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Conformationally controlled reactions of 14-membered lactones Yu, Hongping 2000

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Conformationally Controlled Reactions of 14-Membered Lactones by  -  Hongping Y u M.Sc, Tsinghua University, 1994  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF Doctor of Philosophy in THE FACULTY OF GRADUATE STUDIES DEPARTMENT OF CHEMISTRY We accept this thesis as conforming to the required standard:  THE UNIVERSITY OF BRITISH COLUMBIA August, 2000 © Hongping Yu, 2000  • •- ' ;  In  presenting  degree freely  at  this  the  available  copying  of  department publication  of  in  partial  fulfilment  University  of  British  Columbia,  for  this or  thesis  reference  thesis by  this  for  his thesis  and  scholarly  or for  her  Department The University of British Columbia Vancouver, Canada  (2/88)  I  I further  purposes  gain  the  shall  requirements  agree  that  agree  may  representatives.  financial  permission.  DE-6  study.  of  be  It not  that  the  allowed  advanced  Library shall  by  understood be  an  permission for  granted  is  for  the  make  extensive  head  that  without  it  of  copying my  my or  written  11  Abstract Hydrolysis reactions were performed on two comformationally biased 14-membered lactones 11 and 12 to investigate the effect of the ring conformations of these lactones on the hydrolysis reaction rates. Hydroboration reactions were carried out at the double bond of compound 14 for the purpose of achieving regioselectivity under the control of ring conformations. The two products of the hydroboration reaction, 37 and 38, were subjected to methylation at the a- positions of the ester carbonyl groups to probe the possibility of achieving diastereoselectivity. The face selectivity at the double bond in macrolide 43 was also investigated using hydroboration and epoxidation reactions.  1. Hydrolysis of conformationally biased 14-membered lactones The reaction rates of the hydrolysis of lactones 11 and 12, under both acidic and basic conditions, were predicted to be different based on the understanding of their lowest energy conformations. The reactions between the lactones and sodium methanethiolate were expected to have relatively similar reaction rates due to the reaction mechanisms. To support these predictions, the two lactones were synthesized by multistep syntheses. The X-ray structures of both lactones were obtained, which were the same as the expected lowest energy conformations. Molecular mechanics calculations and DNMR studies indicated that the majority of the molecular populations of both lactones existed under these lowest energy conformations. The results of the hydrolysis of these two lactones proved the validity of our predictions. The results were further rationalized by molecular mechanics calculations  Ill  performed on 11 and 12 as well as the transition state analogues for the hydrolysis of 11 and 12, structures A and B .  2. Hydroboration of the double bond in lactone 1 4 Hydroboration of the double bond in lactone 1 4 produced two regioisomers, 3 7 and 3 8 , with low regioselectivity. The regiochemistry of these two products was determined chemically, through the cleavage of the epoxide in 5 4 which was found to be highly regioselective. These results were rationalized using molecular mechanics calculations.  3. Methylation reactions at the a- position of the carbonyl groups in 3 7 and 3 8 Methylation of the silyl ether of 3 8 was achieved with 10 : 1 ( 4 1 : 4 2 ) diastereoselectivity, while only 1.4 : 1 ( 3 9 : 4 0 ) selectivity was achieved from methylation of the silyl ether of 3 7 . The relative stereochemistries in these products were determined by correlating their conformational behavior with their H NMR spectra and with molecular !  mechanics calculations.  4. Hydroboration and epoxidation of the double bond in macrolide 4 3 Face selectivity in (39+41)  43  was found to be low upon both hydroboration ( ( 4 2 + 4 0 )  = 1.6 : 1) and epoxidation ( 4 5  : 44  :  = 1.7 : 1 @ 25°C; 2.3 : 1 @ 0°C) of the double  bond. The reaction results were rationalized using molecular mechanics calculations.  V  Table of Contents Abstract  ....  Table of Contents  • ii ......v  List of Figures  x  List of Tables  xiii  List of Schemes  xv  Abbreviations  xvi  Acknowledgements  xix  Chapter One Introduction  1  1.1 Conformational Analysis  2  1.1.1 Conformational Analysis of Six-Membered Rings  3  1.1.2 Conformational Analysis of Medium- and Large-Ring Systems  4  1.1.3 Conformational Analysis of 14-Membered Rings  5  1.1.3.1 The Lowest Energy Conformation of Cyclotetradecane  5  1.1.3.2 Substituents on the Lowest Energy Conformation of 14-Membered Rings  8  f. 1.3.3 Heteroatoms and sp Centers on the Lowest Energy Conformation of a 2  14-Membered Ring  8  1.1.3.4 Methods Used In the Investigation of Large Ring Conformations  11  1.1.3.5 The Description of Large Ring Conformations  13  1.2 Conformationally Controlled Reactions in Medium- and Large-Ring Compounds  14  1.2.1 The Seminal Work of Still and Coworkers  15  1.2.2 Contributions by Vedejs and Coworkers  20  1.2.3 Previous Work By Weiler and Coworkers  22  1.2.4 Applications of Conformationally Controlled Reactions in Organic Synthesis  25  1.2.5 An Interesting Development: Molecular Workbench  26  1.2.6 Summary  27  1.3 Research Objectives  29  vi 1.4 Ring Closing Metathesis  Chapter Two Hydrolysis of Conformationally Biased Macrocyclic Lactones 2.1 Ester Hydrolysis  30  33 34  2.1.1 Acid Catalyzed Hydrolysis of Macrocyclic Lactones  37  2.1.2 Base Mediated Hydrolysis of Macrocyclic Lactones  40  2.1.3 Reaction Between MeS" and Macrocyclic Lactones  40  2.1.4 The Effect of the Lowest Energy Conformations of Lactones 11 and 12 on the Rate Constants for Hydrolysis and Reaction with MeS" 2.2 Synthesis of Lactones 11 and 12 2.2.1 Synthesis of 6-Hepten-l-ol (17) and 7-Octenoic acid (18)  41 44 45  2.2.2 Synthesis of 5,5-Dimethyl-7-octenoic acid (19) and 4,4-Dimethyl6-hepten-l-ol(20) 2.2.3 Synthesis of RCM Precursors 15 and 16  47 48  2.2.4 Synthesis of 5,5-Dimethyl-13-tridecanolide (11) and 10,10-Dimethyl-13tridecanolide (12) 2.3 Conformational Analysis of Lactones 11 and 12  49 51  2.3.1 X-ray Crystal Structures for Lactones 11 and 12  52  2.3.2 Results of Molecular Mechanics Calculations on 11 and 12  54  2.3.3 DNMR Studies of Lactones 11 and 12  58  2.3.4 Summary  62  2.4 Hydrolysis of Lactones 11 and 12  62  2.4.1 Base Mediated Hydrolysis of 11,12 and 36  63  2.4.2 Acid Catalyzed Hydrolysis of 11,12 and 36  64  2.4.3 Lactone Ring-Openning with MeSNa  66  2.5 Rationalization of the Relative Rates of the Lactone Hydrolysis Using Molecular Mechanics Calculations 2.6 Summary  68 73  Chapter Three Conformationally Controlled Regio- and Stereoselectivity of 14-Membered Lactones  75  3.1 Synthesis of 10,10-Dimethyl-7-tridecenolide (14)  78  3.2 Hydroboration Reactions of 10,10-Dimethyl-7-tridecenolide (14): a Regioselectivity Study  79  3.2.1 Result of the Hydroboration Reactions of 14  80  3.2.2 Regiochemistry Assignment of the Hydroboration Products of 14  81  3.2.3 Rationalization of the Reaction Results  84  3.2.3.1 Hydroboration  84  3.2.3.2 Cleavage of the Epoxide Moiety in 54  86  3.2.3.3 Insights Into the Lowest Energy Conformations of 14 and 54  87  3.3 Alkylation Reactions of the Silyl Ether Derivatives of 7-Hydroxyl-10,10-dimethyl Tridecanolide (37) and 8-Hydroxyl-10,10-dimethyl Tridecanolide (38): a Study of Diastereoselectivity  89  3.3.1 Results of the Alkylation Reactions of Silyl Ethers 60 and 61, Derived from Alcohols 37 and 38 respectively  90  3.3.2 Relative Stereochemistries in the Alkylation Products of 37 and 38 3.3.2.1 Assignment of the Relative Stereochemistries Between 39 and 40  93 93  3.3.2.1.1. Interpretation of the Chemical Shifts in the 'H NMR Spectra of  39, 40 and 37  95  3.3.2.1.2 Analysis of the Coupling Constants in the H NMR Spectra of !  39, 40 and 37.  98  3.3.2.1.3 Varied Temperature (VT) H NMR Studies of 39 and 40  105  3.3.2.2 Assignment of the Relative Stereochemistry Between 41 and 42  109  l  3.3.2.2.1. Interpretation of the Chemical Shifts in the *H NMR Spectra of  41, 42 and38  Ill  3.3.2.2.2 Analysis of the Coupling Constants in the 'H NMR Spectra of  41,42 and 38 3.3.3 Rationalization of the Alkylation Results for the Silyl Ethers of 37 and 38 3.4 Face Selectivity Studies of the Hydroboration and Epoxidation of 43  112 118 122  3.4.1 Hydroboration of 43.....  122  3.4.2 Epoxidation of 43  124  3.5 Summary  125  viii  Chapter Four Experimental  128  4.1 General  128  4.2 Hydrolysis  131  4.2.1 Base Mediated Hydrolysis  131  4.2.2 Acid Catalyzed Hydrolysis  131  4.2.3 Lactone Ring-Openning with MeSNa  132  4.3 Synthetic Methods  133  4.3.1 5,5-Dimethyl-13-tridecanolide (11)  133  4.3.2 LOJO-Dimethyl-n-tridecanolide (12)  134  4.3.3 5,5-Dimethyl-13-tridec-7-enolide (13)  135  4.3.4 10,10-Dimethyl-13-tridec-7-enolide (14)....  136  4.3.5 6-Heptenyl-5',5'-dimethyl-7'-octenoate (15)  137  4.3.6 4,4-Dimethyl-6-heptenyl 7'-octenoate (16)  138  4.3.7 6-Hepten-l-ol (17)  139  4.3.8 7-Octenoic Acid (18)  '. 140  4.3.9 5,5-Dimethyl-7-octenoic Acid (19) 4.3.10 4,4-Dimethyl-6-hepten-l-ol (20)  142 .,  4.3.11 2-(6'-Hydroxy 1 hexoxyl) Tetrahydropyran (23)  143 144  4.3.12 2-(6'-Oxohexoxyl) Tetrahydropyran (24)  145  4.3.13 2-(6'-Hexenoxyl) Tetrahydropyran (25)...  147  4.3.14 6-Heptenyl Tosylate (26)  148  4.3.15 6-Heptenyl Cyanide (27)  149  4.3.16 3,3-Dimethyl Glutaric Anhydride (28)  150  4.3.17 3,3-Dimethyl-6-valerolactone (29)  151  4.3.18 4,4-Dimethyl Tetrahydropyran-2-ol (30)  152  4.3.19 3,3-Dimethyl-5-hexen-l-ol (31)  153  4.3.20 3,3-Dimethyl-5-hexenyl Tosylate (32)  154  4.3.21 Methyl-5,5-dimethyl-2-methylcarboxylatyl-7-octenoate (33)  155  4.3.22 3,3-Dimethyl-5-hexenyl Cyanide (34)  156  4.3.23 4,4-Dimethyl-6-heptenoic Acid (35)  157  4.3.24 Hexyl Undecanoate (36)  .  158  4.3.25 10J0-Dimethyl-7-hydroxyl-13-tridecanolide (37) and 10,10-Dimethyl-8-hydroxyl-13-tridecanolide (38)  159  4.3.26 10,10-Dimethyl-8-hydroxyl-13-tridecanolide (38)  162  4.3.27 (25*, 7i?*)-7-hydroxyl-2,10,10-Trimethyl-13-tridecanolide (39) and (25*, 75'*)-7-hydroxyl-2,10,10-Trimethyl-13-tridecanolide (40)  163  4.3.28 (25*, 85*)-8-hydroxyl-2,10,10-Trimethyl-13-tridecanolide (41) and (25*, 8i?*)-8-hydroxyl-2,10,10-Trimethyl-13-tridecanolide (42)  165  4.3.29 (25*, 7i?*)-7-hydroxyl-2,10,10-Trimethyl-13-tridecanolide (39), (25*, 75*)-7-hydroxyl-2,10,10-Trimethyl-13-tridecanolide (40), (25*, 85*)-8-hydroxyl-2,10,10-Trimethyl-13-tridecanolide (41), and (25*, 8i?*)-8-hydroxyl-2,10,10-Trimethyl-13-tridecanolide(42)  167  4.3.30 (£s)-2,10,10-Trimethyl-13-tridec-7-enolide (43)  168  4.3.31 (25*, 7R*, 8i?*)-7,8-epoxy-2,10,10-Trimethyl-13-tridecanolide (44) and (25*, 75*, 85*)-7,8-epoxy-2,10,10-Trimethyl-13-tridecanolide (45)  169  4.3.32 2-(7'-Hydroxyl heptoxyl) Tetrahydropyran (47)  171  4.3.33 2-(7'-Oxoheptoxyl) Tetrahydropyran (48)  172  4.3.34 2-(7'-Heptenoxyl) Tetrahydropyran (49)  173  4.3.35 7-Octen-l-ol (50)  174  4.3.36 5-Hexenyl Tosylate (52)  175  4.3.37 Methyl 2-methylcarboxylatyl-7-octenoate (53)  176  4.3.38 10,10-Dimethyl-7,8-epoxy-13-tridecanolide (54)  178  4.3.39 7-Chloro-10,10-dimethyl-8-hydroxyl-13-tridecanolide (55)  179  4.3.40 7-Chloro-10,10-dimethyl-8-oxo-13-tridecanolide (56)  180  4.3.41 10,10-Dimethyl-8-oxo-13-tridecanolide (57)  181  4.3.42 10,10-Dimethyl-7-trimethylsilyloxyl-13-tridecanolide (60)  183  4.3.43 10,10-Dimethyl-8-trimethylsilyloxyl-13-tridecanolide (61)  184  4.3.44 Benzyl Undecanoate (66)  185  References  186  Appendix I H NMR and IR Spectra  193  Appendix II Second Set of Data for the Hydrolysis of 11,12 and 36  240  J  X  List of Figures Figure 1.1. The lowest energy conformation of tetracyclodecane  5  Figure 1.2. Symmetric properties of the lowest energy conformation of tetracyclodecane ... 6 Figure 1.3. The comer (*) and pseudocomer (**) positions..  7  Figure 1.4. Transannular interactions within the lowest energy conformation of cyclotetradecane  7  Figure 1.5. Number of gauche interactions experienced by the various exterior positions.... 8 Figure 1.6. Possible transannular interactions experienced by the carbonyl oxygen  9  Figure 1.7. The conformations of 1,3,8,10-tetraoxacyclotetradecane, 4, cyclotetra  decanone, 5, and cyclotetradecane oxime, 6 (top view)  found by X-ray crystallography  10  Figure 1.8. Three possible arrangements of the ester function in the lowest energy conformations of the 14-membered ring lactone  10  Figure 1.9. The lowest energy conformation of tetracyclodecane and the corresponding polar map  14  Figure 1.10. The orientation of the double bonds in cyclohexene, cyclooctene, and cyclodecene  18  Figure 1.11. Low energy conformations of the enolate in Entry 2 (Table 1.2) and the corresponding products  Figure 1.12. Local conformational analysis for Entries 22 to 27 (Table 1.2)  19 20  Figure 1.13. The local conformations of the Z and E cycloalkenes containing an allylic methyl group  22  Figure 1.14. Molecular workbenches for stereoselective additions to olefins  26  Figure 1.15. Heteroatom as residence site for the catalyst in the RCM  32  Figure 2.1. Formation of the tetrahedral intermediate in base mediated hydrolysis of 11 and 12  42  Figure 2.2. The reactions of lactones 11 and 12 with MeS"  43  Figure 2.3. X-ray crystal structures of lactones 11 and 12  52  Figure 2.4. Polar maps of the X-ray crystal structures of 11 and 12 Figure 2.5. Polar maps of the calculated lowest energy conformations of lactones 11  54  and 12  58  Figure 2.6. Variable temperature 500 MHz H NMR of 11 in CDsCeDsiCT^Cb (1:1)  60  Figure 2.7. Variable temperature 500 MHz *H NMR of 12 in CD C6D5:CD Cl2 (1:1)  61  !  3  2  Figure 2.8. Linear relationships between ln([a] /[a]) and time for the base mediated 0  hydrolysis of lactones 11 and 12, and ester 36  63  Figure 2.9. Linear relationships between ln([a] /[a]) and time for the acid catalyzed 0  hydrolysis of lactones 11 and 12, and ester 36  65  Figure 2.10. Linear relationships between ln([a] /[a]) and time for the reactions 0  between MeSNa and lactones 11 and 12, and ester 36  67  Figure 2.11. Polar maps for the calculated lowest energy conformations of structures A and B  72  Figure 3.1. Suggested mechanism of the hydroboration reaction....  79  Figure 3.2. Characteristic *H NMR signals for 56 and 57  83  Figure 3.3. The two lowest energy conformations of compound 54 and their relative strain energies  86  Figure 3.4. The two possible local conformations in the low energy conformations of compound 54  87  Figure 3.5. The lowest energy conformation of 12 and the expected lowest energy conformations of 14 and 54  88  Figure 3.6. Top views of the expected and calculated lowest energy conformations for compounds 14 and 54  89  Figure 3.7. 'H NMR spectra (500 MHz) of the reaction mixtures from the alkylation of 37 and 38  92  Figure 3.8. 500 MHz *H NMR spectra of 39, 40, and 37  94  Figure 3.9. Conformational analysis of compounds 12, 37, 39, and 40  97  Figure 3.10. Downfield H NMR signals correlate to the two protons at position 13 in l  39, 40 and 37  99  Figure 3.11. 400 MHz H NMR spin decoupling experiments between the two protons at l  position 13 in compound 39 (Spectrum 2, Figure 3.10)  101  Figure 3.12. 500 MHz VT *H NMR spectra of 39  107  Figure 3.13. 500 MHz VT H NMR spectra of 40  108  !  xii  Figure 3.14. 500 MHz H NMR spectra of 41, 42 and 38 !  Figure 3.15. Conformational analysis of compounds 12, 38, 41, and 42 Figure 3.16. Downfield 'H NMR signals correlate to the two protons at position 13 in 41, 42 and 38  List of Tables Table 1.1. The three lowest energy conformations of cyclotetradecane  12  Table 1.2. Conformationally controlled reactions investigated by Still and coworkers  15  Table 1.3. Conformationally controlled reactions investigated by Vedejs and coworkers Table 1.4. Conformationally controlled reduction reactions investigated by Weiler  20 23  Table 1.5. Conformationally controlled alkylation reactions investigated by Weiler... .24 Table 2.1. Endocyclic torsional angles of the X-ray crystal structures of 11 and 12  53  Table 2.2. Low energy conformations of lactone 11 found during a conformational search  55  Table 2.3. Low energy conformations of lactone 12 found during a conformational search  56  Table 2.4. Endocyclic torsional angles of the calculated lowest energy conformations of  11 and 12  57  Table 2.5. Rate constants for the base mediated hydrolysis of 11,12 and 36  64  Table 2.6. Relative rate constants for the acid catalyzed hydrolysis of 11,12 and 36  66  Table 2.7. Rate constants for the reactions of MeS" with 11,12 and 36  68  Table 2.8. Calculated lowest energy conformations of lactones 11 and 12 as well as structures A and B  70  Table 2.9. Endocyclic torsional angles for the calculated lowest energy conformations of structures A and B  71  Table 3.1. Product ratios obtained from the hydroboration of 10,10-dimethyl-7-tridecenolide, 14  81  Table 3.2. The three lowest energy conformations of 14 found by molecular mechanics calculations  85  Table 3.3. Calculated low energy conformations, dihedral angles and J values for compound 39  102  Table 3.4. Calculated low energy conformations, dihedral angles and J values for compound 40  103  xiv -3  Table 3.5. Calculated low energy conformations, dihedral angles and J values for compound 37  104  Table 3.6. Calculated low energy conformations, dihedral angles and J values for 3  compound 38  115  Table 3.7. Calculated low energy conformations, dihedral angles and J values for compound 41  116  Table 3.8. Calculated low energy conformations, dihedral angles and J values for 3  compound 42  117  Table 3.9. Four lowest energy conformations of structure C found by molecular mechanics calculations  ."  120  Table 3.10 Four lowest energy conformations of structure D found by molecular mechanics calculations  121  XV  List of Schemes Scheme 1.1. The mechanism of the RCM reaction  Scheme 2.1. Predicted lowest energy conformations of 11 and 12  30 34  Scheme 2.2. The mechanism of the (a) acid catalyzed and (b) base mediated ester hydrolysis  35  Scheme 2.3. The mechanism for the acid catalyzed hydrolysis of macrocyclic lactones  37  Scheme 2.4. Base mediated hydrolysis of macrocyclic lactones  40  Scheme 2.5. Retrosynthetic analysis of lactone 11  44  Scheme 2.6. Retrosynthetic analysis of lactone 12  45  Scheme 2.7. Synthesis of 6-hepten-l-ol (17) and 7-octenoic acid (18)  46  Scheme 2.8. Synthesis of 5,5-dimethyl-7-octenoic acid (19) and 4,4-dimethyl-6hepten-l-ol (20)  Scheme 2.9. Synthesis of the RCM precursor 15 and 16  Scheme 2.10. RCM for the synthesis of the macrocyclic olefins 13 and 14 Scheme 2.11. Hydrogenation of 13 and 14 producing lactones 11 and 12  47  49 50 51  Scheme 3.1. Hydroboration and alkylation reactions chosen for the purpose of regioand diastereoselectivity studies with 14-membered ring lactones  76  Scheme 3.2. Hydroboration and epoxidation reactions chosen to investigate possible face selectivity with 14-membered ring lactone 43  77  Scheme 3.3. Synthesis of 7-octenoic acid, 18  78  Scheme 3.4. Hydroboration of (£)-10,10-dimethyl-7-tridecenolide (14)  80  Scheme 3.5. Chemical conversions for the determination of the regiochemistry of the hydroboration products of 14  Scheme 3.6. Alkylation at the a-position of the ester carbonyl group in 37 and 38 Scheme 3.7. Reactions involved in the diastereoselectivity study  82 90 91  Scheme 3.8. Alkylation at the a-position of the ester carbonyl in 14  122  Scheme 3.9. Hydroboration of the double bond in 43  123  Scheme 3.10. Epoxidation of the double bond in 43  124  xvi  Abbreviations and Symbols  8  chemical shift  Ac  acetyl  aq.  aqueous  atm  atmosphere  9-BBN  9-borabicyclo[3.3.1]nonane  Bu  butyl  cone.  concentrated  Cy  cyclohexyl  d  doublet  D  deuterium  DCC  dicyclohexylcarbodiimide  DCI  desorption chemical ionization  DHP  dihydropyran  DIBAH  diisobutylaluminum hydride  DMAP  4-dimethylaminopyridine  DMF DMPU  A^A^-dimethylformamide l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone  DMSO  dimethyl sulfoxide  DNMR  dynamic nuclear magnetic resonance  EI  electron ionization  Et  ethyl  EtOAc  ethyl acetate  G  Gibbs free energy  GC  gas chromatography  Hz  hertz  /'Pr  isopropyl  IR  infrared (spectroscopy)  J  coupling constant (in NMR)  kcal  kilocalorie  k  rate constant  LAH  lithium aluminum hydride  LDA  lithium diisopropylamide  m  multiplet  M  mole per litre  mCPBA  me/a-chloroperbenzoic acid  Me  methyl  mp  melting point  m/z  mass-to-charge ratio  NMR  nuclear magnetic resonance  NOE  nuclear Overhauser effect  P  para  PCC  pyridinium chlorochromate  Ph  phenyl  ppm  parts per million  xviii PPTS  pyridinium /?ara-toluenesulfonate  pyr  pyridine  RB  round bottom  RCM  ring closing metathesis  R  retention factor or ration-to-front  f  rt  room temperature  s  singlet  t  triplet  TBAF  tetrabutylammonium fluride  tert  tertiary  THF  tetrahydrofuran  TLC  thin layer chromatography  TMS  trimethylsilyl  Ts  tosyl  UV  ultraviolet  VT  varied temperature  v/v  volume to volume ratio  w  wide (NMR signal)  xix  Acknowldgements  First and foremost, I would like to express my gratitude toward my supervisor, Dr. Larry Weiler, for his guidance, advice, support, and patience during the course of this study. I am particularly grateful to Dr. Mike Pungente for his advice and support at the final stage of the research and his patience and tremendous help during the preparation of this thesis. I would like to thank my guidance committee, Dr. Edward Piers, Dr. Martin Tanner and Dr. Michael Wolf, for their guidance at the last stage of the research and for reading my thesis and providing supportive advice and comments. I am thankful to my lab mates, especially Andre Hodder, for his help during the beginning of my research, Bill Goldring, for his help in using various lab instruments and NMR facility and for his useful suggestions and discussions. I would like to thank the NMR department, Liane Darge, and Marietta Austria, for running my samples and for their instruction in the use of the NMR equipment. I would also like to thank Dr. Nick Burlinson for his help in performing VT experiments. I am grateful to Dr. Peter Borda for the microanalysis, Dr. Steve Rettig for the X-ray crystallographic studies, and all the service personnel in the Mass Spectroscopy department. I would like to acknowledge the Natural Sciences and Engineering Research Council of Canada for the financial support of this research. Finally, I would like to thank my family and friends for their support and encouragement through out my graduate study, especially my wife, Fang, for her support and patience.  