, 94%; (c) HS0, CHOH, A, 94%; (d) NaH, CHCOCHCOOCH, THF, DMF, rt; then 185, A.  a  6  3  6  2  3  2  4  3  The diester 186 was decarboxylated under strongly acidic conditions to give the keto acid 187.  The desired gem-dimethyl group was introduced using Grignard  chemistry to give the hydroxy acid 188. The hydroxy acid 188 was cyclized with the Yamaguchi procedure using triethylamine and 2,4,6-trichlorobenzoyl chloride, and subsequent reaction with a catalytic a m o u n t of D M A P under high dilution conditions give the gem-dimethyl lactone 189 (Scheme 34). The three-step reaction sequence 2 8  proceeded in 10% yield with the Grignard reaction having the lowest yield of the sequence. The H NMR spectrum of 189 contained a two-proton signal at 2.23 p p m for 1  the C-2 methylene protons, as well as a six-proton singlet at 1.41 ppm for the geminal methyl groups. The IR spectrum of 189 contained a band at 1725 cm" and the 1  219  CN M R spectrum contained a signal at 173.49 p p m , both for the lactone carbo  13  The H R M S and chemical analysis data were also consistent with the structure of 18  Scheme 34. Synthesis of 2,2-Dimethyloxacyclotridecane (190)  189  190  Key: (a) H C I (cone), CHOH, H0, A, 84%; (b) CHMgBr, CHCI, 0 °C, 27%; (c) EtN, THF, 2,4,6-trichlorobenzoyl chloride, rt; then DMAP, toluene, A, 44%; (d) NaBH, BFEt0, THF, rt; then triglyme, 26%.  a  3  2  3  2  2  3  4  3  2  With the lactone 189 in hand, the remaining portion of the synthesis involved  conversion of the lactone into the macrocyclic ether. It was found that the reaction  sterically hindered lactones with Lawessons ' reagent 48 or related thionation reagents  would not proceed, and an alternative was needed. The alternative was the dir  reduction of a lactone with sodium borohydride in the presence of boron trifluor  etherate to give the cyclic ether directly. This was originally applied in the literatu  with success to a steroidal system. W h e n applied to our system, this methodolo 3 6  w a s also successful and gave the macrocyclic ether 190 in 26% yield (Scheme 34).  220  4.3.2  Conformational Analysis of 2,2-Dimethyloxacyclotridecane (190) The H NMR  spectrum of 190 at rt in CDCI contained a two-proton triplet at  1  3.31  ppm,  3  a two-proton multiplet between 1 . 5 0 1 . 5 5 ppm,  between 1 . 2 9 1 . 4 4 ppm, 3.31  ppm was assigned to the C-13  to the C-14  and  13 lines. The C-13  C-15  low-field signals at 74.19  carbons. The  ppm.  18-proton multiplet The downfield signal at  protons, and the singlet at 1.12  geminal methyl groups. The  C  NMR  13  ppm was assigned  spectrum contained  and 59.96 ppm were assigned to the C-2  signal at 39.27 ppm  quaternary carbon C-2, C-15  and a six-proton singlet at 1.12  an  was  assigned to C-3  while the signal at 26.16  ppm was  adjacent to  and  the  assigned to the C-14  and  geminal methyl groups. The assignment of the remaining H and C signals was 1  13  aided by COSY, H M Q C , and H M B C 2 D N M R experiments (Table 51).  The overlap of  s o m e signals in these spectra prevented the complete assignment of the NMR data. The H R M S data was also consistent with the composition of 190.  Table 51. H and C NMR Assignments for 2,2-Dimethyloxacyclotridecane (190) in CDCI at R o o m Temperature 1  13  3  Position  H NMR  1  a  C NMR  13  a  74.19  14,15 a  1.40  39.27  not  assigned"  1.42  24.32  1.53  29.26  3.31  59.96  1.12  26.16  The chemical shift values are in ppm referenced to CHCI (H) and CDCI (C). Due to signal overlap these signals could not be unambiguously assigned. 1  1 3  3  b  3  A series of D N M R experiments were carried out on 190 in a 4:1 Freon 21 and  Freon 22 as solvent (Figure 45).  The  H NMR  1  mixture of  spectrum at 220  K  contained four signals and was similar to the rt spectrum with broadening of the signals at the lower temperature. The signal for the C-13  protons broadened at intermediate  221 temperatures to give a pair of signals with chemical shift 3.35 and 3.23 ppm at low temperature. The upfield signal of this pair was slightly broader at low temperatures.  Since a pair of signals was observed for these protons at low temperature, it is believ that a single major conformation of 190 is present at low temperature. The signal for the C-12 protons p to the ether oxygen also broadened as the temperature was lowered. The coalescence temperature for both the C-13 and the C-12 proton signals was 160 K . At low temperature, the signal for the C-12 protons split to give signals at 1.68 and 1.59 ppm. The lineshape of the signals in the methylene envelope region of the spectra also changed as the temperature was lowered, however overlap of these signals prevented a detailed analysis. The signal for the C-2 geminal methyl groups broadened as the temperature was lowered, but even at 125 K, the lowest temperature in this D N M R experiment, only one signal was observed for these protons.  A gem-dimethyl substituted carbon is restricted to a corner position  in  1 3 m e m b e r e d conformations. If located at any other position in the ring, one of the methyl groups is directed to the interior of the ring and a severe transannular steric interaction results.  1 0 5  There are eight possible [13333] conformations where the  oxygen a t o m is adjacent to a corner position. These are the conformations with the oxygen a t o m at the 2- 3- 5- 6-, 8- 9- 11- or 12-positions (page 182, Table 36 numbering). Three other conformations were also considered as possible low energy conformations of 190 (page 184, Table 37). The [12433] conformation from Table 37 was immediately disqualified from this set of conformations since the C-2 gem-dimethyl group cannot be located at a corner position in such a conformation.  222  223  [13333]  [12334]  The A5 value for the C-13  [13324]  protons in the low temperature spectra of 190 is small.  In the [13333]-2 conformation of 190, the H-13 proton is deshielded by the anisotropy e x o  of the C-11/C-12 bond. This proton is also shielded by a van repulsion between H-13do and e n  H-10do- The  der Waals steric  A5 value for the H-13  e n  conformation is predicted to be of an intermediate magnitude. The C-13  protons in this A6 value for  the  protons is predicted to be of an intermediate value in the [13333] conformations  with the ether oxygen a t o m at the 3- 5- 11-  and 12-positions as well. In the [13333]  conformation with the oxygen a t o m at the 6-position, the H-13 proton is deshielded e x o  by the anisotropy of the C-11/C-12 bond. It is also shielded as a result of van  der  Waals steric interactions between both H-10do and H-3do with H-13do- The two e n  e n  e n  van  der Waals shielding effects are in opposition to the anisotropic deshielding effect and a small A5 value is predicted. A similarly small A5 value is predicted for the [13333] conformations with the oxygen a t o m at the 8- and 9-positions. The A5 values of the C-13  protons in the [12334] and  [13324] conformations are predicted to be of an  intermediate value as the result of a deshielding of the H-13 proton by the anisotropy e x o  of the C-11/C-12 bond, and one opposing van der Waals shielding effect.  224  [13333]-6  [13333]-8  [13333]-9  On the basis of the observed chemical shift difference of the C-13 protons in macrocyclic ether 190, the likely low energy conformations were narrowed to the above three [13333] conformations. These are all consistent with the D N M R data where at low temperature, the H-13 proton is assigned to the downfield signal at 3.35  ppm,  e x o  and the H-13d proton to the signal at 3.23 e n  0  ppm.  The signal for H-13d was broader e n  than that of H-13. The H-13do proton is expected to have two e x o  constants ( J , J 3  g e m  e n  ) , while the H-13 proton has only one e x o  0  large coupling  large coupling constant  (Jgem)-  The  A8 value for the signals of the C-12 protons also was  small in the  low  temperature D N M R spectra. In each of the above three remaining conformations, the C-12  methylene carbon is at a corner position. The H-12 a  proton is deshielded by the  anisotropy of the C 1 0 / C 1 1 bond, but shielded by the anisotropy of the O / C 1 3 bond. Thus, the D N M R data is in agreement with the predicted A5 of the C-12  protons in each  of these three conformations, and the identity of the low energy conformation cannot be narrowed further with the data available.  A molecular mechanics search for low energy conformations of 190 was performed with the Monte Carlo technique and  the MM3* force field. The global  m i n i m u m conformation was the [13333]-9 conformation 190-A (Table 53).  The second  conformation found was 190-B, 0.41 kcal/mol higher in energy. A total of six conformations were found within 1 kcal/mol of the global m i n i m u m . The relative populations of these conformations at different temperatures were calculated from the relative energies obtained from the MM3* calculations (Table 52).  The results of these  225 calculations suggest that conformation 190-A is the major conformation over the  temperature range studied. This is in agreement with the results of the D N M R stu which gave data that was consistent with conformation 190-A.  Table 52.  Conformer  3  Thermodynamic Values for the Five Lowest Energy Conformations of 190  Skeleton  Relative Energy (kcal/mol)  298 K  Population (%) 170 K  125 K  3  190-A  [13333]-9  0.00  41.3  59.2  72.1  190-B  [12334]  0.41  20.8  17.8  14.1  190-C  [13333]-5  0.55  16.3  11.6  7.9  190-D  [12343 '] '  0.79  10.9  5.8  3.0  190-E  [13333]-2  0.80  10.7  5.5  2.9  Strain energies are relative to the lowest energy conformation calculated with th MM3* force field.  226 Table 53.  L o w Energy Conformations of 2,2-Dimethyloxacyclotridecane (190) Skeleton  Conformer  a  Relative Energy (kcal/mol)  190-A  [13333]-9  0.00  190-B  [12334]  0.41  190-C  [13333J-5  0.55  190-D  [12343 '] '  0.79  190-E  [13333]-2  0.80  Strain energies are relative to the global m i n i m u m conformation calculated with t MM3* force field.  227 The energies of the transition states involved in the interconversion of conformations of the macrocyclic ether 190 were determined from the rate of exchange between a pair of averaged signals in the D N M R spectra. Once known, the rate of exchange was used to calculate the free energy of activation (AG*) with the coalescence temperature (T) c  in Chapter 1.  At low  separated by 58 Hz. the  also obtained from the D N M R spectra and the equations  temperature, the  signals of the  C-13 protons of 190 were  This corresponded to a transition state barrier of 7.6 kcal/mol with  coalescence temperature of 160 K. The signals for the  separated by 48 Hz.  C-12 protons were  The coalescence temperature for the signals of these protons was  also 160 K for a transition state energy of 7.7 kcal/mol. The average of these values is 7.7 ± 0.1 kcal/mol. Since m o v e m e n t of the gem-dimethyl group from the corner position  would result in transannular steric interactions involving an endo methyl group rather than the lower energy hydrogen-hydrogen transannular interactions of  the  unsubstituted ether, the transition state energy for the interconversion of conformations of this gem-dimethyl ether is larger than that of the unsubstituted 1 3 m e m b e r e d ether 168 (6.8 kcal/mol).  4.4.1  Synthesis of 3,3-Dimethyloxacyclotridecane (193)  The  final  1 3 m e m b e r e d  macrocyclic  3,3-dimethyloxacyclotridecane (193). The  ether  prepared  here was  gem-dimethyl substituents of 193 could be  introduced through alkylation at C-2 of lactone 165. First, the Baeyer-Villiger oxidation of cyclododecanone (93) was The  performed with trifluoroperacetic acid to give lactone 165.  gem-dimethyl substituents were introduced individually via a sequential double  alkylation with LDA  to generate the anion at C-2  of the  lactone, and  alkylation with  methyl iodide to give ultimately the gem-dimethyl lactone 192 (Scheme 35). step reaction sequence proceeded in 27% contained a signal at 4.11 at 1.13  ppm for the C-13  an absorption at 1715  ppm for the C-12  and C-14 cm'  1  Lawesson s ' reagent 48 was  yield overall. The H NMR 1  The three-  spectrum of 192  methylene protons and a six-proton singlet  geminal methyl groups. The  IR spectrum contained  for the lactone carbonyl. Formation of a thionolactone with not attempted as this reaction was  of sterically hindered lactones. The 1 4 4  k n o w n to fail in the case  conversion of this lactone to the macrocyclic  228 ether 193 was  performed via the direct reduction with sodium borohydride in the  presence of boron trifluoride etherate to give the macrocyclic ether 193 in a very modest yield of 6%.  36  Unlike the reduction of lactone 189 with a gem-dimethyl group at  C-12, the reduction of the C-2 gem-dimethyl lactone 192 was  m o r e difficult and would  not proceed at r o o m temperature. Refluxing conditions were found to be necessary.  Scheme 35. Synthesis of 3,3-Dimethyloxacyclotridecane (193)  a  O  93  165  191  192  193  Key: (a) UHP, TFAA, NaHP0, CHCI, 0 °C, 90%; (b) LDA, THF, -78 °C; then Mel, 43%; (c) LDA, THF, -78 °C; then Mel, 70%; (d) BFEt0, NaBH, THF, rt; then triglyme, A, 6%.  a  2  4  2  2  3  2  4  4.4.2 Conformational Analysis of 3,3-Dimethyloxacyclotridecane (193) The H NMR 1  spectrum of 193 contained a two-proton triplet at 3.40  two-proton singlet at 3.05  ppm,  ppm,  a  a two-proton broad quintet between 1.49-1.53 ppm, a  16-proton multiplet between 1 . 1 9 1 . 4 4 ppm, and a six-proton singlet at 0.84 downfield signals at 3.40  and 3.05  ppm were assigned to the protons of C-13  respectively (Table 54).  The data from a COSY experiment was  ppm. and  The C-2  used to assign the  229  signal at 1 . 5 1 p p m to the C-12 protons. The high-field singlet was assigned to th and C-15 geminal methyl groups. The H R M S data was also consistent with the composition of 193.  The C N M R spectrum of 193 contained 13 lines. The t w o lowest field signal 1 3  at 78.58 and 71.06 p p m were assigned to C-2 and C-13, the carbons adjacent ether oxygen.  The signals at 34.22 and 37.14 p p m were assigned to the  C-3 quaternary carbon, and the adjacent C-4 methylene carbon. The signal at  25.95 p p m was m o r e intense than the other signals and was assigned to the C-1  C-15 geminal methyl groups on this basis. The assignment of other C and H signa 13  1  was aided b y COSY, H M Q C , and H M B C 2 D N M R experiments (Table 54). D u e overlap of the N M R signals the portion of the ring opposite to the ether oxygen not be assigned.  Table 54. H and C N M R Assignments for 3,3-Dimethyloxacyclotridecane (193) in CDCI at R o o m Temperature 1  1 3  3  Position 2  H NMR  1  a  3.05  C NMR  1 3  a  78.58 34.22  13 14, 15 a  1 . 2 8  37.14  not  assigned"  1 . 4 1  25.15  1 . 5 1  28.45  3.40  71.06  0.84  25.95  The chemical shift values are in p p m referenced to CHCI (H) and CDCI (C). D u e to signal overlap these signals could not be unambiguously assigned. 1  3  b  1 3  3  230  The low temperature H N M R spectra of 193 were obtained in a 4 : 1 mixture 1  Freon 2 1 and Freon 22 as solvent (Figure 46). The spectrum of 193 at 220 K similar to the rt spectrum with broadening of the signals at the lower temperature. signals of the C-13 protons broadened at intermediate temperature to give a pair  signals at 3 . 7 5 and 3.25 p p m at low temperature. In contrast, the signal for the  protons was essentially unchanged at all but the lowest temperatures examined in t D N M R study. Broadening of the C-2 proton signal below 150 K was observed.  Similarily, the signal for the C-12 protons was largely unchanged over the temperat  range examined with the signal broadening at the lowest temperatures. The signal f the geminal methyl groups also broadened at intermediate temperatures with a  coalescence temperature of 155 K . At 130 K this signal was split into t w o equall  intense signals at 0 . 9 1 and 0.77 p p m . Since one pair of intense signals were obs  for the geminal methyl groups, only one major conformation of 193 is present at l temperature.  231  232 A gem-dimethyl substituted carbon is  restricted to  1 3 m e m b e r e d conformations. If located at any methyl groups is pointing into the ring and  a corner position in  other position in the ring, one  of  the  a severe transannular steric interaction  results. There are nine possible [13333] conformations where the oxygen a t o m is 1 0 5  located p to a corner position. These are the conformations with the oxygen a t o m at the 2- 3- 5- 6-, 8- 9- 11-  or 12-positions (page 182, Table 36 numbering). The other  conformations in Table 37 (page 184)  were also considered as ring skeletons for  low  energy conformations of 193.  [13324]  The A8 value for the C-13  [12433]  [12433]  protons in the low temperature spectra of 193 is large.  In the [13333] conformation of 193 with the oxygen a t o m at the 2-position, the H-13o 6 X  proton is deshielded by the anisotropy of the C-11/C-12 bond. The H-13  protons in this conformation is predicted to be large. The  A8 value for  H-13  p  the  proton in the  [13333] conformation of 193 with the oxygen a t o m at the 3-position, is at a corner position, and  is deshielded by the anisotropy of the C-11/C-12 bond, but shielded by  233 the anisotropy of the O/C-2  bond. The A5 value for the C-13  protons is predicted to be  small in this conformation, as well as for the [13333] conformations with the ether oxygen at the 5- 6- 8- 9-, 11- and 12-positions.  The A5 value of the C-13  protons in the [12334] conformation is predicted to be  large as the result of a deshielding of the H-13 proton by the anisotropy of the e x o  C-11/C-12 bond. In the [13324] conformations presented above, the A5 is predicted to be small as the result of a deshielding of the H-13 proton by the anisotropy of the e x o  C-11/C-12 bond, with either an opposing additional anisotropic shielding effect, or an opposing van der Waals shielding effect. Small A8 values are also predicted for C-13  the  protons in the [12433] conformations.  [13333]  [12334]  On the basis of the observed chemical shift differences of the C-13  protons in  macrocyclic ether 193, the n u m b e r of likely low energy conformations was narrowed to  the above two conformations. These are both consistent with the observed D N M R data for the C-13  protons where at low temperature, the H-13 proton is assigned to the  downfield signal at 3.75 ppm,  e x o  and  the  H-13d proton to the e n  0  signal at 3.25 ppm  (Figure 46).  