XX  For  the late Professor Larry Weiler  Chapter One Introduction  Early interest in macrocyclic compounds stemmed from the discovery of muscone 1 and civetone 2, which were isolated from musk oil and were of commercial importance in the perfume industry.  For commercial and scientific reasons, Ruzicka ' '  1,2  3 4 5  and Prelog  6  continued the investigation of medium- and large-ring hydrocarbon compounds. o  1  2  To date, numerous medium- and large-ring compounds have been found to exist in nature. Many of these possess interesting biological activities and are of medicinal importance. Among them, 12- to 16-membered macrocyclic lactones, which were defined by Woodward as "macrolides", are an important group of antibiotics. The chemistry of macrolide compounds, including their isolation, characterization, derivatization and total synthesis, is an important part of modern organic chemistry. Pikromycin (3), the first macrolide antibiotic to be isolated, was obtained from a strain of streptomyces in 1950.  9  2  3 To date, more than 90 compounds belonging to this group have been discovered, and numerous  derivatives  have  been  obtained  by  chemical  methods  and microbial  transformation. Since the mid 1970s, macrolide antibiotics have been popular targets of total 7  syntheses and continue to be so. ' ' ' As a result, new concepts, strategies and methods 10  11  12  13  have been developed to deal with the structurally unique macrocyclic ring systems. Among these, conformational analysis and conformationally controlled reactions involving mediumand large-ring compounds are two important aspects of macrolide chemistry.  1.1 Conformational Analysis Conformational analysis, especially when applied to small ring systems, is an important aspect of modern organic chemistry. It is a very useful tool in the interpretation of chemical transformations and reaction mechanisms as well as steric and electronic effects associated with organic compounds. However, the conformational analysis of various medium- and large-ring compounds is still a challenging task because of the flexibility associated with these rings.  3  1.1.1 Conformational Analysis of Six-Membered Rings The first suggestion that cyclohexane exists in two puckered arrangements, later termed as "chair" and "boat" conformations, came from Sachse in 1890, when most 14  chemists at the time believed that cyclohexane was a planar regular hexagon. Decades later, in 1923, Huckel provided the first experimental evidence supporting Sachse's hypothesis by the synthesis of both the cis and trans isomers of decalin. However, it was not until the 15  early 1940s, when Hassel published his electron diffraction studies on chlorocyclohexane, that this new concept was totally accepted. ' Another breakthrough came in 1950, when 16 17  Barton demonstrated the power of conformational analysis by rationalizing the results of the 18  organic reactions in these systems that had previously puzzled chemists. In the midpart of the 20 century, conformational analysis of six-membered ring th  systems was so successful that it became an essential part of current organic chemistry textbooks, and is widely used to explain and predict the outcome of organic reactions in the six-membered ring systems, as well as those with six-membered ring-like transition states. ' The beauty of this theory lies in its simple principle: among the equatorial and 19 20  axial positions in the energy minimum chair conformation of the six-membered ring, the sterically more demanding groups prefer the equatorial rather than the axial positions. The 21  success of conformational analysis of six-membered ring systems was one of the forces that motivated the studies of the conformations of medium- and large-ring compounds: are there also basic rules in the understanding of these ring systems?  4  1.1.2 Conformational Analysis of Medium- and Large-Ring Systems At first glance, the conformational analysis of medium- and large-ring compounds is overwhelmingly complex, since these rings are very flexible and can exist in many different conformations. The conformational details remained obscure until 1961, when Dunitz demonstrated that the ring skeleton of a variety of cyclodecane derivatives existed in virtually the same conformation, and concluded that this particular ring conformation must  22 represent a potential energy minimum. A significant advance came two years later. In 1963, Dale proposed that in mediumand large-ring systems, the only strain free, saturated carbon skeletons were those that were superimposible on the diamond lattice, an extended network of ideal carbon - carbon bond lengths and angles. He suggested that since the odd membered rings would not fit the diamond lattice, they were not strain free. He also pointed out that medium-ring cycloalkanes were strained because of the transannular interactions between the "inward" hydrogens. These rings would adopt conformations that reach a compromise between angle strain, torsional energy, and transannular hydrogen repulsion. In addition, by studying space filling models, Dale also noticed that in order to avoid excessive gauche interactions and fill space efficiently, these ring systems tend to adopt "rectangular" conformations with two parallel methylene chains linked by bridges of minimum length.  24  Based on these principles, Dale proposed the low energy conformations for the even membered cycloalkanes with carbon atoms between 6 and 16. These analyses agreed with 24  the earlier X-ray structure results of cyclododecane,  and azacyclododecane hydrochloride, 97  and were also confirmed later by the X-ray crystal structures of cyclotetradecane 9R diazacylcotetradecane.  and 1,8-  5 Following the qualitative recognition of these low energy conformations, Dale conducted semi-quantitative calculations of the enthalpies of medium- and large-rings using Dreiding models which have correct C-C bond length and tetrahedral bond angles. The 29  strain energies of medium- and large-rings were later calculated by Anet and coworkers using molecular mechanics calculations. '  30 31  1.1.3 Conformational Analysis of 14-Membered Rings 1.1.3.1 The Lowest Energy Conformation of Cyclotetradecane According to Dale's proposal, the lowest energy conformation of cyclotetradecane is "rectangular", and that fits onto the diamond lattice. This minimum energy conformation has two 4-bond parallel methylene chains linked by two 3-bond bridges (Figure 1.1). This 24  conformation belongs to the C2h symmetry point group, which contains a C 2 axis and a plane of symmetry. It has four diastereotopic methylene groups (Figure 1.2).  Side view  Figure 1.1. The lowest energy conformation of tetracyclodecane.  Top view  6  plane of symmetry  The C2 axis and the plane of symmetry  The four diastereotopic methylene groups  Figure 1.2. Symmetric properties of the lowest energy conformation of tetracyclodecane.  In this particular conformation, there are four "comer atoms" located at the joint points of the four-bond chain and the three-bond bridge (Figure 1.1). A corner atom is defined as an atom flanked on either side by gauche dihedral angles of the same sign with anti dihedral angles surrounding the gauche torsions (i.e. 180°, 60°, 60°, 180° or 180°, -60°, -60°, 180°) (Figure 1.3). However, in some cases, ' the conformation involves atoms that are flanked by gauche dihedral angles of different signs (i.e. 180°, 60°, -60°, 180°). These atoms are referred to as the pseudocomer atoms (Figure 1.3).  7  1 180° |  - °1 60  -60° 180°  I  60° 180°  Figure 1.3. The corner (*) and pseudocorner (**) positions.  Within this lowest energy conformation, the two hydrogen atoms of each of the four corner methylene groups point away from the ring to avoid transannular interactions. The remaining ten methylene groups have one of their two hydrogen atoms pointing "inward", experiencing different degrees of transannular interactions (Figure 1.4).  Figure 1.4. Transannular interactions within the lowest energy cyclotetradecane.  conformation of  8  1.1.3.2 Substituents on the Lowest Energy Conformation of 14-Membered Rings It has been found that within medium- and large-ring compounds, atoms with geminal substituents prefer to be located at the corner positions to avoid the severe transannular interactions. ' Since any one of the fourteen methylene groups in cyclotetradecane has an 34 35  equal chance to occupy any one of the positions in its lowest energy conformation, the introduction of geminal groups into the ring can usually simplify the conformational analysis by destroying this equality. While monosubstituted atoms can occupy any position in the ring, the substituent must point "outwards" from the ring. Depending on the position of the monosubstituted atom, the substituent will experience a number of gauche interactions with the methylene groups in the ring (Figure 1.5). This may influence the positional preference of these monosubstituted atoms.  number of gauche interactions  a  1: b, c, d, e 2: a  Figure 1.5. Number of gauche interactions experienced by the various exterior positions.  1.1.3.3 Heteroatoms and sp Centers on the Lowest Energy Conformation of a 14-Membered Ring 2  The replacement of a carbon atom with a heteroatom, such as an oxygen or a nitrogen atom, removes transannular and gauche interactions by losing either one or two hydrogens (or substituents). Thus the preferred location of the heteroatom is the position where it can  9 remove the maximum number of transannular and gauche interactions to reach the energy minimum. It is obvious that the midpoint of the four-bond chain in the lowest energy conformation of cyclotetradecane is the most preferred position for a heteroatom (Figure 1.4 and Figure 1.5). The introduction of a functional group with an sp carbon, such as a carbonyl (C=0) or an imine (C=N-), can also remove the inward hydrogen and stabilize the conformation. At first glance, its preferred location should be the same as that favored by the heteroatoms. However, at this location, the oxygen of the carbonyl group (or the nitrogen of the imine group) is partially inward and may experience serious transannular interactions (Figure 1.6). The favored positions, in fact, are those next to the comer positions, where the carbonyl oxygen (or the nitrogen of the imine group) does not encounter any transannular interactions.  H  Figure 1.6.  The  Possible transannular interactions experienced by the carbonyl oxygen.  above  analyses fit  the  earlier X-ray  structures  of  1,3,8,10-tetraoxa-  cyclotetracecane, 4, cyclotetradecanone, 5, and cyclotetradecane oxime, 6 (Figurel.7), 36  37  38  as well as the results of dynamic NMR (DNMR) studies of various macrocyclic ether rings.  39  10  O  o  Figure 1.7. The conformations of 1,3,8,10-tetraoxacyclotetradecane, 4, cyclotetradecanone, 5, and cyclotetradecane oxime, 6 (top view) found by X-ray crystallography.  A 14-membered ring is large enough to accommodate an s-trans ester group, which is ~3 kcal/mol more stable than its s-cis isomer. ' Within the lowest energy conformation of 40 41  the 14-membered ring, there are only three possible arrangements of the ester group, under which the ester group is s-trans and coplanar, and the oxygen and the carbonyl of the ester group are away from the comer position (Figure 1.8). Among these three conformations, conformation a is more stable than b and c, since both the oxygen and C=0 group are located at their preferred positions.  a  b  c  Figure 1.8. Three possible arrangements of the ester function in the lowest energy conformations of the 14-membered ring lactone.  11 A recent X-ray crystallographic study of tridecanolactone, 7, showed that its crystal 42  structure was indeed the same as conformation a in Figure 1.8. The results of molecular mechanics calculations for 7 were also reported. The three calculated lowest energy 42  conformations were exactly the three conformations showed in Figure 1.8. The calculated relative energies are 0.000 kcal/mol, 0.005 kcal/mol, and 0.040 kcal/mol for conformations a, c, and b respectively.  7  1.1.3.4 Methods Used In the Investigation of Large Ring Conformations There are often many functional groups and substituents associated with large ring natural products, and these functional groups and substituents can be in conflict with each other energetically. Under these circumstances, the lowest energy conformation of the ring is usually different from the lowest energy conformation of its corresponding hydrocarbon ring. This often makes it very challenging or even impossible to determine the lowest energy conformation of the ring simply by conformational analysis on paper. 1 T  Efforts to investigate the conformations of large rings have included the use of C and *H NMR spectroscopy, ' ' ' NOEDs 39 43 44 45  4 6  and IR. ' ' However, the most successful 47  48  49  technique has been X-ray crystallography. ' Dunitz concluded that "any conformation 50 51  observed in a molecular crystal can not be far from an equilibrium structure of the isolated molecule. X-ray analysis thus provides information about the preferred conformations of molecules although it has nothing to say about the energy differences between them".  12 Besides these experimental methods, molecular mechanics has been a useful and reliable tool in assisting the conformational analysis of medium- and large-ring systems. ' ' ' For some systems, it becomes the only available method to find the lowest 39 51 44 45  energy conformation and to estimate the relative energies of different conformers. The use of computer conformational searches together with experimental methods, particularly X-ray crystallography and DNMR, can provide detailed information of the conformations of these ring systems. ' ' ' For example, two low energy conformations of cyclotetradecane that 39  42  51  53  are nonsuperimposible on the diamond lattice were found by molecular mechanics calculations (Table 1.1).  Table 1.1. The three lowest energy conformations of cyclotetradecane. Conformation  top view  [3434]  [3344]  side view  strain energy  3  0.0 kcal/mol  1.1 kcal/mol  2.4 kcal/mol [3335]  Calculated with the MM2* force field.  13  1.1.3.5 The Description of Large Ring Conformations In Table 1.1, the conformations of the large ring compound cyclotetradecane are described using a bracket with a series of numbers, a shorthand notation developed by Dale. The numbers represent the number of bonds between two corner atoms. It starts with the smallest number, followed by the smaller one of its two neighboring numbers, such that the direction is determined. This system was revised later to include the use of primed numbers to describe the number of bonds between a corner and a pseudo corner atom, or the number of bonds between two pseudo corner atoms. The numbers are ordered around the ring in the 33  following priority: corner - corner > corner - pseudocorner > pseudocorner - pseudocorner. In some cases, alphabetical letters were used to designate different conformations. For example, Ogura and coworkers used letters A, B, C, and D to describe conformations of macrolide Oleandomycin, in which conformation A is the same as the conformation [3434]. '  54 55  However, a more direct and accurate way of describing the large ring conformations is with the use of polar maps. ' 56  57,58  The polar map of the [3434] conformation of  cyclotetradecane is showed in Figure 1.9. In the polar map, the concentric circles represent the degrees of the dihedral angles, and those numbers around the outside of the map corresponds to each endocyclic bond in the ring (Figure 1.9).  14  Figure 1.9. The lowest energy conformation of tetracyclodecane and the corresponding polar map.  1.2. Conformationally Controlled Reactions in Medium- and Large- Ring Compounds The understanding of the conformations of 6-membered ring systems and the distinction between the axial and equatorial positions of the chair conformation have lead to the understanding of the stereoselectivities in these ring systems. One example is the conformationally controlled reduction of 4-terr-butylcyclohexanone. The reduction gave a 9 59  : 1 ratio of the trans and cis products, which can be rationalized using the chair conformation of the ring. LiAIH  OH  4  (CH ) C 3  3  OH  H  .0  (CH ) C.  H  + (CH ) C. 3 3  3 3  trans  CIS  For the medium- and large-ring systems, it is not surprising that the development of conformational analysis is accompanied by the exploitation of conformationally controlled reactions in these systems.  15  1.2.1 T h e S e m i n a l W o r k o f S t i l l a n d C o w o r k e r s In 1981, Still and Galynker published a paper entitled "Chemical consequences of conformation in macrocyclic compounds induction".  an effective approach to remote asymmetric  One of the objectives of their work was to verify that conformationally  controlled stereoselection could be a common feature of medium- and large-ring systems. A second purpose was to show that, other than the use of absolute stereochemical control to set up remote diastereomeric relationships, the use of preexisting substrate chirality far from the reaction site to control the reaction stereoselectivity could be a general and viable method in organic synthesis. Still and Galynker studied the reactions of various simple monosubstituted medium60  and  large-ring compounds, including monomethylated 8-, 9-, and 10-membered cyclic  ketones and 9- to 12-membered lactones. The reactions involved kinetic enolate alkylation of saturated ketones and lactones, catalytic hydrogenation and the conjugate addition of dimethylcuprate to a, /^-unsaturated ketones and lactones (Table 1.2).  Table  1.2.  Entry  Conformationally controlled reactions investigated by Still and coworkers.  60  Starting material  Major product  % of the  major isomer(s)  >95 2  98  3  >99 \  4  91  16 Table 1.2. Conformationally controlled reactions investigated by Still (continued). Entry  Starting material  Major product  % of the major isomers  17  Table 1.2. Conformationally controlled reactions investigated by Still (continued). Entry  » .3  Starting material  .  X X ?  Xp  Major product  -  XX/ X ^  % of the major isomers  18 All of the reactions involved an olefinic function as the reaction site either in the starting materials or in the reaction intermediates. By comparing the conformation of cyclohexene with those of cyclooctene and cyclodecene, Still found that in small ring systems, such as the 6-membered ring, although the ring is usually highly biased by a single substituent, the two faces of the double bond are not overwhelmingly different. In addition, the diastereoselectivity resulting from the reactions of small ring systems is almost always significantly lower than that suggested by the A-values of the biasing substituent. While in the medium- and large-ring systems, the olefinic function tends to align perpendicular to the ring so as to minimize transannular interactions. This arrangement highly differentiates the two faces of the double bond: one blocked by the back of the ring and the other face open to the environment (Figure 1.10). Still concluded that "various addition reactions would occur largely or perhaps exclusivelyfromthe less hindered, peripheral face of the olefinic linkage".  Figure 1.10. cyclodecene.  The orientation of the double bonds in cyclohexene, cyclooctene, and  With respect to transition state energies, Still assumed that those pathways leading smoothly from relatively low energy starting conformations to relatively low energy product conformations would be preferred. Those pathways either starting from or leading to highly strained conformations of reactants or products should be ignored. Moreover, only the  19 pathways connecting a starting material conformation with a closely related product conformation should be considered. Following the above principles and utilizing molecular mechanics calculations, the product distributions of reactions listed in Table 1.2 were rationalized semi-quantitatively. For example, in Entry 2, the molecular mechanics calculation found four low energy conformations of the enolate within 4 kcal/mol of each other (Figure 1.11). Among these, conformations C and D lead to products with higher energies. These can then be omitted since the energies of the corresponding transition states would be high as a result of developing transannular strain. The calculated energy difference between A and B, or their corresponding products, was then used to explain the diastereoselectivity of the reaction.  0.0 kcal/mol  1.5 kcal/mol  0.2 kcal/mol  0.5 kcal/mol  0.0 kcal/mol  1.7 kcal/mol  2.9 kcal/mol  2.3 kcal/mo  D Figure 1.11. Low energy conformations of the enolate in Entry 2 (Table 1.2) and the corresponding products. When the methyl group is at a corner position, it has little influence on the diastereoselectivity. This is the case for Entries 5 and 13 (Table 1.2).  20 The results of some of the reactions, such as Entries 22 to 27 (Table 1.2), were rationalized using "local" conformational analysis. In these reactions, the methyl group in the starting material is located on the carbon next to the ester oxygen. The local conformation of the enolate - double bond is fixed regardless of the changes of the ring conformation (Figure 1.12).  preferred  not preferred  Figure 1.12. Local conformational analysis for Entries 22 to 27 (Table 1.2).  