The A8 value of the low temperature signals of the C-2 protons in 193 was either zero, or very small. In the above [13333]-2 conformation, the C-2 methylene carbon is adjacent to a corner position. Thus, the H-2 proton is deshielded by the anisotropy of e x o  the C-3/C-4 bond and shielded by a van der Waals steric interaction between H-2do e n  234 and H-5 . These opposing effects s u m to a small A5 value. The H-2 proton in e n d 0  P  [12334] conformation is deshielded b y the anisotropy of the C-3/C-4 bond. This resu  in a large A5 value for the C-2 protons in this conformation. Thus, of the t w o rem conformations, the [13333]-2 conformation is the best fit to the D N M R signals of C-2 and C-13 protons of 193.  The averaging of the C-3 geminal methyl groups of 193 is slow at low  temperature and a pair of signals of equal intensity at 0 . 9 1 and 0.77 p p m are vis  the low temperature D N M R spectra. The presence of this pair of signals indicates th a conformational interconversion process that results in exchange of the geminal  methyl groups is slow at the low temperature. The unambiguous assignment of the  signals at 0 . 9 1 and 0.77 p p m to the C-3 and C-3 methyl groups cannot be m a a  P  this data.  A molecular mechanics search for the low energy conformations of 193 w a s  carried out with the Monte Carlo technique and the MM3* force field. The glob  m i n i m u m conformation was the [13333]-2 conformation 193-A (Table 55). The second  conformation 193-B was 0.69 kcal/mol higher in energy. A total of six conformation were found within 1 kcal/mol of the global m i n i m u m . The relative populations of conformations at different temperatures were calculated from the relative energies  obtained from the MM3* calculations (Table 56). The results of these calculations  suggest that conformation 193-A is the major conformation over the temperature range studied. This is in agreement with the above analysis of the D N M R data.  235 Table 55.  L o w Energy Conformations of 3,3-Dimethyloxacyclotridecane (193) Skeleton  Relative Energy (kcal/mol)  193-A  [13333]-2  0.00  193-B  [13324]  0.69  193-C  [12433]  0.86  193-D  [13333J-12  0.94  Conformer  a  Strain energies are relative to the global m i n i m u m conformation calculated with th MM3* force field.  236 Table 56.  Conformer  a  Thermodynamic Values for the Five Lowest Energy Conformations of 193  Skeleton  Relative Energy (kcal/mol)  298 K  Population (%) 165 K  130 K  3  193-A  [13333]-2  0.00  51.4  76.7  86.6  193-B  [13324]  0.69  15.9  9.3  5.9  193-C  [12433]  0.86  12.0  5 . 6  3.1  193-D  [13333]-12  0.94  10.5  4.4  2.3  193-E  [13234 '] '  0.96  10.1  4.1  2.1  Strain energies are relative to the lowest energy conformation calculated with th MM3* force field. The energies of the transition states involved in the interconversion of  conformations of the macrocyclic ether 193 were determined from the rate of exchang  between a pair of averaged signals in the D N M R spectra. Once known, the rate exchange was used to calculate the free energy of activation (AG*) with the  coalescence temperature (T) also obtained from the D N M R spectra and the equatio c  in Chapter 1. At low temperature, the signals for the C-13 protons were separate 248 Hz. This gave a transition state energy of 7.2 kcal/mol at the coalescence temperature of 160 K . The signal for the C-14 and C-15 geminal methyl groups  also split to give a pair of signals 70 Hz apart with a coalescence temperature of 1  This corresponded to a transition state energy of 7 . 3 kcal/mol. The average of the  values is 7 . 3 ±0.1 kcal/mol. Again this value is higher than the transition state en observed for the unsubstituted 1 3 m e m b e r e d ether 168 (6.8 kcal/mol). L o w energy conformational interconversion pathways accessible b y the unsubstituted ether 168, are higher in energy and inaccessible in the case of this gem-dimethyl substituted ether.  4.5.1  Conclusion  The syntheses of the 1 3 m e m b e r e d macrocyclic ethers 168, 171, 179, and 180  were carried out via the Baeyer-ViNiger ring expansion of the ketones 93 and 174  237 give intermediate lactones 165 and 175.  Further reaction of these lactones under  thionation conditions and subsequent radical reduction gave the macrocyclic ethers.  The diastereomeric ethers 179 and 180 were prepared under both hydrogenation and  radical reduction conditions with low stereoselectivity observed under both conditions.  The configuration of the methyl substituents in 179 and 180 was determined b y chir GC analysis.  The macrocyclic ether 190 was prepared via the cyclization of hydroxy acid 18  with the Yamaguchi reagent to give lactone 189. The direct reduction of the lacton  with sodium borohydride in the presence of boron trifluoride etherate was employed give macrocyclic ether 190.  The macrocyclic ether 193 was prepared via the reduction of lactone 192. However, even under refluxing conditions, the boron trifluoride mediated sodium borohydride reduction of this lactone proceeded in low yield.  The conformation of these 1 3 m e m b e r e d ethers was analyzed with data from H-DNMR experiments. The low-temperature chemical shift difference of protons with 1  signals that were averaged at rt, were generally in agreement with predictions based anisotropy and van der Waals shielding effects in the low energy conformations.  Although m a n y different possible conformations for these large ring compounds exist,  only a few conformations were found to be appreciably populated at r o o m temperat  and below. Generally the conformations were consistent with the substituents located exo to the ring, with geminal substituted carbon atoms occupying corner positions exclusively. These results were consistent with the molecular mechanics calculations. In general, the non-diamond lattice [13333] conformation was preferred just as in  case of cyclotridecane. Thus, the introduction of the oxygen a t o m in these macrocyc ethers did not have a significant effect on the conformation of the ring.  The transition state energies for the conformational interconversion were  determined from the H D N M R experiments to be in the range of 6 . 8 to 9 . 7 kca 1  238  The transition state energies of the gem-disubstituted ethers 190 and 193 were bot larger than that of the unsubstituted 1 3 m e m b e r e d ether 168.  As expected, the  transition state energy values obtained for these macrocyclic compounds with an od  numbered ring size were in general smaller than those obtained for the 1 4 m e m b e ethers.  This is in agreement with the greater conformational mobility of the  1 3 m e m b e r e d rings and their non-diamond lattice based conformations. These conformations are in general m o r e distorted and higher in strain energy than the diamond lattice conformations.  4.6.1 General C o n c l u s i o n  The reduction of a lactone was s h o w n to be an effective m e t h o d for the preparation of 13- and 1 4 m e m b e r e d macrocyclic ethers. In the case of sterically  hindered lactones, the m e t h o d involving a thionolactone intermediate^ failed, and a  direct reduction of the lactone was employed instead. The observed stereoselectivity  of the reductions leading to the dialkylated ethers 103, 104, 179, and 180 w a s low under both radical and hydrogenation conditions.  The 1 4 m e m b e r e d ethers were in general found to have conformations whic were superimposable on the diamond lattice, while the 1 3 m e m b e r e d ether were conformationally less regular, and not superimposable on the diamond lattice.  Comparison of the conformations of the 13- and 1 4 m e m b e r e d ethers showed the a  substituents to have a similar impact for both ring sizes. In the case of the structu  similar ethers 103 and 179 (R* R*) vs. 104 and 180 (S*, R*), the (S*, R*) isomers w  predominantly one conformation, while the (R*, R*) isomers had multiple low-energy conformations. Entropy contributions were largely not considered in the calculations  performed here. However, it is likely that in the case of the (R*, R*) isomers descri  above and in other macrocycles having several conformations with low energies the  m a y be significant entropic contributions due to the interconversion of those low-lyin conformations.  239  CHAPTER 5 EXPERIMENTAL  5.1.1  General  Unless otherwise stated, all reactions were performed under a nitrogen atmosphere in flame- or oven-dried glassware. Elevated temperature reactions were performed in either a silicone oil bath or with a Glas-Col heating mantle heated to desired temperature. Low  the  temperature reactions were performed in a cold bath  prepared as follows: -78 °C (dry  ice, acetone), -40 °C (dry  ice, acetonitrile), -20  °C  (dry  ice, carbon tetrachloride), 0 °C (ice, water).  Anhydrous solvents were obtained by distillation. Diethyl ether, tetrahydrofuran (THF)  and  toluene were distilled from sodium. Methylene chloride was  calcium hydride. Dimethyl formamide and pressure from calcium hydride. (bp 35-60 °C) was  distilled from  dimethyl sulphoxide were distilled at reduced  The low boiling fraction of petroleum ether  used. Toluene and  1,2-dichloroethane were deoxygenated with the  freeze-pump-thaw method. Methylene chloride and  cyclohexane were deoxygenated  by sparging with nitrogen for 30 minutes. Otherwise the solvent was  used as received  from the supplier.  Reagents were purified according to the  procedure given in the literature.  1 8 5  Unless otherwise noted, reagents were purchased from the  Aldrich Chemical Co.  Alkyllithium reagents were standardized by titration with 2,5-dimethoxybenzyl alcohol in THF  at 0 °C to a faint red colour indicative of the endpoint. Urea hydrogen peroxide 1 8 6  (UHP) and  was  either purchased from Aldrich or prepared by the  Giguere. Tri(n-butyl)tin hydride was  b y the  either purchased from Aldrich or prepared  1 8 7  m e t h o d of Kuivila and Beumel.  according to the  1 8 8  m e t h o d of Cannizzo and  purchased from BDH  Chemicals Ltd.  m e t h o d of Lu, Hughes,  The Tebbe reagent 32 Grubbs.  1 5 3  was prepared  Adams' Catalyst (Pt0) was  Pyridinium p-toluenesulfonate was  the m e t h o d of Miyashita, Yoshikoshi, and  2  prepared by  Grieco. Zinc-copper couple was prepared 1 4 7  240 according to the m e t h o d of Shank and Shechter.  1 8 9  The Grubbs' catalyst 9 w a s  prepared by Mr. Andre Hodder according to the m e t h o d of Schwab, Grubbs, and Ziller. The Jones reagent w a s prepared via the m e t h o d of Eisenbraun. 1 6 6  1 7 9  Analytical gas-liquid chromatography (GC) w a s performed on a Hewlett-Packard  model 5880A gas chromatograph, equipped with a split m o d e capillary injection system  and a flame ionization detector. The stationary phase consisted of a either an O V 1  or a DB-210 capillary column of dimensions 0.22 m m x 1 2 m . Chiral GC column  Cyclodex-B (Chromatographic Specialties Inc.) and |3-Dex 360 (Supelco) both having dimensions of 0.25 m m x 30 m were also employed. Helium was used as the gas in all cases.  The concentration or evaporation of solvents under reduced pressure refers to the use of a Buchi rotary evaporator. A brine solution refers to a saturated NaCl solution. Thin layer chromatography (TLC) w a s performed on commercially available  aluminum backed plates of silica gel 60 (Merck 5554, 0 . 2 m m thickness). TLC pla were visualized with ultraviolet light (254 n m ) or 1% p-anisaldehyde spray. Flash chromatography was performed using silica gel 60, 230-400 mesh, supplied b y 0 9 1  E. Merck Co. In m o s t cases a solvent system was chosen such that the desired  product had an R of approximately 0.30-0.35 on TLC. Radial chromatography w a s f  performed using a Harrison Chromatotron model 8924. The adsorbant used w a s sili gel 60,  PF54 2  with g y p s u m binder supplied b y E M Science. In m o s t cases a solv  system was chosen such that the desired product had an R of approximately 0.10-0 f  on TLC.  Melting points were performed using a Mel-Temp II apparatus (Lab Devices USA) and are uncorrected. Isomerization reactions were performed under photolysis conditions with the sample immersed in a 0 . 0 0 1 4 M KCr0 solution and a 450 2  4  Hanovia m e d i u m pressure mercury vapour lamp.  Infrared (IR) spectra were recorded on a B o m e m Michelson 100 FT-IR spectrometer with internal calibration.  IR spectra were taken on either  2 4 1  deuteriochloroform or carbon tetrachloride solutions held between t w o NaCl plates o 4m m thickness with an internal well of 0 . 2 m m thickness.  Proton nuclear magnetic resonance (H N M R ) spectra were recorded on eith 1  deuteriochloroform or benzene-cf solutions using a Bruker W H 4 0 0 (400 MHz), or 6  Bruker AMX-500 (500 MHz) spectometer. Chemical shifts are given in parts per mil  ( p p m ) on the 8 scale, referenced to chloroform (8 7.24) or benzene (8 7.15) as inte  standard. Signal multiplicity, coupling constants, and integration ratios are indicated in parentheses. The abbreviations used to denote N M R signal multiplicities are as  follows: br (broad), s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet),  (sextet), m (multiplet), dd (doublet of doublets), dt (doublet of triplets), ddd (doubl doublet of doublets), etc.  Proton and carbon dynamic nuclear magnetic resonance spectra were recorded  on Freon 21 (CHCIF) and Freon 22 (CHCIF) (4:1) solutions using a Bruker AM 2  2  (H, 500 MHz, C, 125 MHz) spectrometer. Carbon nuclear magnetic resonance 1  13  (C N M R ) spectra were recorded on either deuteriochloroform or benzene-d solution 1 3  6  using a Bruker AMX-500 (125 MHz) spectrometer. Chemical shifts are given in pa per million ( p p m ) on the 8 scale, using deuteriochloroform (8 77.0) or benzene-d 6  (8 128.0) as internal standard.  L o w resolution mass spectra (LRMS) in electron ionization (El) m o d e were  recorded on a Kratos-AEI model M S 50 spectrometer. LRMS in chemical ionizatio  (CI) m o d e were recorded on either a Kratos M S 80 spectrometer or a Kratos Conc  H Q spectrometer. LRMS in desorption chemical ionization (DCI) m o d e were recorded  on a Delsi N e r m a g R10-10 C spectrometer. Only peaks with greater than 20% rela intensity or those which were analytically useful are reported.  High resolution mass spectra (HRMS) in El m o d e were recorded on a Kratos model M S 50 spectrometer. H R M S in CI m o d e were recorded on either a Kratos spectrometer or a Kratos Concept II H Q spectrometer.  242  Microanalyses were performed b y Mr.  Peter. Borda in the Microanalytical  Laboratory at the University of British Columbia on a Carlo Erba Elemental Analyzer Model 1106  5.1.2  or a Fisons CHN-0 Elemental Analyzer Model 1108.  Conformational Analysis Methods  BATCHMIN, a part of the M A C R O M O D E L molecular modelling developed b y Still and  coworkers. w a s used to calculate the 1 9 1  program  global m i n i m u m  conformations of the macrocyclic ethers studied in this work. A starting structure was chosen, r a n d o m variations to internal coordinates were applied (torsional angles), the new structure was  minimized using either the MM2* or the MM3* force field parameters,  and the result was  compared with conformations found during previous conformational  search steps. After this resulting structure had  been either stored as a new unique  conformer or rejected as a duplicate, the cycle was  repeated. This method is k n o w n as  the Monte Carlo Multiple M i n i m u m Search (MCMM). The are  based on the  MM2 and  MM2* and  MM3* force fields  MM3 parameter sets developed by Allinger and  1 9 2  1 9 3  coworkers.  5.1.3  Chemical Methods  13-Tridecanolide (87)  (a) Baever-Villiaer Oxidation of Cvclotridecanone (86) with 70% Trifluoroacetic anhydride (0.44 (0.10  mL,  3.1  mL, 3.1  m m o l ) in CHCI (6 mL) 2  2  mmol), was at -10  Hydrogen Peroxide  added to a solution of 70%  °C and  the  reaction was  H0  stirred for  2  2  243 45 minutes. A solution of cyclotridecanone (86) (61 mg, 0.31 m m o l ) in CHCI (3 mL) 2  2  was added dropwise via syringe followed by solid NaHP0 (0.22 g, 1.6 mmol), and the 2  4  resultant mixture was stirred for three hours. The reaction was diluted with CHCI, 2  2  sequentially washed with 10% KOH solution, 10% NaS0 solution and brine, and dried 2  3  over anhydrous MgS0. The extracts were filtered and the solvent was removed under 4  reduced pressure. Column chromatography of the residue with 2% ethyl acetate in petroleum ether as eluant gave lactone 87 (24 mg, 39%) as a pale yellow oil.  IR(CDCI): 2934, 2861, 1719, 1447, 1251, 1051 cm'; 1  3  H NMR (500 MHz, CDCI): 5 4.11-4.13 (m, 2 H), 2.34-2.36 (m, 2 H), 1 . 6 0 1 . 6 6 (m, 4 H),  1  3  1 . 2 2 1 . 4 4 (m, 16 H);  C NMR (125 MHz, CDCI): 5 173.92, 63.25, 34.36, 27.64, 26.22, 26.04, 25.86, 25.66  13  3  24.72, 24.63, 24.03, 23.70, 22.77; LRMS (El) m/z (relative intensity): 212 (M, 32), 194 (39), 152 (79), 137 (32), 124 (64), +  110 (100), 98 (94), 83 (44); H R M S (El) m/z calculated for Ci H 0 : 212.1776, found: 212.1775; 3  24  2  Analysis calculated for Ci H 0 : C, 73.54; H, 11.39. Found: C, 73.40; H, 11.43. 3  24  2  (b) Baeyer-ViNiger Oxidation of Cyclotridecanone (86) with UHP Trifluoroacetic anhydride (1.9 mL, 14 m m o l ) was added via syringe to a mixture of cyclotridecanone (86) (0.42 g, 2.1 mmol), urea hydrogen peroxide (1.20 g, 12.8 mmol), and NaHP0 (2.09 g, 14.7 m m o l ) in CHCI (20 mL) stirred at 0 °C and the reaction 2  4  2  2  was stirred for 18 hours with slow warming to rt. The reaction was diluted with CHCI, 2  2  sequentially washed with saturated NaHC0 solution, saturated NaS0 solution, 3  2  2  3  water and brine, and dried over anhydrous MgS0. The extracts were filtered and the 4  solvent was removed under reduced pressure to give lactone 87 (0.43 g, 96%) as a  pale yellow oil with spectral data in agreement with that reported above. This materia was used in subsequent reactions without further purification.  244  2-Oxacyclotetradecanethione (88)  A solution of lactone 87 (0.21  g, 0.97  m m o l ) in toluene (5 mL) was  a suspension of Lawessons ' reagent 48 (0.87 reaction was  heated at reflux for 4.5  were combined, and  the  solvent was  g, 2.2 m m o l ) in toluene (5 mL)  days. The  through cotton, and the solid residue was  added via cannula to  reaction was  and  the  cooled to rt, filtered  rinsed with diethyl ether. The  organic layers  removed under reduced pressure. Column  chromatography of the residue with 2% ethyl acetate in petroleum ether as eluant gave thionolactone 88 (0.16  IR(CDCI ): 3154, 3  H NMR  (500  1  MHz,  g, 73%)  as a yellow oil.  2908, 1445,  1273,  1198,  1019,  829  cm"; 1  CDCI ): 5 4.46-4.48 (m, 2 H), 2.85-2.88 (m, 2 H), 1 . 7 4 1 . 8 2 (m, 2 H), 3  1.67-1.73 (m, 2 H), 1 . 4 3 1 . 4 8 (m, 2 H), 1 . 1 6 1 . 3 9 (m, 14 1 3  C NMR  (125  MHz,  H);  CDCI ): 5 224.66, 71.37, 47.14, 27.25, 27.00, 26.09, 25.97, 25.84, 3  25.03, 24.38 (2), 23.39, 23.19; LRMS (El) m/z (relative intensity): 228 (M, +  4), 195 (21),  95 (48),  83 (47),  69 (68),  55  (100); H R M S (El) m/z calculated for Ci H OS: 228.1548, found: 228.1547; 3  24  Analysis calculated for Ci H OS: C, 68.37; H, 10.59. Found: C, 68.12; H, 10.54. 