1.2.2 Contributions B y Vedejs and Coworkers After the seminal work by Still, Vedejs and coworkers studied the epoxidation and osmylation of 12-membered cycloalkenes and unsaturated lactones (Table 1.3). '  Table 1.3. Conformationally controlled reactions investigated by Vedejs and coworkers. Entry  Starting material  Major product  % of major isomers  Reference  22 This research was based on the concept of "local conformational control". All of the starting materials have either an ally lie methyl or ethyl group. The ally lie methyl (or ethyl) group prefers to occupy a pseudoequatorial position, thus differentiating the two faces of the double bond (a and b, Figure 1.13). However, in the case of E alkene systems, bulky incoming reagents may interact with a pseudoequatorial allylic methyl (or ethyl) group. This can lead to the increased importance of the conformers with the methyl (or ethyl) occupying a pseudoaxial position (c, Figure 1.14). This analysis by Vedejs explains the enhanced diastereoselectivity associated with Z olefins over the E olefins.  a  b  c  Figure 1.13. The local conformations of the Z and E cycloalkenes containing an allylic methyl group. The lower diastereoselectivity associated with the lactones (Entries 9 to 14, except for Entry 11) compared to that with the cycloalkenes (Entries 1 to 8) was thought to be caused by the conflict between the ester group and the olefinic function (Table 1.3), which narrows the energy difference among their low energy conformations. A computer search for the low energy  conformations  using the MACROMODEL  program (molecular  mechanics  calculations) assisted in rationalizing these experimental results.  1.2.3 Previous Work By Weiler and Coworkers  636 4 6 5 6 6 6 7 6 8  In the mid 1980s, our laboratory began investigating the conformationally controlled reductions and alkylations of 14- and 16-membered lactones and lactams (Table 1.4).  23 Table 1.4. Conformationally controlled reduction reactions investigated by Weiler. Entry Starting material  Products  Reducing agent  Product ratio Ref.  b. K-selectride  83 : 17  c. LS-selectride  89 : 11  a. N a B H , C e C l  3  63 : 37  a. N a B H , C e C l  3  87 : 13  4  4  a. N a B H  b. K-selectride  78 : 22  c. L-selectride  89 : 11  d. LS-selectride  30 : 70  a. N a B H 4  60 : 40  b. L-selectride  89 : 11  64  75 : 25  4  b. N a B H , M n C l c. L-selectride 4  98:2 >99 : 1  2  d. BU4NBH4  40 : 60  e. Bu NBH4, L i B r  90 : 10  4  f. B u N B H , M n C l 4  a. L-selectride  +  64  90:10  e. M A D  4  65  50 : 50  4  a. N a B H  65  2  63 67  97 : 3  >99 : 1  67  ( ) : The product ratio o f the corresponding lactones.  25 Two conclusions were drawn from the results of the reduction reactions summarized in Table 1.4. Firstly, the two faces of the ketone carbonyl group were not overwhelmingly biased. In reactions 1, 3, and 4, the diastereoselectivity was hydride donor dependent, the bulkier the hydride donor, the higher the diastereoselectivity. Secondly, the reduction of the /?-keto lactone (Entries 5 and 6) could be influenced by chelation between the cation in the reaction solution and the two carbonyl oxygens. The addition of cations with high chelating ability, such as Li and Mn , increased the diastereoselectivity significantly. The alkylation of the lactams (Entries 12 to 14) showed higher diastereoselectivity than that of the lactones (Entries 7 to 11). Local conformational analysis was used in rationalizing these results (Figure 1.12).  1.2.4 Applications of Conformationally Controlled Reactions in Organic Synthesis A number of natural product syntheses exploiting medium- and large-ring conformations in achieving stereoselectivity were reported by the late 1970s.*''"'"'" This approach has been used in many syntheses since then. For example, in the total synthesis of (±)-3-deoxyrosaranolide 8, the two chiral centers in starting material 7 were used to control the stereochemistry when introducing the additional seven chiral centers.  73  O  O  26  1.2.5 An Interesting Development: Molecular Workbench An interesting development related to the conformationally controlled reactions is the introduction of the "molecular workbench". ' It involves either a chiral olefinic substrate 74 75  and an achiral workbench or an achiral olefinic substrate and a chiral workbench. The substrate and the workbench form a macrocyclic ring, where one of the two faces of the double bond in the substrate is shielded by the ring. This allows diastereoselective epoxidation and osmylation at the double bond in the substrate (Figure 1.14). stereocontrolled  chiral workbench  ri  9  id  t e m  Figure 1.14. Molecular workbenches for stereoselective additions to olefins.  P  | a t e  27 However, the selectivity varies with the length of the substrate chain, the configuration of the double bond in the substrate or the addition reagent. The product ratio can drop from >9:1 to 1:1 simply by increasing the ring size by one carbon or by changing the configuration of the double bond from E to Z.  1.2.6 Summary The previous studies have illustrated the possibilities of achieving diastereoselectivity under the control of the medium- and large-ring conformations. This approach has been used in many organic syntheses. In general, the method used for the rationalization of the conformationally controlled reactions can be summarized as follow:  • Peripheral attack assumption: The incoming reagent prefers attacking the outward face of a double bond in a medium- or large-ring compound. • Low energy conformation approach: Only the low energy conformations of the starting material or intermediate and the low energy conformations of the product are considered as the candidate for the energy analysis. There should be only limited conformational alteration between the starting material or intermediate and the product. • Local conformational control approach: For certain substrates, such as cycloalkenes with monosubstituted allylic positions or lactones (or lactams) of secondary alcohols  (secondary  amines),  the local  conformation of the reaction site remains the same under different low energy  28 conformations of the ring. The local conformation determines the result of the stereoselectivity.  • Molecular mechanics calculations: Molecular mechanics calculations are very useful tools in finding the low energy conformations of the medium- and large-ring systems and their corresponding energies.  It should be noted that the use of conformationally controlled reactions of mediumand large-ring systems as a method of controlling stereochemistry is not widely accepted. The shortcomings of this method are viewed to be the following:  • The lack of understanding of the medium- and large-ring conformations Although the lowest energy conformations of simple medium- and large-ring compounds, such as even membered cycloalkanes and their simple derivatives, are either known or easy to predict, the lowest energy conformations of more complicated rings are still hard to predict without careful conformational searches by molecular mechanics programs. • The flexibility of medium- and large-ring systems One of the features of the medium- and large-ring systems is that it may have a large number of low energy conformations within a small energy range. Sometimes this will lead to low selectivity and make it very difficult to predict the experimental results. For example, in a recent synthesis of (±) - patulolide C, the epoxidation of lactone 9 surprisingly gave a 1 : 1 mixture of the two possible products.  29  50%  50%  • The lack of experimental results Although it has been 20 years since Still introduced the concept of conformationally controlled reactions in medium- and large-ring systems, not enough research has been done in this field. All of the large ring (>10-membered) lactones (and lactams) that have been worked on so far are those of secondary alcohols (or secondary amines). The chiral centers of these compounds are close to the reaction site.  1.3 Research Objectives This thesis describes reactivity studies of 14-membered lactones containing geminal dimethyl groups. The geminal dimethyl groups are introduced for the purpose of biasing the ring conformation. This research tries to answer three questions: i) will the conformations of lactones 11 and 12 influence the rate of the hydrolysis of the ester functions such that the hydrolysis of 11 is faster than that of 12? ii) will the conformations of lactone 14 influence the regioselectivity of the hydroboration reactions at its olefinic function? iii) will it be possible to achieve diastereoselectivity upon alkylation of 37 and 38 which containing stereogenic centers remote from the reaction site?  30 1.4 Ring Closing Metathesis In the synthesis of the medium- and large-ring compounds, ring cyclization is usually one of the crucial steps. Various types of reactions have been used to form these rings. In recent years, the development of the ring closing olefin metathesis (RCM) reaction has provided an extremely useful tool for the synthesis of medium- and large-rings. While RCM has been a routine tool for the synthesis of 5-, 6-, and 7-membered carbo- and heterocycles for a number of years, the use of RCM in the synthesis of large rings has been demonstrated only recently. ' '  77 78 79  The reaction involves a sequence of [2+2] cycloadditions between a metal alkylidene and the double bonds of the substrate and cycloreversion steps (Scheme l.l). ' 79  Q [M]  Catalyst  o >  80  H C=CH 2  [M] = CH  2  Scheme 1.1. The mechanism of the RCM reaction.  [M]  2  31  The catalysts used in the RCM reactions are transition metal alkylidenes. ' "' " !S1 !  !  Although several early transition metal alkylidenes are highly active as catalyst for RCM, their use in organic synthesis is limited because of their intolerance to protic functional groups and impurities. ' ' In contrast, ruthenium alkylidene 10, developed by Grubbs and coworkers, is stable and active in the presence of polar and protic moieties such as alcohols, R7  RR  RQ  aldehydes, ketones, carboxylic acids, esters, amides, and water. ' '  Because of this  development and the high efficiency of RCM in cyclization reactions, this method has been the target of intensive studies recently. ' '  77 90 91  PCy  3  Ru PCy  Ph 3  10  Studies have found that the presence and the position of a polar functional group in the RCM precursor are important to the success of this reaction. ' * For example, the 92 93  94  heteroatoms may serve as coordination sites that hold the metal alkylidene and the substrate double bond close together (Figure 1.15a). However, if the metal alkylidene is located at a position such that it can form a stable five- or six-membered ring by chelation between the metal and the heteroatom, then the catalyst is "trapped" in an unproductive complex (Figure 1.15b and 1.15c). This will seriously lower the yield of the reaction.  32  Figure 1.15. Heteroatom as residence site for the catalyst in the RCM.  Another important factor that influences the RCM is steric hindrance. A methyl group at the allylic position of the substrate will decrease the yield of this reaction dramatically.  92  RCM is applied in the syntheses of the 14-membered lactones studied in this research work. Based on the above discussion, the position of the double bonds for the cyclization reaction was chosen to prevent the formation of the unproductive complex and to be remote from any sterically hindered sites, in this case, the geminal dimethyl groups.  33  Chapter Two Hydrolysis of Conformationally Biased Macrocyclic Lactones  Described in this chapter are the conformational analyses of lactones 11 and 12 and the influence the lowest energy conformations of 11 and 12 have on the reaction rates of the hydrolysis of the ester groups in these two ring systems.  X  X  11  12  The only difference between lactones 11 and 12 is the direction of the ester groups relative to the geminal dimethyl groups. The reason that we choose to study these two lactones is based on their conformational analyses. From the discussion in Section 1.1, we know that the [3434] conformation is the lowest energy conformation for cyclotetradecane and cyclotridecanolide. Also known is that the geminal dimethyl groups prefer to be located at the corner positions. Based on this knowledge, the lowest energy conformations of 11 and 12 can be predicted (Scheme 2.1).  34  [3434] conformation of cyclotetradecane  U V  Geminal dimethyl group at corner position  [3434]  The lowest energy conformation of 11  [3434]  The lowest energy conformation of 12  Scheme 2.1. Predicted lowest energy conformations of 11 and 12.  If the above prediction is accurate, under these lowest energy conformations, the two ester groups are in different environments. What we are interested in is how this difference will affect the reaction rates for the hydrolyses of these two lactones.  2.1 Ester Hydrolysis The mechanism of the ester hydrolysis differs as the reaction condition changes. The acid catalyzed hydrolysis (Scheme 2.2a) is an equilibrium process, in which H functions as +  the catalyst. In contrast, base mediated ester hydrolysis (Scheme 2.2b) is not an equilibrium process. The last step in the base mediated mechanism, in which the acid is converted into  35 the carboxylate salt, is essentially irreversible, and one equivalent of OH" is consumed during the reaction.  95  (a) Acid catalyzed ester hydrolysis  o  II  rY  *la(fost) R'  .c  +  H 0  |  -^==:  +  3  H  R'  A*  *.,,(fest)  +  2  F K ^ O ^  H  H O:  H-'o  z  , ^Cr" R  H  _, OH  OH  H 0  ^ *-2a(fest)  -s  pi  R - C - o '  „ H-OH  /I  2  +  3  =  *-3.(slOW)  +  :  |_|  ,  R - C - 0  H  R^  R  +  O  H  H 0  +  2  R'OH  \OH ,  O  H  ?.  ±22  +  ^  H  +  H0 2  •  7-^-  st)  X  +  H  3°  +  R ^ O H  (b) Base mediated ester hydrolysis  M  *ib(slow)  .C^  .R' O^  Scheme 2.2. hydrolysis.  + "OH  ?  *2b(fa?t)  %(fast)  0  R-C-OR' — — • I *-2b(slow)R^ ^ O H HO +  * lb (fast)  R  O  0  a v  +  R  0  H  O "  The mechanisms of the (a) acid catalyzed and (b) base mediated ester  In the case of acid catalyzed ester hydrolysis (Scheme 2.2a), the rates of formation of the tetrahedral intermediate (fea and k.^ are much lower than either the rates of the collapses of the tetrahedral intermediate (&. and ^ ), or the rates of the proton transfers (k\ 2a  and  &.4a).  a  However, for the majority of the alkyl esters, the collapse of the tetrahedral  36 intermediate back to the ester has a similar rate as the collapse to form the alcohol and the protonated acid. This means that k-2 and fo are of the same magnitude and both contribute to a  a  the rate of the hydrolysis. By the use of the steady-state approximation for the tetrahedral 95  intermediate, the rate of disappearance of the ester, E , can be expressed as  d  r  96  *la£2a*3a[E][H ][H 0]2 +  2  E 1  £-la(A-2a + ^3a)  where r is time. As in the acid catalyzed ester hydrolysis, the formation of the tetrahedral intermediate in the base mediated ester hydrolysis (Scheme 2.2b) is the slowest step. Using the steadystate approximation for the tetrahedral intermediate, the rate of the disappearance of the ester, E , can be expressed as  95  *ib*2b[E][-OH]  d [ E ]  ~dT  ..  =  (2)  *-ib + hb  where t is time. However, in the case of primary alkyl esters, the forward collapse of the tetrahedral intermediate is faster than the backward collapse  (fob > foib)-  The rate of the  07  hydrolysis is thus largely determined by the rate of the addition step.  Furthermore, because  of the structural similarity between the two lactones, the ratios for the rates of the forward and backward collapse must be similar. Therefore it is safe to simplify Equation 2 to Equation 3  = * [E]rOH] lb  (3)  37 On the other hand, the reaction between the strong nucleophile MeS and an ester is -  believed to proceed through an SN2 mechanism. ' '  98 99 100  k s  {?  »  C  +  MeSR'  The rate of disappearance of the ester, E, can be expressed as Equation 4 ffl-=  *[E][MeS-]  (4)  s  2.1.1 Acid Catalyzed Hydrolysis of Macrocyclic Lactones Equation 1 can be applied to the acid catalyzed hydrolysis of macrocyclic lactones (Scheme 2.3). It can be rewritten as [a]  *la*2a*3a[a][H ]|H Op +  d  2  0') d  £-la(£-2a + *3a)  /  H  <?'  HO OH +  a  b  3a  3a  ^<~„.. \  V  /  H 0 3  +  c  K  4a  *Ma  Scheme 2.3. The mechanism for the acid catalyzed hydrolysis of macrocyclic lactones.  38 When the reaction is performed with a large excess of water, and the water concentration is kept essentially constant during the reaction, the reaction is said to be pseudo first-order. If we use &  ac  id  to represent all of the constant terms in Equation 1', that is  *lafoa*3a[H ][H20] +  ^acid  2  (^)  =  £-la(*-2a  +  foa)  Equation 1' can be simplified as  ^=*acid[a]  d")  Upon rearrangement, Equation 1" becomes Equation 6 below,  =£ cid'  (6)  a  [a]  where [a] is the initial concentration of lactone a, and t is time. According to Equation 6, 0  & id ac  is the slope of the linear relationship between time t and ln([a] /[a]), which can be 0  obtained experimentally, simply by monitoring the change in lactone concentration with time. Based on Equation 5, it is obvious that this observed rate constant,  & cid, a  is influenced  not only by the rate of formation of the tetrahedral intermediate (fo ), but also by the basicity a  of the carbonyl group (k\Jk.\a), by the rates of the forward and backward collapse of the tetrahedral intermediate (h /(k. +k3 )), and by the concentrations of the acid ([FT]) and water a  2a  a  ( [ H 0 ] ) . In the case of the hydrolyses of lactones 2  1 1 and 1 2 , we need to compare the rates of  formation of the tetrahedral intermediates (k ) (Section 2.1.4). In order to achieve this, all of 2a  the above influencing factors in k \d must be known. Since the concentration factors ([H ] +  ac  39 and [H2O]) are easy to control, the remaining two factors, the basicities of the ester carbonyl groups (&i /&-ia)  m  e  r a t e s  a  ° f collapse of the tetrahedral intermediates (fo /(^-2a+foa)) a  become the main concerns. The only structural difference between lactone 11 and 12 is the position of the ester groups with respect to the geminal dimethyl groups. However, the two ester carbonyl groups in these two lactones are far removed from the geminal dimethyl groups. No significant structural or steric differences should arise between these two lactones which would differentiate the enviroment of the carbonyl oxygen. It is reasonable therefore, to assume that the two carbonyl groups in lactones 11 and 12 have similar basicities. The ratio between the rates of the forward collapse and the backward collapse of the tetrahedral intermediate in the hydrolysis of lactone 11 should also be similar to that of lactone 12. Since the collapse of the tetrahedral intermediate is a very fast process compared with the formation of the tetrahedral intermediate, the energy barriers from the tetrahedral intermediate to the transition states in both directions are small. This means both transition 95  states resemble the tetrahedral intermediate, and little change should occur except for the partial collapse of the C-OH bond (backward) or the C - O C H 2 - bond (forward). It is therefore reasonable to suggest that the nature of the leaving groups ("OH and " O C H 2 - ) determines the rates of the collapse. Since in both lactones 11 and 12, the leaving groups are either hydroxide ("OH) or long chain primary alkoxide (~OCH -), it is reasonable that the ratios for 2  the rates of the forward and backward collapses are similar.  40  2.1.2 Base Mediated Hydrolysis of Macrocyclic Lactones Similar to the analyses in Section 2.1.1, Equation 3 can be applied to the base mediated macrocyclic lactone hydrolysis (Scheme 2.4).  b  e  d  Scheme 2.4. Base mediated hydrolysis of macrocyclic lactones. Equation 3 can be rewritten as - ^  = *ibirOH][a]  0')  If the reaction is performed with a large excess of OH", it becomes a pseudo first-order reaction. Upon integration, Equation 3' becomes Equation 7,  l i^I°= k n  [a]  base  t  (7)  where [a] is the initial concentration of lactone, t is time, and &base &ib[OH"]. 0  =  Again, the observed rate constant, &base, can be obtained experimentally. Since the concentration of the base (["OH]) can be easily controlled, the rate constant of the formation of the tetrahedral intermediate, ku» can be calculated.  2.1.3 Reaction Between MeS" and Macrocyclic Lactones When Equation 4 is applied to the reaction between MeS" and macrocyclic lactones, we can rearrange it to give Equation 4', where [a] is the concentration of the lactone.  41  d[a] dt  (4')  = * [MeS"][a] s  If the reaction is performed with MeS" in large excess, this reaction would be pseudo firstorder. The above equation can be rearranged to give Equation 8,  In  (8)  [a]  where [a]0 is the initial concentration of lactone, / is time, and ^Mes"= &[MeS"]. s  The observed rate constant, k es~, can be obtained experimentally. Since the M  concentration of methane thiolate ([MeS"]) is known, the rate constant of the reaction, k , can s  be calculated.  2.1.4 The Effect of the Lowest Energy Conformations of Lactones 11 and 12 on the Rate Constants for Hydrolysis and Reaction with MeS" In the case of lactones 11 and 12, we can use the base mediated hydrolysis reaction to analyze the influence of their conformations on the reaction rate. Beginning with the lowest energy conformations of lactones 11 and 12, the energy barriers leading to formation of the corresponding tetrahedral intermediates should be different (Figure 2.1). In the case of 12, the oxide of the resulting tetrahedral intermediate is positioned "inward", towards the center of the macrocyclic ring. This positions the oxide into a hydrophobic "pocket", which limits possible stabilization by solvation. Furthermore, this oxide is at a ring position experiencing the highest number of transannular interactions. On the other hand, although the oxide of the tetrahedral intermediate from 11 is being pushed inward, it occupies a ring position where the least number of transannular interactions are expected, and is much more open for solvation (Figure 2.1).  