3  24  245 2-(Methylthio)oxacyclotetradecane (89)  A solution of lithium triethylborohydride in THF solution of thionolactone 88 (81 reaction was  mg,  0.36  (1.8  mL,  1.8  m m o l ) in THF  stirred for 30 minutes. Methyl iodide (0.14  m m o l ) was  (5 mL)  at -78  added to a °C and  mL, 2.2 m m o l ) was  the  added, and  the reaction was  stirred for a further 30 minutes at -78 °C, and then allowed to slowly  w a r m to rt. The  solution was  3M  N a O H solution (3 mL)  diluted with diethyl ether and cooled to -78 °C. Aqueous and  30%  H0 (1.5 2  2  mL)  The  solution was  stirred for 20 minutes at -78  reaction was  sequentially washed with saturated NaS0 solution, water, and brine,  and  °C and  were added sequentially. then allowed to w a r m to rt. 2  dried over anhydrous MgS0. The 4  2  3  extracts were filtered and  the  solvent was  removed under reduced pressure to give mixed thioacetal 89 (79 mg, 91%) Thioacetal 89 was  unstable and was  (M+18), 245 (M+1); +  +  H R M S (El) m/z calculated for CHOS: 244.1861, found: 244.1856. 1 4  as an  used immediately without further purification.  LRMS (DCI(+), a m m o n i a ) m/z: 262 2 8  The  oil.  246 Oxacyclotetradecane (90)  A deoxygenated solution of tri(n-butyl)tin hydride (0.38 (10 mg)  in toluene (2.6  mL)  was  mL,  1.4  added over three hours via  deoxygenated solution of mixed thioacetal 89 (57 mg, 0.23 toluene (15  mL)  solvent was  removed under reduced pressure. The  m m o l ) and AIBN syringe p u m p to a  m m o l ) and AIBN (5 mg)  in  heated at reflux. After the addition of the tri(n-butyl)tin hydride, the  column chromatography of the  residue with 2%  tin compounds were removed by  ethyl acetate in petroleum ether.  Further column chromatography using AgN0 impregnated silica with petroleum ether 3  as eluant gave ether 90 (20 mg, 43%)  as a pale yellow oil.  IR(CDCI): 3932, 2860, 1442,  1266,  3  H NMR  (500  1  MHz,  1351,  CDCI): 5 3.41  1119,  1038  (t, J = 5.5 Hz, 4 H), 1.57  3  cm"; 1  (quint, J = 5.5 Hz, 4 H),  1.29-1.43 (m, 16 H), 1 . 2 1 1 2 7 (m, 2 H); C  13  NMR  (125  MHz,  CDCI): 5 68.58 (2), 28.59 (2), 26.34 (2), 25.15 3  (2), 24.37 (2),  23.42 (2), 23.19; LRMS (DCI(+), a m m o n i a ) m/z (relative intensity): 216  (M +18, 97), +  199 (M+1, 100); +  H R M S (El) m/z calculated for CiH 0: 198.1984, found: 198.1991; 3  2 6  Analysis calculated for CiH 0: C, 78.72; H, 13.21. Found: C, 79.08; H, 13.18. 3  2 6  247 2-Methyl-2-(methylthio)oxacyclotetradecane (91)  Methyllithium in diethyl ether (1.7 thionolactone 88 (73  mg, 0.32  1.7  m m o l ) was  m m o l ) in THF  stirred for 40 minutes at -78 ° C . reaction was  mL,  (5 mL)  added to a solution of  at -78  Methyl iodide (0.12  mL,  reaction was  diluted with diethyl ether, and  water and brine, and dried over anhydrous MgS0. The  m m o l ) was  added, the  finally allowed to  sequentially washed with  extracts were filtered and  the  removed under reduced pressure to give the mixed thioketal 91 (74  mg,  4  90%)  1.9  the reaction was  stirred for an additional 20 minutes at -78 ° C , and was  w a r m to rt. The  solvent was  ° C and  as a pale yellow oil.  Thioketal 91 was  unstable and  was  used immediately  without further purification.  LRMS (El) m/z (relative intensity): 258 (M, +  (100), 43  1), 211 (26),  97 (22),  83 (30),  (65);  H R M S (El) m/z calculated for Ci H OS: 258.2018, found: 258.2027. 5  30  71 (35),  59  248 2-Methyloxacyclotetradecane (92)  A deoxygenated solution of tri(/7-butyl)tin hydride (2.2 in toluene (7.8  mL)  was  mL, 8.2 m m o l ) and AIBN (10  mg)  added over ten hours via syringe p u m p to a deoxygenated  solution of mixed thioketal 91 (0.21  g, 0.82  m m o l ) and AIBN (5 mg)  in toluene (10  mL)  heated at reflux. After addition of the tri(n-butyl)tin hydride solution, the solvent was removed under reduced pressure. Column chromatography of the  residue with 2%  ethyl acetate in petroleum ether as eluant removed the tin compounds. Further column  chromatography using AgN0 impregnated silica with petroleum ether as eluant gave 3  ether 92 (0.11  g, 63%)  as a pale yellow oil.  IR(CDCI): 2929, 2859, 1459, 3  H NMR  (500  1  MHz,  CDCI): 6 3.61  C  13  NMR  (125  MHz,  (ddd,  1340,  1130,  1098,  1039  (dt, J = 9.2, 4.2 Hz, 1 H), 3.43  3  Hz, 1 H), 3.22 21 H), 1.09  1372,  J = 3.0, 9.2, 10.6  cm"; 1  (ddq,  J = 3.1, 9.2,  6.2  Hz, 1 H), 1.65-1.73 (m, 1 H), 1 . 1 0 1 . 6 1 (m,  (d, J = 6.2 Hz, 3 H);  CDCI): 5 73.32, 65.99, 36.42, 29.00, 26.48, 26.22, 25.46, 25.27, 3  24.93, 24.66, 23.84, 23.19, 22.99, 19.82; LRMS (El) m/z (relative intensity): 212 (96),  55 (97),  43  (M, 4), 197 (23), +  109 (25),  97 (73),  82 (100), 69  (37);  H R M S (El) m/z calculated for CiH 0: 212.2140, found: 212.2140; 4  2 8  Analysis calculated for C H 0: C, 79.18; H, 13.29. Found: C, 79.23; H, 13.70. 1 4  2 8  249  (Z/E)-1-(Trimethylsiloxy)cyclotridecene (95) and (96)  O T M S  1,1,1,3,3,3-Hexamethyldisilazane (0.21 (0.13  mL,  1.0  mL,  1.0  m m o l ) and  m m o l ) were added sequentially via  cyclotridecanone (86) (0.10  g, 0.51  m m o l ) and  trimethylsilyl chloride  syringe to  a  lithium iodide (0.13  mixture of  g, 1.0 m m o l ) in  CHCI (5 mL), and the reaction was stirred for 19 hours in the dark at rt. Triethylamine 2  (0.14  2  mL,  1.0  m m o l ) was  added to the reaction mixture, and  additional 30 minutes. The  reaction was  it was  stirred for  an  diluted with diethyl ether, and sequentially  washed with saturated NaHC0 solution, brine and dried over anhydrous MgS0. The 3  4  extracts were filtered and the solvent was chromatography of the residue (GC  removed under reduced pressure.  Column  ratio 95:96, 83:17) with petroleum ether as eluant  gave silyl enol ethers 95 (86 mg, 63%)  and 96 (12 mg, 9%) both as colourless oils.  95 (Z) IR (CDCI3): 2929, 2857, 1670, H NMR  (500  1  MHz,  CD): 5 4.44 6  6  1451,  1362,  1252,  1164,  1047,  (t, J = 7.3 Hz, 1 H), 2.10  947, 850  C NMR  (125  MHz,  1  (dt, J = 7.3, 6.7 Hz, 2 H),  2.01-2.03 (m, 2 H), 1.50-1.55 (m, 2 H), 1 . 3 3 1 . 4 6 (m, 16 H), 0.14 13  cm";  (s, 9 H);  CD): 6 150.17, 110.67, 36.11, 28.32, 26.82, 26.70, 26.69, 26.09 6  6  25.94, 25.91, 25.74, 25.12, 24.87, 0.63  (3);  LRMS (El) m/z (relative intensity): 268 (M, 15), 143 (72), +  130 (92),  73 (100);  H R M S (El) m/z calculated for CiHOSi: 268.2222, found: 268.2215; 6  3 2  Analysis calculated for CiHOSi: C, 71.57; H, 12.01. Found: C, 71.71; H, 11.89. 6  3 2  250 96 ( £ )  IR (CDCI3): 2929, 2859, 2353, 1659,  H NMR  (500 MHz,  1  1452,  1252,  1135,  859  cm'; 1  C D ): 5 4.66 (t, J = 7.3 Hz, 1 H), 2.17 (t, J = 6.6 Hz, 2 H), 2.04 6  J = 7.3, 6.7 Hz, 2 H), 1 . 6 4 1 . 6 8 (m, 2 H), 1.32-1.45 (m, 16 H), 0.21 1 3  C NMR  (125  MHz,  (dt,  6  (s, 9 H);  C D ): 8 151.70, 108.47, 29.48, 29.33, 28.76 (2), 27.58, 27.22, 6  6  26.54, 25.66, 25.23, 25.21, 24.50, 0.50 LRMS (El) m/z (relative intensity): 268 (M,  (3);  17), 143 (75),  +  130 (100), 73  (97);  H R M S (El) m/z calculated for CiH OSi: 268.2222, found: 268.2222. 6  32  2-Methylcyclotridecanone (97)  0  (a) Ring Expansion/Alkvlation of 1-Dibromomethvlcyclododecanol (94) A solution of n-butyllithium in hexanes (4.5  mL, 6.3 m m o l ) was  via syringe p u m p to a solution of dibromoalcohol 94 (1.07 at -78 °C.  The  reaction was  stirred for 10 minutes at 0 °C. and methyl iodide (0.56  g, 2.99  stirred for 30 minutes at -78 The  reaction was  added over 30 minutes m m o l ) in THF  (10  °C, w a r m e d to 0 °C,  cooled to -78 °C and  H M P A (1.0  mL, 9.0 m m o l ) were added simultaneously. The  was  mL)  The  diluted with diethyl ether, and the organic layer  sequentially washed with saturated CuS0 solution, saturated NaS0 solution, 4  brine, and was  quenched with 1 M HCI,  and  reaction was  stirred for 30 minutes, w a r m e d to rt, and stirred for an additional two hours at rt. reaction was  mL)  dried over anhydrous MgS0. The 4  2  extracts were filtered, and  2  3  the solvent  removed under reduced pressure. Column chromatography of the residue with 2%  ethyl acetate in petroleum ether as eluant, followed by recrystallization from hexanes gave ketone 97 (65 mg, 10%)  as white needles.  251 mp: 31-33 °C; IR (CDCI3): 2933, 2862, 1703, 1595, 1491, 1214, 1017, 792 cm"; 1  H NMR (500 MHz, CDCI): 5 2.60 (ddq, J = 3.6, 7.1, 6.9 Hz, 1 H), 2.57 (ddd, J = 3.8,  1  3  9.5, 16.4 Hz, 1 H), 2.30 (ddd, J = 3.8, 7.6, 16.4 Hz, 1 H), 1 . 7 2 1 . 7 9 (m, 1 H), 1 . 6 0 1 . 6 7 (m, 1 H), 1 . 4 6 1 . 5 3 (m, 1 H), 1 . 0 9 1 . 3 7 (m, 17 H), 1.01 (d, J = 6.9 Hz, 3H);  C NMR (125 MHz, CDCI): 5 215.52, 46.19, 40.17, 32.86, 26.55, 26.26, 26.09, 25.57  13  3  25.24, 24.93, 24.36, 24.30, 22.61, 16.94; L R M S (El) m/z (relative intensity): 210 (M, 22), 111 (20), 98 (36), 83 (42), 69 (58), 55 +  (100), 41 (54); H R M S (El) m/z calculated for Ci H 0: 210.1984, found: 210.1985; 4  26  Analysis calculated for Ci H 0: C, 79.94; H, 12.46. Found: C, 79.69; H, 12.30. 4  26  (b) M A B R Mediated Alkylation of (Z/E)-1-(Trimethvlsiloxv)cvclotridecene (95) and (96) A solution of M A B R was generated by the addition of trimethylaluminum in hexanes (6.0 mL, 12 m m o l ) to a solution of 4-bromo-2,6-di-fe/if-butylphenol (3.42 g, 12.0 m m o l ) in CHCI (24 mL) and the reaction was stirred for 2.5 hours at rt. An aliquot of the 2  2  M A B R solution (33 mL, 6.6 m m o l ) was added to a solution of silyl enol ethers 95 and 96 (1.27 g, 4.73 m m o l ) in CHCI (50 mL) at -40 °C and the reaction was stirred for 2  2  20 minutes. Methyl triflate (1.1 mL, 9.5 m m o l ) was added, and the reaction was stirred with slow warming to rt over 15 hours. The reaction was diluted with CHCI, and 2  2  sequentially washed with 1 M HCI, saturated NaHC0 solution, brine, and dried ov 3  anhydrous MgS0. The extracts were filtered and the solvent was r e m o v e d under 4  reduced pressure. Column chromatography of the residue with 2% ethyl acetate in petroleum ether as eluant gave ketone 97 (0.79  g, 79%)  spectral data in agreement with that reported above.  as a pale yellow oil with  252 13-Tetradecanolide (98)  (a) Baever-Villiger Oxidation of 2-Methvlcvclotridecanone (97) with Hydrogen Peroxide Trifluoroperacetic acid was generated from 70% H0 (0.50 mL, 2  trifluoroacetic anhydride (1.8 this peracid (0.47 mL, 0.49  13 m m o l ) in CHCI (1.3 2  2  4  stirred for five hours at 0 °C.  g, 3.1 m m o l ) in CHCI (0.50 2  at 0 °C.  An aliquot of  2  mL),  and the reaction was mL,  stirred for a further two hours at 0 °C. T h e  poured into water, neutralized with saturated NaHC0 solution  and the organic layer was the solvent was  mL)  An additional aliquot of trifluoroperacetic acid (0.55  added, and the reaction was  reaction mixture was  2  1 1m m o l ) a n d  1 . 5m m o l ) was added to a mixture of ketone 97 (0.10 g,  m m o l ) and NaHP0 (0.43  1.7 m m o l ) was  mL,  2  3  dried over anhydrous MgS0. The extracts were filtered and 4  removed under reduced pressure. Column chromatography of  the  residue with 2% ethyl acetate in petroleum ether as eluant gave impure lactone 98 (74 mg, 66%;  GC ratio 98:97, 94:6)  as a pale yellow oil.  The  unreacted ketone 97 was  inseparable from lactone 98 using either column chromatography or HPLC.  (b) Derivatization of 2-Methvlcvclotridecanone (97) into 2-Methylcvclotridecane oxime (99)  Sodium acetate (0.19 g, 2.2 m m o l ) and hydroxylamine hydrochloride (0.14 g, 2.0 mmol), were added to a mixture of ketone 97 and 98:97, 86:14) in methanol (3 mL) and the reaction was reaction was  stirred for 17.5  GC ratio  hours at rt.  The  poured into water, extracted with diethyl ether, and dried over anhydrou  MgS0. The extracts were filtered and 4  pressure. The  lactone 98 (90 mg;  oxime 99 was  the  solvent was removed under reduced  identified by comparison to an authentic sample using  253 TLC analysis.  1 2 6  Column chromatography of the residue with 2% ethyl acetate in  petroleum ether as eluant gave lactone 98 (46 m g ) as a pale yellow oil.  IR(CDCI): 2933, 2861, 1715, 1448, 1345, 1253, 1179, 1128, 1 0 3 7 cm"; 1  3  H N M R (500 MHz, CDCI): 8 4.98 (sext, J = 6 . 3 Hz, 1 H), 2.39 (ddd, J = 3.  1  3  Hz, 1 H), 2.24 (ddd, J = 3.4, 8.6, 1 4 . 4 Hz, 1 H), 1 . 5 2 1 . 7 2 (m, 4 H), 1 6 H), 1 . 1 9 (d, J = 6.3Hz, 3 H); CN M R (125 MHz, CDCI): 8 173.62, 69.93, 35.03, 34.51, 26.32, 26.19, 25.88,  1 3  3  25.55 (2), 24.82, 23.97, 23.87, 22.11, 20.28;  L R M S (El) m/z (relative intensity): 226 (M, 2), 208 (14), 1 8 2 (15), 1 1 1 (29), 98 ( +  (49), 69 (58), 55(100), 4 1 (76); H R M S (El) m/z calculated for CH60: 226.1933, found: 226.1927; 1 4  2  2  Analysis calculated for Ci H 0 : C, 74.29; H, 11.58. Found: C, 74.20; H, 11.45. 4  26  2  (c) Baeyer-Vi Niger Oxidation of 2-Methvlcyclotridecanone (97) with U H P  Trifluoroacetic anhydride (2.4 m L , 1 7 m m o l ) w a s added via syringe to a mixture ketone 97 (0.55 g, 2 . 6 mmol), U H P (1.47 g, 1 5 . 6m m o l ) and NaHP0 (2.58 g, 2  4  1 8 . 2 m m o l ) in CHCI (30 m L ) at 0 ° C and the reaction w a s stirred with slow war 2  2  rt over 1 2 hours. The reaction w a s diluted with CHCI, and sequentially washed w 2  2  water, saturated NaS0 solution, saturated NaHC0 solution, brine, and dried over 2  2  3  3  anhydrous MgS0. The extracts were filtered, and the solvent w a s removed unde 4  reduced pressure. Column chromatography of the residue with 1 % ethyl acetate  petroleum ether gave lactone 98 (0.57 g, 97%) as a pale yellow oil with spectral da agreement with that reported above.  254 2-Methylene-14-methyloxacyclotetradecane (100)  A solution of Tebbe reagent 3 2 solution of lactone 98 (25  mg, 0.11  (10 pL, 1.3 pmol) stirred in THF rt overnight. The  in toluene (0.22  3 8 1 5 3  mmol), D M A P (20 mg,  86%)  m m o l ) was 0.13  reaction mixture was  added to a  mmol), and pyridine  (2 mL) at -40 °C and the reaction was  ether as eluant, and the solvent was 100 (21 mg,  mL, 0.22  w a r m e d slowly to  filtered through basic alumina with petroleum  removed under reduced pressure to give alkene  as a pale yellow oil.  Enol ether 100 was  unstable and  was used  immediately without further purification.  IR (CDCI3): 2930, 2859, 1647,  1455,  1375,  LRMS (El) m/z (relative intensity): 224  1274,  (M, +  1132  100),  cm"; 1  166 (24),  125 (20),  96 (25),  71  (24);  H R M S (El) m/z calculated for Ci H 0: 224.2140, found: 224.2138. 5  28  3-Methyl-2-oxacyclotetradecanethione (101)  A solution of lactone 98 (0.41  g, 1.8 m m o l ) in toluene (10 mL) was  a suspension of Lawessons ' reagent 48 (1.46  g, 3.62  added via cannula to  m m o l ) in toluene (10 mL) and  the  255 reaction was  heated at reflux for five days. The  the solid residue was the  solvent was  reaction was  rinsed with diethyl ether. The  cooled to rt, filtered, and  organic layers were combined, and  removed under reduced pressure. Column chromatography of  residue with petroleum ether as eluant gave thionolactone 101 (0.34 yellow oil.  IR (CDCI): 2930, 2860, 1455,  1357,  3  H NMR  (500 8.0,  MHz,  13.0  CDCI): 5 5.62  Hz, 1 H), 2.73  (ddd,  C  NMR  (125  MHz,  g,  17%).  1289,  (ddq,  3  1 . 1 7 1 . 4 2 (m, 16 H), 1.30 13  as a  Further column chromatography with 2% ethyl acetate in petroleum ether as  eluant gave recovered lactone 98 (0.07  1  g, 77%)  the  1181 , ' 1094,  773  cm"; 1  J = 7.4, 3.7, 6.3 Hz, 1 H), 2.86  J = 4.6, 7.4,  13.0  (ddd,  J = 5.1,  Hz, 1 H), 1 . 6 7 1 . 7 5 (m, 4 H),  (d, J = 6.3 Hz, 3 H);  CDCI): 6 224.35, 78.27, 47.50, 34.83, 27.70, 26.16, 26.01, 25.80 3  25.76, 25.22, 24.08, 23.77, 22.27, 19.06; L R M S (El) m/z (relative intensity): 242 (66),  55(100), 41  (M, +  3), 209  (30),  109 (24),  98 (38),  83 (35),  69  (85);  H R M S (El) m/z calculated for Ci H OS: 242.1704, found: 242.1704; 4  26  Analysis calculated for Ci H OS: C, 69.36; H, 10.81. Found: C, 69.23; H, 10.67. 4  26  2-Methyl-2-(methylthio)-14-methyloxacyclotetradecane (102)  Methyllithium in diethyl ether (0.39 thionolactone 101 (44 mg, 0.18 was  mL,  0.54  m m o l ) in THF  m m o l ) was (5 mL)  stirred for 30 minutes. Methyl iodide (36  reaction was  uL,  added to a solution of  stirred at -78 °C and the reaction 0.58  m m o l ) was  added and  the  stirred for 15 minutes at -78 °C, w a r m e d to rt, and stirred for an additional  15 minutes at rt. The  reaction was  diluted with diethyl ether, and  sequentially washed  256 with water, brine, and dried over anhydrous MgS0. The extracts were filtered and  the  4  solvent was removed under reduced pressure to give mixed thioketal 102 (39 mg, as a pale yellow oil.  Thioketal 102 was  unstable and was  80%)  used immediately without  further purification.  LRMS (El) m/z (relative intensity): 272 (M , 3), 225 (61), 209 (32), +  123 (26),  109  (56),  95 (70), 83 (69), 69 (85), 55 (98), 43 (100); HRMS (El) m/z calculated for Ci H OS: 272.2174, found: 272.2169. 6  32  (2R*, 14/?*) and (2S*, 14/?*)-Dimethyloxacyclotetradecane (103) and (104)  (a) Reduction of 2-Methylene-14-methyloxacvclotetradecane (100) with Adams' Catalyst Adams' catalyst was added to a solution of alkene 100 (62 mg, 0.28 ether (5 mL) and the mixture was  m m o l ) in diethyl  stirred under H overnight at rt. The 2  reaction was  filtered through silica with diethyl ether as eluant, and the solvent was removed under reduced pressure. Radial chromatography of the residue (GC  ratio 103:104, 49:51)  with petroleum ether as eluant gave ethers 103 (8.0 mg, 13%)  and 104 (7.7  mg,  both as oils.  103(2/?*, 14/?*)  IR (CDCI): 2928, 2859, 1457,  1374,  3  H NMR  1  (500  MHz,  CDCI): 5 3.65 3  1.18-1.43 (m, 20 H), 1.08  1135,  1059  cm"; 1  (sext, J = 6.2 Hz, 2 H), 1.63  (d, J = 6.2 Hz, 6 H);  (sext, J = 6.2 Hz, 2 H),  13%)  257 1 3  C NMR (125 MHz, CDCI ): 8 69.02 (2), 33.64 (2), 26.56 (2), 25.34 (2), 25.15 (3), 3  23.13 (2), 19.63 (2); LRMS (El) m/z (relative intensity): 226 (M, 14), 211 (14), 182 (23), 111 (37), 97 (69), +  83 (80), 69 (86), 55 (100), 41 (73); H R M S (El) m/z calculated for Ci H O: 226.2297, found: 226.2294; 5  30  Analysis calculated for Ci H O: C, 79.58; H, 13.36. Found: C, 79.42; H, 13.37. 5  30  104 (2S*, 14/?*)  IR (CDCI): 2928, 2860, 1458, 1371, 1330, 1123, 1051 cm"; 1  3  H NMR (500 MHz, CDCI ): 8 3.54 (ddq, J = 4.2, 5.7, 6.2 Hz, 2 H), 1 . 1 8 1 . 4 9 (m, 22 H),  1  3  1.10 (d, J = 6.2 Hz, 6H); 1 3  C NMR (125 MHz, CDCI ): 8 71.77 (2), 36.10 (2), 26.41 (2), 26.17 (2), 25.55 (2), 3  24.86, 22.95 (2), 21.18 (2); LRMS (El) m/z (relative intensity): 226 (M, 11), 211 (9), 111 (31), 97 (61), 83 (87), 69 +  (87), 55(100), 41 (74); H R M S (El) m/z calculated for Ci H O: 226.2297, found: 226.2294. 5  30  (b) Reduction of 2-Methvl-2-(methylthio)-14-methvloxacvclotetradecane (102) with Tri(/7-butvl)tin Hydride A deoxygenated solution of tri(/?