42 OH  "OH Transannular interaction  Figure 2.1. Formation of the tetrahedral intermediates in the base mediated hydrolysis of 11 and 12. This difference means that, for the base mediated hydrolysis, the activation energy for the formation of the tetrahedral intermediate arising from 12 should be higher than that from 11. In other words, kib (Equation 3') for 11 is expected to be larger than that for 12. The above analysis considers the lowest energy conformations of the two lactones as rigid structures. However, these rings are actually flexible, even though the majority of the molecular populations may exist in the lowest energy conformations. Therefore, higher energy conformations of the two lactones may compete with the lowest energy conformations during the hydrolysis reactions. According to Curtin-Hammett principle, ' 101  102  the reaction of two conformational isomers may proceed through a minor conformation instead of tlie major conformation if the minor conformation provides access to the lowest energy transition state. In our case, the above rate comparison between the hydrolysis of lactone 11 and 12 is valid only if the reaction pathways from the lowest energy conformations to the corresponding tetrahedral intermediates (Figure 2.1) are the most  43 favorite pathways. Since either one or both of the strain energies of the starting material and product should be reflected at the transition state, previous studies  60  assumed that those  pathways leading smoothly from relatively low energy starting geometries to relatively low energy product conformations will be preferred. We will use MACROMODEL program to search for low energy conformations of 11 and 12 as well as analogues of the transition state, and calculate their relative strain energies. We thus can determine the most favored reaction pathways and compare them to the expected pathways shown in Figure 2.1. For the acid catalyzed hydrolyses of 11 and 12, a similar analysis can be made for the step leading to the formation of the corresponding tetrahedral intermediates. The rate constant that correlates to this step,foa(Scheme 2.3), should be larger for the hydrolysis of 11 than that for the hydrolysis of 12. In the case of the reactions between MeS" and lactone 11, as well as MeS" and 12, no significant steric difference is expected to occur during the formation of the two corresponding transition states (Figure 2.2). These reactions are expected to have similar activation energies, and hence, the rate constants, k (Equation 4') should be similar. s  MeS"  Figure 2.2. The reactions of lactones 11 and 12 with MeS".  44 2.2 Synthesis of Lactones 11 and 12 Ring closing metathesis (RCM) was applied in the syntheses of lactones 11 and 12. As discussed in Section 1.3, the reaction site for the cyclization was chosen such that it: (a) is distant from the sterically demanding geminal dimethyl groups; (b) avoids the positions where the unproductive complex could form; (c) is at a position where the formation of the trans double bond is favored by the low energy conformations of the ring being formed. Based on these considerations, esters 15 and 16 were used as the precursors of RCM for the synthesis of 11 and 12 respectively. These two RCM precursors were formed by the coupling between alcohol 17 and acid 19 to give 15, as well as alcohol 18 and acid 20 to yield 16. These alcohols (17 and 18) and acids (19 and 20) were obtained from the commercially available diol 21 and diacid 22 (Schemes 2.5 and 2.6).  Scheme 2.5. Retrosynthetic analysis of lactone 11.  45  Scheme 2.6. Retrosynthetic analysis of lactone 12.  2.2.1 Synthesis of 6-Hepten-l-ol (17) and 7-Octenoic acid (18) Alcohol 17 and acid 18 ' were synthesized from the same starting material, 1,6103  104  hexane diol, 21 (Scheme 2.7). To begin, diol 21 was monoprotected using the method of Nishiguchi and coworkers  105  by reaction with DHP and acidic resin Amberlite IR-120 in  toluene giving 23. This monoprotected diol 23 was then oxidized to the corresponding aldehyde 24 under the Swern  106  conditions. A Wittig reaction between aldehyde 24 and  methyl triphenylphosphonium bromide in THF produced olefin 25 in 78% yield. Finally,  46 removal of the THP ether of 25 with 4-methyltoluene sulfonic acid in MeOH liberated alcohol 17. A portion of alcohol 17 was further elaborated to give acid 18. To this end, alcohol 17 was treated with tosyl chloride in pyridine to produce tosylate 26. Tosylate 26 underwent chain extension by reaction with potassium cyanide to give nitrile 27. Finally nitrile 27 was hydrolyzed to produce the desired acid 18.  Key: (a) DHP, Amberlite IR-20, toluene, r. t., 85%; (b) (COCl) , DMSO, Et N, CH C1 , 78°C, 75%; (c) Ph P CH Br\ w-BuLi, THF, 0°C, 78%; (d) MeOH, p-MeC H S0 H, r. t., 95%; (e) Pyridine, p-MeC H S0 Cl, 0°C, 90%; (f) KCN, MeCN, refluxing, 80%; (g) Ethylene glycol, NaOH, 150°C, then HC1, 82%. 2  3  2  +  3  3  6  6  4  2  Scheme 2.7. Synthesis of 6-hepten-l-ol (17) and 7-octenoic acid (18).  4  3  2  47  2.2.2 Synthesis of 5,5-Dimethyl-7-octenoic acid (19) and 4,4-Dimethyl-6-hepten-l-ol (20) Commercially available 3,3-dimethyl glutaric acid, 22, was the common starting material for the synthesis of acid 19 and alcohol 20 (Scheme 2.8).  32  34  35  O  Key: (a) (CH CO) 0, refluxing, 75%; (b) NaBH , THF, r. t., then HC1, 78%; (c) DIBAH, THF, 0°C, 82%; (d) Ph P CH Br-, «-BuLi, THF, 0°C, 75%; (e) Pyridine, p-MeCetLSOzCl, 0°C, 90%; (f) CH (COOMe) , NaH, THF, 0°C, 87%; (g) NaOH, H 0, then HC1, 100°C, 85%; (h) KCN, MeCN, refluxing, 80%; (i) Ethylene glycol, NaOH, 150°C, then HC1, 80%; 0) LiAlfL, THF, 0°C, 95%. 3  2  4  +  3  2  3  2  2  Scheme 2.8. Synthesis of 5,5-dimethyl-7-octenoic acid (19) and 4,4-dimethyl-6-hepten-l-ol (20).  48  The method developed by Little and Muller  107  was used in the synthesis of compound  30 from 22. In the first step, acid 22 was refluxed in acetic anhydride to form 3,3-dimethyl glutaric anhydride, 28, which was subsequently reduced with sodium borohydride to give lactone 29. Lactone 29 was further reduced with DIBAH to give cyclic hemiacetal 30. A Wittig reaction between hemiacetal 30 and methyl triphenylphosphonium bromide in THF produced 3,3-dimethyl-5-hexen-l-ol, 31, which was further treated with tosyl chloride in pyridine to give tosylate 32. A portion of tosylate 32 underwent chain extension by reaction with dimethyl malonate and NaH to give ester 33. Hydrolysis of ester 33 followed by decarboxylation gave the desired acid 19. A second portion of tosylate 32 underwent chain extension by reaction with potassium cyanide to yield nitrile 34. Nitrile 34 was hydrolyzed by reaction with NaOH in ethylene glycol, followed by HC1 workup to give acid 35,  108  which  was reduced using LiAlH4 to produce the desired alcohol 20.  2.2.3 Synthesis of R C M Precursors 15 and 16 Alcohol 17 and acid 19, as well as acid 18 and alcohol 20, were coupled together using DCC and DMAP to form the RCM precursor 15 and 16 respectively (Scheme 2.9).  49  Key: (a) DCC, DMAP, CH C1 , r. t., 80%. 2  2  Scheme 2.9. Synthesis of the RCM precursor 15 and 16.  2.2.4 Synthesis of 5,5-Dimethyl-13-tridecanolide (11) and 10,10-DimethyI-13tridecanolide (12) RCM was applied to the ring cyclization step to form the two macrocyclic olefins 13 oo  and 14. Grubbs' catalyst was prepared and used for the RCM to generate 13 and 14 in good yields (Scheme 2.10).  50  X  X  15  13  £:Z=95 :5 Cl...  X  X  PCy |  3  ci-R =\ u  I  PCy  Ph H  h  3  Grubbs' Catalyst  E:Z=96  :4  14  16 Key: (a) Grubbs' catalyst, CH C1 , 90%. 2  2  Scheme 2.10. RCM for the synthesis of the macrocyclic olefins 13 and 14.  Both of the RCM reactions leading to the macrocyclic olefins 13 and 14 produced mixtures of E and Z isomers. The E isomers were the major products in both cases. The configurations of the double bonds were determined by the coupling constants between the vinyl protons. The product ratios for both RCM reactions were measured by both GC and proton NMR spectroscopy. Since the double bonds in 13 and 14 were hydrogenated in the next step, the two isomers were not separated at this stage. Macrocyclic olefins 13 and 14 were hydrogenated separately in EtOH to produce the two lactones 11 and 12, respectively (Scheme 2.11).  51  X  X  Key: (a) 10% Pd/C, EtOH, r.t, 95%.  Scheme 2.11. Hydrogenation of 13 and 14 producing lactones 11 and 12.  2.3 Conformational Analysis of Lactones 11 and 12 Since the rationale for the expected outcomes of the hydrolyses experiments was based on the assumption that the lowest energy conformations of lactones 11 and 12 were both the [3434] conformations, and that the majority of the molecular populations of both lactones existed under their lowest energy conformations, it was essential to obtain experimental evidence to support these assumptions. X-ray crystallography, DNMR, and molecular mechanics calculations were used in the conformational studies of these two lactones.  52  2.3.1 X-ray Crystal Structures for Lactones 11 and 12 The X-ray crystal structures of lactones 11 and 12 were obtained. In the solid state these two compounds exist in the [3434] conformations as predicted (Figure 2.3).  0(2)  11  12  Figure 2.3. X-ray crystal structures of lactones 11 and 12.  The endocyclic torsional angles associated with the above X-ray crystal structures are listed in Table 2.1. The corresponding polar maps are shown in Figure 2.4.  53  Table 2.1. Endocyclic torsional angles of the X-ray crystal structures of 11 and 12. Bond '1  a  3  Torsional Angles (°) Lactone 11 Lactone 12 150.3 65.4  2  65.6  -63.0  3  -176.3  -68.5  4  57.5  176.7  5  53.5  -59.3  6  -171.8  -54.3  7  174.9  178.4  8  -54.9  -178.6  9  -58.2  52.7  10  175.4  60.6  11  -64.6  -167.3  12  -60.6  65.6  13  174.8  87.9  14  179.3  178.1  The bond between Cl and C2 is bond 1, and the bond between C2 and C3 is bond 2, so on and so  forth.  54  12  11  Figure 2.4. Polar maps of the X-ray crystal structures of 11 and 12.  2.3.2 Results of Molecular Mechanics Calculations on 11 and 12 Molecular mechanics calculations were performed on lactones 11 and 12 using the program MACROMODEL  with MM3*  force  field parameters. For lactone  11,  conformational search revealed four low energy conformations within a 2 kcal/mol range (Table 2.2).  55  Table 2.2. Low energy conformations of lactone 11 found during a conformational search. Conformation  Side view  Top view  Relative strain energy (kcal/mol)  Population % 25°C -100°C  [3434]  [3344]  [3344]  [3344]  For lactone 12, four low energy conformations were also found having relative strain energies in the range of 2 kcal/mol (Table 2.3).  56 Table 2.3. Low energy conformations of lactone 12 found during a conformational search. Conformation  Side view  Top view  Relative strain energy (kcal/mol)  Population % 25°C -100°C  [3434]  [3344]  [3344]  [3344]  The calculated lowest energy conformations for both lactones are consistent with their X-ray crystal structures. The endocyclic torsional angles of the calculated lowest energy conformations for both compounds (Table 2.4) are very close to those found in the X-ray crystal structures (Table 2.1). The difference is within the range of 1-2°. The polar maps of these two calculated lowest energy conformations (Figure 2.5) are also consistent with those of the X-ray structures (Figure 2.4).  57  Table 2.4. Endocyclic torsional angles of the calculated lowest energy conformations of 11 and 12. Bond  3  Torsional Angles(°) Lactone 11 Lactone 12  1  65.5  147.4  2  66.7  -61.6  3  -175.0  -69.1  4  56.5  177.7  5  54.8  -59.4  6  -173.6  -55.8  7  177.1  178.3  8  -55.0  -175.0  9  -58.3  53.7  10  -176.5  58.1  11  -67.0  -170.5  12  -58.2  67.4  13  171.8  87.5  14  -179.0  -178.4  The bond between Cl and C2 is bond 1, and the bond between C2 and C3 is bond 2, so on and so forth.  58  Figure 2.5. Polar maps of the calculated lowest energy conformations of lactones 11 and 12.  By comparing the calculated lowest energy conformations of lactones 11 and 12 with their X-ray crystal structure, we established that these conformations are indeed the lowest energy conformations of the two lactones. The calculations also suggest that the majority of the molecular populations, 81% for 11 and 75% for 12, exist under the lowest energy conformation at room temperature. These figures increased to 96% for 11 and 93% for 12 at -100°C. In order to obtain experimental evidence in supporting that the calculated molecular population distribution is valid, DNMR was performed on these two lactones.  2.3.3 DNMR Studies of Lactones 11 and 12 The room temperature 'H NMR spectra of 11 and 12 are less complex than the low temperature spectra due to the rapid interconversions among the different conformations. Because of the rapid interconversions, the two protons on each methylene group are averaged  59 by rapid exchange of their environments, and therefore correlate to one signal in H NMR spectra. However, as the temperature is lowered, this rate of interconversion decreases. When the temperature is dropped to the point where the time needed for the conformational interconversion is longer than the 'H NMR time scale, the signal for the two protons on each methylene group will split. If more than one conformation exists at that temperature, then more than one set of signals can be seen in the 'H NMR spectrum. Since the results of the molecular mechanics calculations indicated that essentially all of the molecules of lactones 11 and 12 should exist in their lowest energy conformations at -100°C, one set of signals was expected for the low temperature spectra of these lactones. The H NMR spectra of 11 and 12 were obtained at various temperatures using a 1:1 !  mixture of deuterated toluene and deuterated dichloromethane as solvent. It was clear from these experiments that, for both compounds, their low temperature spectra had only one set of signals (Figure 2.6 and 2.7). It is also of interest to note that at low temperature, the chemical shift difference between the two protons of the methlyne group next to the ester oxygen is much wider for 12 (@ 2.9 and 4.6 ppm, A5 = 1.7 ppm) than that for 11 (@ 3.8 and 4.0 ppm, A8 = 0.2 ppm).  A8 = 0.2 ppm  AS = 1.7 ppm  O  11  12  60  62  2.3.4 Summary The conformational analyses of lactones 11 and 12 were achieved using X-ray crystallography and molecular mechanics calculations. The credibility of the results of the molecular mechanics calculations was supported by DNMR studies of these two lactones. Two conclusions were drawn from these studies: (i) the expected [3434] conformations are the lowest energy conformations for both lactones; (ii) the majority of the molecular populations of both lactones exist under these lowest energy conformations.  2.4 Hydrolysis of Lactones 11 and 12 In this study, lactones 11 and 12 were hydrolyzed under both acidic and basic conditions. Under the basic conditions, the base (OH") was used in large excess. A third experiment involved the reaction of NaSMe with lactones 11 and 12, where NaSMe was employed in large excess. For the purpose of comparison, acyclic ester 36 was also reacted under these conditions. Each of these reactions was performed twice and the results were essentially identical (Appendix II).  GC was used to follow the progress of these reactions by monitoring the disappearance of the starting material. Aliquots of the reaction solution were withdrawn at regular time intervals using a syringe. These samples were quenched and diluted with water. The diluted aliquots were extracted with diethyl ether until no further starting material was detected by GC. An internal standard was then added into the extracted solution. This solution was finally analyzed by GC.  63  2.4.1 Base Mediated Hydrolysis of 11,12 and 36 The plot of ln([a]o/[a]) vs time for the base mediated hydrolysis of lactones 11 and 12, as well as ester 36 are shown in Figure 2.8.  Hydrolysis of 11,12 and 36 under basic conditions at 20 °C 2.50 -  Time (minute)  • Lactone 11 ft Lactone 12 A Ester 36 Lactone 11, y=0.0096x-0.0136, R2=0.9971 Lactone 12, y=0.0066x+0.0872, R2=0.9803  Ester 36,  y=0.0076x+0.0123, R2=0.9943  Figure 2.8. Linear relationships between ln([a]o/[a]) and time for the base mediated hydrolysis of lactones 11 and 12, and ester 36.  These experiments were performed using the solvent system of water : dioxane = 1:2 (v/v) at 20 °C. The OH" concentrations were 0.1147M, 0.2117M and 0.0991M for 11,  64 12 and 36 respectively. Since the slope of the lines in Figure 2.8 are the observed rate constants Abase, the rate constants &ib can be calculated using Abase and the concentrations of OH" (Section 2.1.2). The results are shown in Table 2.5.  Table 2.5. Rate constants for the base mediated hydrolysis of 11,12 and 36. Compound  "OH concentration rOH](M)  Observed constant Abase Cs) -1  11  0.1147  1.6 xlO"  4  12  0.2117  1.1 xlO"  4  36  0.0991  1.3 xlO"  4  Rate constant k (M s ) [  l  lb  1.4 x 10"  3  0.52 x 10"  3  1.3 x 10"  3  These results show that the rate constant (ku,) for the base mediated hydrolysis of lactone 11 is approximately 3 times larger than that for lactone 12, while lactone 11 and ester 36 have similar rate constants. This trend is consistent with our predictions, although the difference is not as pronounced as we expected. These results also suggest that our conformational and kinetic analyses are reasonable.  2.4.2 Acid Catalyzed Hydrolysis of 11,12 and 36 The plot of ln([a] /[a]) versus time for the acid catalyzed hydrolysis of lactones 11 0  and 12, as well as ester 36 are shown in Figure 2.9.  65  Hydrolysis of 11,12 and 36 under acidic conditions at 58 °C 2.5  T  700 Time (minute) •  Lactone 11  •  Lactone 12  A  Ester  36  Lactone 11, y=0.0039x+0.0406, R2=0.9939 Lactone 12, y=0.0013x+O.0209, R2=0.9941 Ester 36,  y=0.0036x-0.0025, R2=0.9988  Figure 2.9. Linear relationships between ln([a]o/[a]) and time for the acid catalyzed hydrolysis of lactones 11 and 12, and ester 36.  These experiments were performed using the solvent system water : dioxane =1:2 (v/v) at 58°C. The H* concentration was 0.390M for all three hydrolyses of 11, 12 and 36. The slopes of the lines in Figure 2.9 are the observed rate constants k , where acid  66 £  a d d  (Equation 5, Section 2.1.1). Since k\ , k.\ , kj and &-3 were not  =  a  a  a  a  *-la(*-2a + ^3a)  known, it was impossible to obtain the rate constant & from the observed rate constant Ar idac  2a  However, based on the analysis in Section 2.1.1, the basicities of the carbonyl oxygens in these three compounds are the same, and the ratios between the forward and backward collapse rates of the tetrahedral intermediates for the three compounds are similar. Therefore, it is possible to calculate the relative rate constants for these reactions (Table 2.6). Table 2.6. Relative rate constants for the acid catalyzed hydrolysis of 11,12 and 36. Compound  Concentration of H & H20(M) +  Observed constant A id (s ) _1  aC  Relative rate constant £ * 2a  11  0.390 & 18.5  6.5 xlO"  5  3.0  12  0.390 & 18.5  2.2 x 10"  5  1.0  36  0.390 & 18.5  6.0 xlO"  5  2.8  * obtained under the assumption that the basicities of the carbonyl oxygens are the same among the three compounds.  The rate constant (£ ) for the acid catalyzed hydrolysis of lactone 11 is 2a  approximately 3 times larger than that of lactone 12, while lactone 11 and ester 36 have similar rate constants. This trend was seen in the base mediated hydrolysis, and was therefore what we had expected here. Again, the difference between the magnitude of & among the 2a  three compounds is not as significant as expected.  2.4.3 Lactone Ring-openning with MeSNa The plot of ln([a] /[a]) versus time for the reaction between MeSNa and lactones 11 0  and 12, as well as ester 36 is shown in Figure 2.10.  67  Reactions between MeSNa and 11,12 and 36 at 20 ° C 3.50 -  200  Time (minute) •  Lactone 11  & Lactone 12 •  Ester  36  Lactone 11, y=0.0203x-0.0483, R2=0.9907 Lactone 12, y=0.0153x-K).0165, R2=0.9959 Ester  36, y=O.0074x-K).0O07, R2=0.9874  Figure 2.10. Linear relationships between ln([a]o/[a]) and time for the reactions between MeSNa and lactones 11 and 12, and ester 36.  These experiments were performed in DMPU at 20°C. The concentration of MeS" used was 0.500M for reaction with each of 11, 12 and 36. Since the slopes of the lines in Figure 2.10 correspond to the observed rate constants ^Mes, the rate constants k can be s  calculated using &Ms" and the concentration of MeS" (Section 2.1.3). These results are shown e  in Table 2.7.  68  Table 2.7. Rate constants for the reactions of MeS" with 11,12 and 36. Compound  MeS" concentration [MeS"] (M)  Observed rate constant W (s") 1  Rate constant h (M-'s" ) 1  11  0.500  3.4 xlO"  6.8 xlO"  12  0.500  2.6 xlO"  5.2 xlO"  36  0.500  1.2 xlO"  2.5 xlO"  4  4  4  4  4  4  As we expected, the rate constants for reactions of MeS" with the two lactones, 11 and 12, were similar. However, it is interesting to note that the rate constant for the reaction of acyclic ester 36 with MeS" is smaller than those for the lactones.  In general, all of the experimental results fulfilled our expectations based on conformational and kinetic analysis. However, the conformational effects were not as significant as we had expected. In order to rationalize this discrepancy, molecular mechanics calculations were performed to determine the activation energy differences for the hydrolyses of 11 and 12.  2.5 Rationalization of the Relative Rates of the Lactone Hydrolysis Using Molecular Mechanics Calculations In order to calculate the rate constants for the hydrolyses reactions, we needed the activation energies. However, it was not possible to calculate the energies of the transition states. Structures with similar strain energies to the tetrahedral intermediates had to be used to simulate the transition states. Structures A and B were chosen for this purpose for 11 and 12 respectively.  69  X  X  A  B  A conformational search revealed that the lowest energy conformation of structure A adopts the [3434] conformation. However, for structure B, the lowest energy conformation is no longer the [3434] conformation. The carbon bearing the geminal dihydroxyl groups twisted such that the inward hydroxyl group is away from the center of the ring in the lowest energy conformation (Table 2.8).  70  Table 2.8. Calculated lowest energy conformations of lactones 11 and 12 as well as structures A and B. Compound  a  Side view  Top view  Relative strain energy (kcal/mol)  Lactone 11  Lactone 12  Structure A  Structure B  The relative free energy was calculated as in water solution. b  The strain energy of 11 was considered as zero, and the strain energy of 12 is relative to that of 11.  0  The strain energy of A was considered as zero, and the strain energy of B is relative to that of A.  The endocyclic torsional angles for the lowest energy conformations of structures A and B are listed in Table 2.9, and their polar maps are shown in Figure 2.11.  71  Table 2.9. Endocyclic torsional angles for the calculated lowest energy conformations of structures A and B. Bond  3  Torsional Angles(°) Structure A Structure B  1  52.6  65.5  2  71.7  -72.9  3  -179.0  -63.8  4  55.2  -173.5  5  54.6  -56.9  6  -173.5  -56.4  7  175.9  176.9  8  -55.3  -166.9  9  -57.9  53.2  10  176.4  57.1  11  -67.2  -158.2  12  -58.3  68.0  13  -178.5  178.3  14  -173.3  -176.2  The bond numbers are analogous to the corresponding lactones.  72  A  Figure  2.11.  B  Polar maps for the calculated lowest energy conformations of A and  B.  By comparing the endocyclic torsional angles (Table 2.9) and polar maps (Figure 2.11) for the lowest energy conformations of structures A and B with those of lactones 1 1 and 1 2 (Table 2.1, 2.4 and Figure 2.4, 2.5), we can clearly see that the lowest energy conformation essentially remained constant from lactone 11 to structure A . However, from lactone 1 2 to structure B , bond 13 and the neighboring bonds in their lowest energy conformations have undergone single-bond rotation. The routes from the lowest energy conformations of lactones 11 and 1 2 to the lowest energy conformations of structures A and B must be favored, because they started and ended up with the lowest energy conformations and progressed with little disturbance to the gross conformations. Thus it is reasonable to use the energy data in Table 2.8 to calculate the difference in the activation energies between the  73 hydrolyses of lactones 11 and 12. Since this assumes that the difference in the transition state energies is 1.18 kcal/mol, and the energy difference between the starting materials is 0.23 kcal/mol (Table 2.8), the proposed difference in the activation energies is 0.95 kcal/mol. The differences in the activation energies calculated from the experimental ratios of the reaction rate constants are 0.72 kcal/mol for acid catalyzed hydrolysis and 0.56 kcal/mol for base mediated hydrolysis of lactones 11 and 12. These are very close to the calculated value of 0.95 kcal/mol.  2.6 Summary In this part of the research, two macrocyclic lactones, 11 and 12, were synthesized. The lowest energy conformations of 11 and 12 were predicted based on previous knowledge of medium- and large-ring conformations. Also expected was that these lowest energy conformations were populated far more than any other conformations. These expectations were confirmed by X-ray structures of both compounds and molecular mechanics calculations. The results of the calculations were further supported by 'H DNMR studies of  11 and 12. Based on these conformational understandings, the rate of hydrolysis for lactone 11 was predicted to be greater than that for lactone 12 under both acidic and basic conditions. Furthermore, both lactones should have similar rates of reaction with sodium methyl sulfide. Experimentally, this was shown to be the case. Also found was that the rate of hydrolysis of lactone 12 was similar to that of acyclic ester 36 under both acidic and basic conditions. Experimentally, the difference between the rates of hydrolysis of lactones 11 and 12 were not as pronounced as expected. In order to rationalize the results, two structures, A and  74 B, were chosen as models to simulate energetically the transition states. The lowest energy conformations of lactones 11 and 12, as well as transition state analogues A and B were found by conformational searches using molecular mechanics calculations. Minor conformational alternations were found between 11 and A, as well as between 12 and B. The calculated energy difference between the lowest energy conformations of lactones 11 and 12, as well as between the lowest energy conformations of A and B were found. These calculated energy differences were used to represent the energy differences between the starting materials and the energy differences between the transition states. Thus the difference between the two activation energies was estimated. This calculated activation energy difference is in agreement with those calculated from the experimental rate data. The results of this study indicate that the conformations of macrocyclic compounds do have influence on their chemical properties. However, the conformational effects were not significant due to the flexibility of these ring systems.  75  Chapter Three Conformationally Controlled Regio- and Stereoselective Reactions of 14-Membered Lactones  As discussed in Chapter one, geminal dimethyl groups prefer to be located at the corner positions of 14-membered ring systems to avoid transannular interactions. The geminal dimethyl groups in lactones 11 and 12 are expected to stabilize the lowest energy conformations of the two lactones. This conformational effect was shown in the hydrolysis experiments of these two lactones. This encouraged us to study structurally similar lactones in reactions other than hydrolysis. This chapter describes studies probing the possibility of achieving regio- and diastereoselectivity  by exploiting the conformational bias of  14-membered rings.  Hydroboration of the double bond in 10,10-dimethyl-7-tridecenolide, 14, was chosen for the purpose of studying possible regioselectivity. The two possible products, 7-hydroxyl-10,10dimethyl tridecanolide, 37, and 8-hydroxyl-10,10-dimethyl tridecanolide, 38, were subsequently alkylated at the a- positions of the ester carbonyl groups to probe possible diastereoselectivity. Since the hydroxyl groups in 37 and 38 are remote from the alkylation sites, they were used to influence the stereochemical outcome of the alkylation reactions through conformational control (Scheme 3.1).  76  Hydroboration and alkylation reactions chosen for the purpose of regio- and diastereoselectivity studies with 14-membered ring lactones. S c h e m e 3.1.  Alkylation at the cr-position of the ester carbonyl group in 14 would introduce a stereogenic center into the ring to form 2,10,10-trimethyl-7-tridecenolide, 43. This  77 stereogenic center may differentiate the accessibility of the two faces of the double bond in 43 under the influence of the ring conformation. Hydroboration and epoxidation reactions at this double bond were used to investigate possible face selectivity (Scheme 3.2).  41  42  Scheme 3.2. Hydroboration and epoxidation reactions chosen to investigate possible face selectivity with 14-membered ring lactone 43.  78  3.1 Synthesis of 10,10-Dimethyl-7-tridecenolide (14) The synthesis of compound 14 was described earlier in Chapter Two (Scheme 2.2.4). This compound was re-synthesized in a slightly different way in this chapter to save steps. The intermediate, 7-octenoic acid, 18, was synthesized from either heptane-1,7-diol, 46, or 5-hexene-l-ol, 51, as described in this chapter (Scheme 3.3), instead of from hexane-l,6-diol, 21, as in Chapter Two (Scheme 2.6).  Key: (a) DHP, Amberlite IR-20, toluene, r. t., 85%; (b) (COCl) , DMSO, Et N, CH C1 , 78°C, 82%; (c) Ph P CH Br\ n-BuLi, THF, 0°C, 80%; (d) MeOH, PPTS, r. t., 95%; (e) Jones reagent, acetone, r. t., 90%. (f) Pyridine, p-MeC H S0 Cl, 0°C, 90%; (g) CH (COOMe) , NaH, THF, 0°C, 87%; (h) NaOH, H 0, 90°C, then HC1, DMF, reflux, 75%. 2  3  +  3  3  6  2  2  Scheme 3.3. Synthesis of 7-octenoic acid (18).  2  4  2  2  2  79 The RCM reaction produced two isomers with the cis and trans configuration of the double bond (Scheme 2.10). The major isomer, the trans isomer, was enriched using a AgNC<3 impregnated silica gel radial chromatographic plate, ' 109  110  to -99% purity.  3.2 Hydroboration Reactions of 10,10-Dimethyl-7-tridecenolide (14): a Regioselectivity Study The hydroboration reaction is regioselective towards unsymmetric alkenes. The regioselectivity of the hydroboration reaction is controlled by both steric and electronic factors: the boron binds to the less hindered carbon. Oxidation of the resulting alkylborane with hydrogen peroxide gives an alcohol with the hydroxyl group on the less hindered carbon (Figure 3.1).  111  Figure 3.1. Suggested mechanism of the hydroboration reaction.  In the case of 10,10-dimethyl-7-tridecenolide, 14, both of the vinyl carbons are monosubstituted. One possible factor that may lead to regioselectivity on hydroboration of 14 is  80 the influence of the ring conformations, which may render one of the vinyl carbons more accessible over the other. 3.2.1 Result of the Hydroboration Reactions of 14 Three different hydroboration reagents were used for the reactions, borane dimethyl sulfide, disiamyl borane and 9-BJ3N (Scheme 3.4). The reactions were performed at room temperature in THF. The oxidation step was carried out at 0°C for 30 minutes using H2O2 and NaOH. Two regioisomers were obtained from this reaction with a combined yield of 85%. The products were separable on TLC, and were separated and purified by silica gel column chromatography. The product ratio was based on the isolated yields.  s  (1) ^ B - H , T H F , r.t.  HO  v v  + (2) H 0 , NaOH, 0°C 2  2  14  37  OH  <V  0  38  Scheme 3.4. Hydroboration of (£)-10,10-dimethyl-7-tridecenolide (14).  We were not able to assign the regiochemistry to the two products according to their !  H NMR spectra. This was achieved chemically, and will be discussed in Section 3.2.2. The  product ratios are listed in Table 3.1.  81  Table 3.1.  Product ratios obtained from the hydroboration of tridecenolide, 14.  10,10-dimethyl-7-  a  Hydroboration reagent  37  38  Borane dimethylsulfide  1.0  1.1  84  Disiamylborane  1.2  1.0  82  1.4  1.0  78  9-BBN a  Overall yield (%)  isolated product ratios.  3.2.2 Regiochemistry Assignment of the Hydroboration Products of 14 In order to determine the regiochemistry of the two hydroboration products of 14, the chemical conversions illustrated in Scheme 3.5 were carried out (Scheme 3.5).  82  ™  57  56  Key: (a) MCPBA, CH C1 , r. t., 92%; (b) Cone. HC1, THF, r. t., 95%; (c) PCC, CH C1 , r. t, 85%; (d) Zn, HOAc, THF, r. t., 90%; (e) K-selectride, THF, -15°C, 84%. 2  2  2  2  Scheme 3.5. Chemical conversions for the determination of the regiochemistry of the hydroboration products of 14. Epoxidation of the double bond in 10,10-dimethyl-7-tridecenolide, 14, gave epoxide 54. This epoxide was opened by reaction with concentrated hydrochloric acid in THF giving 55. Surprisingly, only one of the two possible products was obtained. The hydroxyl group in 55 was then oxidized with PCC to give compound 56. Reaction of 56 with zinc removed the chloride, giving 57. Further reduction of the ketone group in 57 gave compound 38, one of the regioisomers obtained from the hydroboration of compound 14.  83 The structures of two of the above compounds, 56 and 57, were used to deduce the regiochemistry of 55 and 38. In the 'H NMR spectrum of 56, a quartet appears at 2.5 ppm which belongs to the two protons of the methylene group at position 9 (Figure 3.2). This is characteristic of 56 instead of the other possible regioisomer 58. In the 'fi NMR spectrum of 57, the singlet at 2.3 ppm correlated to the two protons at position 9. This ruled out the other regioisomer 59 (Figure 3.2).  Figure 3.2. Characteristic 'FI NMR signals for 56 and 57.  84  3.2.3 Rationalization of the Reaction Results 3.2.3.1 Hydroboration Hydroboration of the double bond in macrolide 14 resulted in little or no regioselectivity, although a general trend appears which suggests that bulky hydroborating reagents prefer to bind to the vinyl carbon away from the quaternary center. Previous studies, both experimental ' ' ' 112  113  114  115  and theoretical, '  116 117  suggest an early  transition state for hydroboration reactions. We therefore performed conformational searches of the starting material 14 using MACROMODEL. More than 40 low energy conformations were found within 2 kcal/mol of the lowest energy conformation. However, the local conformations of the double bond in these low energy conformers are similar. This can be seen in the three lowest energy conformations found by the calculations (Table 3.2). In these conformations, the two vinyl carbons have similar environments. No significant steric reason exists to differentiate the accessibility of the hydroboration reagent toward the two vinyl carbons. It is not surprising that non-hindered borane reagents can bind to both vinyl carbons with equal chances.  85  Table 3.2. The three lowest energy conformations of 14 found by molecular mechanics calculations. 3  Conformation Side view  Top view  Relative strain energy (kcal/mol)  0.00  0.14  0.29  O  calculated as in chloroform solution.  86  3.2.3.2 Cleavage of the Epoxide Moiety in 54 The highly regioselective cleavage of the epoxide in compound 54 leading to only one product, 55, was an unexpected result. A conformational search using MACROMODEL was performed on the starting material 54. Twenty low energy conformations were found within 2 kcal/mol of the lowest energy conformation. The two lowest energy conformations are shown in Figure 3.3 alone with their relative strain energies.  Side view  Top view  0.00 kcal/mol  0.63 kcal/mol  Figure 3.3. The two lowest energy conformations of compound 54 and their relative strain energies.  In all of the 20 low energy conformers, the local conformations about the epoxide moieties remained consistent with that of either the lowest energy conformer or with that of the second lowest energy conformer. Under these two local conformations, the attack of carbon at position 8 by Cl" is hindered by the pseudoaxial methyl group (Figure 3.4). This  87 explains why only the isomers with the hydroxyl group at position 8 and chloride at position 7 were obtained.  Hindered  Figure 3.4. The two possible local conformations in the low energy conformations of compound 54.  3.2.3.3 Insights Into the Lowest Energy Conformations of 14 and 54 From molecular mechanics calculations, it was determined that compounds 14 and 54 have the same lowest energy conformation. However, this lowest energy conformation is not the conformation we had expected. The expected lowest energy conformations for 14 and 54 were those similar to the lowest energy conformation of lactone 12. In Chapter two, we performed conformational analysis on lactone 12, which suggested a [3434] conformation as its lowest energy conformation. This suggestion proved to be consistent with the X-ray structure of 12 and the lowest energy conformation found by molecular mechanics calculations. Based on that knowledge, similar [3434] conformations were thought to be the most likely lowest energy conformations for 14 and 54 (Figure 3.5). Since the replacement of - C H 2 - C H 2 - with an olefin function or an epoxide in the lowest energy conformation of 12 at position 7 and 8 removed  88 two inward hydrogens, this was expected to further stabilize the [3434] conformation. Furthermore, these expected lowest energy conformations could also be used to rationalize the experimental results of the hydroboration of 14 and the regioselective cleavage of the epoxide moiety in 54. However, the lowest energy conformation for compounds 14 and 54 found through a molecular mechanics conformational search is a [3'4'3'4'] conformation.  O Expected lowest energy conformation of 54  Figure 3.5. The lowest energy conformation of 12 and the expected lowest energy conformations of 14 and 54.  The question is why these expected conformations did not show up as the lowest energy conformations for 14 and 54 in the calculations? By comparing the calculated lowest energy conformations with the expected conformations, we found that in the calculated ones, the ester group and the double bond (or the epoxide) located at the three bond sides of the ring, while in the expected lowest energy conformations they were located at the four bond sides (Figure 3.6). It is very possible that the inside of the expected lowest energy conformations were too "empty" to support the ring without collapsing. In other words, these  89 arrangements were not space efficient. While the interaction between the inward protons on the four-bond sides in the calculated conformations supported the rectangular structure of the ring without the possibility of collapsing. We concluded that the calculated results are reasonable. Compound 14  Expected [3434] lowest energy conformaitons  Compound 54  I R  I O  Calculated [3'4'3'4'] lowest energy conformations  Figure 3.6. Top views of the expected and calculated lowest energy conformations for compounds 14 and 54.  3.3 Alkylation Reactions of the Silyl Ether Derivatives of 7-HydroxyI-10,10-dimethyI Tridecanolide (37) and 8-Hydroxyl-10,10-dimethyl Tridecanolide (38): a Study of Diastereoselectivity Hydroboration of the double bond in 14 produced two regioisomers, 37 and 38, both possessing a newly formed stereogenic center. We were interested in seeing how these newly formed stereogenic centers would influence the relative stereochemistry of the alkylation reactions at the a-position of the ester carbonyl group (Scheme 3.6). Since the stereogenic  90 centers are remote from the reaction site, 5 and 6 bonds away in 37 and 38 respectively, these centers can only influence the diastereoselectivity of the alkylation reactions through the ring conformations.  HO.  HO.  37  f ^ O H  38  HO„  39  r ^ O H  41  40  'OH ^ |  +  42  Scheme 3.6. Alkylation at the a-position of the ester carbonyl group in 37 and 38.  3.3.1 Results of the Alkylation Reactions of Silyl Ethers 60 and 61, Derived From Alcohols 37 and 38 Respectively The hydroxyl groups in both 37 and 38 were reacted separately with trimethyl silyl chloride to form silyl ethers 60 and 61, respectively (Scheme 3.7). Alkylation of these two silyl ethers, 60 and 61, was performed at -78°C in THF, using LDA as the base and Mel as the alkylating reagent.  91  Scheme 3.7. Reactions involved in the diastereoselectivity study.  92 The first difficulty encountered during this study was determining the ratios of the alkylation products. Neither 62 and 63 nor 64 and 65 were separable by GC. Although 62 and 63, as well as 64 and 65, could be separated by silica gel chromatography, it was not known if the TMS group could survive this process of purification. As a result of this concern, the TMS group was removed using TBAF following the alkylation reaction. Unfortunately, the products, 39 and 40 as well as 41 and 42 still could not be separated by GC. This problem was finally solved using 'H NMR spectroscopy. The lowest field signals in the 'H NMR spectra of 39, 40 and 37 are far enough apart for quantitative analysis. This is also true for the spectra of 41, 42 and 38. The 'H NMR reaction mixtures were recorded and the result are shown in Figure 3.7.  Mixture from 37  Mixuture from 38  Figure 3.7. 'H NMR spectra (500 MHz) of the reaction mixtures from the alkylation of 37 and 38.  93 From these spectra, the following product ratios were found.  39:40= 1.4: 1 41 : 42= 10 : 1 The second difficulty encounted in this study, the assignment of the relative stereochemistries of these alkylation products, is discussed in Section 3.3.2.  3.3.2 Relative Stereochemistries in the Alkylation Products of 37 and 38 Although two of the four alkylation products are solids at room temperature, attempts to grow X-ray crystallographic quality crystals were unsuccessful. Without X-ray structures, we relied on  NMR spectra and conformational analysis to determine the relative  stereochemistries of 39 and 40 as well as 41 and 42. For the purpose of comparison, compound 37 is used in the assignment of the relative stereochemistry for 39 and 40, and compound 38 is used in the assignment of the relative stereochemistry of 41 and 42.  3.3.2.1 Assignment of the Relative Stereochemistries Between 39 and 40 The 'H NMR spectra of 39, 40, and 37 are shown in Figure 3.8. Proton decoupling experiments were performed on the three downfield signals in each of these three spectra. These experiments indicated that, in Spectrum 1, the two signals at 3.45 ppm and 4.85 ppm, in Spectrum 2, the two signals at 4.05 ppm and 4.25 ppm, and in Spectrum 3, the two signals at 3.65 ppm and 4.55 ppm, correlated to the two protons on the carbon at position 13. The analyses will focus on these six signals, elucidating structural information from the comparison of their chemical shifts and coupling constants.  Spectrum 3  ee  «o  s 5  so  AS  A  a  3  S  3  O  Figure 3.8. 500 MHz *H NMR spectra of 39, 40, and 37.  2 8  20  ,  1  5  1  0  0  5  95  3.3.2.1.1. Interpretation of the Chemical Shifts in the *H NMR Spectra of 39,40 and 37 The distances (the AS-values) between the two signals under concern in each spectrum vary. They are 1.4 ppm, 0.2 ppm, and 0.9 ppm in Spectra 1, 2, and 3 respectively. The question becomes how can we interpret these chemical shift differences in terms of structural differences? In Chapter One, we have established that the [3434] conformation was the lowest energy conformation of lactone 12, and at low temperature (180K), literally all the molecules existed under this conformation. In other words, the H NMR spectrum obtained at 180K was l  actually the spectrum of this lowest energy conformer. In this spectrum, the two signals that correlate to the two protons on the carbon at position 13 were found to have a A8-value of 1.7 ppm. In fact, for lactone 12, two enantiomeric conformations have the same energy and are both the lowest energy conformations (Figure 3.9a). At low temperature, the conversion between these two conformers is slow, which makes the proton exchange at each methylene group slower than the NMR time scale, leading to a spliting of the signals. In compounds 39, 40, and 37, the hydroxyl group at position 7 and the methyl group at position 2 should have little direct electronic influence on the chemical shifts of the protons at position 13, since they are remote. Their influences on the chemical shifts of the protons at position 13 have to be realized through their effects on ring conformations. For compound 37, the hydroxyl group should not influence the ring conformation to change from the [3434] lowest energy conformation found for lactone 12. However, it will bias the ring conformation to one of the two [3434] conformations (Figure 3.9b). Under this lowest energy conformation, the NMR signals corresponding to the two protons at position 13 should have a A8-value of -1.7 ppm. However, at room temperature, a substantial portion of the  96 molecular populations exist under other conformations. The rapid conversion between these conformations should result in a A5-value less than 1.7 ppm. The experimental A8-value was found to be 0.9 ppm, in agreement with our prediction. Conformational analysis of compound 40 suggests that the hydroxyl group at position 7 and the methyl group at position 2 should both offer stabilizing influences to support the [3434] conformation as the lowest energy conformation (Figure 3.9c). Therefore at room temperature, a smaller percentage of the molecular populations of compound 40, compared with those of compound 37, should exist with conformations other than the lowest energy conformation. The A8-value of the two *H NMR signals corresponding to the two protons at position 13 in 40 is expected to be between 0.9 ppm and 1.7 ppm. While in compound 39, either the hydroxyl group at position 7 or the methyl group at position 2 is projecting inward in both of the [3434] conformations (Figure 3.9d). These [3434] conformations are expected to have relatively high energies, and therefore are unlikely to be the lowest energy conformation. It is possible that the above "conflict" between the hydroxyl group and the methyl group will result in greater conformational mobility for 39, and narrow down the energy differences between the low energy conformations. These conformations are thus similarly populated. The rapid conversion between these similarly populated low energy conformations is expected to result in a decrease in the A8-value (< 0.9 ppm) corresponding to the two protons at position 13. Based on the above analysis, we tentatively assign Spectrum 1 to compound 40 and Spectrum 2 to compound 39.  