-butyl)tin hydride (1.5 mL, 5.5 m m o l ) and AIBN (cat.) in toluene (8.5 mL) was added over ten hours via syringe p u m p to a deoxygenated solution of mixed thioketal 102 (0.15 g, 0.55 m m o l ) and AIBN (cat.) in toluene (20 mL) heated at reflux. The solvent was removed under reduced pressure, and column chromatography of the residue (GC ratio 103:104, 52:48) with 1% ethyl acetate in petroleum ether as eluant removed the tin compounds. Further radial chromatography with petroleum ether as eluant gave ethers 103 (13.0 mg, 10%) and 104 (13.3 mg,  11%) both as pale yellow oils with spectral data in agreement with that reported above  258 (c) Reduction of 2-Methvl-2-(methvlthio)-14-methyloxacvclotetradecane (102) with Tris(trimethvlsilvl)silane (TTMSH) AIBN (cat.) and TTMSH (0.54  mL, 0.17  of mixed thioketal 102 (47 mg,  0.17 m m o l ) in toluene (20 mL)  heated at reflux for 24 hours. The  m m o l ) were added to a deoxygenated solution  solvent was  and  the  reaction was  removed under reduced pressure, and  column chromatography of the residue with petroleum ether as eluant followed by 1% ethyl acetate in petroleum ether as eluant gave ethers 103 and  104 (17  mg, 43%;  GC  ratio 103:104, 57:43) as a pale yellow oil with spectral data in agreement with that reported above.  (Z/£)-1-(Trimethylsiloxy)-2-methylcyclotridecene  (105)  O T M S  1,1,1,3,3,3-Hexamethyldisilazane (0.68 m L , 3.2 m m o l ) and trimethylsilyl chloride (0.41  mL,  3.2 m m o l ) were added sequentially via syringe to a mixture  2-methylcyclotridecanone (97)  (0.33  in CHCI (10 mL)  the  2  2  at rt, and  Triethylamine (0.45 mL, 30 minutes. The  g, 1.6 m m o l ) and  3.2 m m o l ) was added and the reaction was stirred for  reaction was  diluted with diethyl ether, and  3  the solvent was  silyl enol ethers (0.43  g, 3.2 m m o l )  reaction was stirred for three days in the dark.  saturated NaHC0 solution, brine, and were filtered and  lithium iodide (0.43  of  sequentially washed with  dried over anhydrous MgS0. The extracts 4  removed under reduced pressure to give a mixture of  g, 94%) as a pale yellow oil.  purification in the subsequent reaction.  This mixture was  used without  259 LRMS (El) m/z (relative intensity): 282  (M\  9), 157 (22),  144 (65),  129 (8), 73 (100), 41  (21); H R M S (El) m/z calculated for CiHOSi: 282.2379, found: 282.2376. 7  3 4  2,2-Dimethylcyclotridecanone (106)  O  A solution of M A B R was (3.0  mL, 6.0 m m o l ) to a solution of 4-bromo-2,6-di-fe/t-butylphenol (1.71  in CHCI (12 2  2  mL)  and  M A B R solution (12 (0.43  generated by the addition of trimethylaluminum in hexanes  the reaction was mL,  2.3  m m o l ) was  g, 1.5 m m o l ) in CHCI (10 2  stirred for one  mL)  2  20 minutes. Methyl triflate (0.34  mL,  at -40 3.0  sequentially washed with 1 M HCI,  dried over anhydrous MgS0. The  hour at rt. An aliquot of  the  added to a solution of silyl enol ethers 105 °C and  m m o l ) was  stirred with slow warming to rt overnight. The and  g, 6.00 m m o l )  the  reaction was  added, and  reaction was  the  stirred for reaction was  diluted with diethyl ether,  water, saturated NaHC0 solution, brine, and 3  extracts were filtered and the solvent was removed  4  under reduced pressure. Column chromatography of the residue with 2% ethyl acetate in petroleum ether as eluant followed by radial chromatography with petroleum ether as eluant gave ketone 106 (0.11 H NMR  (500  1  MHz,  C  NMR  (125  MHz,  as a pale yellow oil.  CDCI): 8 2.48-2.51 (m, 2 H), 1 . 6 1 1 . 6 6 (m, 2 H), 1 . 4 7 1 . 5 1 (m, 2 H), 3  1 . 2 0 1 . 3 4 (m, 16 H), 1.09 13  g, 33%)  (s, 6 H);  CDCI): 8 216.09, 47.77, 40.75, 35.63, 26.83, 26.61, 26.52, 25.30, 3  25.12, 24.62 (2), 24.38, 24.33, 22.14, 21.76; LRMS (El) m/z (relative intensity): 224 (83),  55 (80),  (M, +  19), 111 (17),  97 (29),  83 (32),  41 (100);  H R M S (El) m/z calculated for CiH 0: 224.2140, found: 224.2142. 5  2 8  69 (67),  56  260 Methyl 11-bromoundecanoate (110)  Concentrated sulfuric acid (3 mL) was  added to a solution of 11-bromoundecanoic acid  109 (19.27 g, 76.72 m m o l ) in methanol (100 for nine hours. The was  solvent was  mL) and the solution was  removed under reduced pressure, and the resultant oil  diluted with diethyl ether. The  ether solution was  saturated NaHC0 solution, water, brine, and the solvent was  washed sequentially with  dried over anhydrous MgS0.  3  extracts were filtered and  heated at reflux  The  4  removed under reduced pressure.  Column  chromatography of the residue with diethyl ether as eluant gave ester 110 (25.98 g, 82%)  as a pale yellow oil.  This material was  used in subsequent reactions without  further purification. Column chromatography of a sample of 110 (ca.  100  mg) with  2% ethyl acetate in petroleum ether as eluant gave pure 110 with spectral data in agreement with that reported earlier in our laboratory.  1 4 0  IR(CCU): 2931, H NMR  (500  1  2857, 1741,  MHz,  2 H), 1.80 1.29 C  13  NMR  CDCI): 5 3.62 3  1437,  1360,  (s, 3 H), 3.36  1174  cm"; 1  (t, J = 7.0 Hz, 2 H), 2.25  (t, J = 7.5  (quint, J = 7.0 Hz, 2 H), 1 . 5 4 1 . 6 0 (m, 2 H), 1.35-1.40 (m, 2 H),  (m, 10 (125  1461,  MHz,  Hz, 1.22-  H);  CDCI): 5 174.15, 51.32, 34.01, 33.85, 32.76, 29.27, 29.23, 29.11, 3  29.04, 28.65, 28.08, 24.86; LRMS (El) m/z (relative intensity): 280 199 (7), 87 (45),  74 (100), 55 (23),  (Br, M, 1), 278 8 1  41  +  (Br, M, 1), 249 7 9  +  (2), 247  (2),  (20);  H R M S (El) m/z calculated for; calculated for Ci H 0 Br: 280.0861, found: 280.0855; 81  2  Ci H 0 Br: 278.0881, found: 278.0875. 79  2  23  2  23  2  261 Methyl 12-carbomethoxy-13-oxotetradecanoate (111)  Methyl acetoacetate (20.1 sodium hydride (7.44  mL,  g, 186  186  m m o l ) was  added dropwise to a suspension of  m m o l ) in a mixture of THF  and  DMF  (3:1,  400  mL)  After the effervescence had subsided, ester 110 (25.98 g, 93.04 m m o l ) was the reaction over three hours, and the mixture was resultant solution was  at rt. added to  heated at reflux for two days. The  concentrated under reduced pressure, diluted with CHCI, and 2  sequentially washed with 1 M HCI, extracts were filtered and  2  water, brine, and dried over anhydrous MgS0. The 4  the solvent was  removed under reduced pressure to give  crude diester 111 (32 g, 109%). This material was  used in subsequent reactions  without further purification. Column chromatography of a sample of 111 (ca. 100  mg)  with 5% ethyl acetate in petroleum ether as eluant gave pure 111 as a white solid for analysis.  mp: 42-43 °C; IR (CCI): 2932, 2857, 1743, 4  H NMR  (500  1  MHz,  1721,  CDCI): 6 3.68  (s, 3 H), 1.78  7.5 Hz, 2 H), 1 . 1 1 1 . 2 9 (m, 14 C NMR  13  (125  MHz,  1357,  (s, 3 H), 3.61  3  (t, J = 7.5 Hz, 2 H), 2.17  1436,  1273,  1171  (s, 3 H), 3.37  cm'; 1  (t, J = 7.3 Hz, 1 H),  (quint, J = 7.3 Hz, 2 H), 1.56  2.25  (quint, J =  H);  CDCI): 5 203.15, 174.20, 170.34, 59.66, 52.22, 51.32, 34.01, 3  29.32, 29.27, 29.21, 29.17, 29.12, 29.04, 28.67; LRMS (El) m/z (relative intensity): 314 (M, +  (97),  87 (36),  69 (24),  55 (55),  43  1), 283 (8), 251 (5), 129 (18),  116 (100), 98  (49);  H R M S (El) m/z calculated for CiHo0: 314.2093, found: 314.2090; 7  Analysis calculated for  C17H30O5:  3  5  C, 64.94; H, 9.62.  Found: C, 64.82; H,  9.66.  262 13-Oxotetradecanoic acid (112)  A solution of diester 111 (10.06 g, 32.00 m m o l ) in a mixture of concentrated HCI, methanol, and water (3:1:1, 112 mL) was was  cooled, diluted with water, and  combined, washed with brine, and filtered and (6.71  the solvent was  g, 87%)  heated at reflux for nine hours. The reaction  extracted with diethyl ether. The  organics were  dried over anhydrous MgS0. The  extracts were  4  removed under reduced pressure to give keto acid 112  as a white solid. This material was  used in subsequent reactions without  further purification. Column chromatography of a sample of 112 (ca.  100  mg) with  4% methanol in CHCI gave pure 112 with spectral data in agreement with that 2  2  reported earlier in our laboratory.  1 4 0  mp: 64-66 °C; IR(CCI): 3045, 2929, 2856, 1713, 4  H NMR  (500  1  MHz,  CDCI): 6 2.38  1433,  1359,  C  NMR  (125  MHz,  1166  (t, J = 7.3 Hz, 2 H), 2.30  3  3 H), 1 . 4 9 1 . 6 2 (m, 4 H), 1 . 1 3 1 . 3 2 (m, 14 13  1289,  cm"; 1  (t, J = 7.5 Hz, 2 H), 2.10  (s,  H);  CDCI): 5 209.52, 179.76, 43.76, 34.01, 29.74, 29.42, 29.34, 29.3 3  (2), 29.14, 29.11, 28.99, 24.64, 23.83; LRMS (El) (33),  m/z (relative intensity): 242 67 (18),  58 (100), 43 (88),  41  (M, +  1), 224  (2), 98 (18),  83 (21),  (26);  H R M S (El) m/z calculated for CiH 0: 242.1882, found: 242.1885. 4  26  3  81 (13),  69  263 13-Hydroxy-13-methyltetradecanoic acid (113)  A solution of methylmagnesium bromide in diethyl ether (5.2 to a solution of keto acid 112 (1.27 the reaction was  g, 5.24  mL, 16 m m o l ) was added  m m o l ) in diethyl ether (20 mL) at 0 °C  stirred with slow warming to rt overnight. The  diluted with diethyl ether, and  acidified with 1 M HCI.  sequentially washed with water and extracts were filtered and  brine, and  the solvent was  chromatography of the residue with 20% gave hydroxy acid 113 (0.58  g, 43%)  The  and  reaction mixture was  organic layer was  dried over anhydrous MgS0. 4  removed under reduced pressure.  The  Column  ethyl acetate in petroleum ether as eluant  as a white solid.  mp: 50-52 °C; IR (CDCI): 3607, 2930, 2856, 1709, 3  H NMR  (500  1  1.44 C  13  NMR  MHz,  CDCI): 6 2.31  (125  29.13  MHz,  cm"; 1  (t, J = 7.5 Hz, 2 H), 1.61  3  (t, J = 6.1 Hz, 2H),  1195,  1 . 2 3 1 . 3 4 (m, 16 H), 1.19  (s, 6 H);  CDCI): 5 179.16, 71.31, 43.92, 34.02, 30.10, 29.45 (3), 29.32, 3  (2), 28.99, 24.69, 24.27;  LRMS (DCI(+), a m m o n i a ) m/z (relative intensity): 276 258  (quint, J = 7.5 Hz, 2 H),  (M, +  (M +18, 100), +  259  (M+1, 32), +  100);  H R M S (Cl(+), isobutane) m/z calculated for  C15H31O3  (M+1) 259.2273, found: +  259.2272; Analysis calculated for CiHo0: C, 69.72; H, 11.70. Found: C, 69.58; H, 11.58. 5  3  3  264 13-Methyl-13-tetradecanolide (114)  Triethylamine (0.28 1.8  mL, 2.0 m m o l ) was  m m o l ) in THF  (20  mL)  added to a solution of hydroxy acid 113 (0.46  at rt and  the  reaction was  2,4,6-Trichlorobenzoyl chloride (0.28  mL,  stirred for a further two  reaction mixture was  hours. The  1.8 m m o l ) was  stirred for added and  g,  15 minutes. the reaction was  filtered and concentrated  under reduced pressure. Trace amounts of solvent were removed under high v a c u u m over one  hour. A solution of the resultant mixed anhydride in toluene (100  mL)  was  divided into two portions and simultaneously added via syringe p u m p to two solutions of D M A P (0.88 was  g, 7.2 m m o l ) in toluene (600  mL) at reflux over 40 hours. The reaction  concentrated under reduced pressure, diluted with diethyl ether, and sequentially  washed with water, 1 M HCI, anhydrous MgS0. The  saturated NaHC0 solution, brine, and 3  extracts were filtered and  4  the  solvent was  dried over removed under  reduced pressure. Column chromatography of the residue with 1 % ethyl acetate in petroleum ether gave lactone 114 (0.16  g, 54%)  IR(CCU): 2932, 2861,  1727,  1368,  H NMR  3  (500  1  MHz,  1462,  C  NMR  (125  MHz,  1200,  1174,  1150,  1082  cm"; 1  CDCI): 5 2.15-2.17 (m, 2 H), 1.76-1.79 (m, 2 H), 1.48-1.53 (m, 2 H),  1.21-1.40 (m, 16 H), 1.35 13  1385,  as a colourless oil.  (s, 6 H);  CDCI): 6 172.14, 81.89, 38.56, 34.55, 27.16 3  (2), 26.98, 26.72,  26.64, 26.07, 25.55, 24.86, 24.03, 23.65; LRMS (El) m/z (relative intensity): 240 (M, +  111 (39),  98 (52),  83 (54),  51), 225 (39),  69 (100), 55 (83),  41  182 (69),  167 (19),  125  (20),  (63);  H R M S (El) m/z calculated for Ci H 80 : 240.2089, found: 240.2084; 5  2  2  Analysis calculated for CiH 0: C, 74.95; H, 11.74. Found: C, 75.13; H, 11.74. 5  28  2  265 2,2-Dimethyloxacyclotetradecane (116)  Boron trifluoride etherate (0.88  mL,  7.0  m m o l ) and  sodium borohydride (0.06  1.6 m m o l ) were added to a solution of lactone 114 (56.1 (2 mL) at rt and the reaction was and  the  reaction was  stirred for  16 hours at rt.  The  reaction was  diluted with diethyl ether. The  3  and  extracts were filtered and  combined with additional crude 116 (29.2  mg, 64%)  ether 116 (50.6  mg, 51%)  4  (500  MHz,  NMR  (125  MHz,  1381,  CDCI): 5 3.25  1363,  1276,  1202,  (t, J = 6.4 Hz, 2 H), 1.57  3  1.23-1.43 (m, 20 H), 1.13 C  solvent was  70%).  This  obtained from lactone  ethyl acetate as eluant gave  as a colourless oil.  IR (CCI): 2928, 2860, 1462,  13  mg,  the  mg, 0.203 m m o l ) in a second reaction carried out under similar conditions.  Radial chromatography of the combined residue with 0.5%  H NMR  quenched with  ether layer was  removed under reduced pressure to give crude ether 116 (37.1  1  mL) was added  3  4  114 (48.7  THF  sequentially washed with saturated NaHC0 solution, water, brine,  dried over anhydrous MgS0. The  material was  0.233 m m o l ) in  stirred for 45 minutes. Triglyme (1.0  saturated NaHC0 solution, and separated and was  mg,  g,  1179,  1088,  1031  cm"; 1  (quint, J = 6.4 Hz, 2 H),  (s, 6 H);  CDCI): 5 73.88, 58.88, 37.97, 28.34, 26.69, 26.66 (2), 26.39, 3  26.15, 25.15, 24.56, 24.50, 23.52, 23.38, 20.33; LRMS (El) m/z (relative intensity): 226 (M, +  (100), 55  1), 211 (22),  97 (12),  83 (15),  (21);  H R M S (El) m/z calculated for C H O: 226.2297, found: 226.2295. 1 5  3 0  69 (19),  59  266 2-Methyl-13-tridecanolide (117)  A solution of n-butyllithium in hexanes (8.0  mL, 20 m m o l ) was  diisopropylamine (3.0  (9.0  mL, 23 m m o l ) in THF  stirred for 15 minutes, w a r m e d to 0 °C, and aliquot of this LDA (0.43  solution (2.6  g, 2.0 m m o l ) in THF  Methyl iodide (0.25  mL)  at -78 °C and  the reaction was  stirred for an additional 15 minutes. An  mL, 2.6 m m o l ) was  (5 mL) and the reaction was  mL, 3.0 m m o l ) was  added to a solution of  added to a solution of lactone 87 stirred for four hours at -78  added, the reaction was  stirred for 15 minutes  at -78 °C, w a r m e d to rt, and stirred for an additional 15 minutes at rt. The diluted with diethyl ether, and anhydrous MgS0. The  the  solvent was  reduced pressure. Column chromatography of the residue with 2% petroleum ether gave lactone 117 (0.38  IR(CCU): 2934, 2860, 1732, H NMR  (500  1  MHz,  1 H), 2.51 H), 1.12 C NMR  13  (125  1461,  CDCI): 5 4.24  g, 84%)  1349,  1170,  (dt, J = 11.0,  3  (ddq,  reaction was  sequentially washed with water, brine, and  extracts were filtered and  4  dried ove  removed under ethyl acetate in  as a pale yellow oil.  1088  cm"; 1  5.5 Hz, 1 H), 3.97  (dt, J = 11.0,  5.3  J = 3.2, 9.8, 7.0 Hz, 1 H), 1.55-1.65 (m, 4 H), 1 . 1 5 1 . 4 8 (m,  Hz, 16  (d, J = 7.0Hz, 3H); MHz,  CDCI): 8 176.87, 63.16, 39.70, 33.79, 27.73, 26.17, 26.05, 26.04, 3  24.65, 24.47, 24.00, 23.59, 22.82, 17.61; LRMS (El) m/z (relative intensity): 226 (M, +  (53),  °C.  74 (81),  69 (68),  55 (100), 42  H R M S (El) m/z calculated for  5), 208 (4), 117 (37), (82);  Ci H 60 : 226.1933, 4  2  2  97 (45),  found: 226.1930.  87 (23),  83  267 2,2-Dimethyl-13-tridecanolide (118)  An aliquot of LDA lactone 117 (0.34  solution (3.0  g, 1.5 m m o l ) in THF  nine hours at -78 °C. was  stirred for  mL, 3.0  reaction was  117) was  added to a solution of  (5 mL) at -78 °C and the reaction was  Methyl iodide (0.28  15 minutes at -78  15 minutes. The  m m o l ) (see  mL, 4.5 m m o l ) was  °C, w a r m e d to rt, and  stirred for  added and  stirred for  diluted with diethyl ether, and was  the reaction  an additional  washed with water,  brine, and dried over anhydrous MgS0. The extracts were filtered and the solvent was 4  removed under reduced pressure. Column chromatography of the ethyl acetate in petroleum ether gave lactone 118 (0.31  IR(CCU): 2934, 2861,  1728,  H NMR  3  (500  1  MHz,  1464,  1390,  1321,  1162,  C  NMR  (125  MHz,  1136  as a pale yellow oil.  cm"; 1  CDCI): 6 4.04-4.07 (m, 2 H), 1 . 6 2 1 . 6 6 (m, 2 H), 1 . 4 5 1 . 4 8 (m, 2 H),  1 . 2 6 1 . 4 1 (m, 12 H), 1 . 1 3 1 . 2 2 (m, 4 H), 1.15 13  g, 86%)  residue with 2%  (s, 6 H);  CDCI): 5 178.21, 63.20, 42.72, 40.68, 28.03, 26.53, 26.18, 25.92, 3  25.68 (2), 24.32, 23.69, 22.71, 22.62, 22.47; LRMS (El) m/z (relative intensity): 240 (M, 62), 222 +  83 (31),  69 (38),  55  (15),  153 (42),  97 (29),  88 (100),  (32);  H R M S (El) m/z calculated for Ci5H 0 : 240.2089, found: 240.2086; 28  2  Analysis calculated for C H 0 : C, 74.95; H, 11.74. Found: C, 74.93; H, 11.92. 15  28  2  268 3,3-Dimethyloxacyclotetradecane (119)  Boron trifluoride etherate (2.0  mL, 16 m m o l ) and sodium borohydride (0.14  were added to a solution of lactone 118 (125 reaction was  mg, 0.520 m m o l ) in THF  stirred for 40 minutes at rt. Triglyme (2.0  mL) was  was  heated at reflux for three hours. The  reaction was  was  quenched with saturated NaHC0 solution. The 3  extracts were filtered and  the  solvent was  IR (CCI): 2935, 2859, 1463, 4  H NMR  (500  1  MHz,  1382,  CDCI): 8 3.38 3  1118  C  13  NMR  (125  MHz,  added and the reaction  dried over anhydrous  ethyl acetate in petroleum  as a pale yellow oil.  cm"; 1  (t, J = 5.4 Hz, 2 H), 3.03  5.4 Hz, 2 H), 1 . 1 8 1 . 4 2 (m, 18 H), 0.84  the  removed under reduced  pressure. Column chromatography of the residue with 0.5% ether as eluant gave ether 119 (25 mg, 11%)  mL) and  ether layer was sequentially  washed with saturated NaHC0 solution, water, brine, and 4  (5.0  diluted with diethyl ether, and  3  MgS0. The  g, 3.6 m m o l )  (s, 2 H), 1.55  (quint, J =  (s, 6 H);  CDCI): 8 77.38, 68.81, 37.43, 34.09, 28.81, 26.79, 26.61, 26.12 3  (2), 25.79, 24.17, 24.07, 22.84, 22.81, 20.39; LRMS (Cl(+), a m m o n i a ) m/z (relative intensity): 244  (M +18, 30), 227 +  (M+1, 100); +  H R M S (Cl(+), isobutane) m/z calculated for CiH 0 (M+1): 227.2375, found: +  5  3 1  227.2374; Analysis calculated for  C15H30O:  C, 79.58; H, 13.36. Found: C, 79.51; H, 13.39.  269 8-Bromo-1-octanol (121)  48%  HBr (12.1  71.19  mL, 107 m m o l ) was  m m o l ) in benzene (300  added to a solution of 1,8-octanediol (120) (10.41 g,  mL)  and the solution was  Stark conditions for 48 hours. The organic layer was reduced pressure. The  residue was  heated at reflux under Dean-  collected and concentrated under  diluted with diethyl ether, and sequentially washed  with saturated NaHC0 solution, brine, and dried over anhydrous MgS0. The extracts 3  were filtered and  the  4  solvent was  removed under reduced pressure. Column  chromatography of the residue with 20% gave alcohol 121 (13.65 g, 92%)  ethyl acetate in petroleum ether as eluant  as a pale yellow oil with spectral data in agreement  with that reported in the literature.  1 4 5  IR (CCI): 3635, 3378, 2932, 2858, 1453, 4  H NMR  (500  1  MHz,  CDCI): 5 3.57 3  (br s, 1 H), 1.80  1050  cm"; 1  (t, J = 6.7 Hz, 2 H), 3.35  (quint, J = 6.9 Hz, 2 H), 1.51  (t, J = 6.9 Hz, 2 H),  1.85  (quint, J = 6.7 Hz, 2 H), 1 . 3 5 1 . 4 1  (m, 2 H), 1 . 2 6 1 . 