97  Molecular mechanics calculations were performed on compounds 39, 40, and 37. As expected, the calculated lowest energy conformations of 37 and 40 were found to be the [3434] conformations that we suggested. Furthermore, the calculations also suggest that at  98 room temperature 65% of the molecular populations of 37 and 82% of the molecular populations of 40 existed in their lowest energy [3434] conformations. These calculations support our interpretation of the A5-values for compounds 37 and 40. Calculations also revealed that the lowest energy conformation of 39 was no longer the [3434] conformation, and more encouragingly, the two lowest energy conformations found have the same energy and are equally populated. This result strongly supports Our rationale offered for the small chemical shift difference (the A5-value) between the two signals found in the *H NMR spectrum of 39. We were not able, however, to provide a rationale for why the two protons at position 13 had such a large difference in their chemical shifts under the [3434] conformation. Furthermore, we could not assign the two protons to the two NMR signals. Although the above analyses are self satisfied without knowing these details, we analyzed the coupling constants of the H NMR signals corresponding to the position 13 protons to provide more !  evidence to support our conclusion. This analysis is discussed in the following section.  3.3.2.1.2 Analysis of the Coupling Constants in the *H NMR Spectra of 39, 40 and 37 Similar to the chemical shift analyses, here for the coupling constant analysis we will focus solely on the two protons at position 13 in all three compounds, 39, 40 and 37. In all these compounds, each of the two protons couples with three other protons: one on the same carbon (J) and two on the adjacent carbon (position 12) ( Js). Therefore, the multiplicity of the signal for each of the two protons is expected to be a doublet of doublet of doublets (ddd). The related signals in spectra 1,2, and 3 were enlarged and the coupling constants are provided, as illustrated in Figure 3.10.  99  4 0 O  4 6 O  470  Figure 3.10. Downfield and 37.  4 6 O  4 3 O  4 4 O  4 3 O  4 2 O  4 .1 O  4 O D  380  360  370  3 O O  NMR signals correlate to the two protons at position 13 in 39, 40  100 The signals of interest in Spectra 1 and 3 are clean and resolved. The downfield signal has six peaks in spectrum 1 and eight peaks in spectrum 3. The upfield signal has only three peaks in both spectra. It is obvious that for both spectra, the J values are 10.8 Hz. The two J 2  3  values for the upfield signals in both spectra are again the same, 10.8 Hz and <1 Hz. The two J values for the downfield signal in Spectrum 1 are both 3.5 Hz, while the two J values corresponding to the downfield signal in Spectrum 3 are 2.8 and 4.5 Hz. It is interesting to note that in both spectra 1 and 3, the upfield signals reveal one •3  -J  large J value (>10 Hz), and one small J value (< 1 Hz). According to the Karplus -3  relationship, a large J indicates that the dihedral angle between the two coupled protons is either close to 0° or close to 180°, while a small J value indicates that the dihedral angle is 3  close to 90°. Since these compounds undergo rapid conformational interconversion at room temperature, it is not likely for a proton to have fixed dihedral angles with its neighboring protons. The only explanation for the observed J values is that for these two lactones, most 3  of the molecules exist in the conformations having dihedral angles, between the protons under consideration, consistent with these J values. •  9  "3  The corresponding J and J values associated with the signals in Spectrum 2 are not as obvious. The J values were found to be ~11 Hz. Spin decoupling experiments were performed in an attempt to determine the V values. Unfortunately, these decoupling experiments did not result in the well-resolved splitting patterns we had anticipated (Figure 3.11). The V values, therefore, had to be estimated based on the width of the signals. The widths of both signals are 12 Hz. It is therefore reasonable to estimate that the J values are 5•3  7 Hz, which is a typical J value for protons that can rotate freely. This indicates that either "3  the majority of the molecular populations exist with conformations that give modest J  101 values, or that the rapid conversion between different conformations with similar populations averages the J value.  Decoupled at 4.24 ppm  -i  4.3  •  1  1  4.2  4.1  ~~"—~~i  4.0  ppm  Figure 3.11. 400 MHz H NMR spin decoupling experiments between the two protons at position 13 in compound 39 (Spectrum 2, Figure 3.10). l  102 Next, we related the above information to the structures of compounds 37, 39 and 40 using molecular mechanics calculations. The low energy conformations within 2 kcal/mol were found by molecular mechanics calculations for 39 (Table 3.3), 40 (Table 3.4), and 37 (Table 3.5). Their relative strain energies, calculated dihedral angles, and corresponding J 3  values are also included in these tables. -3  Table 3.3.  Calculated low energy conformations, dihedral angles and J values for compound 39. a  Relative Conformation 39a  39b  39c  39d  39e  H  free energy  %@  %@  (kcal/mol)  298K  0.000  45.8  0.068  1.118  1.385  1.839  40.8  6.9  4.4  2.1  200K  DA (degree)  51.5  43.3  3.1  1.6  0.5  H  3 R  s  (Hz)  DA (degree)  (Hz)  73.8  0.6  -43.0  4.5  -170.7  11.2  72.6  1.8  -69.3  11.4  173.1  2.2  46.2  0.8  -71.4  3.9  -66.1  11.6  176.6  2.6  49.3  1.0  68.0  3.4  77.5  0.4  -39.9  5.1  -167.0  10.8  75.6  1.4  70.6  0.8  -46.4  3.9  -173.9  11.4  69.2  3.2  d  d  J  3  The calculations were performed as in chloroform solution. The upper row J and DA values correspond to the pro-R proton at position 12, and the lower row J and DA values correspond to the pro-S proton at position 12. Pro-R proton at position 13. Pro-S proton at position 13. DA = dihedral angle. a  3  0  d  103  Table 3.4.  Calculated low energy conformations, dihedral angles and J values for compound 40. 3  a  Relative Conformation  40a  40b  40c  40d  H  H  b R  C S  energy  %@  %@  (kcal/mol)  298K  200K  DA (degree)  J  (Hz)  DA (degree)  (Hz)  0.000  81.60  92.7  68.1  2.3  -174.7  11.5  -47.5  3.7  69.7  0.9  69.3  2.2  -173.2  11.4  -46.2  3.9  71.3  0.8  70.5  2.0  -45.1  4.1  71.7  0.7  -73.8  0.6  42.9  4.5  170.7  11.2  -72.6  1.8  1.134  1.510  2.854  12.03  6.37  5.2  2.0  d  3  d  . -172.8  J  3  11.4  The calculations were performed as in chloroform solution. The upper row V and DA values correspond to the pro-R proton at position 12, and the lower row J and DA values correspond to the pro-S proton at position 12. Pro-R proton at position 13. Pro-S proton at position 13. DA = dihedral angle. a  3  c  d  104  Table 3.5.  Calculated low energy conformations, dihedral angles and J values for compound 37. a  Relative free Conformation 37a  37b  37c  37d  37e  37f  37g  H  energy  %@  %@  (kcal/mol)  298K  0.000  65.32  1.199  1.297  1.373  1.409  1.719  1.891  8.63  7.32  6.43  6.05  3.58  2.68  3  200K  DA (degree)  -  -  -  -  -  -  -  H  R  V  C S  (Hz)  DA (degree)  J (Hz)  -67.4  2.4  175.4  11.6  48.2  3.6  -69.0  1.0  -70.1  2.1  172.5  11.3  45.4  4.1  -71.9  0,7  -72.3  1.8  170.9  11.2  43.2  4.5  -73.6  0.6  71.8  0.7  -45.6  4.0  -172.7  11.3  70.0  2.1  -68.0  2.4  174.3  11.5  47.6  3.7  -70.1  0.9  67.7  1.1  -49.5  3.4  -176.7  11.6  66.1  2.6  -69.3  2.2  173.7  11.4  46.3  3.9  -70.7  0.8  d  d  3  The calculations were performed as in chloroform solution. The upper row J and DA values correspond to the pro-R proton at position 12, and the lower row J and DA values correspond to the pro-S proton at position 12. Pro-R proton at position 13. Pro-S proton at position 13. DA = dihedral angle. 3  c  d  ,  105  The results of these calculations for compound 37 (Table 3.5) indicate that at room temperature, 90% of its molecular populations (conformations 37a, b, c, e, and g) exist in conformations where the pro-R proton at position 13 has two small J values, and the pro-S proton has one small and one large J values. Only 10% of the molecular populations 3  (conformations 37d and 37f) have this J value trend reversed. These calculated J values fit the experimental data (Spectrum 3) quite well. For compound 40 (Table 3.4), the calculated results indicate that at room temperature, literally all the molecules (conformations 40a, b, and c) exist in conformations where the proS proton at position 13 has a small and a large J values, while the pro-R proton has two 3  modest J values. These results fit the J values in Spectrum 1. However, the calculations for compound 39 (Table 3.3) suggest that about half of the molecular populations (conformations 39a, d, and e) exist in conformations where the pro-R proton has a small and a large J values, while the other half of its populations 3  (conformations 39b and 39c) have this trend reversed. The rapid interconversion between •a  these conformations will result in two averaged J values at -6 Hz for the pro-R proton. The pro-S proton has two modest values, which means the overall J values should be somewhere 3  around ~4Hz. These J values fit those in Spectrum 2. Based on the above analyses, Spectrum 1 is assigned to 40 and Spectrum 2 to 39. This assignment is consistent with the assignment of 40 and 39 based on chemical shift analyses (Section 3.3.2.1.1). 3.3.2.1.3 Varied Temperature (VT) *H NMR Studies of 39 and 40 The molecular mechanics calculations performed on compounds 39 and 40 also suggest that at low temperature (200K), most of the molecular populations (-95%) of 39  106 exists in two major low energy conformations (conformations 39a and 39b, Table 3.3), while most of the molecular populations (~93%) of 40 exist in a single lowest energy conformation (conformation 40a, Table 3.4). Therefore, we expect to see two sets of signals in the low temperature 'H NMR spectra for compound 39 and only one set of signals in the low temperature *H NMR spectra for compound 40. The VT 'H NMR spectra of 39 (Figure 3.12) and 40 (Figure 3.13) are consistent with the results of molecular mechanics calculations. At 200K, more than one set of proton signals appeared in the *H NMR spectra of 39, while there was no splitting in the 'H NMR spectra of 40.  107 302K  260K  240K  220K  210K  200K  i  1  5.0  Figure 3.12.  ——i  1  4.0  1  1  3.0  1  „„  m  500 MHz VT *H NMR spectra of 39.  1  2.0  1  1  1.0  1  1  0.  302K  260K  240K  220K  200K  185K  I  1  T  1  4.0  5.0  1  :  1  3.0  1  „ „  Figure 3.13. 500 MHz VT U NMR spectra of 40. l  m  1  2.0  1  1  1.0  1  1  0.  109 In summary, the room temperature 'H NMR spectra of the two diastereoisomers 39 and 40 indicated that these two compounds should have distinctive conformational behaviors. These distinctive conformational behaviors were related to their structures by conformational analyses and molecular mechanics calculations. The validity of the conformational analyses and molecular mechanics calculations was further supported by low temperature 'H NMR spectra of these two compounds. Based on these studies, we have assigned Spectrum 1 to 40 and Spectrum 2 to 39.  3.3.2.2 Assignment of the Relative Stereochemistry Between 41 and 42 The approach used in determining the relative stereochemistries of 39 and 40 is used here for isomers 41 and 42. The H NMR spectra of 41, 42 and 38 are shown in Figure 3.14. l  Proton decoupling experiments were performed on the three downfield signals in each of these three spectra. These experiments indicate that the two signals at 3.54 ppm and 4.75 ppm in Spectrum 4, the two signals at 3.76 ppm and 4.55 ppm in Spectrum 5, and the two signals at 3.62 ppm and 4.65 ppm in Spectrum 6, correlate to the two protons at position 13. The analyses will only focus on these six signals to elucidate structural information from their chemical shifts and coupling constant values.  110  Spectrum 4  Spectrum 5  Spectrum 6  7B  7 0  OB  SO  SS  SO  A B  AO  3 0  JO  Figure 3.14. 500 MHz *H NMR spectra of 41,42 and 38.  2S  2D  1S  10  05  Ill  3.3.2.2.1. Interpretation of the Chemical Shifts in the *H NMR Spectra of 41,42 and 38 The A5-values between the two 'IT NMR  signals under consideration vary in each  spectrum. These A5-values are 1.21 ppm, 0.79 ppm, and 1.03 ppm in Spectra 4, 5, and 6 respectively (Figure 3.14). The conformational analyses of 12, 38, 41, and 42 are shown in Figure 3.15.  o a.  , / ^  12  50%  50%  b. 38  Minor  Major  c. 42 Major  d. 41 Minor  Figure 3.15. Conformational analysis of compounds 12, 38, 41, and 42.  H  3  A5=1.7ppm  112 Due to the relatively high flexibility of large ring compounds compared to 6membered ring systems, and the relatively small size of the hydroxyl group, the pseudo 1,3diaxial interaction between the hydroxyl group at position 8 and one of the two methyl groups at position 10 in 38, 41 and 42 is expected to be small. Therefore the [3434] conformation may still be the lowest energy conformation for compounds 38 and 42. However, this interaction must destabilize these lowest energy conformations and make them less populated when compared to those of 37 and 40 in Section 3.3.2.1.1. Similar to compound 39 in Section 3.3.2.1.1, compound 41 is not likely to have the [3434] conformation as its lowest energy conformation. The above analyses were supported by the molecular calculations for compounds 38, 41 and 42. Similar to the analyses for compounds 37, 39 and 40 (Section 3.3.2.1.1), and based on the above conformational analyses, we believe that the distance between the two *H NMR signals (the A8-values) correlate to the two protons at position 13 should have the following sequences: 1.7  ppm  > A842 > A838 > A841  Therefore, we can assign Spectrum 4 to 42 and Spectrum 5 to 41.  3.3.2.2.2 Analysis of the Coupling Constants in the U NMR Spectra of 41, 42 and 38 l  The related signals in Spectra 4, 5, and 6 were enlarged and shown with their coupling constants in Figure 3.16. Each of the six signals of interest are well resolved. Each of the three downfield signals has two modest J values, and each of the three upfield signals has one large and one small J values. Interestingly, the difference between the two J values (2.8 and 5.3 Hz) for the downfield signal in Spectrum 5 is the largest and the difference  113 between the two J values (2.3 and 9.4 Hz) for the upfield signal in Spectrum 5 is the 3  smallest among the three spectra. The J values for the downfield signals (3.1 and 4.6 Hz) 3  and upfield signals (1.5 and 10.8 Hz) in Spectrum 4 are very close to those for the downfield signals (3.1 and 4.8 Hz) and upfield signals (1.8 and 10.8 Hz), respectively, in Spectrum 6 (compound 38). In order to relate these J values to the structural information of the three 3  compounds, we performed molecular mechanics calculations on compounds 38 (Table 3.6), 41 (Table 3.7), and 42 (Table 3.8).  114  4 O O  ABO  4 7 0  400  4  a  O  4 4 O  4 3 O  4 2 O  4 1 O  4 O O  3 B O  3 O O  370  3 BO  3 S O  Spectrum 6  Figure 3.16. Downfield 'H NMR signals correlate to the two protons at position 13 in 41, 42 and 38.  115  Table 3.6.  Calculated low energy conformations, dihedral angles and J values for compound 38. a  Relative Conformation 38a 38b 38c  38d 38e  38f 38g  H  free energy  %@  %@  (kcal/mol)  298K  200K  0.000  44.27  0.201 0.837 1.254 1.352  1.842 1.930  31.52 10.78 5.33 4.52  1.97 1.70  DA  H  b R  DA  C S  (degree)  J (Hz)  (degree)  (Hz)  68.1  2.3  -174.7  11.5  -47.6  3.7  69.6  0.9  68.5  2.3  -173.9  11.4  -47.1  3.8  70.5  0.8  72.3  1.8  -171.0  11.2  -43.3 .  4.4  73.5  0.6  69.4  2.2  -173.6  11.4  -46.3  3.9  70.8  0.8  66.0  2.6  -176.7  11.6  -49.5  3.4  67.9  1.1  -55.3  2.6  62.7  1.5  -171.6  11.9  -53.6  4.7  58.3  3.9  176.0  11.9  -56.9  2.2  60.8  1.8  d  3  d  The calculations were performed as in chloroform solution. The upper row V and DA values correspond to the pro-R proton at position 12, and the lower row J and DA values correspond to the pro-S proton at position 12. Pro-R proton at position 13. Pro-S proton at position 13. DA = dihedral angle. a  3  c  d  116 Table 3.7. Calculated low energy conformations, dihedral angles and J values for compound 41. a  Relative free Conformation  41a  41b  41c  41d  41e  41f  41g  41h  41i  41j  41k  H  energy  %@  %@  (kcal/mol)  298K  0.000  38.97  0.481  0.754  0.897  1.089  1.113  1.290  1.651  1.723  1.844  1.949  17.30  10.91  8.57  6.19  5.95  4.41  2.40  2.12  1.73  1.45  (Hz)  J (Hz)  76.1  0.5  -41.0  4.9  -168.5  10.9  74.5  1.5  -56.1  4.2  -174.1  11.9  60.1  1.8  -57.9  2.2  63.6  1.5  -53.4  2.7  178.8  11.8  61.8  3.3  154.3  10.5  36.4  7.8  -90.2  0.5  151.9  8.6  70.5  0.8  -46.5  3.9  -173.9  11.4  69.1  2.2  -53.5  4.7  -170.0  11.9  62.1  1.5  -54.4  2.8  70.8  0.8  -46.4  3.9  -173.4  11.4  69.4  2.2  -70.5  2.0  172.2  11.3  44.8  4.2  -72.5  0.7  71.6  0.7  -45.6  4.0  -172.9  11.4  69.9  2.1  81.5  0.3  -36.8  5.6  -163.2  10.3  78.5  1.1  56.7  2.4  -61.5  1.6  173.1  11.9  54.8  4.5  200K 57.1  d  8.5  5.9  3.6  3.4  2.2  0.87  0.73  0.53  0.34  V  c s  DA (degree)  DA (degree)  16.9  H  b R  d  3  The calculations were performed as in chloroform solution. The upper row V and DA values correspond to the pro-R proton at position 12, and the lower row J and DA values correspond to the pro-S proton at position 12. Pro-R proton at position 13. Pro-S proton at position 13. DA = dihedral angle. a  3  b  c  d  117  Table 3.8. Calculated low energy conformations, dihedral angles and J values for compound 42. a  Relative Conformation 42a  H  free energy  %@  %@  kcal/mol  298K  0.000  71.48  H  b R  V  C S  200K  DA (degree)  (Hz)  86.4  69.3  2.2  -173.5  11.4  -46.4  3.9  70.8  0.8  67.0  2.5  -174.9  11.5  -48.5  3.5  69.5  0.9  72.6  1.8  -170.7  11.2  -43.0  4.5  73,7  0.6  65.9  2.7  -176.9  11.6  -49.6  3.4  67.7  1.1  d  DA J (degree) (Hz) d  3  1  42b  42c  42d  1.000  1.065  1.791  13.21  11.83  3.47  6.9  5.8  0.9  The calculations were performed as in chloroform solution. The upper row V and DA values correspond to the pro-R proton at position 12, and the lower row V and DA values correspond to the pro-S proton at position 12. Pro-R proton at position 13. Pro-S proton at position 13. DA = dihedral angle. a  c  d  The calculations for compound 38 indicate that more than 98% of the molecular populations exist in conformations (conformations 38a - 38e and 38g, Table 3.6) where the pro-S proton at position 13 has one large and one small J value and the pro-R proton has two 3  modest Vvalues. The calculations for compound 42 (Table 3.8) have similar results as those for compound 38. However, the calculations for compound 41 suggest that a substantial amount of the molecules exist in conformations with reversed J values (conformations 41b, d, f, and h, Table 3.7). This leads to a decrease in the difference between the two overall J 3  118 values for the pro-R proton and an increase in the difference between the two overall J values for the pro-S proton at position 13 in compound 41. We can, therefore, assign spectrum 4 to compound 42 and spectrum 5 to compound 41 by correlating the calculated results to the J values obtained from the spectra. This assignment is the same as the 3  assignment in Section 3.3.2.2.1, which was based on the chemical shift information. Surprisingly, the low temperature  NMR study failed to show the split of the proton  signals of compound 41, which was anticipated based on molecular mechanics calculations. We are not able to provide an explanation for this discrepancy.  3.3.3 Rationalization of the Alkylation Results for the Silyl Ethers of 37 and 38 As discussed in Section 1.2.1, Still and coworkers successfully rationalized many 60  alkylation reaction results by using the population distributions of the enolates to explain the diastereoselectivities of the reactions. However, the MACROMODEL program we have is not equipped to deal with charged structures. Since the energies under consideration in these calculations are the relative strain energies, it is reasonable to use the corresponding enol structure in the calculations. In order to rationalize the results of the alkylation reactions for the silyl ether of compounds 37 and 38, two structures, C and D, were therefore chosen to simulate energetically the enolates in the calculations of their strain energies.  119  A conformational search of structure C revealed four low energy conformations within a 2 kcal/mol range (Table 3.9). Based on the assumption of peripheral addition (discussed in Section 1.2.1), each of the three lowest energy conformations, collectively representing approximately 99% of the molecular populations, would give rise to the major product obtained by experiment after methylation. Compared to the experimental result (10:1 selectivity, Section 3.3.1), the calculated selectivity of 99%> is slightly higher. For structure D, a conformational search produced six low energy conformations within a 2 kcal/mol range (Table 3.10). However, according to these results and peripheral addition assumption (Section 1.2.1), more than half (65%) of the molecular populations exist in the two lowest energy conformations that would give rise to the minor product obtained by experiment after methylation. As discussed in Section 1.2.1, according to Still and coworkers, only those reaction routes that connect the low energy conformer of the starting 60  material to the low energy conformer of the product without undergoing major changes in the overall conformation should be favored. In our case, the low energy conformations of the alkylation products found by molecular mechanics calculations are far different from those low energy conformations of Structure D in Table 3.10. It is, therefore, hard for us to base the selectivity of the reaction on the molecular population distributions of the starting  120 material (Structure D). However, these calculations suggest that the diastereoselectivity must be low for this reaction.  Table 3.9. Four lowest energy conformations of structure C found by molecular mechanics calculations." Conformation Relative strain Relative populations Side view Top view energy (kcal/mol) @ -78°C (%)  Calculated as in aqueous solution.  121  Table 3.10. The Four lowest energy conformations of structure D found by molecular mechanics calculations." Conformation Relative strain Relative populations Side view Top view energy (kcal/mol) @-78°C(%)  OTMS  OTMS  Calculated as in aqueous solution.  OTMS  122  3.4 Face Selectivity Studies of the Hydroboration and Epoxidation of 43 Alkylation of 14 at the or-position of the ester carbonyl group also introduces a stereogenic center to the ring (Scheme 3.8).  14  43  Key: (a) i) LDA, THF, -78°C ii) Mel, 85%.  Scheme 3.8. Alkylation at the a-position of the ester carbonyl in 14.  Hydroboration and epoxidation of the double bond in 43 were performed to investigate the possibility of achieving face selectivity under the influence of the stereogenic center and ring conformation. The results of these investigations are discussed in the following sections.  3.4.1 Hydroboration of 43 The hydroboration reaction of 43 was performed at room temperature in THF, using B H 3 » M e 2 S  as the hydroborating reagent. Four products were obtained from this reaction in an  82% overall yield (Scheme 3.9). The four products were separated using silica gel column  123 chromatography. Structural determinations were achieved by comparing *H NMR spectral data obtained with that of the products of the alkylation reactions in Section 3.3.  41  42  Key: (a) i) B H M e S , THF, r. t., ii) H 0 , NaOH, 0°C, 82%. 3  2  2  2  Scheme 3.9. Hydroboration of the double bond in 43.  Upon separation, the four isomers were weighed, and the relative ratio was found to be:  39:40:41:42= 1.0:1.3:1.0:1.8 The hydroboration reaction resulted in two pairs of face selective products, 39 + 41 and 40 + 42. However, the face selectivity was low:  (42 + 40): (39 + 41.) = 1.6: 1.0  124 As discussed in Section 1.2.1, it is assumed that in the medium- and large-ring systems, the addition reactions of a double bond will occur from the less hindered peripheral face of the olefinic function. In order to rationalize the face selectivity of the hydroboration reaction of the double bond in 43, molecular mechanics calculations were performed on the starting material, compound 43. More than twenty low energy conformations were found within a 2 kcal/mol range. The calculations also found that at room temperature, 65% of the molecular populations of 43 exist in conformations that would lead to the major products upon hydroboration. This is in agreement with the experimental result.  3.4.2 Epoxidation of 43 Epoxidation of the double bond in 43 was performed in CH2CI2 using mCPBA at room temperature, 0°C and -78°C (Scheme 3.10). However, no reaction was observed for three days at -78°C. At both room temperature and 0°C, two products were obtained from the reaction.  43  44  Key: (a) mCPBA, CH C1 , 0°C or r. t, 90%. 2  2  Scheme 3.10. Epoxidation of the double bond in 43.  45  125  The relative stereochemistry of the two products was not known. However, previous studies ' 118  119  suggested relative early transition state for the hydroboration reactions.  Furthermore, studies '  61 62  of the epoxidation reaction in medium- and large-ring systems  suggested that it is safe to use the conformations of the starting material to predict the face selectivity of the epoxidation reactions. Therefore, based on the results of the calculations performed on compound 43 (Section 3.4.1), we expected that only modest face selectivity would be achieved, and could suggest that compound 45 would be the major product. The ratios of the products were determined using GC: 44 : 45 = 1 : 1.7 at room temperature 44 : 45 = 1 : 2.3  at 0°C  The calculated results are in agreement with these experimental results.  3.5 Summary The hydroboration of the double bond in lactone 14 produced two regioisomers, 37 and 38, with little or no regioselectivity. The regiochemistry of the two products was determined by comparing their spectral data with that of compound 38, which was synthesized as shown in Scheme 3.5. In this synthesis, the cleavage of the epoxide in 54 was found to be highly regioselective. Molecular mechanics calculations were performed on compound 14 in order to rationalize the results of the hydroboration reactions. The calculations indicate that, in the low energy conformations of 14, the two vinyl positions have similar environments. The  126 hydroboration reagents are not likely to differentiate the two positions, therefore low selectivity is expected. Molecular mechanics calculations were also performed on compound 54 to rationalize the highly regioselective cleavage of the epoxide in compound 54. The calculations suggest that, in the low energy conformations of 54, the epoxidal position close to the tertiary center is hindered by the geminal dimethyl groups, which leads to the highly regioselective cleavage of the expoxide. The lowest energy conformations for compounds 14 and 54 found by molecular mechanics calculations are in fact not the expected [3434] conformations, but rather the P ^ W ] conformations. This is believed to be the case because the [3434] conformations are not space efficient. Dale suggested that large ring compound tended to adopt conformations 24  with two parallel chains linked by bridges of minimum length in order to fill space v  efficiently. However, this rationale has not been applied before in rings with less than 16 members. The methylation of the silyl ether of 38 was achieved with 10 : 1 (41 : 42) diastereoselectivity, while only 1.4 : 1 (39 : 40) selectivity was achieved with that of 37. The relative stereochemistries  in these products were determined by correlating their  conformational behavior with their *H NMR spectra using molecular mechanics calculations. Molecular mechanics calculations were also performed on two structures, C and D, in an effort to rationalize the diastereoselectivity of the methylation of 37 and 38, respectively. The diastereoselectivity indicated by the calculations agree with the experimental results for compound 37, but not for compound 38. Since the selectivity of the reaction is determined by  127 its transition state, and we chose to use the starting material in the calculations, it is not surprising that the calculations failed to correlate well in this case. The face selectivity of the double bond in 43 was low with both the hydroboration  reaction ((42+40): (39+41) = 1.6 : 1) and the epoxidation reaction (45 : 44 = 1.7 : 1 @ 25°C; 2.3 : 1 @ 0°C). The reaction results were rationalized using molecular mechanics calculations. From our research we found that it is possible to achieve good diastereoselectivity in large-ring systems under the influence of the ring conformation. We also found that molecular mechanics calculations is a useful tool in rationalization of the reaction results.  128  Chapter Four Experimental  4.1 General Unless otherwise stated, all reactions were performed under nitrogen using flame- or oven-dried glassware. Elevated temperatures were achieved using either a silicone oil bath or a Glas-Col heating mantle. Cold temperature baths were prepared as follows: -78°C (dry ice, acetone), -40°C (dry ice, acetonitrile), -15°C (dry ice, ethylene glycol), 0°C (ice, water). Anhydrous solvents were obtained by distillation. Methylene chloride, triethyl amine, and diisopropyl amine were distilled from calcium chloride. Dimethyl formamide (DMF) and dimethyl sulfoxide (DMSO) were distilled at reduced pressure from calcium hydride. Diethyl ether and tetrahydrofuran (THF) and toluene were distilled from sodium. Methanol was distilled from magnesium. Low boiling point petroleum ether (bp 35-60°C) was used. The deoxygenation of methylene chloride was achieved by sparging with nitrogen for 20-30 minutes. Otherwise the solvents were used as received from the supplier. Unless otherwise stated, reagents were purchased from Aldrich Chemical Co. They were purified according to the procedures given in the literature.  Alkyllithiums were  standardized by titration against diphenylacetic acid in THF at room temperature. The Jones reagent was prepared via the method of Eisenbraun.  191  according to the method of Schwab, Grubbs, and Ziller.  QQ  The Grubbs catalyst was prepared  129 Standard solutions of NaOH and MeSNa were prepared by dissolving accurately weighed base in volumetric flask. HC1 solution was standardized by titration against the NaOH standard solution. Thin layer chromatography (TLC) was performed on commercially available aluminum backed plates of silica gel 60 (Merck 5554, 0.2 mm thickness). TLC plates were visualized with ultraviolet light (254 nm) or 1% p-anisaldehyde spray. 230-400 mesh silica gel supplied by E. Merck. Co. was used for flash chromatography.  A solvent system was  chosen such that the desired product had an Rf value of approximately 0.3 on TLC. Radial chromatography was performed using a Harrison Chromatotron model 8924. The plate used in the chromatotron was prepared using silica gel 60, P F 2 5 4 with gypsum binder supplied by EM Science. Melting points were performed using a Mel-Temp II apparatus (Lab Devices USA) and are uncorrected. Analytical gas-liquid chromatography (GC) was performed on a Hewlett-Packard model 5880A gas chromatograph, equipped with a split mode capillary injection system and a flame ionization detector. An OV-101 or a DB-210 capillary column of dimensions 0.22mm x 12m was used. Helium was used as the carrier gas in all cases. Infrared (IR) spectra were recorded on a Bomem Michelson 100 FT-IR spectrometer with internal calibration. IR spectra were taken in either chloroform or deuteriochloroform solutions in NaCl cell of 0.2mm thickness. Proton nuclear magnetic resonance ( H NMR) spectra were recorded on either a l  Bruker AC-200 (200MHz) or a Bruker AMX-500 (500MHz) using deuteriochloroform as the solvent. Chemical shifts are given in parts per million (ppm) on the 5 scale, referenced to  130 chloroform (7.24ppm) as the internal standard. Carbon ( C) NMR spectra were recorded on a Bruker AC-200 (50MHz). Varied temperature proton nuclear magnetic resonance (VT 'H NMR) spectra were recorded on a Bruker AMX-500 (500MHz) using deuteriomethylene chloride and toluene-dg (v/v, 1:1) as the solvent. Low resolution mass spectra (LRMS) in electron ionization (EI) mode were recorded on a Kratos-AEI model MS 50 spectrometer. LRMS in chemical ionization (CI) mode were recorded on either a Kratos MD 80 spectrometer or a Kratos Concept II HQ spectrometer. LRMS in desorption chemical ionization (DCI) mode were recorded on a Delsi Nermag R1010 C spectrometer. Only peaks with greater than 20% relative intensity or those which were analytically useful are reported. High resolution mass spectra (HRMS) in EI mode were recorded on a Kratos-AEI model MS 50 spectrometer. HRMS in CI mode were recorded on either a Kratos MS 80 spectrometer or a Kratos Concept II HQ spectrometer. Microanalyses were performed by Dr. Peter Borda in the Microanalytical Laboratory at the University of British Columbia on a Carlo Erba Elemental Analyzer Model 1106 or a Fisons CHN-0 Elemental Analyzer Model 1108. Conformational analyses were performed using MACROMODEL modelling program. The calculation used MM3* force field parameters. ' 123  124 125  molecular  131  4.2 Hydrolysis 4.2.1 Base Mediated Hydrolysis The following is a typical procedure for the base mediated hydrolysis of the macrocyclic lactones reported in this thesis. Lactone 11 (24 mg, 0.10 mmol) was dissolved in a mixture of water (10 mL) and dioxane (20 mL) in a 50 mL RB flask. The reaction temperature was kept at 20°C using a water bath. NaOH (200.0 mg, 5.000 mmol) was then added into the flask under stirring. Once all of the NaOH had dissolved (~2 minutes), the first sample (2.00 mL) was withdrawn from the reaction mixture using a syringe, and the moment the first sample was obtained was considered as (time) t = 0. Additional samples were withdrawn at 30 minute intervals. Each sample was neutralized upon withdrawal with 0.34 mL of 1M HC1, and diluted with 10 mL water. This aqueous solution was extracted with Et20 (3 x 6.00 mL), which contained an internal standard (ester 66). The extract was analyzed by GC. The ratio between the GC signals of lactone 11 and ester 66 was used as the concentration of the lactone ([a], Chapter two).  4.2.2 Acid Catalyzed Hydrolysis The following is a typical procedure for the acid catalyzed hydrolysis. Lactone 11 (24 mg, 0.1 mmol) was dissolved in a mixture of 1.171M HC1 (10 mL) and dioxane (20 mL), in a 50 mL RB flask. The reaction temperature was raised to 58°C by water bath. Samples (2.00 mL) were withdrawn from the reaction mixture using syringes, and the moment the first sample obtained was considered as time t = 0. Additional samples were withdrawn at 60 minute intervals. Each sample was neutralized upon withdrawal with 0.78 mL of 1M NaOH solution, and diluted with 10 mL water. This aqueous solution was extracted with Et 0 (3 x 2  132 6.00 mL), which contained an internal standard (ester 66). The extract was analyzed by GC. The ratio between the GC signals of lactone 11 and ester 66 was used as the concentration of the lactone ([a], Chapter two).  4.2.3 Lactone Ring-Openning with MeSNa The following is a typical procedure for the MeS" mediated hydrolysis. Lactone 11 (24 mg, 0.1  mmol) was dissolved in 10 mL of 0.5M dimethylpropylene urea (DMPU)  solution of MeSNa, in a 20 mL RB flask. The reaction temperature was kept at 20°C by water bath. Samples (1.00 mL) were withdrawn from the reaction mixture using syringes, and the moment the first sample obtained was considered as time t = 0. Additional samples were withdrawn at 15 minute intervals. Each sample was neutralized upon withdrawal with 0.5 mL of IM HC1, and diluted with 10 mL water. This aqueous solution was extracted with Et.20 (3 x 6.00 mL), which contained an internal standard (ester 66). The extract was analyzed by GC. The ratio between the GC signals of lactone 11 and ester 66 was used as the concentration of the lactone ([a], Chapter two).  133  4.3 Synthetic Methods 4.3.1 5,5-Dimethyl-13-tridecanolide (11)  X 11 Lactone 13 (30 mg, 0.12 mmol), Ethanol (10 mL), and 5% Pd/C (5 mg) were added into a 25 mL round bottom flask. The mixture was stirred under hydrogen (latm) at room temperature for 5 h. The catalyst was removed by filtration, and the solvent was removed under reduced pressure. 29 mg (95%) solid was obtained.  IR(CHC1 ): 2942, 2862, 1719, 1450, 1260, 1131, 1066, 1013 cm ; -1  3  'H NMR (500MHz, ^-toluene/CD Cl ): 5 3.99 (t, J= 6.5 Hz, 2H), 2.13 (t, J= 6.1 Hz, 2H), 2  2  1.49 (m, 2H), 1.38 (m, 4H), 1.26 (m, 6H), 1.12 (m, 2H), 1.03 (m, 4H), 0.78 (s, 6H); 13  C NMR (50MHz, CDC1 ): 6 173.92, 62.49, 39.43, 38.51, 35.81, 32.47, 28.99 (2), 27.17, 3  26.50,25.77, 23.44, 21.56, 20.33, 20.16; LRMS (DCI(+), ammonia) m/z (relative intensity): 258 (M +18, 100), 241 (M +l, 64), +  +  240 (M , 18), 129(56); +  HRMS (DCI(+), ammonia) m/z calculated for C15H32O2N (M +18) 258.2433, +  found: 258.2432; Analysis calculated for C H 80 : C, 74.95; H, 11.74. Found: C, 74.90; H, 11.80. 15  2  2  134 4.3.2 10,10-Dimethyl-13-tridecanolide (12)  X 12  Lactone 14 (30 mg, 0.12 mmol), Ethanol (10 mL), and 5% Pd/C (5 mg) were added into a 25 mL round bottom flask. The mixture was stirred under hydrogen (1 atm) at room temperature for 5 h. The catalyst was removed by filtration, and the solvent was removed under reduced pressure. 29 mg (95%) solid was obtained.  IR(CHC1 ): 2941, 2862, 1722, 1448, 1355, 1255, 1209, 1166, 1125, 1049 cm" ; 1  3  'H NMR (500MHz, ^-toluene/CD Cl ): 5 3.99 (t, J= 5.6 Hz, 2H), 2.20 (t, J= 6.2 Hz, 2H), 2  2  1.54 (m, 2H), 1.19-1.36 (m, 12H), 1.06 (m, 4H), 0.78 (s, 6H); 13  C NMR (50MHz, CDCI3): 5 173.71, 64.29, 38.86, 35.77, 32.61, 32.40, 28.89 (2), 26.64, 26.30, 24.72, 24.48, 24.45, 24.33, 20.76;  LRMS (DCI(+), ammonia) m/z (relative intensity): 258 (M +18, 100), 241 (M +l, 26), +  +  240 (M , 7); +  HRMS (DCI(+), ammonia) m/z calculated for C15H32O2N (M +l8) 258.2433, +  found: 258.2437; Analysis calculated for C 1 5 H 2 8 O 2 : C, 74.95; H, 11.74. Found: C, 74.92; H, 11.79.  135  4.3.3 5,5-Dimethyl-13-tridec-7-enolide (13)  X 13 Ester 15 (0.0665 g, 0.250 mmol) was dissolved in deoxygenated C H 2 C I 2 (50 mL). Grubb's catalyst (10.3 mg, 0.0125 mmol) was dissolved in a second 50 mL of deoxygenated CH2CI2.  These two solutions were added in dropwise into C H 2 C I 2 (100 mL) in a 500 mL  flask at room temperature in 5 h. The resulting mixture was stirred for overnight, and then exposed to air for another 3 h. The solvent was removed under reduced pressure. Flash column chromatography of the residue with petroleum ether and diethyl ether (v/v = 95/5) as the eluent yielded 0.056 g (90%) of clear liquid.  IR (CHCI3): 2939,2863, 1720,1460,1386, 1366,1265, 1128,976 cm ; -1  *H NMR (500MHz, CDCI3): 5 5.26-5.45 (m, 2H), 4.14 (t, J= 5.4 Hz, 2H), 2.29 (t, J= 6.2 Hz, 2H), 2.01 (m, 2H), 1.89 (d, 2H), 1.58 (m, 4H), 1.33 (m, 4H), 1.17 (m,2H), 0.85 (s,6H); 13  C NMR (50MHz, CDC1 ): 5 174.10, 132.30, 128.45, 62.93, 45.94, 39.29, 35.54, 33.06, 3  31.37,27.96 (2), 27.45, 27.22, 23.30,20.12; LRMS (DCI(+), ammonia) m/z (relative intensity): 256 (M +18, 100), 239 (M +l, 66), +  +  238 (M , 24), 237 (21), 129 (52); +  HRMS (DCI(+), ammonia) m/z calculated for C15H30O2N (M +l 8) 256.2277, +  136 found: 256.2276.  4.3.4 10,10-Dimethyl-13-tridec-7-enolide (14)  X 14 Ester 16 (0.0665 g, 0.250 mmol) was dissolved in deoxygenated  CH2CI2 (50  mL).  Grubb's catalyst (10.3 mg, 0.0125 mmol) was dissolved in a second 50 mL of deoxygenated  CH2CI2. These two  solutions were added in dropwise into  CH2CI2 (100  mL) in a 500 mL  flask at room temperature in 5 h. The resulting mixture was stirred for overnight, and then exposed to air for another 3 h. The solvent was removed under reduced pressure. Flash column chromatography of the residue with petroleum ether and diethyl ether (v/v = 95/5) as the eluent yielded 0.057 g (90%) of clear liquid.  IR(CHC1 ): 2944, 2861, 1719, 1457, 1384, 1366, 1340, 1129, 1061, 975 cm ; -1  3  'H NMR (500MHz, CDC1 ): 5 5.24-5.41 (m, 2H), 4.17 (t, J= 5.1 Hz, 2H), 2.31 (m, 2H), 3  2.03 (m, 2H), 1.87 (d, J= 7.1 Hz, 2H), 1.23-1.63 (m, 10H), 0.89 (s, 6H); 13  C NMR (50MHz, CDCI3): 6 173.92, 132.34, 128.14, 64.41, 44.64, 36.82, 34.30, 32.78, 31.63, 27.98 (2), 27.95, 26.54, 25.04, 23.60;  LRMS (DCI(+), ammonia) m/z (relative intensity): 256 (M +18, 100), 239 (M +l, 41), +  238 (M , 9), 83 (26); +  +  137 HRMS (DCI(+), ammonia) m/z calculated.for C15H30O2N (M +18) 256.2277, +  found: 256.2277.  4.3.5 6-Heptenyl-5',5'-dimethyl-7'-octenoate (15)  Acid 19 (0.34 g, 2.0 mmol) was dissolved in CH C1 (10 mL) in a 50 mL RB flask. 2  2  DCC (0.48 g, 2.2 mmol) and DMAP (24 mg) were then added into the flask. Alcohol 17 (0.24g, 2.0 mmol) was added into the mixture in 5min. The reaction was stirred at room temperature for 48 h. Water (30 mL) was then added into the mixture. The aqueous phase was extracted with Et 0 (3 x 20 mL). The combined organic phase was washed with water (2 2  x 20 mL) and brine (20 mL), and dried over anhydrous MgSGv Filtration removed the drying reagent. The dried solution was concentrated under reduced pressure. Flash column chromatography of the residue with petroleum ether and diethyl ether (v/v = 95/5) as the eluent yielded 0.48 g (80%) of clear liquid.  IR (CHCI3): 3078, 2930, 2860, 1723, 1639, 1462, 1388, 1366, 1278, 1133,997,914 cm" ; 1  H NMR (200MHz, CDC1 ): 8 5.69-5.89 (m, 2H), 4.90-5.02 (m, 4H), 4.04 (t, J= 6.6 Hz,  l  3  2H), 2.26 (t, J= 7.3 Hz, 2H), 2.06 (q, J= 6.8 Hz, 2H), 1.93 (d,J= 7.6Hz, 2H),  138 1.10-1.70 (m, 10H), 0.88 (s, 6H); 13  C NMR (50MHz, CDC1 ): 5 137.86, 138.69, 135.55, 116.72, 114.47, 64.29, 46.33,41.29, 3  35.06, 33.59, 33.05, 28.48, 26.84 (2), 25.41, 22.60, 19.72; LRMS (EI) m/z (relative intensity): 267 (M +l, 1), 266 (M , 2), 225(51), 153 (5), 135 (9), +  +  129 (100), 111 (87), 97 (19), 83 (45), 69 (51), 67 (21), 55 (85); HRMS (EI) m/z calculated for C17H30O2 (M ) 266.2246, found: 266.2245. +  4.3.6 4,4-Dimethyl-6-heptenyl 7'-octenoate (16)  16 Acid 18 (0.28 g, 2.0 mmol) was dissolved in CH C1 (10 mL) in a 50 mL RB flask. 2  2  DCC (0.48 g, 2.2 mmol) and DMAP (24 mg) were then added into the flask. Alcohol 20 (0.28 g, 2.0 mmol) was added into the mixture in 5 min. The reaction was stirred at room temperature for 48 h. Water (30 mL) was then added into the mixture. The aqueous phase was extracted with Et 0 (3 x 20 mL). The combined organic phase was washed with water 2  (2 x 20) and brine (20 mL), and dried over anhydrous MgS04. Filtration removed the drying reagent. The dried solution was concentrated under reduced pressure. Flash column chromatography of the residue with petroleum ether and diethyl ether (v/v = 95/5) as the eluent yielded 0.47 g (80%) of clear liquid.  