3 2 (m, 6 H); C  13  NMR  (125  MHz,  CDCI): 5 62.74, 33.89, 32.67, 32.57, 29.11, 28.60, 27.98, 25.54; 3  LRMS (DCI(+), a m m o n i a ) m/z (relative intensity): 228  (Br, M +18, 100), 8 1  +  226 (Br, 7 9  M +18, 98); +  H R M S (Cl(+), isobutane) m/z calculated for CH 0 Br (M+1): 211.0521, found: 8 1  8  +  1 8  211.0529; calculated for CH 0 Br (M+1): 209.0541, found: 209.0537. 7 9  8  1 8  +  270 8-Bromooctanal (122)  A solution of dimethylsulfoxide (3.0  mL,  42 m m o l ) in CHCI (10 mL) 2  cannula to a solution of oxalyl chloride (1.8 -78 10.6  °C.  The  resulting solution was  m m o l ) in CHCI (10 mL) 2  2  was  40 minutes. Triethylamine (7.4  mL, 21 m m o l ) in CHCI (50 2  stirred for two  minutes and  added via cannula and  mL,  53 m m o l ) was  collected. The  the  added and  for an additional 10 minutes then w a r m e d to rt. The organic layer was  was  2  mL)  mixture was the  mixture was stirred quenched with water,  the  The  organic layers were combined, sequentially washed with water and 4  extracts were filtered and  under reduced pressure. Column chromatography of the  extracted with CHCI. 2  2  brine, and  the solvent was r e m o v e d  residue with 10%  acetate in petroleum ether as eluant gave aldehyde 122 (1.98  g,  stirred for  and  dried over anhydrous MgS0. The  stirred at  alcohol 121 (2.21  reaction was  aqueous layer was  2  added via  g, 90%)  ethyl  as a pale yellow  oil. IR (CCI): 2934, 2859, 1711, 4  H NMR  1  (500 J = 1.7,  MHz,  1436,  CDCI): 5 9.72 3  7.4 Hz, 2 H), 1.81  1288,  937  cm"; 1  (t, J = 1.7 Hz, 1 H), 3.36  (t, J = 6.8 Hz, 2 H), 2.38  (dt,  (quint, J = 6.8 Hz, 2 H), 1 . 5 6 1 . 6 2 (m, 2 H), 1 . 3 7 1 . 4 2  (m, 2 H), 1 . 2 8 1 . 3 1 (m, 4 H); C  13  NMR  (125  MHz,  CDCI): 5 202.57, 43.72, 33.76, 32.58, 28.84, 28.39, 27.83, 21.83 3  L R M S (DCI(+), a m m o n i a ) m/z (relative intensity): 226  (Br, M +18, 86), 8 1  +  224 (Br, 7 9  M +18, 100); +  H R M S (Cl(+), isobutane) m/z calculated for CH 0 Br (M+1): 209.0364, found: 8 1  8  +  1 6  209.0373; calculated for CHi0 Br (M+1): 207.0385, found: 207.0377; 7 9  8  +  6  Analysis calculated for CHOBr: C, 46.39; H, 7.30. 8  1 5  Found: C, 46.64; H,  7.25.  271 8-Bromooctanal ethylene acetal (123)  A solution of aldehyde 122 (1.82 PPTS (0.45  g, 8.79  mmol), ethylene glycol (2.5  g, 1.8 m m o l ) in benzene (100  conditions for 12 hours. The resultant oil was  solvent was  mL) was  heated at reflux under Dean-Stark  removed under reduced pressure, and  the  diluted with diethyl ether, sequentially washed with saturated NaHC0  solution, water, and brine, and dried over anhydrous MgS0. The 4  and the solvent was residue with 10% 93%)  mL, 44 mmol), and  extracts were filtered  removed under reduced pressure. Column chromatography of the ethyl acetate in petroleum ether as eluant gave acetal 123 (2.06  as a pale yellow oil.  IR(CCU): 2936, 2861,  1461,  H NMR  3  (500  1  MHz,  2 H), 3.34  1407,  CDCI): 5 4.78  1136,  1039,  942  cm; 1-  (t, J = 5.0 Hz, 1 H), 3.87-3.92 (m, 2 H), 3.77-3.82 (m,  (t, J = 6.9 Hz, 2 H), 1.80  (quint, J = 6.9 Hz, 2 H), 1.59  (ddd,  J = 6.9,  9.6, 5.9 Hz, 2 H), 1 . 3 4 1 . 4 1 (m, 4 H), 1 . 2 6 1 . 3 2 (m, 4 H); C  13  NMR  (125  MHz,  CDCI): 5 104.48, 64.72 (2), 33.80, 33.71, 32.67, 29.20, 28.54, 3  27.93, 23.82; LRMS (DCI(+), a m m o n i a ) m/z (relative intensity): 270  (Br, M +18, 7), 268 (Br, 8 1  +  7 9  M +18, 7); +  H R M S (Cl(+), isobutane) m/z calculated for CiHo0 Br (M+1) 253.0626, found: 8 1  0  2  2  +  :  253.0627; calculated for C H O Br (M+1): 251.0647, found: 251.0638. 7 9  1 0  2 0  2  +  g,  272 5-(1 ',3'-Dithian-2'-yl)-1 -pentanol (125)  Boron trifluoride etherate (10.0 m L , 81.3 m m o l ) was added dropwise to a solutio  1,3-propanedithiol (124) (5.4 m L , 54 m m o l ) and dihydropyran (6.0 m L , 66 m m o l  CHCI (100 m L ) at 0 °C, and the reaction was stirred for 19.5 hours with slow w 2  2  to rt. The reaction was quenched with water, and sequentially washed with 3 M solution, water, brine and dried over anhydrous MgS0. The extracts were filtered 4  the solvent was removed under reduced pressure. Column chromatography of the  residue with 30% ethyl acetate in petroleum ether as eluant gave alcohol 125 (8.74 84%) as a pale yellow oil.  I R (CCU): 3635, 2939, 2902, 1457, 1423, 1276, 1051, 909 cm"; 1  H N M R (500 MHz, CDCI): 5 4 . 0 1 (t, J = 7 . 0 Hz, 1 H), 3.58-3.61 (m, 2 H),  1  3  4 H), 2.04-2.10 (m, 1 H), 1.52-1.85 (m, 7 H);  CN M R (125 MHz, CDCI): 5 62.43, 47.39, 35.08, 32.14, 30.35 (2), 25.91, 22.82;  1 3  3  LRMS (El) m/z (relative intensity): 192 (M, 31), 119 (100), 85 (26), 45 (30), 42 (2 +  H R M S (El) m/z calculated for C Hi 0S : 192.0643, found: 192.0641. 8  6  2  273 5-(1',3'-Dithian-2'-yl)-1-(2"-tetrahydropyranyloxy)pentane (126)  A solution of alcohol 125 (8.73 g, 45.4 mmol), dihydropyran (5.0 mL, 55 mmol), and PPTS (2.28 g, 9.08 m m o l ) in CHCI (100 mL) was stirred at rt for 23 hours. The 2  2  resultant solution was sequentially washed with saturated NaHC0 solution, brine and 3  dried over anhydrous MgS0. The extracts were filtered and the solvent was r e m o v e d 4  under reduced pressure. Column chromatography of the residue with 10% ethyl acetate in petroleum ether as eluant gave dithiane 126 (12.02 g, 96%) as a pale yellow oil with spectral data in agreement with that reported earlier in our laboratory.  1 4 1  IR(CCI): 2912, 1454, 1441, 1423, 1351, 1323, 1276, 1241, 1200, 1182, 1137, 1122, 4  1076, 1033, 970, 908, 869 cm"; 1  H NMR (500 MHz, CDCI): 5 4.51 (dd, J = 4.1, 3.0 Hz, 1 H), 3.99 (t, J = 6.9 Hz, 1 H),  1  3  3.79 (ddd, J = 2.7, 7.6, 10.9 Hz, 1 H), 3.68 (dt, J = 9.7, 6.2 Hz, 1 H), 3.43 (ddd, 3.6, 5.2, 10.9 Hz, 1 H), 3.32 (dt, J = 9.7, 6.2 Hz, 1 H), 2.73-2.84 (m, 4 H),  1.43-  2.08 (m, 14 H); C NMR (125 MHz, CDCI): 5 98.69, 67.02, 62.13, 47.37, 35.14, 30.60, 30.32 (2),  13  3  29.18, 25.91, 25.36, 23.31, 19.48; L R M S (El) m/z (relative intensity): 276 (M, 4), 191 (100), 119 (26), 85 (66), 42 (23); +  H R M S (El) m/z calculated for Ci H 0 S : 276.1218, found: 276.1211; 3  24  2  2  Analysis calculated for Ci H 0 S : C, 56.48; H, 8.75. Found: C, 56.68; H, 8.90. 3  24  2  2  274  9-(1',3'-Dithian-2'-yl)-13-(2"-tetrahyclropyranyloxy)-tridecanal ethylene acetal (127)  A solution of n-butyllithium in hexanes (31 mL, 31 m m o l ) was dithiane 126 (8.64  g, 31.3  m m o l ) in THF  added to a solution of  (50 mL) at -20 °C and the reaction was stirred  at -20 °C for five hours. A solution of bromide 123 (3.13 was  added via cannula. This reaction was  and  stirred for an additional hour at rt.  g, 12.5  m m o l ) in THF  The  reaction was  quenched with saturated  4  with water, brine, and dried over anhydrous MgS0. The  sequentially washed  extracts were filtered and  4  with 10%  mL)  stirred for one hour at -20 °C, w a r m e d to rt,  NHCI solution and diluted with diethyl ether. The ether layer was  solvent was  (10  the  removed under reduced pressure. Column chromatography of the residue  ethyl acetate in petroleum ether as eluant gave dithiane 127 (2.75  g, 49%)  as  a pale yellow oil. IR (CCU): 2917, H NMR  (500  1  2863, 1458,  MHz,  1354,  CDCI): 5 4.78 3  H), 3.77-3.92 (m, 5 H), 3.70  1276,  1132,  1077,  1034,  945,  (dd, J = 4.8, 5.0 Hz, 1 H), 4.53  908  cm"; 1  (dd, J = 3.1, 2.7 Hz, 1  (dt, J = 9.7, 6.6 Hz, 1 H), 3.42-3.47 (m, 1 H),  3.35  (dt, J = 9.7, 6.7 Hz, 1 H), 2.73-2.76 (m, 4 H), 1 . 7 6 1 . 9 1 (m, 6 H), 1 . 2 3 1 . 6 8 (m, 22 C NMR  13  H); (125  MHz,  CDCI): 5 104.56, 98.74, 67.14, 64.71 3  (2), 62.20, 53.22, 38.12,  37.90, 33.77, 30.67, 29.74, 29.60, 29.39, 29.28, 25.91 23.83,20.79,19.54;  (2), 25.47, 25.41, 23.92  275 LRMS (El) m/z (relative intensity): 446 (M, +  73  33), 361 (27),  289  (45),  275 (22),  85 (100),  (70);  H R M S (El) m/z calculated for Analysis calculated for  C23H42O4S2:  C23H42O4S2:  446.2524, found: 446.2523;  C, 61.84; H, 9.48.  Found: C, 62.12; H,  9.60.  9-Oxo-13-(2'-tetrahydropyranyloxy)-tridecanal ethylene acetal (128)  Mercuric perchlorate (2.96  g, 6.52  dithiane 127 (2.65  m m o l ) and  g, 5.93  (40 mL) and the reaction was  m m o l ) in water (2 mL)  was  calcium carbonate (0.71  stirred for 20 minutes at rt. The  added to a mixture of g, 7.1 m m o l ) in  reaction was  THF  diluted with  diethyl ether and filtered. The filtrate was  washed with brine, and dried over anhydrous  MgS0. The  the  extracts were filtered and  4  solvent was  pressure. Column chromatography of the residue with 15% ether as eluant gave ketone 128 (1.70  IR (CCU): 2939, 2866, 1716, H NMR  (500  1  MHz,  CDCI): 8 4.78 3  3.77-3.92 (m, 5 H), 3.69 = 9.7, 6.3 Hz, 1 H), 2.38 (m, 22 C NMR  13  (125  1458,  g, 80%)  1410,  1358,  removed under reduced ethyl acetate in petroleum  as a pale yellow oil.  1130,  1078,  (t, J = 4.8 Hz, 1 H), 4.51  1035  cm"; 1  (dd, J = 2.7, 4.0 Hz, 1 H),  (dt, J = 9.7, 6.4 Hz, 1 H), 3.42-3.47 (m, 1 H), 3.33 (t, J = 7.2 Hz, 2 H), 2.33  (dt, J  (t, J = 7.5 Hz, 2 H), 1 . 2 1 1 . 8 0  H); MHz,  CDCI): 5 211.11, 104.57, 98.78, 67.09, 64.74 (2), 62.23, 42.70, 3  42.38, 33.78, 30.66, 29.25, 29.20, 29.18, 29.03, 25.40, 23.90, 23.74, 20.61, 19.56;  276 L R M S (El) m/z (relative intensity): 355  (M, +  1), 255  (18),  98 (13),  85 (71),  73 (100), 55  (17); H R M S (El) m/z calculated for CoH50: 355.2484, found: 355.2488. 2  3  5  9-Methylene-13-(2'-tetrahydropyranyloxy)-tridecanal ethylene acetal (129)  A solution of Tebbe reagent 3 2  38153  to a solution of ketone 128 (1.66 (0.20  mL, 2.5 m m o l ) in THF  (100  in toluene (18 mL, 9.3 m m o l ) was  g, 4.66  mmol), D M A P (0.68  added via syringe  g, 5.6 m m o l ) and pyridine  mL) stirred at -40 °C and the reaction was  slow warming to rt over 20 hours. The  reaction mixture was  alumina with petroleum ether as eluant and the filtrate was r e m o v e d under reduced pressure and  stirred with  filtered through basic  collected. The  solvent was  column chromatography of the residue with 5%  ethyl acetate in petroleum ether as eluant gave alkene 129 (0.88  g, 53%)  as a pale  yellow oil.  IR (CCU): 2909, 1644, H NMR  (500  1  MHz,  1451,  CDCI): 5 4.81 3  C  1323,  1132,  1132,  1035,  (t, J = 4.8 Hz, 1 H), 4.66  945,  892  (s, 2 H), 4.55  cm; 1-  (dd, J =  2.9,  4.0 Hz, 1 H), 3.80-3.94 (m, 5 H), 3.71  (dt, J = 9.5, 6.7 Hz, 1 H), 3.45-3.49 (m, 1  H), 3.36  (t, J = 7.6 Hz, 2 H), 1.95  (dt, J = 9.5, 6.5 Hz, 1 H), 2.00  H), 1 . 2 2 1 . 8 3 (m, 22 13  1354,  NMR  (125  MHz,  (t, J = 7.5 Hz, 2  H);  CDCI): 6 149.85, 108.68, 104.66, 98.76, 67.41, 64.78 (2), 62.23, 3  35.94, 35.76, 33.87, 30.73, 29.47, 29.42, 29.40, 29.26, 27.73, 25.48, 24.37, 24.03, 19.61;  277 LRMS (El) m/z (relative intensity): 354 (M , 3), 269 (10), 208 (5), 155 (6), 85 (100), 73 +  (47), 55 (8); HRMS (El) m/z calculated for C i H 0 : 354.2770, found: 354.2768; 2  38  4  Analysis calculated for C iH 80 : C, 71.15; H, 10.80. Found: C, 71.42; H, 10.89. 2  3  4  13-Hydroxy-9-methylenetridecanal (130)  A solution of alkene 129 (0.84  g, 2.4 m m o l ) and PPTS (0.12  g, 0.47  m m o l ) in acetone  and water (10:1, 50 mL) was heated at reflux for 20 hours. The acetone was removed under reduced pressure, and the reaction mixture was diluted with diethyl ether. The organic layer was  sequentially washed with saturated NaHC0 solution, brine, and 3  dried over anhydrous MgS0. The extracts were filtered and the solvent was removed 4  under reduced pressure. Column chromatography of the  residue with 30% ethyl  acetate in petroleum ether as eluant gave hydroxy aldehyde 130 (0.48  g, 90%)  as a  colourless oil.  IR (CCI): 3635, 3437, 3076, 2932, 2859, 2716, 4  H NMR  (500  1  MHz,  2 H), 2.40  CDCI): 5 9.73 (t, J = 1.7 Hz, 1 H), 4.68 3  (dt, J = 1.7, 7.4 Hz, 2 H), 2.01  1.0, 7.6 Hz, 2H), C NMR  13  (125  MHz,  1729,  1644,  1427,  (s, 2 H), 3.64  1052,  891  (t, J = 6.4  (dt, J = 1.0, 7.5 Hz, 2 H), 1.97  cm"; 1  Hz,  (dt, J =  1 . 5 2 1 . 6 4 (m, 4 H), 1 . 2 5 1 . 5 1 (m, 10 H);  CDCI): 5 202.90, 149.64, 108.87, 62.90, 43.88, 35.90, 35.72, 3  32.48, 29.21, 29.13, 29.09, 27.65, 23.87, 22.04;  278 LRMS (DCI(+), a m m o n i a ) m/z (relative intensity): 244  (M +18, 100), +  227  (M+1, 47); +  H R M S (Cl(+), isobutane) m/z calculated for CiH0(M+1): 227.2011, found: +  4  2 7  2  227.2012.  13-Hydroxy-9-methylenetridecanoic acid (131)  Silver nitrate (3.50  g, 20.3  m m o l ) and  sodium hydroxide (1.64  added to a solution of hydroxy aldehyde 130 (0.46 (1:1,  50 mL)  and  the mixture was  g, 2.03  g, 41.0  m m o l ) were  m m o l ) in THF  and water  stirred at rt for six hours in the dark. The reaction  mixture was filtered and the solid residue was washed with ethyl acetate. The aqueous layer was  acidified with 1 M HCI  and extracted with ethyl acetate. The  were combined, washed with brine, and were filtered and  the  chromatography of the (0.15  g, 30%)  solvent was  residue with 4%  (500  4  methanol in CHCI gave hydroxy acid 131 2  2  as a colourless oil.  4  H NMR  dried over anhydrous MgS0. The extracts  removed under reduced pressure. Column  IR (CCI): 3639, 2933, 2858, 1712, 1  organic layers  MHz,  2 H), 2.01  CDCI): 6 4.68 3  1644,  1434,  (s, 2 H), 3.64  (t, J = 7.5 Hz, 2 H), 1.97  1054,  891  cm"; 1  (t, J = 6.3 Hz, 2 H), 2.32  (t, J = 7.6 Hz, 2 H), 1.61  (t, J = 7.4  (quint, J = 7.4  Hz, Hz,  2 H), 1 . 4 5 1 . 5 7 (m, 4 H), 1 . 2 3 1 . 4 1 (m, 8 H); C  13  NMR  (125  MHz,  CDCI): 5 179.13, 149.67, 108.89, 62.84, 35.84, 35.71, 32.34, 3  29.03, 28.96 (2), 28.87, 27.56, 24.65, 23.88; LRMS (DCI(+), a m m o n i a ) m/z (relative intensity): 260 (M+18, 93), 243 +  (M+1, 100); +  279 H R M S (Cl(+), isobutane) m/z calculated for CiH03 (M+1): 243.1960, found: +  4  2 7  243.1961; Analysis calculated for CiH 0. C, 69.38; H, 10.81. Found: C, 69.52; H, 11.00. 4  26  3  9-Methylene-13-tridecanolide (132)  Triethylamine (49 uL, 0.35 0.31  m m o l ) in THF  (31  m m o l ) was mL)  and  added to a solution of hydroxy acid 131 (76  the  2,4,6-Trichlorobenzoyl chloride (48  reaction was  uL, 0.31  stirred for an additional two hours. The  stirred for  m m o l ) was  reaction was  15  minutes at  added and  filtered and  mg,  rt.  the reaction was  concentrated under  reduced pressure. Trace amounts of solvent were removed under high v a c u u m ove two hours. A solution of the resultant mixed anhydride in toluene (150 via syringe p u m p to a solution of D M A P (0.23 reflux over six hours. The  reaction was  g, 1.9 m m o l ) in toluene (31 mL) heated at  concentrated under reduced pressure, diluted  with diethyl ether, sequentially washed with 1 M HCI, and  dried over anhydrous MgS0. The 4  mL) was added  saturated NaHC0 solution, brine, 3  extracts were filtered and  the  solvent was  removed under reduced pressure. Radial chromatography of the residue with 1 % ethyl acetate in petroleum ether as eluant gave lactone 132 (37 mg, 52%)  as a pale yellow  oil.  IR (CCI): 2935, 2862, 1734, 4  H NMR  1  (500  MHz,  CDCI): 8 4.67 3  (br t, J = 7.6 Hz, 2 H), 1.96 (m, 8 H);  1643,  1452,  1243,  1138,  1084,  892  cm"; 1  (s, 2 H), 4.11-4.13 (m, 2 H), 2.32-2.35 (m, 2 H), (br t, J = 7.8 Hz, 2 H), 1.58-1.64 (m, 6 H), 1 . 2 6 1 . 5 6  2.05  280 C  13  NMR  (125  MHz,  CDCI): 5 173.63, 149.28, 110.37, 63.09, 34.81, 34.25, 33.14, 3  27.62, 26.18, 25.73, 25.56, 24.66, 24.40, 23.51; LRMS (El) m/z (relative intensity): 224 (69),  55 (56),  41  (M, +  20),  109 (45),  96 (75),  95 (62),  81 (100), 67  (56);  H R M S (El) m/z calculated for  C14H24O2:  224.1776, found: 224.1776.  9-Cyclopropyl-13-tridecanolide (133)  Chloroiodomethane (80 0.53  uL, 1.1  m m o l ) was  added to a solution of diethylzinc (54  m m o l ) in deoxygenated CICHCHCI (2 mL) at 0 °C and the reaction was 2  2  seven minutes. A solution of lactone 132 (59 CICHCHCI (1 mL) 2  was  2  additional ten  added via  minutes at 0 °C.  saturated NaS0 solution and 2  2  3  diluted with CHCI. The 2  2  The  mg,  cannula and  0.26  the  reaction was  4  stirred for  m m o l ) in deoxygenated  reaction was  stirred for  quenched with a 1:1  an  mixture of  saturated NHCI solution, slowly w a r m e d to rt, 4  aqueous layer was  extracts were filtered and  the  and  extracted with CHCI, the organic layers 2  were combined, sequentially washed with water and MgS0. The  u,L,  brine, and  solvent was  2  dried over anhydrous  removed under reduced  pressure. Column chromatography of the residue with 1 % ethyl acetate in petroleum ether as eluant gave lactone 133 (54 mg, 85%)  IR (CCI): 3069, 2933, 2860, 1733, 4  H NMR  1  (500  MHz,  1458,  as a pale yellow oil.  1247,  1171,  1137,  1086  cm'; 1  CDCI): 8 4.09-4.14 (m, 2 H), 2.34-2.37 (m, 2 H), 1 . 6 0 1 . 6 7 (m, 4 H), 3  1 . 4 6 1 . 5 2 (m, 2 H), 1 . 1 0 1 . 3 7 (m, 12 H), 0.16 J = 1.9, 7.4 Hz, 2 H);  (dd, J = 1.9, 7.4 Hz, 2 H), 0.13  (dd,  281 C  13  NMR  (125  MHz,  CDCI): 8 173.87, 63.03, 34.69, 34.37, 33.73, 27.91, 26.31, 25.75 3  25.70, 24.63, 21.92, 21.73, 18.24, 12.26 LRMS (El) m/z (relative intensity): 238 81 (100), 67 (95),  55 (68),  41  (M,  (2);  12), 209 (33),  +  123 (25),  110 (77),  95  (98),  (74);  H R M S (El) m/z calculated for CiH 0: 238.1933, found: 238.1927. 5  26  2  9,9-Dimethyl-13-tridecanolide (134)  Adams' catalyst was  added to a solution of lactone 133 (51 mg, 0.21  acid (2 mL) and the mixture was  stirred under H for 22 hours at rt. The 2  diluted with diethyl ether and filtered. The and  the  organic layers were combined. The  NaHC0 solution, water and 3  were filtered and  the  m m o l ) in acetic  brine, and  solvent was  solid residue was solution was  reaction was  rinsed with diethyl ether  washed with saturated  dried over anhydrous MgS0. The extracts 4  removed under reduced pressure. Column  chromatography of the residue with 2% ethyl acetate in petroleum ether as eluant gave lactone 134 (37 mg, 73%)  IR(CCU): 2941, H NMR  (500  1  2861,  MHz,  as a pale yellow oil.  1733,  1464,  C NMR  (125  MHz,  1250,  1145,  1086  cm"; 1  CDCI): 6 4.10-4.12 (m, 2 H), 2.33-2.35 (m, 2 H), 1.56-1.65 (m, 4 H), 3  1 . 0 5 1 . 3 8 (m, 14 H), 0.82 13  1364,  (s, 6 H);  CDCI): 5 173.70, 62.99, 37.87, 37.84, 35.11, 32.37, 29.16 3  28.82, 26.65, 25.96, 25.82, 24.30, 19.66, 19.22;  (2),  282 LRMS (El) m/z (relative intensity): 240 (M , 5), 166 (23), +  (94), 41  96 (100), 81 (50), 69 (65),  55  (63);  HRMS (El) m/z calculated for CisHzsOz: 240.2089, found: 240.2087.  7,7-Dimethyl-2-oxacyclotetradecanethione (135)  A solution of lactone 134 (36  mg, 0.15  m m o l ) in toluene (5 mL)  suspension of Lawessons ' reagent 48 (0.12  g, 0.30  was  added to a  m m o l ) in toluene (10 mL) and  the  reaction was heated at reflux for five days. The reaction was cooled to rt, filtered, and the solid residue was  rinsed with diethyl ether. The filtrate was  concentrated under  reduced pressure, and column chromatography of the residue with petroleum ether as eluant gave thionolactone 135 (18 mg, 47%)  IR(CCI): 2942, 2861, 4  H NMR  (500  1  MHz,  1463,  1383,  1362,  1293,  as a yellow oil.  1262,  1199,  1139,  1119,  C NMR  (125  MHz,  cm"; 1  CDCI): 8 4.46-4.50 (m, 2 H), 2.87-2.91 (m, 2 H), 1.75-1.80 (m, 2 H), 3  1 . 6 0 1 . 6 6 (m, 2 H), 1 . 2 7 1 . 3 9 (m, 8 H), 1 . 0 2 1 . 1 6 (m, 6 H), 0.83 13  1085  (s, 6 H);  CDCI): 5 224.28, 70.86, 47.85, 38.23, 37.45, 32.34, 29.17 3  (2),  28.14, 26.56, 25.96 (2), 24.79, 19.64, 19.13; LRMS (El) m/z (relative intensity): 256 (M, 34), 223 (34), 201 (100), 167 (50), +  H R M S (El) m/z calculated for CHOS: 256.1861, found: 256.1856. 1 5  2 8  149  (28);  283 2-(Methylthio)-10,10-dimethyloxacyclotetradecane (136)  A solution of lithium triethylborohydride in THF solution of thionolactone 135 (14 reaction was added and  m m o l ) was (5 mL)  Methyl iodide (21  stirred for 15 minutes at -78  pL, 0.33  2  2  unstable and was  stirred for  °C, and  2  w a r m e d to rt.  2  3  extracts were filtered and  the  The  as an oil.  Thioacetal 136  +  H R M S (Cl(+), isobutane) m/z calculated for CiHOS (M+1): 273.2252, found: +  3 3  the  removed under  used immediately without further purification.  6  °C.  reaction was  LRMS (Cl(+), isobutane) m/z (relative intensity): 273 (M+1, 16), 225 (100);  273.2252.  an  brine, and dried over  solvent was  reduced pressure to give mixed thioacetal 136 (14 mg, 94%) was  the  m m o l ) was  H0 (ca. 0.5 mL) were added and  sequentially washed with saturated NaS0 solution, water, and 4  °C and  diluted with diethyl ether and cooled to -78  Aqueous 3 M N a O H solution (ca. 1 mL) and 30%  anhydrous MgS0. The  added to a  at -78  stirred for 30 minutes, w a r m e d to rt, and  additional 30 minutes. The reaction was  solution was  mL, 0.28  mg, 0.056 m m o l ) in THF  stirred for 30 minutes at -78 °C. the reaction was  (0.28  284 6,6-Dimethyloxacyclotetradecane (137)  A deoxygenated solution of tri(n-butyl)tin hydride (0.14 in toluene (9.8  mL)  was  m m o l ) and AIBN (cat.)  added over ten hours via syringe p u m p to a deoxygenated  solution of mixed thioacetal 136 (14 (10 mL) heated at reflux. The chromatography of the  mL, 0.52  mg,  0.052 m m o l ) and  solvent was  AIBN (cat.) in toluene  removed under reduced pressure. Column  residue with petroleum ether as  eluant removed the  tin  compounds. Further chromatography using AgN0 impregnated silica with petroleum 3  ether as eluant gave ether 136 (7.9  mg, 67%)  IR(CDCI): 2937, 2861,  1116  1451,  3  H NMR  (500  1  MHz,  1357,  CDCI): 5 3.43  C  13  NMR  (m, 6 H), 0.84 (125  MHz,  cm-; 1  (t, J = 5.3 Hz, 2 H), 3.42  3  (quint, J = 5.3 Hz, 2 H), 1.54 1.17  as an oil.  (t, J = 5.4 Hz, 2 H),  1.60  (quint, J = 5.4 Hz, 2 H), 1 . 2 9 1 . 4 2 (m, 10 H),  1.11-  (s, 6 H);  CDCI): 5 68.17, 67.70, 38.88, 37.76, 32.39, 29.32 (2), 29.19, 3  28.74, 26.48, 26.22, 23.54, 22.47, 19.84, 18.46; LRMS (El) m/z (relative intensity): 226 (M, +  16), 211  (4), 152 (13),  115 (13),  96(100), 82(15), 69(16); H R M S (El) m/z calculated for CiHO: 226.2297, found: 226.2296. 5  3 0  109  (16),  285 6-Bromo-1-hexanol (139)  48%  HBr  178.5  (30 mL, 0.27  mol)  was  m m o l ) in benzene (400  added to a solution of 1,6-hexanediol (138) (21.10 g, mL)  and  the solution was  Stark conditions for 68 hours. The organic layer was reduced pressure. The solution was and  resultant oil was  heated at reflux under Dean-  collected and concentrated under  diluted with diethyl ether, and  the ether  sequentially washed with saturated NaHC0 solution, water and brine, 3  dried over anhydrous MgS0. The 4  extracts were filtered and  the  removed under reduced pressure to give alcohol 139 (29.23 g, 90%) This material was  solvent was as a yellow oil.  used in subsequent reactions without further purification.  chromatography of a small sample of 139 (ca.  100  mg)  with 20%  Column  ethyl acetate in  petroleum ether as eluant gave pure 139 with spectral data in agreement with that reported earlier in our laboratory.  1 4 1  IR (CCI): 3634, 3353, 2935, 2862, 1459, 4  H NMR  (500  1  MHz,  CDCI): 5 3.58 3  (br s, 1 H), 1.82  1435,  1279,  (t, J = 6.7 Hz, 2 H), 3.36  (quint, J = 6.9 Hz, 2 H), 1.52  1052,  952  cm"; 1  (t, J = 6.9 Hz, 2 H),  1.93  (quint, J = 6.7 Hz, 2 H), 1 . 3 9 1 . 4 5  (m, 2 H), 1 . 3 0 1 . 3 6 (m, 2 H); C  13  NMR  (125  MHz,  CDCI): 6 62.51, 33.72, 32.59, 32.35, 27.81, 24.82; 3  LRMS (DCI(+), a m m o n i a ) m/z (relative intensity): 200  (Br, M +18, 100), 8 1  +  198 (Br, 7 9  M +18, 99); +  H R M S (Cl(+), isobutane) m/z calculated for CHi0 Br (M+1): 183.0208, found: 8 1  6  +  4  183.0202; calculated for CHi0 Br (M+1): 181.0228, found: 181.0226. 7 9  6  4  +  286 6-Bromohexanal (140)  A solution of dimethylsulfoxide (11.4 m L , 160 m m o l ) in CHCI (17 m L ) was adde 2  2  cannula to a solution of oxalyl chloride (7.0 m L , 80 m m o l ) in CHCI (90 m L ) at 2  2  The solution was stirred for t w o minutes and alcohol 139 (7.20 g, 39.8 m m o l ) in  (40 m L ) was added via cannula. This mixture was stirred for 15 minutes at -78  Triethylamine (28 m L , 0.20 mol) was added, the mixture was stirred for 5 minutes  w a r m e d to rt. The reaction was quenched with water, and the organic layer w a  collected. The aqueous layer was extracted with CHCI. The organic layers were 2  2  combined, sequentially washed with water and brine, and dried over anhydrous MgS The extracts were filtered and the solvent was removed under reduced pressure. Column chromatography of the residue with 10% ethyl acetate in petroleum ether  eluant gave aldehyde 140 (5.41 g, 76%) as a pale yellow oil with spectral data agreement with that reported earlier in our laboratory.  1 4 1  I R (CDCI): 2939, 2863, 2728, 1724, 1430, 1 2 5 7 cm'; 1  3  H N M R (500 MHz, CDCI): 5 9 . 7 6 (t, J = 1 . 7 Hz, 1 H), 3 . 3 9 (t, J = 6.7 Hz,  1  3  J = 1 . 7 , 7 . 2 Hz, 2 H), 1 . 8 6 (quint, J = 6 . 7 Hz, 2 H), 1 . 6 1 1 . 6 7 (m, 2 H (m, 2 H); CN M R (125 MHz, CDCI): 5 202.13, 43.65, 33.34, 32.43, 27.65, 21.17;  13  3  LRMS (DCI(+), a m m o n i a ) m/z (relative intensity): 1 9 8 (Br, M +18, 56), 1 9 6 (Br, 8 1  +  7 9  M +18, 61), 1 7 8 (Br, M, 100); +  7 9  +  H R M S (Cl(+), isobutane) m/z calculated for CH 0 Br (M+1): 179.0072, found: 7 9  6  179.0070.  1 2  +  287 6-Bromohexanal ethylene acetal (141)  A solution of aldehyde 140 (4.95 PPTS (1.39  g, 5.52  mmol), ethylene glycol (7.7  m m o l ) in benzene (200  conditions for 21 hours. The residue was  g, 27.6  solvent was  mL) was  3  extracts were filtered and acetal 141 (5.50  g, 90%)  mol),  and  heated at reflux under Dean-Stark  removed under reduced pressure and  diluted with diethyl ether. The ether solution was  saturated NaHC0 solution, water and  mL, 0.14  brine, and  the solvent was  the  sequentially washed with  dried over anhydrous MgS0. 4  The  removed under reduced pressure to give  as a pale yellow oil.  This material was  used in subsequent  reactions without further purification. Column chromatography of a small sample of 141 (ca.  100  mg)  with 5%  ethyl acetate in petroleum ether as eluant gave pure 141 with  spectral data in agreement with that reported earlier in our laboratory.  1 4 1  IR (CDCI): 2947, 2875, 1460, 3  H NMR  (500  1  MHz,  2 H), 3.38  1435,  CDCI): 5 4.83  1407,  1360,  1237,  1136,  1041,  946  cm"; 1  (t, J = 5.0 Hz, 1 H), 3.90-3.97 (m, 2 H), 3.79-3.86 (m,  3  (t, J = 6.8 Hz, 2 H), 1 . 8 2 1 . 8 8 (m, 2 H), 1 . 6 1 1 . 6 7 (m, 2 H), 1 . 4 1 1 . 4 9  (m, 4 H); C  13  NMR  (125  MHz,  CDCI): 5 104.39, 64.84 (2), 33.67, 33.63, 32.68, 28.04, 23.13; 3  LRMS (El) m/z (relative intensity): 223 (100), 45  (Br, M, 18), 221 8 1  +  (Br, M, 17), 83 (27), 7 9  +  (22);  H R M S (El) m/z calculated for CH 0 Br (M-1): 223.0157, found: 223.0156; 8 1  8  1 4  +  2  calculated for CH 0 Br (M-1): 221.0177, found: 221.0183. 7 9  8  1 4  2  +  73  288 6-Bromo-1-(2'-tetrahydropyranyloxy)-hexane (142)  A solution of alcohol 139 (5.00 PPTS (1.38  g, 5.52  2  mL)  2  was  mL,  33 mmol), and  stirred at rt for 15 hours.  2  2  dried over anhydrous MgS0. The  extracts were filtered and  4  removed under reduced pressure to give bromide 142 (7.08  a pale yellow oil.  The  diluted with CHCI, sequentially washed with saturated NaHC0  brine, and  the solvent was  mmol), dihydropyran (3.0  m m o l ) in CHCI (100  resultant solution was solution and  g, 27.6  This material was  g, 97%)  as  used in subsequent reactions without further  purification. Column chromatography of a small sample of 142 (ca.  100 mg) with  5% ethyl acetate in petroleum ether as eluant gave pure 142 with spectral data in agreement with that reported earlier in our laboratory.  1 4 1  IR(CCI): 2940, 2865, 1454,  1440,  4  980, H NMR  906,  (500  1  870  MHz,  1351,  1323,  (125  MHz,  1135,  1121,  1077,  1032,  1  CDCI): 5 4.51 3  (dd, J = 2.8, 4.4 Hz, 1 H), 3.80  (dt, J = 9.5, 6.9 Hz, 1 H), 3.44  3.31-3.37 (m, 3 H), 1 . 3 1 1 . 8 1 (m, 14 C NMR  1201,  cm";  3.3 Hz, 1 H), 3.68  13  1273,  (ddd,  (ddd,  J = 11.1,  J = 11.1,  7.9,  2.5, 4.0 Hz, 1 H),  H);  CDCI): 5 98.75, 67.26, 62.22, 33.68, 32.64, 30.66, 29.44, 27.88, 3  25.39, 25.36, 19.57; LRMS (El) m/z (relative intensity): 265 (Br, M-1, 8 1  163 (33),  115 (35),  101 (33),  +  85 (100), 67 (30),  31), 263 (Br, M-1, 7 9  55 (80),  41  +  31),  165  (63);  H R M S (El) m/z calculated for CnHO Br (M-1): 265.0626, found: 265.0638; 8 1  2 0  +  2  calculated for CnHO Br (M-1): 263.0647, found: 263.0649. 7 9  2 0  2  +  (31),  289 7-(1\3'-Dithian-2'-yl)-heptanal ethylene acetal (143)  A solution of n-butyllithium in hexanes (22.5 mL, 33.8 m m o l ) was added to a solution of 1,3-dithiane (4.06 g, 33.8 m m o l ) in THF (60 mL) at -20 °C and the reaction was stirred for two hours. A solution of b r o m o acetal 141 (5.00 g, 22.5 m m o l ) in THF (50 mL) was added and the solution was stirred for one hour, w a r m e d to rt, and stirred for an additional hour at rt. The reaction was quenched with saturated NHCI solution, and 4  diluted with diethyl ether. The ether solution was sequentially washed with water and brine, and dried over anhydrous MgS0. The extracts were filtered and the solvent was 4  removed under reduced pressure. Column chromatography of the residue with 10% ethyl acetate in petroleum ether as eluant gave dithiane 143 (3.95 g, 67%) as a pale yellow oil.  IR(CCU): 2912, 1457, 1423, 1276, 1137, 1038, 942, 909 cm; 1 -  H NMR (500 MHz, CDCI): 5 4.79 (t, J = 5.4 Hz, 1 H), 3.99 (t, J = 7.1 Hz, 1 H), 3.87-  1  3  3.92 (m, 2 H), 3.78-3.82 (m, 2 H), 2.75-2.85 (m, 4 H), 1.29-2.08 (m, 12 H); C NMR (125 MHz, CDCI): 8 104.46, 64.73 (2), 47.47, 35.23, 33.67, 30.37 (2), 29.02,  13  3  26.42, 25.96, 23.68; LRMS (El) m/z (relative intensity): 262 (M, 81), 155 (21), 119 (63), 73 (100); +  H R M S (El) m/z calculated for Ci H 0 S2: 262.1061, found: 262.1065; 2  22  2  Analysis calculated for CiH 0S: C, 54.92; H, 8.45. Found: C, 54.99; H, 8.60. 2  2 2  2  2  290 7-(1',3'-Dithian-2'-yl)-13-(2"-tetrahydropyranyloxy)-tridecanal ethylene acetal (144)  A solution of n-butyllithium in hexanes (12.6 dithiane 143 (3.59  g, 13.7  m m o l ) in THF  mL, 16.4  added via cannula and the reaction was stirred for an additional hour at rt.  NHCI solution and 4  filtered and  the  brine, and  solvent was  gave dithiane 144 (1.38  H NMR  (500  MHz,  stirred for one The  reaction was  1.92 C NMR  13  1 H), 3.33  1353,  MHz,  ether solution was sequentially  extracts were  Column  ethyl acetate in petroleum ether as eluant  1275,  1133,  1078,  (t, J = 4.8 Hz, 1 H), 4.53  1033,  907  cm"; 1  (dd, J = 2.9, 4.2 Hz, 1 H),  (dt, J = 9.7, 6.9 Hz, 1 H), 3.45  (dt, J = 9.7, 6.7 Hz, 1 H), 2.73-2.76 (m, 4 H),  (m, 6 H), 1 . 2 7 1 . 6 9 (m, 22  (125  was  quenched with saturated  4  3.88-3.94 (m, 2 H), 3.78-3.84 (m, 3 H), 3.68 J = 3.8, 5.0, 10.9,  mL)  as a pale yellow oil.  CDCI): 6 4.80 3  (10  hour at -20 °C, w a r m e d to rt,  removed under reduced pressure.  g, 38%)  IR (CCU): 2940, 2865, 1459,  m m o l ) in THF  dried over anhydrous MgS0. The  chromatography of the residue with 10%  1  g, 17.0  diluted with diethyl ether. The  washed with water and  added to a solution of  (50 mL) at -20 °C and the reaction was stirred  for two hours. A solution of bromide 142 (4.51  and  m m o l ) was  (ddd, 1.77-  H);  CDCI): 5 104.50, 98.73, 67.46, 64.75 (2), 62.20, 53.24, 38.12, 3  38.00, 33.78, 30.69, 29.66, 29.64, 29.61, 26.07, 25.92 (2), 25.49, 25.43, 23.9 23.93, 23.82, 19.59;  291 LRMS (El) m/z (relative intensity): 446 (M, +  H R M S (El) m/z calculated for Analysis calculated for  C23H42O4S2:  C23H42O4S2:  13), 261 (31),  85 (100), 73  (49);  446.2524, found: 446.2518;  C, 61.48; H, 9.48.  Found: C, 61.62; H,  9.62.  7-Oxo-13-(2'-tetrahydropyranyloxy)-tridecanal ethylene acetal (145)  Mercuric perchlorate (3.42  g, 7.54  dithiane 144 (3.06  m m o l ) and  g, 6.85  (40 mL) at rt and the reaction was  m m o l ) in water (2 mL)  was  added to a mixture of  calcium carbonate (0.82  stirred for 20 minutes. The  g, 8.2 m m o l ) in  reaction was  THF  diluted with  diethyl ether and filtered. The filtrate was washed with brine, and dried over anhydrous MgS0. The 4  extracts were filtered and  the  solvent was  removed under reduced  pressure. Column chromatography of the residue with 20% ether as eluant gave ketone 145 (1.50  IR (CCU): 2940, 2866, 1716, H NMR  (500  1  MHz,  1454,  CDCI): 6 4.81 3  g, 61%)  1409,  1358,  (m, 1 H), 3.34  as a colourless oil.  1133,  (t, J = 4.8 Hz, 1 H), 4.54  3.89-3.94 (m, 2 H), 3.80-3.85 (m, 2 H), 3.69 (dt, J = 9.5, 6.6 Hz, 1 H), 2.36  ethyl acetate in petroleum  1078,  1033  cm"; 1  (dd, J = 2.7, 4.2 Hz, 1 H),  (dt, J = 9.5, 6.8 Hz, 1 H), 3.42-3.49 (t, J = 7.4 Hz, 2 H), 2.35  (t, J = 7.4  Hz, 2 H), 1 . 4 7 1 . 8 2 (m, 15 H), 1 . 2 6 1 . 4 2 (m, 8 H); C NMR  13  (125  MHz,  CDCI3): 5 211.32, 104.51, 98.84, 67.49, 64.80 (2), 62.32, 42.69,  42.58, 33.67, 30.75, 29.55, 29.10, 29.06, 26.04, 25.47, 23.77 (2), 23.70, 19.6  292 L R M S (El) m/z (relative intensity): 356  (M,  H R M S (El) m/z calculated for  356.2563, found: 356.2559;  C20H36O5:  +  6), 271  (14),  211  (37),  85 (66),  73 (100);  Analysis calculated for CoH60: C, 67.38; H, 10.18. Found: C, 67.67; H, 10.03. 2  3  5  7-Methylene-13-(2'-tetrahydropyranyloxy)-tridecanal ethylene acetal (146)  (a) Reaction of Ketone 145 with Tebbe Reagent 3 2 A solution of Tebbe reagent 32  in toluene (12.6  syringe to a stirred solution of ketone 145 (1.50 5.1 m m o l ) and was  pyridine (0.20  j e 1 5 3  g, 4.21  mL, 2.5 m m o l ) in THF  slowly w a r m e d to rt over 20 hours. The  mL,  (100  8.42  added via  mmol), D M A P (0.62  g,  mL) at -40 °C and the reaction  reaction mixture was  alumina with petroleum ether as eluant and the filtrate was removed under reduced pressure, and  m m o l ) was  filtered through basic  collected. The  column chromatography of the  5% ethyl acetate in petroleum ether as eluant gave alkene 146 (1.05  solvent was residue with  g, 70%)  as a pale  yellow oil.  IR (CCU): 2936, 2862, 1643, H NMR  1  (500  MHz,  1459,  CDCI): 5 4.81 3  1354,  1132,  1078,  (t, J = 4.9 Hz, 1 H), 4.64  1033,  892  cm;  (s, 2 H), 4.54  1 -  (dd, J =  3.2,  4.2 Hz, 1 H), 3.89-3.94 (m, 2 H), 3.79-3.85 (m, 3 H), 3.69  (dt, J = 9.5, 6.9 Hz, 1  H), 3.44-3.48 (m, 1 H), 3.35  (t, J = 7.6 Hz, 2 H),  1.95  (dt, J = 9.5, 6.7 Hz, 1 H), 1.96  (t, J = 7.6 Hz, 2 H), 1 . 2 6 1 . 8 3 (m, 22  H);  293 C  13  NMR  (125  MHz,  CDCI): 6 150.01, 108.48, 104.60, 98.78, 67.58, 64.77 (2), 62.26, 3  35.93, 35.85, 33.82, 30.73, 29.67, 29.26, 29.20, 27.68, 27.63, 26.10, 25.46, 23.92, 19.64; LRMS (El) m/z (relative intensity): 354 (M, +  4), 269  (14),  208  (16),  85 (100), 73  (51);  H R M S (El) m/z calculated for CiH 0: 354.2770, found: 354.2764; 2  38  4  Analysis calculated for CiH 0: C, 71.15; H, 10.80. Found: C, 71.35; H, 11.00. 2  38  4  (b) Reaction of Ketone 145 with Wittig Reagent A solution of n-butyllithium in hexanes (100  mL, 160 m m o l ) was  of triphenylphosphonium iodide (65.26 g, 161.4 reaction was  stirred for  40.36 m m o l ) in THF 16 hours at 0 °C.  (100  The  with diethyl ether. The and  one  hour at 0 °C.  mL) was  m m o l ) in THF  (350  mL) at 0 °C and  the  A solution of ketone 145 (14.39 g,  added via cannula and  reaction was  added to a suspension  the reaction was  stirred for  concentrated under reduced pressure and diluted  ether solution was  dried over anhydrous MgS0. The 4  sequentially washed with water and brine, extracts were filtered and  the  solvent was  removed under reduced pressure. Column chromatography of the residue with 10% ethyl acetate as eluant gave alkene 146 (9.41  g, 66%)  as a pale yellow oil with spectral  data in agreement with that reported above.  13-Hydroxy-7-methylenetridecanal (147)  A solution of alkene 146 (0.95 and water (10:1, 50 mL) was  g, 2.7 m m o l ) and  PPTS (0.14  g, 0.54  heated at reflux for 20 hours. The  under reduced pressure, and the reaction mixture was  m m o l ) in acetone  acetone was removed  diluted with diethyl ether. The  294 ether solution was  washed with saturated NaHC0 solution, brine, and 3  anhydrous MgS0. The  extracts were filtered and  4  the  solvent was  removed under  reduced pressure. Column chromatography of the residue with 30% petroleum ether as eluant gave hydroxy aldehyde 147 (0.52  g, 86%)  IR (CCI): 3635, 2933, 2859, 2715,  892  1730,  4  H NMR  (500  1  MHz,  CDCI): 6 9.73 3  (t, J = 6.6 Hz, 2 H), 2.40 J = 7.4, 2 H), 1.54 C  13  NMR  (125  MHz,  1643,  1455,  1048,  (t, J = 1.7 Hz, 1 H), 4.66  dried over  ethyl acetate in as a colourless oil.  cm; 1 -  (br d, J = 3.4 Hz, 2 H),  3.61  (dt, J = 1.7, 7.4 Hz, 2 H), 1.95-1.99 (m, 4 H), 1.62 (quint,  (quint, J = 6.6 Hz, 2 H), 1 . 2 7 1 . 4 4 (m, 10  H);  CDCI): 5 202.81, 149.66, 108.76, 62.95, 43.82, 35.85, 35.70, 3  32.70, 29.11, 28.82, 27.67, 27.41, 25.59, 21.92; LRMS (DCI(+), a m m o n i a ) m/z (relative intensity): 244  (M+18, 37), 227 +  (M+1, 15); +  H R M S (Cl(+), isobutane) m/z calculated for C H 0 (M+1): 227.2011, found: +  14  27  2  227.2011.  13-Hydroxy-7-methylenetridecanoic acid (148)  A solution of NaCI0 (21.26 g, 235.1  m m o l ) and  2  2  4  water (100  mL)  (5.06  m m o l ) and 2-methyl-2-butene (60 mL) in f-butyl alcohol (250  g, 22.4  reaction was  was  NaHP0 (21.51 g, 179.3  m m o l ) in  added over four hours to a solution of hydroxy aldehyde 147  stirred at rt overnight. The  pressure, diluted with water, and  reaction was  brine, and  extracts were filtered and the solvent was  and  the  concentrated under reduced  extracted with diethyl ether. The  sequentially washed with water and  mL),  organic layer was  dried over anhydrous MgS0.  removed under reduced pressure.  4  The  Column  295 chromatography of the acid 148  (3.41  g, 63%)  residue with 4%  methanol in CH2CI2 as  as a colourless oil.  IR (CCU): 3637, 3373, 2977, 2933, 2862, 1712, 1  H NMR (500  2.30  MHz, CDCI ): 6 6.14  (br s, 1 H), 4.65  3  (t, J = 7.5  C NMR (125  1644,  1382,  (s, 2 H), 3.60  Hz, 2 H), 1 . 9 4 1 . 9 8 (m, 4 H), 1.61  (quint, J = 6.7 1 3  eluant gave hydroxy  1350,  1120,  (t, J = 6.7  (quint, J = 7.5  891  cm"; 1  Hz, 2 H),  Hz, 2 H),  1.53  Hz, 2 H), 1 . 2 5 1 . 4 3 (m, 10 H);  MHz, CDCI ): 5 178.81, 149.64, 108.66, 62.76, 35.75, 35.65, 33.90, 3  32.42, 28.99, 28.66, 27.56, 27.23, 25.47, 24.51; LRMS (DCI(+), a m m o n i a ) m/z (relative intensity): 260 HRMS (Cl(+), a m m o n i a / m e t h a n e ) m/z calculated for  (M+18, 93), +  C14H27O3  243  (M+1, +  100);  (M+1): 243.1960, found: +  243.1954; Analysis calculated for C i H 6 0 : C, 69.38; H, 10.81. Found: C, 69.63; H, 10.87. 4  2  3  7-Methylene-13-tridecanolide  (149)  Triethylamine (0.32  mL, 2.3 m m o l ) was  2.1  (20  m m o l ) in THF  mL)  at rt and  2,4,6-Trichlorobenzoyl chloride (0.33 stirred for an additional two  added to a solution of hydroxy acid 148  mL,  hours. The  the 2.1  reaction was  stirred for  m m o l ) was  added and  reaction was  filtered and  (0.50  g,  15 minutes. the  reaction was  concentrated under  reduced pressure. Trace a m o u n t s of solvent were removed under high v a c u u m ove two hours. A solution of the resultant mixed anhydride in toluene (100 into two (0.73 was  portions and  g, 6.0  simultaneously added via syringe p u m p to two  m m o l ) in toluene (600  mL)  mL)  was divided  solutions of DMAP  heated at reflux over 40 hours. The reaction  concentrated under reduced pressure and  diluted with diethyl ether. The ether  296  solution was sequentially washed with 1 M HCI, saturated NaHC0 solution, and b 3  and dried over anhydrous MgS0. The extracts were filtered and the solvent w a s 4  removed under reduced pressure. Column chromatography of the residue with 1% ethyl acetate in petroleum ether as eluant gave lactone 149 (0.20 g, 42%) as a colourless oil. I R (CCU): 2935, 2861, 1734, 1643, 1453, 1252, 1149, 1074, 892 cm'; 1  H N M R (500 MHz, CDCI): 5 4.72-4.73 (m, 1 H), 4.70-4.71 (m, 1 H), 4.06-4.08  1  3  2.30-2.33 (m, 2 H), 2.03 (br t, J = 6 . 4 Hz, 2 H), 1 . 9 8 (br t, J = 6 . 6 Hz 1 . 6 6 (m, 6 H), 1 . 1 8 1 . 4 6 (m, 8 H); CN M R (125 MHz, CDCI): 8 173.80, 147.36, 109.83, 63.22, 36.50, 34.16, 31.59,  13  3  27.50, 27.09, 26.36, 25.24, 25.22, 25.06, 24.13;  LRMS (El) m/z (relative intensity): 224 (M, 74), 206 (100), 195 (26), 1 5 1 (21), 1 3 +  123 (41), 109 (88), 95 (48), 8 1 (50), 67 (38), 55 (33), 41 (24); H R M S (El) m/z calculated for  C14H24O2.  224.1776, found: 224.1778;  Analysis calculated for C H240 : C, 74.95; H, 10.78. Found: C, 75.12; H, 10.83. 14  2  7-Cyclopropyl-13-tridecanolide (150)  A catalytic a m o u n t of iodine w a s added to a suspension of zinc-copper couple (0.4  6 . 7 m m o l ) in diethyl ether (50 m L ) and the mixture was stirred at rt for 15 m  Diiodomethane (0.54 m L , 6 . 7 m m o l ) was added and the mixture was stirred fo  additional 15 minutes. A solution of lactone 149 (0.30 g, 1 . 3 m m o l ) in diethyl e  (2 m L ) was added, and the mixture was heated at reflux for 19 hours. Additional  copper couple (0.44 g, 6 . 7 mmol), iodine (cat.) and diiodomethane (0.54 m L , 6 . 7 m  297  were added and the reaction w a s heated at reflux for a further 1 4 hours. The rea  w a s quenched with saturated NHCI solution and filtered. The solid residue w a s rins 4  with diethyl ether. The organic layers were combined, and sequentially washed wit saturated NaHC0 solution, water, and brine, and dried over anhydrous MgS0. 3  4  extracts were filtered and the solvent w a s removed under reduced pressure.  T  Rad  chromatography of the residue with 0.5% ethyl acetate in petroleum ether as eluan gave lactone 150 (0.11 g, 34%) as a pale yellow oil.  I R (CCI): 3070, 2934, 2859, 1724, 1580, 1550, 1448, 1347, 1276, 1206, 1159, 4  1011, 822 cm"; 1  H N M R (500 MHz, CDCI): 5 4.13-4.15 (m, 2 H), 2.35-2.37 (m, 2 H), 1 . 4 6 1 . 7 2 (m  1  3  1 . 1 4 1 . 3 7 (m, 1 2 H), 0 . 1 6 (dd, J = 2.9, 6 . 6 Hz, 2 H), 0 . 1 2 (dd, J = 2.9 H);  CN M R (125 MHz, CDCI): 5 173.80, 63.77, 36.20, 33.28, 32.87, 27.86, 27.67, 26  13  3  24.59, 24.35, 23.85, 23.27, 18.87, 12.22 (2); L R M S (El) m/z (relative intensity): 238 (M, 9), 220 (17), 209 (39), 1 3 7 (24), 1 2 3 +  1 0 9 (49), 95 (74), 8 1 (100), 67 (97), 55 (78), 4 1 (79); H R M S (El) m/z calculated for C H 60 : 238.1933, found: 238.1927. 15  2  2  7,7-Dimethyl-13-tridecanolide (151)  Adams' catalyst w a s added to a solution of lactone 150 (0.11 g, 0 . 4 6 m m o l ) in  acid (10 m L ) and the mixture w a s stirred at rt under H for five hours. The react 2  diluted with diethyl ether and filtered. The solid residue w a s rinsed with diethyl et  298 and  the organic layers were combined. The  NaHC0 solution, washed with brine, and the  solvent was  neutralized with saturated  dried over anhydrous MgS0. The extracts  3  were filtered and  solution was  4  r e m o v e d under reduced pressure. Column  chromatography of the residue with 1% ethyl acetate in petroleum ether as eluant gave lactone 151 (87 mg, 78%)  as a pale yellow oil.  IR (CCI): 2940, 2860, 1736, 4  H NMR  (500  1  MHz,  C  NMR  (125  MHz,  1383,  1277,  1191,  1162,  .1124  cm"; 1  CDCI): 5 4.14-4.16 (m, 2 H), 2.34-2.37 (m, 2 H), 1 . 6 8 1 . 7 3 (m, 2 H), 3  1 . 2 8 1 . 5 6 (m, 4H), 13  1459,  1 . 2 7 1 . 3 5 (m, 4 H), 1 . 1 1 1 . 1 8 (m, 8 H), 0.81  (s, 6 H);  CDCI): 8 173.56, 64.15, 39.23, 37.70, 32.68, 32.21, 29.07 (2), 3  28.09, 27.88, 27.59, 24.47, 24.24, 21.73, 20.88; L R M S (El) 109  m/z (relative intensity): 240 (30),  95 (27),  83 (27),  (M, +  2), 225  69 (100), 55 (58),  (31), 41  207  (37),  138  (73),  124  (69),  (57);  H R M S (El) m/z calculated for Ci H 80 : 240.2089, found: 240.2088. 5  2  2  9,9-Dimethyl-2-oxacyclotetradecanethione (152)  A solution of lactone 151 (87  mg,  0.36  m m o l ) in toluene (5 mL)  suspension of Lawesson s ' reagent 48 (0.29 reaction was  g, 0.72  heated at reflux for 6.5 days. The  The  solid residue was  The  solvent was  was  m m o l ) in toluene (15  reaction was  rinsed with diethyl ether and  mL)  and  the  cooled to rt and filtered.  the organic layers were combined.  r e m o v e d under reduced pressure. Column chromatography of  residue with petroleum ether as eluant gave thionolactone 152 (50 yellow oil.  added to a  mg,  54%)  the  as a  299 IR(CCU): 2941,2859, 1461, 1  H NMR (500  1366,  1293,  1192,  1134,  1054  cm"; 1  MHz, CDCI ): 6 4.51-4.53 (m, 2 H), 2.77-2.80 (m, 2 H), 1.80-1.85 (m, 2 H), 3  1 . 6 6 1 . 7 1 (m, 2 H), 1 . 5 1 1 . 5 7 (m, 2 H), 1 . 2 3 1 . 3 6 (m, 4 H), 1 . 0 9 1 . 2 1 (m, 8 H), 0.80 1 3  (s, 6 H);  C NMR (125  MHz, CDCI ): 5 224.77, 72.23, 44.72, 38.80, 37.41, 32.71, 29.03 (2), 3  28.08, 27.62, 27.10, 26.99, 24.84, 21.50, 21.09; LRMS (El) m/z (relative intensity): 256 (M , 9), 223 (28),  173 (46),  +  83 (24),  69  139 (100), 97  (28),  (31);  HRMS (El) m/z calculated for C i H O S : 256.1861, found: 256.1853. 5  28  2-(Methylthio)-8,8-dimethyloxacyclotetradecane (153)  Lithium triethylborohydride in THF thionolactone 152 (45 mg, 0.18 stirred for 30 minutes at -78 °C. reaction was  (0.89  m m o l ) in THF  m m o l ) was  (5 mL)  Methyl iodide (68  added to a solution of  at -78 °C and  the reaction was  uL, 1.1 m m o l ) was  added and  The  reaction was  Aqueous 3 M N a O H solution (ca.  diluted with diethyl ether and 1 mL)  and  30%  H0 (ca. 2  2  cooled to -78  stirred for 20 minutes at -78 °C, and then w a r m e d to rt. The 2  anhydrous MgS0. The 4  2  3  extracts were filtered and  the  solvent was  reduced pressure to give mixed thioacetal 153 (47 mg, 98%) unstable and was  °C.  1 mL) were added. The  sequentially washed with saturated NaS0 solution, water, brine, and  was  the  stirred for 30 minutes at -78 °C, w a r m e d to rt, and stirred for an additional  30 minutes at rt.  solution was  mL, 0.89  as an oil.  used immediately without further purification.  reaction was dried over  removed under Thioacetal 153  300  LRMS (DCI(+), a m m o n i a ) m/z (relative intensity): 290 (M +18, 21), 273 (M+1, 100); +  +  H R M S (Cl(+), a m m o n i a / m e t h a n e ) m/z calculated for CiHOS (M+1): 273.2252, +  6  3 3  found: 273.2255.  8,8-Dimethyloxacyclotetradecane (154)  A deoxygenated solution of tri(n-butyl)tin hydride (0.47 m L , 1 . 7 m m o l ) and AIBN (  in toluene (9.5 m L ) was added over ten hours via syringe p u m p to a deoxygen  solution of mixed thioacetal 153 (47 m g , 0.17 m m o l ) and AIBN (cat.) in toluene (1 heated at reflux. The solvent was removed under reduced pressure. Column chromatography of the residue with petroleum ether as eluant removed the tin compounds. Radial chromatography with 0.5% ethyl acetate in petroleum ether as eluant gave ether 154 (16 m g , 40%) as an oil.  IR(CDCI): 2936, 2859, 1457, 1361, 1115 cm"; 1  3  H N M R (500 MHz, CDCI): 5 3 . 4 0 (t, J = 5 . 7 Hz, 4 H), 1 . 5 3 1 . 5 8 (m, 4 H), 1 . 4  1  3  4 H), 1.28-1.35 (m, 4 H), 1 . 1 4 1 . 2 4 (m, 8 H), 0 . 8 1 (s, 6 H);  CN M R (125 MHz, CDCI): 6 69.27 (2), 3 8 . 6 1 (2), 32.80, 29.09 (2), 27.90 (2), 27  13  3  (2), 24.80 (2), 21.56 (2); LRMS (El) m/z (relative intensity): 226 (M, 4), 143 (16), 1 2 4 (100), 109 (48), 97 +  95(16), 83(13), 8 1 (16), 69 (26); H R M S (El) m/z calculated for CiHO: 226.2297, found: 226.2294. 5  3 0  301 6-Oxahexadeca-1,15-diene (156)  9-Decenol (155) (0.18 (0.14  mL, 1.0 mol)  g, 1.2 m m o l ) in THF  D M P U (0.15  (2 mL)  was  added to a suspension of potassium hydride  at 0 °C and  ml, 1.2 m m o l ) and  the reaction was  5 b r o m o 1 -pentene (0.20  sequentially via syringe, and the reaction was The  reaction was  stirred for two hours.  mL,  1.2  m m o l ) were added  stirred with slow warming to rt overnight.  diluted with diethyl ether. The  organic layer was  washed with water  and brine, and dried over anhydrous MgS0. The extracts were filtered and the solvent 4  was  removed under reduced pressure. Column chromatography of the residue with 2%  ethyl acetate in petroleum ether gave diene 156 (0.19  g, 84%)  IR(CCU): 3078, 2929, 2857, 1641,  1451,  993,  H NMR  J = 16.6,  (500  1  MHz,  10.5,  H), 3.39  C  NMR  (ddt,  J = 16.6,  (br dd, J = 10.1,  2.02  (br ddt, J = 6.5,  (m, 2 H), 1 . 2 4 1 . 3 8 (m, 10 (125  MHz,  1.9,  1116,  10.1, 1.7,  1.9 Hz, 1 H), 4.91  (t, J = 6.7 Hz, 2 H), 3.37  7.1 Hz, 2H),  13  (ddt,  3  6.5 Hz, 1 H), 5.00  Hz, 1 H), 4.94  1.57  CDCI): 8 5.80  1366,  as a colourless oil.  913  cm; 1 -  6.7 Hz, 1 H), 5.79 1 H), 4.97 (ddt,  J=  (br dd, J = 17.0,  J = 10.5,  (t, J = 6.7 Hz, 2 H), 2.10  (ddt,  17.0,  2.1  2.1, 1.1 Hz, 1  (br ddt, J = 6.7,  1.1,7.2 Hz, 2 H), 1 . 6 2 1 . 6 8 (m, 2 H),  1.7, 1.51-  H);  CDCI): 8 139.21, 138.41, 114.60, 114.09, 70.79, 70.13, 33.78, 3  30.34, 29.76, 29.42 (2), 29.07, 28.95, 28.91, 26.18; LRMS (El) m/z (relative intensity): 224 (74),  68(100), 55 (74),  41  (M, +  1), 154 (4), 99 (35),  95 (24),  83 (34),  69  (79);  H R M S (El) m/z calculated for CiH 0: 224.2140, found: 224.2135; 5  2 8  Analysis calculated for CiH 0: C, 80.29; H, 12.58. Found: C, 80.02; H, 12.55. 5  2 8  302 ( Z / £ ) - O x a c y c l o t e t r a d e c - 5 - e n e (157) and  (158)  A deoxygenated solution of diene 156 (103 deoxygenated solution of Grubbs' catalyst 9 (50  mL)  166  0.448 mol)  (19 mg, 0.24  in toluene (50  mL)  mmol, 5.3 mol%)  and  a  in toluene  were added simultaneously using a syringe p u m p to deoxygenated toluene  (20 mL)  stirred at rt over 24 hours. The  N  during the  2  mg,  gas  24 hours, and  a spatula of silica was  pressure, and acetate in  addition. After the  receiver toluene flask was addition, the added. The  column chromatography of the  petroleum ether as  solution was  solvent was  gently sparged with stirred for a further  removed under reduced  silica absorbed residue with 2% ethyl  eluant removed ruthenium compounds. Radial  chromatography of the residue (43  mg, 49%,  GC ratio 157:158, 59:41) with 0.5%  acetate in petroleum ether gave ethers 157 (22  mg, 25%)  and  158 (15  mg,  ethyl  17%)  both  as pale yellow oils.  157 (Z)  IR (CCU): 3004, 2927, 2859, 2794, 1649, 860 H NMR  1  C  13  NMR  1483,  1452,  1359,  1291,  1117,  1039,  909,  cm; 1-  (500  MHz,  CDCI): 5 5.51 3  (dt, J = 10.7,  7.9 Hz, 1 H), 5.26  (t, J = 5.5 Hz, 2 H), 3.38  2 H), 1.97  (dt, J = 7.1, 7.9 Hz, 2 H), 1 . 5 5 1 . 6 3 (m, 4 H), 1.24-1.45 (m, 10  MHz,  (dt, J = 7.4,  7.4  1 H), 3.41  (125  (t, J = 5.2 Hz, 2 H), 2.22  (dt, J = 10.7, 7.0  Hz, Hz, H);  CDCI): 5 130.87, 129.59, 68.81, 68.69, 29.56, 28.30, 27.35, 26.2 3  26.23, 25.76, 24.23, 23.86, 23.38;  303 L R M S (Cl(+), a m m o n i a ) m / z (relative intensity): 197 (M+1, 100); +  H R M S (Cl(+), isobutane) m / z calculated for Ci H 0 (M+1): 197.1905, found: +  3  25  197.1905; Analysis calculated for Ci H 0: C, 79.53; H, 12.32. Found: C, 79.74; H, 12.47. 3  24  158 ( £ )  IR (CCU): 2929, 2856, 1447, 1359, 1118, 969 cm; 1 -  H NMR (500 MHz, CDCI): 8 5.39 (dt, J = 15.2, 7.1 Hz, 1 H), 5.33 (dt, J = 15.2, 6.9 Hz,  1  3  1 H), 3.48 (t, J = 5.3 Hz, 2 H), 3.37 (t, J = 6.1 Hz, 2 H), 2.11 (ddd, J = 6.9, 6.9, 5.9 Hz, 2 H), 1 . 9 6 2 . 0 2 (m, 2 H), 1 . 6 3 1 . 6 8 (m, 2 H), 1 . 2 4 1 . 5 0 (m, 10 H);  C NMR (125 MHz, CDCI): 8 131.80, 130.61, 69.54, 67.01, 31.64, 29.09, 28.60, 26.5  13  3  26.50, 25.30, 25.16, 23.84, 22.04; L R M S (DCI(+), a m m o n i a ) m/z (relative intensity): 214 (M +18, 67), 197 (M+1, 100); +  +  H R M S (Cl(+), isobutane) m/z calculated for C H 0 (M+1): 197.1905, found: +  1 3  2 5  197.1907; Analysis calculated for Ci H 0: C, 79.53; H, 12.32. Found: C, 79.74; H, 12.46. 3  24  (a) Isomerization of (Z)-Oxacvclotetradec-5-ene (157) with Phenyl Disulfide A catalytic a m o u n t of phenyl disulfide was added to a solution of ether 157 (ca. 0.5 mg) in cyclohexane (1 mL), and the mixture was sparged with N for 15 minutes. The 2  reaction was photolysed with a 450 W m e d i u m pressure Hanovia mercury vapour l a m p for six hours. This gave a mixture of ethers 157 and 158 (GC ratio 157:158, 41:59).  (b) Isomerization of (E)-Oxacvclotetradec-5-ene (158) with Phenyl Disulfide A catalytic a m o u n t of phenyl disulfide was added to a solution of ether 158 (ca. 0.5 mg) in cyclohexane (1 mL), and the mixture was sparged with N for 15 minutes. The 2  reaction was photolysed with a 450 W m e d i u m pressure Hanovia mercury vapour l a m p for six hours. This gave a mixture of ethers 157 and 158 (GC ratio 157:158, 39:61).  304 9-Decenoic acid (159)  A solution of Jones' reagent (ca. (3.00 The  g, 19.2  m m o l ) in acetone (100  reaction was  mixture was The  8 mL)  was  mL)  added to a solution of 9-decenol (155)  stirred at rt until an orange colour persisted.  quenched with 2-propanol, and  filtered through silica, and  neutralized with solid NaHC0. The 3  the solid residue was  rinsed with diethyl ether.  organic layers were combined, washed with water and  anhydrous MgS0. The  extracts were filtered and  4  reduced pressure to give acid 159 (3.08  g, 94%)  the  brine, and  solvent was  dried over  removed under  as a pale yellow oil. This material was  used in subsequent reactions without further purification. Column chromatography of a sample of 159 (ca.  50 mg)  with 4%  methanol in CHCI as eluant gave pure 159 for 2  2  analysis.  IR(CCI): 3080, 2929, 2857, 1711,  1641,  H NMR  J = 10.2,  4  (500  1  2.0,  MHz,  1.7,  CDCI): 8 5.78  1 H), 4.91  (dddt, J = 6.8,  (ddt,  3  1.1,  (ddt,  J = 10.2,  2.0,  1420,  1289, 17.2,  913  1  6.8 Hz, 1 H), 4.96  1.1 Hz, 1 H), 2.32  1.7, 7.1 Hz, 2 H), 1.61  cm"; (ddt,  J=  (t, J = 7.5 Hz, 2 H),  17.2, 2.01  (quint, J = 7.5 Hz, 2 H), 1 . 2 7 1 . 3 8 (m, 8  H); C  13  NMR  (125  MHz,  CDCI): 5 180.54, 139.02, 114.17, 34.08, 33.70, 29.03, 28.96, 3  28.85, 28.80, 24.60; LRMS (El) (34),  m/z (relative intensity): 170 (M, +  69(85), 55(100), 41  1), 152 (14),  110 (39),  96 (25),  84 (40),  83  (76);  H R M S (El) m/z calculated for CiH O: 170.1307, found: 170.1300; 0  1 8  2  Analysis calculated for CiH O: C, 70.55; H, 10.66. Found: C, 70.93; H, 10.89. 0  1 8  2  305 10-Undecen-2-one (160)  Methyllithium in diethyl ether (39 (2.96  g, 17.4  m m o l ) in THF  hours at 0 °C. reaction was  mL, 52 m m o l ) was  (50 mL) stirred at 0 °C and the reaction was  Trimethylsilyl chloride (33 mL, 0.26  4  was  stirred for  two  added via syringe, and  stirred for a further one  extracted with diethyl ether and  water, and  mol) was  stirred with warming to rt over 30 minutes. The  with saturated NHCI solution, and was  added to a solution of acid 159  the  reaction was quenched  hour. The  reaction mixture  the organic layers were combined, washed with  dried over anhydrous MgS0. The 4  extracts were filtered and  the solvent  removed under reduced pressure. Column chromatography of the residue with 5%  ethyl acetate in petroleum ether gave ketone 160 (2.11  IR(CCI): 3078, 2929, 2856, 1718,  1641,  H NMR  J = 17.1,  4  (500  1  MHz,  CDCI): 6 5.76  (ddt,  3  1.9,  1.6 Hz, 1 H), 4.88  2.09  (s, 3 H), 1.99  (ddt,  J = 10.2,  (dddt, J = 1.6,  1.9,  1436,  1360, 10.2,  g, 72%)  1163,  as a pale yellow oil.  1120,  993,  6.7 Hz, 1 H), 4.94  1.1 Hz, 1 H), 2.37  1.1, 6.7, 7.5 Hz, 2 H), 1.53  912  (ddt,  cm"; 1  J=  17.1,  (t, J = 7.5 Hz, 2 H), (quint, J = 7.5 Hz, 2  H), 1 . 3 0 1 . 3 6 (m, 2 H), 1 . 2 2 1 . 2 7 (m, 6 H); C  13  NMR  (125  MHz,  CDCI): 5 209.13, 139.03, 114.12, 43.71, 33.68, 29.76, 29.16, 3  29.06, 28.86, 28.79, 23.78; LRMS (El) m/z (relative intensity): 168 (M, +  (13),  81 (20),  71 (43),  58 (86),  1), 150 (2), 125(10), 111 (12)  43 (100);  H R M S (El) m/z calculated for CnHO: 168.1514, found: 168.1517. 2 0  110 (21),  97  306 2-Hydroxy-10-undecene (161)  A solution of ketone 160 (1.36  g, 8.08  m m o l ) in diethyl ether (10  mL)  was added  dropwise over one hour to a suspension of lithium aluminum hydride (0.31 stirred in diethyl ether (25  mL)  at 0 °C.  overnight. Water (ca.  1.5 mL)  and  added dropwise. The  reaction was  rinsed with diethyl ether. The  The  stirred solution was  w a r m e d slowly to rt  3M N a O H solution (ca. 0.5 mL) were sequentially filtered through celite, and  the solid residue was  organic layers were combined and  removed under reduced pressure to give alcohol 161 (1.32 This material was  g, 8.1 m m o l )  g, 96%)  the  solvent was  as a colourless oil.  used in subsequent reactions without further purification.  chromatography of a sample of 161 (ca. 50 mg) with 4%  Column  methanol in CHCI as eluant 2  2  gave pure 161 for analysis.  IR (CCI): 3626, 3078, 2928, 2856, 1641,  1458,  4  H NMR  (500  1  MHz,  17.1,  1.5,  C  13  NMR  (ddt,  3  1.6 Hz, 1 H), 4.90  Hz, 1 H), 2.01 J =6.1  CDCI): 5 5.78  (ddt,  (dddt, J = 6.7,  1.6,  J = 17.1, J = 10.1,  10.1 1.5,  1376,  1091,  912  cm"; 1  Hz, 6.7 Hz, 1 H), 4.96 1.0 Hz, 1 H), 3.76  (ddt,  J =  (sext, J = 6.1  1.0, 7.1 Hz, 2 H), 1.24-1.47 (m, 12 H), 1.15  (d,  Hz, 3 H);  (125  MHz,  CDCI): 8 139.14, 114.10, 68.10, 39.33, 33.74, 29.56, 29.41, 29.0 3  28.88, 25.71, 23.45; LRMS (El) m/z (relative intensity): 170 (M, +  (56),  81 (67),  69 (52),  68 (49),  67 (52)  1), 152 (2), 110 (27), 55 (62),  45 (100), 41  96 (28),  95 (40),  82  (47);  H R M S (El) m/z calculated for CnH0: 170.1671, found: 170.1671; 2 2  Analysis calculated for CnH0: C, 77.58; H, 13.02. Found: C, 77.31; H, 13.05. 2 2  307 7-Methyl-6-oxahexadeca-1,15-diene (162)  Alcohol 161 (0.59 m L , 3 . 0 m m o l ) w a s added via syringe to a suspension of pot  hydride (1.72 g, 15.0 m m o l ) in D M F (10 m L ) at 0 ° C and the reaction was s  three hours. 5-Bromo-1-pentene (1.8 m L , 15 m m o l ) was added and the reaction w  w a r m e d slowly to rt with stirring overnight. The reaction was diluted with diethyl eth  washed with water and brine, and dried over anhydrous MgS0. The extracts w 4  filtered and the solvent was removed under reduced pressure. Column chromato-  graphy of the residue with 2% ethyl acetate in petroleum ether gave ether 162 (0.5 76%) as a colourless oil.  I R (CCI): 3078, 2974, 2929, 2857, 1641, 1451, 1373, 1340, 1108, 993, 912 cm 4  H N M R (500 MHz, CDCI): 5 5 . 7 9 (ddt, J = 10.4, 17.0, 6 . 8 Hz, 1 H), 5 . 7 8 (d  1  3  17.1,6.6 Hz, 1 H), 4.99 (ddt, J = 17.0, 1 . 8 , 1 . 5 Hz, 1 H), 4.96 (br d, 1 H), 4.93 (br dd, J = 10.4, 1 . 8 Hz, 1 H), 4.89 (br d, J = 10.4 Hz,  = 9.3, 6.5 Hz, 1 H), 3.29-3.34 (m, 2 H), 2.09 (ddt, J = 6.8, 1 . 5 , 7 . 8 H  (br dt, J = 6.6, 7 . 4 Hz, 2 H), 1 . 6 2 (m, 2 H), 1 . 4 5 1 . 5 2 (m, 2 H), 1 . 2 2 1 . H), 1 . 0 9 (d, J = 6 . 1 Hz, 3H);  CN M R (125 MHz, CDCI): 8 139.14, 138.43, 114.54, 114.06, 75.41, 67.61, 36.69,  13  3  33.75, 30.38, 29.64, 29.43, 29.31, 29.05, 28.89, 25.57, 19.68;  LRMS (El) m / z (relative intensity): 238 (M, 1), 113 (21), 95 (23), 7 1 (49), 69 (1 +  (27), 4 1 (50); H R M S (El) m / z calculated for C H O: 238.2297, found: 238.2295; 1 6  3 0  Analysis calculated for CiHO: C, 80.61; H, 12.68. Found: C, 80.81; H, 12.74. 6  3 0  0  308  (Z/E)-14-Methyloxacyclotetradec-5-ene (163) and (164)  A deoxygenated solution of Grubbs' catalyst 9 CHCI (50 2  mL)  2  was  added over three hours via  solution of ether 162 (108 162 solution was was  0.022 mmol, 4.9 mol%)  the  solvent was  mL) stirred at rt. The ether  2  during the addition. The  2  in  syringe p u m p to a deoxygenated 2  gently sparged with N gas  added, and  mg,  mg, 0.455 m m o l ) in CHCI (250  stirred for a further 17 hours, and was  silica was  (18  1 6 6  reaction solution  quenched with EtN (ca. 1 mL).  A spatula of  3  removed under reduced pressure. Column  chromatography of the silica absorbed residue with 1% ethyl acetate in petroleum ether as eluant removed ruthenium compounds. Radial chromatography of the residue (61 mg, 63%,  GC ratio 163:164, 43:57) with 0.3%  ethers 163 (11 mg, 12%)  and 164 (8.0  mg, 8%)  ethyl acetate in petroleum ether gave  both as pale yellow oils.  163 (Z)  IR (CCU): 2928, 2858, 1455, H NMR  (500  1  MHz,  1 H), 3.59 3.23  1372,  CDCI): 5 5.46 3  (ddd,  1338,  1094,  (dt, J = 4.8, 10.2  J = 9.4, 6.3, 2.8 Hz, 1 H), 3.41  912  cm"; 1  Hz, 1 H), 5.26 (ddq,  (dt, J = 5.2,  10.2  Hz,  J = 8.5, 3.5, 6.1 Hz, 1 H),  (dt, J = 2.3, 9.4 Hz, 1 H), 2.47-2.55 (m, 1 H), 2.17-2.25 (m, 1 H), 1 . 9 0 1 . 9 6  (m, 1 H), 1 . 7 4 1 . 8 1 (m, 1 H), 1 . 6 3 1 . 7 0 (m, 1 H), 1.48-1.60 (m, 3 H), 1 . 2 3 1 . 4 2 (m, 10 H), 1.09 C  13  NMR  (125  MHz,  (d, J = 10.6  Hz, 3 H);  CDCI): 5 130.80, 129.88, 73.35, 66.24, 36.09, 30.07, 27.44, 26.4 3  25.86, 25.80, 25.49, 24.26, 23.66, 19.73; LRMS (DCI(+), a m m o n i a ) m/z (relative intensity): 211  (M+1, 68), 210 +  (M, +  76);  H R M S (Cl(+), m e t h a n e / a m m o n i a ) m/z calculated for Ci H 0 (M+1): 211.2062, found: +  4  27  211.2052; Analysis calculated for d H 0: C, 79.94; H, 12.46. Found: C, 80.12; H, 12.52. 4  26  309 164 (E) IR(CCU): 2928, 2857, 1450, 1371, 1342, 1107, 970 cm; 1 -  H NMR  (500 MHz, CDCI) 5: 5.38 (dt, J = 15.5, 6.5 Hz, 1 H), 5.33 (dt, J = 15.5, 6.5 Hz,  1  3  1 H), 3.48 (ddq, J = 10.2, 2.0, 6.2 Hz, 1 H), 3.41 (dt, J = 8.9, 7.3 Hz, 1 H), 3.34 (dt, J = 8.9, 6.2 Hz, 1 H), 2.14-2.21 (m, 1 H), 1.91-2.05 (m, 3 H), 1.62-1.68 (m, 2 H), 1.47-1.54 (m, 2 H), 1.22-1.41 (m, 10 H), 1.11 (d, J = 6.2 Hz, 3 H); C NMR  (125 MHz, CDCI) 5: 131.87, 130.77, 73.71, 65.29, 33.02, 31.58, 28.82, 28.71,  13  3  27.01, 25.86, 25.77, 24.26, 20.43, 20.13; LRMS (DCI(+), a m m o n i a ) m/z (relative intensity): 228 (M +18, 2), 211 (M+1, 86), 210 +  +  (M, 64); +  H R M S (El) m/z calculated for Ci H 0: 210.1984, found: 210.1991; 4  26  Analysis calculated for Ci H 0: C, 79.94; H, 12.46. Found: C, 80.12; H, 12.47. 4  26  (a) Isomerization of (Z)-2-Methvloxacvclotetradec-10-ene (163)  with Phenyl Disulfide  A catalytic a m o u n t of phenyl disulfide was added to a solution of ether 163 (ca. 0.5 mg) in cyclohexane (1 mL) and the mixture was  sparged with N for 15 minutes. 2  The  reaction was photolysed with a 450 W m e d i u m pressure Hanovia mercury vapour lamp for seven hours. This gave a mixture of ethers 163 and 164 (GC ratio 163:164, 29:71).  (b) Isomerization of (E)-2-Methvloxacvclotetradec-10-ene (164)  with Phenyl Disulfide  A catalytic a m o u n t of phenyl disulfide was added to a solution of ether 164 (ca. 0.5 mg) in cyclohexane (1 mL) and the mixture was  sparged with N for 15 minutes. 2  The  reaction was photolysed with a 450 W m e d i u m pressure Hanovia mercury vapour l a m p for seven hours. This gave a mixture of ethers 163 and 164 (GC ratio 163:164, 29:71).  310 12-Dodecanolide (165)  Trifluoroacetic anhydride (5.0 m L , 36 m m o l ) was added via syringe to a mixture cyclododecanone (93) (1.00 g, 5 . 4 9 mmol), urea hydrogen peroxide (3.09 g,  32.9 mmol), and NaHP0 (5.45 g, 38.4 m m o l ) in CHCI (50 m L ) at 0 ° C and 2  4  2  2  reaction was stirred for 2 1 hours with slow warming to rt. The reaction was diluted  CHCI, and was sequentially washed with water, saturated NaS0 solution, saturate 2  2  2  2  3  NaHC0 solution, brine, and dried over anhydrous MgS0. The extracts were filter 3  4  and the solvent was removed under reduced pressure. Column chromatography of th  residue with 2% ethyl acetate in petroleum ether as eluant gave lactone 165 (0.98 90%) as a pale yellow oil.  IR(CDCI): 2934, 2861, 1718, 1446, 1334, 1252, 1147, 1051,836 cm"; 1  3  H N M R (500 MHz, CDCI): 5 4.10-4.12 (m, 2 H), 2.30-2.32 (m, 2 H), 1 . 5 9 1 . 6 6 (m  1  3  1 . 2 1 1 . 4 1 (m, 1 4 H);  CN M R (125 MHz, CDCI): 5 174.21, 64.50, 34.59, 27.38, 26.57, 26.38 (2), 25.42  13  3  25.37, 24.95, 24.44, 24.20;  LRMS (El) m/z (relative intensity): 1 9 8 (M, 3), 180 (6), 162 (6), 155 (3), 1 3 8 (18) +  (24), 98 (63), 84 (57), 69 (62), 55 (100), 4 1 (44); H R M S (El) m/z calculated for CiH 0: 198.1620, found: 198.1617; 2  22  2  Analysis calculated for CiH 0: C, 72.68; H, 11.18. Found: C, 73.11; H, 11.28. 2  22  2  3 1 1 2-Oxacyclotridecanethione (166)  A solution of lactone 165 (0.42 g, 2 . 1 m m o l ) in toluene (5 m L ) was added via c  a suspension of Lawessons ' reagent 48 (1.60 g, 3 . 9 6 m m o l ) in toluene (5 m L ) an  reaction was heated at reflux for 56 hours. The reaction was cooled to rt, filte through cotton, and the solvent was removed under reduced pressure. Column  chromatography of the residue with petroleum ether as eluant gave thionolactone 1 6 (0.42 g, 92%) as a yellow oil.  I R (CDCI): 2935, 2860, 1448, 1277, 1199, 1137, 1046 cm; 1 -  3  H N M R (500 MHz, CDCI): 8 4.49-4.52 (m, 2 H), 2.86-2.88 (m, 2 H), 1.78-1.83 (  1  3  1 . 7 2 1 . 7 7 (m, 2 H), 1 . 4 3 1 . 4 8 (m, 2 H), 1 . 3 0 1 . 3 7 (m, 1 2 H);  CN M R (125 MHz, CDCI): 5 225.20, 72.91, 47.00, 27.30, 26.96, 26.44, 26.11, 25  13  3  25.57, 25.39, 24.87, 24.50; LRMS (El) m / z (relative intensity): 214 (M, 4), 1 8 1 (41), 163(12), 1 1 1 (12), 97 +  (40), 69(52), 55(100), 4 1 (29); H R M S (El) m / z calculated for C12H22OS: 214.1391, found: 214.1394; Analysis calculated for CiHOS: C, 67.24; H, 10.34. Found: C, 67.43; H, 10.55. 2  2 2  312 2-(Methylthio)oxacyclotridecane (167)  Lithium triethylborohydride in THF thionolactone 166 (98 mg, 0.46  (2.3  ml, 2.3  m m o l ) in THF  stirred for 20 minutes. Methyl iodide (0.17  m m o l ) was (5 mL)  added to a solution of  at -78 °C and  mL, 2.8 m m o l ) was  was stirred for 30 minutes followed by slow warming to rt. The diethyl ether and cooled to -78 °C.  The  diluted with  organic layer was  2  stirred for 10 minutes, followed by  sequentially washed with saturated NaS0 2  4  95%)  solution was  2  solution, water, brine, and dried over anhydrous MgS0. The the solvent was  added and the reaction  Aqueous 3 M N a O H solution (5 mL) and 30% H0  (1 mL) were added sequentially and the solution was warming to rt.  the reaction was  2  extracts were filtered and  removed under reduced pressure to give mixed thioacetal 167 (0.10  as an oil. Thioacetal 167 was  unstable and was  3  g,  used immediately without further  purification.  LRMS (DCI(+), a m m o n i a ) m/z (relative intensity): 248  (M+18, 10), 231 +  (57), 183(100); H R M S (El) m/z calculated for CiH 0S: 230.1704, found: 230.1707. 3  2 6  (M+1, 82), +  200  313 Oxacyclotridecane (168)  A deoxygenated solution of tri(n-butyl)tin hydride (1.23 mL, 4.62 m m o l ) and AIBN (cat.) was added in four portions over 26 hours to a deoxygenated solution of thioacetal 167 (75 mg, 0.33 m m o l ) and AIBN (cat.) in toluene (20 mL) heated at reflux. The reaction was heated at reflux for an additional 22 hours. The solvent was r e m o v e d under  reduced pressure, and column chromatography of the residue first with petroleum ether as eluant removed the tin compounds. This was followed by 2% ethyl acetate in petroleum ether as eluant to give crude ether 168.  Further column chromatography  using AgN0 impregnated silica with petroleum ether as eluant gave ether 168 (33 mg, 3  55%) as a pale yellow oil.  IR(CDCI): 2935, 2863, 1441, 1352, 1266, 1124, 1067, 1031 cm"; 1  3  H NMR (500 MHz, CDCI): 5 3.42 (t, J = 5.2 Hz, 4 H), 1.54 (quint, J = 5.2 Hz, 4 H),  1  3  1.41 -1.46 (m, 4 H), 1 . 3 0 1 . 3 8 (m, 12 H); C NMR  13  (125 MHz, CDCI): 5 70.33 (2), 28.54 (2), 26.57 (2), 25.90 (2), 25.04 (2),  24.71  3  (2);  L R M S (El) m/z (relative intensity): 184 (M, 0.8), 166 (2), 137 (5), 123 (10), 109 (24), 95 +  (44), 82 (100), 68 (59), 55 (66), 41 (18); H R M S (El) m/z calculated for Ci H 0: 184.1827, found: 184.1830; 2  24  Analysis calculated for Ci H 0: C, 78.20; H, 13.12. Found: C, 77.98; H, 12.93. 2  24  314 2-Methyl-2-(methylthio)oxacyclotridecane (169)  Methyllithium in diethyl ether (0.39 thionolactone 166 (62 mg, 0.29  mL,  0.47  m m o l ) in THF  m m o l ) was (5.0  mL) at -78 °C and the reaction was  stirred for ten minutes. Methyl iodide (36 at, 0.58 stirred for 10 minutes, and w a r m e d to rt. The  added to a solution of  m m o l ) was  reaction was  sequentially washed with saturated NaHC0 solution and 4  extracts were filtered and  reduced pressure to give mixed thioketal 169 (68 Thioketal 169 was  unstable and was  the mg,  diluted with diethyl ether, brine, and  3  anhydrous MgS0. The  added, the reaction was  solvent was 97%)  dried over removed under  as a pale yellow oil.  used immediately without further purification.  LRMS (DCI(+), a m m o n i a ) m/z (relative intensity): 245 (M+1, 59), 229 (20), +  197 (100);  H R M S (El) m/z calculated for CiHOS: 244.1860, found: 244.1856. 4  2 8  2-Methyleneoxacyclotridecane (170)  A solution of Tebbe reagent 3 2  38,153  in toluene (1.5 mL,  syringe to a solution of lactone 165 (0.10  g, 0.50  pyridine (20  mL)  \xL, 0.25  m m o l ) in THF  (10  1.0  mmol), was  mmol), D M A P (0.07  stirred at -40  °C and  added via  g, 0.6 m m o l ) and the reaction was  315 stirred for 20 hours with slow warming to rt. The  reaction mixture was  filtered through  basic alumina with petroleum ether as eluant, and the organic layers were combined. The solvent was  removed under reduced pressure to give alkene 170 (70 mg, 67%)  a pale yellow oil.  Alkene 170 was  unstable and was  as  used immediately without further  purification.  LRMS (El) m/z (relative intensity): 196 (M, 27), +  (70),  41  125 (9), 97 (22),  71 (100), 55 (75),  43  (63);  H R M S (El) m/z calculated for  C13H24O:  196.1827, found: 196.1826.  2-Methyloxacyclotridecane (171)  (a)  Reduction of 2-Methvl-2-(methvlthio)oxacvclotridecane (169) with Trifn-butvDtin Hydride  Th(/?-butyl)tin hydride (0.15  mL, 0.56  m m o l ) was  solution of mixed thioketal 169 (68 mg, 0.28 and the solution was  added via syringe to a deoxygenated  m m o l ) and AIBN (cat.) in toluene (20  heated at reflux for 2.5 hours. The  solvent was  mL)  removed under  reduced pressure. Column chromatography of the residue with petroleum ether as eluant removed the  tin compounds. Further column chromatography using AgN0  impregnated silica with petroleum ether as eluant gave ether 171 (17 pale yellow oil.  3  mg, 31%)  as a  316 IR(CDCI): 2927, 2859, 1456, 3  H NMR  (500  1  9.2,  MHz,  6.1  C  13  NMR  (125  CDCI): 5 3.67  Hz,  MHz,  (ddd,  1340,  (ddd,  3  Hz, 1 H), 3.23  (d, J = 6.1  1372,  1139,  J = 3.6,  J = 2.6,  9.5,  4.2, 10.3  1091  cm'; 1  9.5 Hz, 1 H), 3.36  (ddq,  J =  3.2,  Hz, 1 H), 1 . 1 7 1 . 6 5 (m, 20 H),  1.09  3H);  CDCI): 5 75.32, 67.64, 36.56, 29.27, 26.69, 26.64, 26.45, 25.46, 3  24.52, 24.31, 23.85, 23.61, 20.20; L R M S (El) (15),  m/z (relative intensity): 198 83 (54),  H R M S (El)  (M, +  4), 183  (12),  152  (13),  109  (20),  97 (37),  85  69 (57), 55(100);  m/z calculated for Ci H 0: 198.1984, found: 198.1986; 3  26  Analysis calculated for C H 0: C, 78.72; H, 13.21. Found: C, 79.00; H, 13.36. 1 3  2 6  (b) Reduction of 2-Methyleneoxacvclotridecane (170) with Adams' Catalyst Adams' catalyst was  added to a solution of alkene 170 (70  ether (5 mL)  mixture was  and  the  mg,  0.36  m m o l ) in diethyl  stirred at rt under H overnight. The  reaction was  2  filtered through silica with diethyl ether as eluant and reduced pressure to give ether 171 (60  mg, 85%)  the  solvent was  removed under  as a pale yellow oil with spectral data  in agreement with that reported above.  ( 2 7 £ ) - 1 - ( T r i m e t h y l s i l o x y ) c y c l o d o d e c e n e (172) and  (173)  O T M S  (a)  Reaction of Cvclododecanone (93) with Hexamethvldisilazane and Trimethylsilyl Iodide  1,1,1,3,3,3-Hexamethyldisilazane (0.23 (0.14  mL,  1.1  mL,  1.1  m m o l ) and  m m o l ) were added sequentially via  cyclododecanone (93) (0.10  g, 0.55  m m o l ) and  trimethylsilyl chloride  syringe to  lithium iodide (0.15  a  mixture of g, 1.1  m m o l ) in  317 CHCI (5 m L ) stirred at rt. The reaction was stirred for 20 hours in the dark. 2  2  Triethylamine (0.15 m L , 1 . 1 m m o l ) was added and the reaction was stirred fo  additional 30 minutes. The reaction w a s diluted with diethyl ether, sequentially wash with saturated NaHC0 solution and brine, and dried over anhydrous MgS0. 3  4  extracts were filtered and the solvent was removed under reduced pressure.  T  Colum  chromatography of the residue (GC ratio 172:173, 48:52) with petroleum ether as eluant gave silyl enol ethers 172 (61 m g , 44%) and 173 (64 m g , 46%) both as colourless oils.  1 7 2 (Z)  IR(CCU): 2929, 2857, 1668, 1451, 1362, 1252, 1168, 1134, 1081, 1031,850 cm;  1 -  H N M R (500 MHz, CD): 5 4.52 (t, J = 7 . 4 Hz, 1 H), 2.14 (dt, J = 7.4, 4.6  1  6  6  (t, J = 6.0 Hz, 2 H), 1 . 4 7 1 . 5 5 (m, 4 H), 1.35-1.45 (m, 1 2 H), 0.14 (s, 9  CN M R (125 MHz, CD): 5 149.76, 111.39, 36.44, 26.88, 26.67, 26.53, 26.22, 25  13  6  6  25.16, 25.14, 25.09, 24.03, 0.59;  LRMS (El) m/z (relative intensity): 254 (M, 15), 239 (7), 1 9 7 (11), 183 (23), 169 (1 +  155 (12), 143 (59), 130 (59), 75 (53), 73 (100); H R M S (El) m/z calculated for Ci H OSi: 254.2066, found: 254.2064; 5  30  Analysis calculated for Ci H OSi: C, 70.80; H, 11.88. Found: C, 71.06; H, 11.88. 5  30  173(E)  IR(CCI): 2930, 2858, 1659, 1467, 1446, 1252, 1234, 1181, 1133, 1108, 942, 87 4  850 cm"; 1  H N M R (500 MHz, CD): 5 4.66 (t, J = 7 . 9 Hz, 1 H), 2.16 (t, J = 6.7 Hz,  1  6  6  J = 7.9, 5 . 7 Hz, 2 H), 1 . 6 3 1 . 6 8 (m, 2 H), 1 . 2 6 1 . 4 2 (m, 1 4 H), 0.20 (s,  C N M R (125 MHz, CD): 5 151.87, 108.53, 28.42, 27.81, 25.06, 25.03, 24.81, 24  13  6  6  24.37, 24.34, 22.77, 22.61, 0.52;  LRMS (El) m/z (relative intensity): 254 (M, 13), 239 (5), 211 (8), 1 9 7 (10),-183 (22 +  169 (12), 155 (13), 143 (60), 130 (58), 115 (14) 75 (52), 73 (100); H R M S (El) m/z calculated for Ci H OSi: 254.2066, found: 254.2060; 5  30  Analysis calculated for C H OSi: C, 70.80; H, 11.88. Found: C, 70.82; H, 11.97. 1 5  3 0  318 (b) Reaction of Cvclododecanone (93) with Triethylamine and Trimethylsilyl Chloride A solution of cyclododecanone (93) (3.65  g, 20.0  syringe to a solution of triethylamine (5.6 (3.1  mL, 24 m m o l ) in DMF  The  reaction was  solution and  (10 mL) was  40 m m o l ) and  (30 mL) and the reaction was  added via  trimethylsilyl chloride  heated at reflux for six hours.  cooled to rt, diluted with hexane, washed with saturated NaHC0  3  brine, and  the solvent was  mL,  m m o l ) in DMF  dried over anhydrous MgS0. The 4  extracts were filtered and  removed under reduced pressure. Column chromatography of  residue with petroleum ether as eluant gave silyl enol ethers 172 and  173 (2.60  the  g,  52%;  GC ratio 172:173, 63:37) as a pale yellow oil with spectral data in agreement with that reported above.  2-Methylcyclododecanone (174)  A solution of M A B R was (3.0  generated by the addition of trimethylaluminum in hexanes  mL, 6.0 m m o l ) to a solution of 4-bromo-2,6-di-terf-butylphenol (1.71  in CHCI (12 2  2  mL)  and  M A B R solution (13.0 and 173 (0.43  the reaction was mL, 2.60  stirred for one  m m o l ) was  hour at rt.  g, 6.00 m m o l )  An aliquot of  added to a solution of silyl enol ethers 172  g, 1.7 m m o l ) in CHCI (10 mL) at -40 °C, and the reaction was 2  20 minutes. Methyl triflate (0.38  2  mL, 3.4 m m o l ) was  with slow warming to rt over 20 hours. The sequentially washed with 1 M HCI, anhydrous MgS0. The 4  the  stirred for  added and the reaction was stirred  reaction was  diluted with CHCI and 2  saturated NaHC0 solution, brine, and 3  extracts were filtered and  the  solvent was  reduced pressure. Column chromatography of the residue with 2% petroleum ether as eluant gave ketone 174 (0.24  2  dried over  removed under ethyl acetate in  g, 71 %) as a pale yellow oil.  319 IR (CDCI3): 2934, 2864, 1709, H NMR  (500  1  6.9,  MHz,  16.2  1469,  CDCI): 6 2.68 3  Hz, 1 H), 2.32  (ddq,  (ddd,  (dddd, J = 3.4, 8.0, 8.0,  1445,  1371,  1028  cm"; 1  J = 3.6, 9.8, 7.0 Hz, 1 H), 2.58  J = 5.2, 7.7,  13.8  1133,  16.2  (ddd,  J = 4.8,  Hz, 1 H), 1 . 6 2 1 . 7 1 (m, 3 H),  Hz, 1 H), 1 . 1 0 1 . 3 1 (m, 14 H), 1.02  1.47  (d, J = 7.0 Hz, 3  H); C  13  NMR  (125  MHz,  CDCI): 6 215.33, 45.49, 37.05, 31.51, 25.82, 25.40, 24.14, 24.08 3  23.84, 22.71, 22.32, 22.06, 16.68; LRMS (El) m/z (relative intensity): 196 (M, +