139  IR (CHCI3): 3078, 2938, 2859, 1723, 1639, 1458, 1361, 1098, 996, 911 cm- ; 1  'H NMR (200MHz, CDCI3): 6 5.68-5.87 (m, 2H), 4.88-5.02 (m, 4H), 4.01 (t, J= 6.6 Hz, 2H), 2.27 (t, J= 7.3 Hz, 2H), 2.04 (q, J= 7.0 Hz, 2H), 1.92 (d, J= 7.3 Hz, 2H), 1.13-1.74 (m, 10H), 0.83 (s, 6H); 13  C NMR (50MHz, CDCI3): 5 173.77, 138.74, 135.37, 116.81, 114.37, 64.99, 46.28, 37.67, 34.90, 34.28, 33.53, 32.78, 28.50, 26.83 (2), 24.82, 23.46;  LRMS (EI) m/z (relative intensity): 266 (M , 1), 225(2), 163 (2), 125 (4), 109 (5), 83 (100), +  97 (19), 69 (15), 67 (8), 55 (45); HRMS (EI) m/z calculated for C 1 7 H 3 0 O 2 (M ) 266.2246, found: 266.2246. +  4.3.7 6-Hepten-l-ol (17)  OH  17 Pyridinium toluene-4-sulfonate (0.67 g, 2.7 mmol) was dissolved in MeOH (200 mL) in a 500 mL RB flask. Compound 25 (8.4 g, 42 mmol) was then added into the flask. The mixture was stirred at room temperature for 24 h. The solvent was removed under reduced pressure, and Et20 (200 mL) was then added to the residue. The solution was washed by water (100 mL), saturated NaHC0 solution (100 mL) and brine (100 mL), and dried over 3  MgS04. Filtration removed the drying reagent. The dried solution was concentrated under reduced pressure. Flash column chromatography of the residue with petroleum ether and ethyl acetate (v/v = 65/35) as the eluent yielded 4.6 g (95%) of clear liquid.  140  IR (CHCI3): 3622, 3078, 2933, 2860, 1639, 1441, 1039 cm" ; 1  'HNMR (200MHz, CDCI3): 8 5.65-5.85 (m, IH), 4.82-5.00 (m, 2H), 3.57 (t, J= 6.4 Hz, 2H), 2.15 (s, IH), 2.00 (m, 2H), 1.50 (m, 2H), 1.30 (m, 4H); 13  C N M R (50MHz, CDC1 ): 8 138.83,114.32, 62.69, 33.68, 32.52,28.65, 25.21; 3  LRMS (DCI(+), ammonia) m/z (relative intensity): 132 (M +18, 79), 114 (M , 6), +  +  96(69), 81 (100); HRMS (DCI(+), ammonia) m/z calculated for C Hi ON (M +18) 132.1388, +  7  8  found: 132.1390.  4.3.8 7-Octenoic Acid (18)  (a) A mixture of nitrile 27 (0.15 g, 1.2 mmol), KOH (0.54 g, 9.6 mmol) in ethylene glycol (2 mL) was stirred at 150 °C for overnight. After cooled to the room temperature, water (20 mL) was added into the mixture. The mixture was washed with ether (2x10 mL). The aqueous layer was acidified using concentrated HC1 and extracted with E12O (3x10 mL). The extractions was then washed by water (20 mL) and brine (20 mL), and dried over MgS04- Filtration removed the drying reagent. The dried solution was concentrated under reduced pressure. Flash column chromatography of the residue with petroleum ether and diethyl ether (v/v = 60/40) as the eluent yielded 0.14 g (82%) of pale yellow oil.  141 (b) Alcohol 50 (0.90 g, 7.0 mmol) was dissolved in acetone (80 mL). Jones reagent (6 mL) was added into the solution in dropwise until the yellow-orange color did not disappear any more. Isopropanol was added slowly into the reaction until the mixture turned into pale blue. After filtration, the solution was neutralized using NaHCC»3. After a second filtration, the mixture was concentrated to 10 mL under reduced pressure. The solution was then diluted using E t 2 0 (50 mL). This solution was washed with 3  M  NaOH (3 x 40 mL). The  aqueous layer was then acidified with concentrated HC1 and extracted with E t 0 (3 x 40 mL). 2  The solution was dried over anhydrous M g S 0 4 . Filtration removed the drying reagent. Removing the solvent under reduced pressure yielded 0.90 g (90%) yellowish oil. (c) A mixture of ester 53 (1.4 g, 6.6 mmol), KOH (1.1 g, 20 mmol) and water (15 mL) were stirred at 80-90 °C for 5 h. The reaction was then cooled to 15 °C, and kept at < 20 °C. The mixture was acidified using concentrated HC1, and extracted with diethyl ether (4 x 50 mL). The combined organic phase was dried over anhydrous  MgS04.  Filtration  removed the drying reagent. The dried solution was concentrated under reduced pressure. The residue was dissolved in 20 mL of DMF, and refluxed for 2 h. After cooled to the room temperature, it was diluted with 80 mL of water. This aqueous solution was extracted with diethyl ether (4 x 50 mL). The combined organic phase was dried over anhydrous  MgS04.  Filtration removed the drying reagent. The dried solution was concentrated under reduce pressure. Flash column chromatography of the residue with petroleum ether and diethyl ether (v/v = 60/40) as the eluent yielded 0.70 g (75%) of yellowish oil.  IR(CHC1 ): 2932, 2860, 1709, 1640, 1420, 1282, 1231, 997 cm" ; 1  3  *H NMR (200MHz, CDC1 ): 8 11.45 (s, w, 1H), 5.65-5.85 (m, 1H), 4.85-5.05 (m, 2H), 3  142 2.33 (t, J= 7.3 Hz, 2H), 2.00 (q, J= 6.8 Hz2H), 1.62 (m, 2H), 1.31 (m, 4H); 13  C NMR (50MHz, CDCI3): 5 180.41, 133.71, 114.44, 34.03, 33.50, 28.46 (2), 24.48;  LRMS (EI) m/z (relative intensity): 143 (M +l, 1), 142 (M , 2), 124 (44), 100 (20), 96 (46), +  +  83 (27), 82 (68), 73 (24), 67 (37), 60 (37), 55 (100); HRMS (EI) m/z calculated for C H i 0 (M ) 142.0994, found: 142.0997; +  8  4  2  Analysis calculated for C H i 0 : C, 67.57; H, 9.92. Found: C, 67.58; H, 9.98. 8  4  2  4.3.9 5,5-Dimethyl-7-octenoic Acid (19)  O  19  OH  A mixture of ester 33 (1.6 g, 6.6 mmol), KOH (1.1 g, 20 mmol) and water (15 mL) were stirred at 80-90 °C for 5 h. The reaction was then cooled to 15 °C, and kept at <20 °C. The mixture was acidified using concentrated HC1, and extracted with diethyl ether (4 x 50 mL). The combined organic phase was dried over anhydrous M g S 0 4 . Filtration removed the drying reagent. The dried solution was concentrated under reduced pressure. The residue was dissolved in 20 mL of DMF, and refluxed for 2 h. After cooled to the room temperature, it was diluted with 80 mL of water. This aqueous solution was extracted with diethyl ether (4 x 50 mL). The combined organic phase was dried over anhydrous MgS04. Filtration removed the drying reagent. The dried solution was concentrated under reduced pressure. Flash column chromatography of the residue with petroleum ether and diethyl ether (v/v = 60/40) as the eluent yielded 0.96 g (85%) of yellowish oil.  143  IR (CHCI3): 2936, 2860, 1708, 1366, 1289, 1116, 998, 914 cm" ; 1  'H NMR (500MHz, CDCI3): 8 5.78 (m, IH), 5.00 (m, 2H), 2.32 (t, J= 7.1 Hz, 2H), 1.93 (d, J= 7.3, 2H), 1.60 (m, 2H), 0.83 (s, 6H); 13  C NMR (50MHz, C D C I 3 ) : 8 179.94, 135.48, 116.81, 46.29, 41.19, 34.74, 33.05, 26.83 (2), 19.42;  LRMS (EI) m/z (relative intensity): 171 (M +l, 0.5), 170 (M , 1), 129 (68), 111 (79), +  +  95 (11), 83 (71), 69 (100), 67 (12), 55 (49); HRMS (EI) m/z calculated for C , H O (M ) 170.1307, found: 170.1309;. +  0  18  2  Analysis calculated for Ci Hi O : C, 70.55; H, 10.66. Found: C, 70.57; H, 10.70. 0  8  2  4.3.10 4,4-Dimethyl-6-hepten-l-ol (20)  OH  20 A THF solution (3 mL) of acid 35 (0.62 g, 4.0 mmol) was added in dropwise to a suspension of L 1 A I H 4 (0.38 g, 10 mmol) in THF (7 mL) at 0 °C. The reaction was allowed to warm slowly to room temperature, and was stirred for overnight. Cooled down to 0 °C, the mixture was neutralized using 10% sulfuric acid, and extracted with diethyl ether (3 x 20 mL). The combined ether solution was washed with water (2 x 20 mL) and brine (30 mL), and was dried over anhydrous MgSO^. Filtration removed the drying reagent. The dried solution was concentrated under reduced pressure. Flash column chromatography of the  144 residue with petroleum ether and diethyl ether (v/v = 70/30) as the eluent yielded 0.53 g (95%) of clear liquid.  IR (CHC1 ): 3622, 3077, 2926, 1638, 1465, 1387, 1366, 1053, 999, 914 cm" ; 1  3  'HNMR (200MHz, CDCI3): 5 5.69-5.89 (m, 1H), 4.92-5.02 (m, 2H), 3.58 (t, J= 6.6 Hz, 2H), 1.93 (d, J= 7.6 Hz, 2H), 1.69 (s, 1H), 1.43-1.58 (m, 2H), 1.16-1.26 (m,2H), 0.83 (s,6H); 13  C NMR (50MHz, CDCI3): 5 135.61, 116.69, 63.74, 46.42, 37.62, 32.79, 27.42, 26.89 (2);  LRMS (EI) m/z (relative intensity): 142 (M , 1), 101 (41), 83 (100), 67 (12), 55 (68); +  HRMS (EI) m/z calculated for C H i 0 (M ) 142.1358, found: 142.1356; +  9  8  Analysis calculated for C Hi 0: C, 76.00; H, 12.76. Found: C, 76.10; H, 12.70. 9  8  4.3.11 2-(6'-Hydroxyl hexoxyl) Tetrahydropyran (23)  Hexane-l,6-diol (11.8 g, 0.10 mol) was dissolved in toluene (150 mL) in a 250 mL Erlenmeyer flask. Acidic resin Amberlite IR-120 (10 g) and 3,4-dihydropyran (DHP) (8.4 g 0.10 mol) was then added into the flask. After being stirred at room temperature for 3 h, the mixture was filtered to remove the resin. The organic solution was washed with saturated NaHC0 solution (2 x 50 mL) and water (2 x 50 mL), then dried over MgS0 . The dried 3  4  solution was filtered to remove the drying reagent and was concentrated under reduced  145 pressure. Flash column chromatography of the residue with petroleum ether and ethyl acetate (v/v = 60/40) as the eluent yielded 17.2 g (85%) of clear liquid.  IR(CHC1 ): 3622, 2940, 2865,1457, 1364,1127, 1075,1030, 902 cm" ; 1  3  'H NMR (200MHz, CDC1 ): 6 4.52 (dd, J= 2.7, 4.2 Hz, 1H), 3.25-3.85 (m, 6H), 3  1.95 (s, 1H),1.25-I.90(m, 14H); 13  C NMR (50MHz, C D C I 3 ) : 5 98.76, 67.44, 62.58, 62.24, 32.56, 30.65, 29.57, 25.97, 25.44, 25.42,19.56;  LRMS (DCI(+), ammonia) m/z (relative intensity): 220 (M +18, 12), 203 (M +l, 20), +  +  136 (100), 102 (52), 85 (62); HRMS (DCI(+), ammonia) m/z calculated for C 1 1 H 2 3 O 3 (M +l) 203.1647, +  found: 203.1650;  Analysis calculated for C 1 1 H 2 2 O 3 : C, 65.31; H, 10.96. Found: C, 65.18; H, 11.10.  4.3.12 2-(6'-Oxohexoxyl) Tetrahydropyran (24)  Oxalyl chloride (1.04 mL, 11.5 mmol) and CH C1 (25 mL) was added into a 100 mL 2  2  RB flask. After being stirred at -78°C for 5 min, DMSO (1.82 mL, 26.0 mmol) was added slowly to the reaction mixture, which was stirred for another 15 min. Compound 23 (2.02 g, 10 mmol) was then added in dropwise into the flask during 15 min. The solution was stirred for another 30 min, and Et^N (6.9 mL, 50 mmol) was added. The cold bath was removed  146 after 10 more minutes and water (20 mL) was added into the mixture. The two phases were separated and the aqueous phase was extracted with C H 2 C I 2 (2 x 20 mL). The extraction was combined with the organic phase, and the combined phase was washed with water (30 mL) and brine (3,0 mL) and dried over anhydrous MgSGv Filtration removed the drying reagent. The dried solution was concentrated under reduced pressure. Flash column chromatography of the residue with petroleum ether and ethyl acetate (v/v = 90/10) as the eluent yielded 1.5 g (75%) of clear liquid.  IR(CHC1 ): 2947, 2872, 1728, 1459, 1375, 1270, 1049, 878 cm" ; 1  3  *H NMR (200MHz, CDC1 ): 5 9.70 (m, 1H), 4.50 (dd, J= 2.9, 4.2 Hz, 1H), 3.60-3.90 3  (m, 2H), 3.20-3.50 (m, 2H), 2.39 (t, J= 7.1 Hz, 2H), 1.20-1.80 (m, 12H); 13  C NMR (50MHz, C D C I 3 ) : 8 202.55, 67.20, 62.34, 43.78, 30.72, 29.45, 25.86, 25.44, 21.88, 19.66;  LRMS (DCI(+), ammonia) m/z (relative intensity): 218 (M +18, 19), 203 (M +l, 11), +  +  102 (100), 85 (55); HRMS (DCI(+), ammonia) m/z calculated for CJ1H24O3N (M +18) 218.1756, +  found: 218.1757; Analysis calculated for C 1 1 H 2 0 O 3 : C, 65.97; H, 10.07. Found: C, 65.68; H, 10.20.  147 4.3.13 2-(6'-Hexenoxyl) Tetrahydropyran (25)  Methyl triphenylphosphonium bromide (9.31 g, 26.1 mmol) was added into THF (75 mL) in a 250 mL RB flask. The mixture was cooled to 0 °C. BuLi solution in hexane (32.5 mL, 1.0 M) was added to the mixture during 15 min. It was stirred for another 30 min. Aldehyde 24 (2.58 g, 12.9 mmol) was then added to the flask in dropwise. The reaction was .stirred at 0°C for another 90 min. Water (100 mL) was then added to the reaction. After the separation of the two phases, the aqueous phase was extracted with E12O (4 x 50 mL). The extraction was combined with the organic phase, and the combined phase was washed with brine (2 x 100 mL) and dried over anhydrous MgSOv Filtration removed the drying reagent. The dried solution was concentrated under reduced pressure. Flash column chromatography of the residue with petroleum ether and ethyl acetate (v/v = 97/3) as the eluent yielded 2.0 g (78%) of clear liquid.  IR(CHC1 ): 3077, 2938, 2862, 1639, 1443, 1350, 1323, 1267, 1201, 1185, 1130, 1071, 3  1030,865,812 cm- ; 1  'H NMR (200MHz, CDC1 ): 8 5.65-5.85 (m, IH), 4.85-4.98 (m, 2H), 3  4.55 (dd, J= 2.9, 5.4 Hz, IH), 3.65-3.85 (m, 2H), 3.27-3.50 (m, 2H), 2.00 (m, 2H), 1.20-1.80 (m, 12H); 13  C NMR (50MHz, CDC1 ): 8 138.93,114.24, 98.81, 67.53, 62.28, 33.69, 30.76, 29:87, 3  28.71, 25.72, 25.49, 19.66;  148 LRMS (DCI(+), ammonia) m/z (relative intensity): 220 (M +18, 3), 203 (M +l, 3), +  +  102 (100), 85 (86); HRMS (DCI(+), ammonia) m/z calculated for Ci H 60 N (M +l8) 216.1964, +  2  2  2  found: 216.1962;  Analysis calculated for C i H 0 : C, 72.68; H, 11.18. Found: C, 72.60; H, 11.20. 2  22  2  4.3.14 6-Heptenyl Tosylate (26)  OTs 26 p-Toluene sulfonyl chloride (2.3 g, 12 mmol) was added to a solution of alcohol 17 (1.1 g, 10 mmol) in pyridine (5 mL), which was stirred at 0 °C in a 20 mL RB flask. The reaction was left for overnight. The mixture was then poured into water (50 mL) which was extracted by Et 0 (3 x 20 mL). The extraction was washed with water ( 2 x 30 mL) and brine 2  (40 mL), then dried over MgS04. Filtration removed the drying reagent. The dried solution was concentrated under reduced pressure. Flash column chromatography of the residue with petroleum ether and diethyl ether (v/v = 80/20) as the eluent yielded 2.4 g (90%) of clear liquid.  IR(CHC1 ): 3074, 2933,2861, 1640, 1599, 1495, 1457, 1357, 1308, 1172, 1098, 1020, 3  959,904, 834 cm" ; 1  'H NMR (200MHz, CDC1 ): 5 7.78 (m, 2H), 7.33 (m, 2H), 5.60-5.82 (m, IH), 3  4.85-5.00 (m, 2H), 4.00 (t, J= 6.4 Hz, 2H), 2.41 (s, 3H), 1.96 (m, 2H),  149 1.60 (m,2H), 1.28 (m,4H); 13  C NMR (50MHz, CDC1 ): 5 144.64, 138.44, 133.23, 129.80, 127.86, 114.59, 70.55, 33.43, 3  28.66,28.13,24.79,21.61; LRMS (DCI(+), ammonia) m/z (relative intensity): 286 (M +l 8, 100), 82 (51); +  HRMS (DCI(+), ammonia) m/z calculated for C14H24O3NS (M +18) 286.1477, +  found: 286.1479.  4.3.15 6-Heptenyl Cyanide (27) CN 27  Oven dried KCN (0.20 g, 3.0 mmol) was dissolved in acetonitrile (2 mL) in a 10 mL RB flask. 18-Crown-8 (3 mg) and tosylate 26 (0.52 g, 2.0 mmol) was then added into the flask. The mixture was refluxed for overnight. After cooled to the room temperature, C H 2 C I 2 (10 mL) was added to the mixture. Filtration removed any solid in the mixture. The solution was then washed with saturated ferrous sulfate solution (10 mL), water (20 mL) and brine (20 mL). The mixture was then dried over  MgS04.  Filtration removed the drying reagent.  The dried solution was concentrated under reduced pressure. Flash column chromatography of the residue with petroleum ether and diethyl ether (v/v = 95/5) as the eluent yielded 0.20 g (80%) of clear liquid.  IR (CHCI3): 3078, 2935, 2862, 2243, 1640, 1428, 997 cm ; -1  W NMR (200MHz, CDCI3): 5 5.65-5.85 (m, IH), 4.86-5.05 (m, 2H), 2.32  X  150 (t, J= 7.1 Hz, 2H), 2.05 (m, 2H), 1.63 (m, 2H), 1.40 (m, 4H); 13  C NMR (50MHz, CDC1 ): 5 138.28, 114.84,33.34, 28.08, 27.98, 25.24, 17.10; 3  LRMS (EI) m/z (relative intensity): 124 (M +l, 18), 123 (M , 5), 122 (29), 95 (32), 94 (100), +  +  82 (31), 80 (28), 67 (15), 55 (74); HRMS (EI) m/z calculated for C H i N (M +l) 124.1126, found: 124.1128. +  8  4  4.3.16 3,3-Dimethyl Glutaric Anhydride (28)  28  3,3-Dimethyl glutaric acid, 22 (8.0 g, 0.050 mol), was refluxed in acetic anhydride (4.7 mL, 0.050 mol) for 3 h. The reaction mixture was then cooled to 10 °C for 30 min. The crystal formed was obtained by vacuum filtration, washed with cold acetic acid (2 mL). The dried product was 5.3 g (75%) white flake crystal with melting point at 123-125 °C.  IR(CHC1 ): 2967,1816,1765, 1373,1339,1302, 1264,1126, 1071, 1020, 996, 964 cm ; -1  3  'H NMR (200MHz, CDC1 ): 5 2.56 (s, 4H), 1.08 (s, 6H); 3  13  C NMR (50MHz, CDC1 ): 5 166.26 (2), 43.72 (2), 29.45,27.52 (2); 3  LRMS (DCI(+), ammonia) m/z (relative intensity): 160 (M +18, 100), 143 (M +l, 6). +  +  151 4.3.17 3,3-Dimethyl-8-valerolactone (29)  X 29 At 0 °C, anhydride 28 (5.0 g, 35 mmol) was dissolved in THF (25 mL). This solution was added in dropwise to a NaBH (2.0 g, 53 mmol) solution in THF (10 mL). The mixture 4  was allowed to warm up to room temperature and stirred for another 3.5 h. The reaction was then cooled back to 0 °C, and quenched by slowly adding 6 M HC1 (17.5 mL). This mixture was extracted with Et20 (3 x 50 mL). The ether solution was washed with water (50 mL) and brine (50 mL), then dried over MgSGv Filtration removed the drying reagent. The dried solution was concentrated under reduced pressure. Flash column chromatography of the residue with petroleum ether and diethyl ether (v/v = 60/40) as the eluent yielded 3.5 g (78%) of clear liquid.  IR(CHC1 ): 2956, 1730, 1464, 1404, 1372, 1315, 1265, 1173, 1140, 1077, 1044, 992 cm ; -1  3  !  H NMR (200MHz, CDC1 ): 6 4.43 (t, J = 6.1Hz, 2H), 2.25 (s, 2H), 1.62 (t, J = 6.1 Hz, 2H), 3  1.02 (s, 6H); 13  C NMR (50MHz, CDC1 ): 5 171.53, 66.51, 44.12, 35.87, 29.68, 28.74 (2); 3  LRMS (DCI(+), ammonia) m/z (relative intensity): 146 (M +18, 100), 129 (M +l, 61). +  +  152 4.3.18 4,4-Dimethyl Tetrahydropyran-2-ol (30)  X ^ O ^ O H  30 Diisobutyl aluminum hydride (DIBAH, 20 mL, IM hexane solution) was added in dropwise to a stirred solution of lactone 29 (2.43 g, 19.0 mmol) in diethyl ether (50 mL) at -20 °C. The reaction mixture was stirred for another 30 min. The reaction was then quenched by adding 15 mL of methanol. The solution was allowed to warm slowly up to room temperature and was stirred for overnight. The resulted suspension was diluted with 30% sodium potassium tartrate aqueous solution (25 mL), and was stirred for another 30 min. The organic layer was separated and washed with 30%> sodium potassium tartrate solution (3x10 mL). The combined aqueous layer was extracted with Et20 (3 x 15 mL). The combined organic layer was dried over  MgSGv  Filtration removed the drying reagent. The dried  solution was concentrated under reduced pressure. The crude product (2.0 g, 82%) needed no further purification.  IR(CHC1 ): 3381,2950, 2872,1604,1459, 1387,1368, 1351,1267,1102, 1077, 1048, 3  1026,993,902 cm" ; 1  J  H NMR (200MHz, CDC1 ): 5 4.88 (m, 1H), 4.07 (s, w, 1H), 3.88 (m, 1H), 3.59 (m, 1H), 3  1.15-1.58 (m, 4H), 0.95 (s, 3H), 0.94 (s, 3H); 13  C NMR (50MHz, CDC1 ): 5 61.42, 45.09, 37.91, 31.67, 29.70, 26.19 (2); 3  LRMS (DCI(+), ammonia) m/z (relative intensity): 130 (M , 36), 113 (100). +  153 4.3.19 3,3-Dimethyl-5-hexen-l-ol (31)  Methyl triphenylphosphonium bromide (7.2 g, 20 mmol) was added into THF (60 mL) in a 250 mL RB flask. The mixture was cooled to 0 °C. 1.0 M solution of BuLi in hexane (24 mL) was added to the mixture during 15 min. It was stirred for another 30 min. Cyclic hemiacetal 30 (1.3 g, 10 mmol) was then added to the flask in dropwise. The reaction was stirred at 0 °C for another 90 min. Water (100 mL) was then added to the reaction. After the separation of the two phases, the aqueous phase was extracted with E t 2 0 (4x50 mL). The extraction was combined with the organic phase, and the combined phase was washed with brine (2 x 100 mL) and dried over anhydrous MgSC^. Filtration removed the drying reagent. The dried solution was concentrated under reduced pressure. Flash column chromatography of the residue with petroleum ether and diethyl ether (v/v = 70/30) as the eluent yielded 0.95 g (75%) of clear liquid.  IR(CHC1 ): 3619, 2942, 1638,1465, 1388,1367,1013,916 cm ; -1  3  *H NMR (200MHz, CDC1 ): 5 5.65-5.85 (m, IH), 4.88-5.00 (m, 2H), 3.63 (t, J= 7.5 Hz, 3  2H), 1.92 (s, IH), 1.90 (d, J= 7.3 Hz, 2H), 1.44 (t, J= 7.5 Hz, 2H), 0.85 (s, 6H); 13  C NMR (50MHz, CDC1 ): 6 135.30, 117.05, 59.72, 46.97, 44.27, 32.50, 27.24 (2); 3  LRMS (DCI(+), ammonia) m/z (relative intensity): 146 (M +18, 100), 129 (M +l, 5), +  +  128 (M , 10), 95 (55), 87 (21), 83 (27); +  HRMS (DCI(+), ammonia) m/z calculated for C H O N (M +l 8) 146.1545, +  8  20  154 found: 146.1544;  Analysis calculated for C H 0 : C, 74.94; H, 12.58. Found: C, 74.99; H, 12.60. 8  ]6  4.3.20 3,3-Dimethyl-5-hexenyl Tosylate (32)  p-Toluene sulfonyl chloride (2.3 g, 12 mmol) was added to a solution of alcohol 31 (1.28 g, 10.0 mmol) in pyridine (5 mL), which was stirred at 0 °C in a 20 mL RB flask. The reaction was left for overnight. The mixture was then poured into water (50 mL), which was extracted by Et20 (3 x 20 mL). The extraction was washed with water (2x30 mL) and brine (40 mL), then dried over MgSC»4. Filtration removed the drying reagent. The dried solution was concentrated under reduced pressure. Flash column chromatography of the residue with petroleum ether and diethyl ether (v/v = 80/20) as the eluent yielded 2.6 g (90%) of clear liquid.  IR (CHC1 ): 2957, 1640, 1599, 1463, 1360, 1175, 1098, 957, 917, 891 cm" ; 1  3  *H NMR (200MHz, C D C I 3 ) : 5 7.77 (m, 2H), 7.33 (m, 2H), 5.58-5.80 (m,TH), 4.85-5.05 (m, 2H), 4.05 (t, J= 7.3 Hz, 2H), 2.42 (s, 3H), 1.88 (d, J= 7.3 Hz, 2H), 1.55 (t, J= 7.3 Hz, 2H), 0.82 (s, 6H); 13  C NMR (50MHz, CDC1 ): 8 144.66, 134.52, 133.25, 129.80, 127.86, 124.48, 117.56, 3  67.93,46.63, 39.65, 32.47, 26.98 (2), 21.62; LRMS (DCI(+), ammonia) m/z (relative intensity): 300 (M +18, 100); +  155 HRMS (DCI(+), ammonia) m/z calculated for C15H26O3NS (M +18) 300.1633, +  found: 300.1635;  4.3.21 Methyl-5,5-dimethyl-2-methylcarboxylatyl-7-octenoate (33) ^  ^  ^  ^  ^ 33  ^ COOMe  Dimethyl malonate (1.45 g, 11.0 mmol) and KI (1.83 g, 11.0 mmol) were added to a solution of tosylate 32 (2.90 g, 10.0 mmol) in THF/DMF (8.5 mL/8.5 mL). The mixture was cooled to 0 °C and stirred for 15 min, and then warm up to 60 °C. The reaction mixture was cooled to room temperature after 24 h. The mixture was diluted with ethyl acetate (100 mL), and washed with water (50 mL) and 1 M HC1 (50 mL). The combined aqueous layer was neutralized with saturated NaHCC»3 solution, and extracted with ethyl acetate (3 x 30 mL). The combined organic phase was washed with NaHCC»3 solution (50 mL) and brine (100 mL), then dried over MgS0 . Filtration removed the drying reagent. The dried solution was 4  concentrated under reduced pressure. Flash column chromatography of the residue with petroleum ether and diethyl ether (v/v = 90/10) as the eluent yielded 2.1 g (87%) of clear liquid.  IR(CHC1 ): 3071,2932,2860, 1740, 1639, 1453, 1387, 1367, 1347, 1291, 1150, 1046, 3  999,913 cm ; -1  *H NMR (200MHz, C D C I 3 ) : 5 5.62-5.85 (m, 1H), 4.87-5.03 (m, 2H), 3.70 (s, 6H), 3.22 (t,J= 7.6 Hz, 1H), 1.95 (d, J= 7.3 Hz, 2H), 1.85 (m, 2H), 1.15 (t, J= 8.0 Hz,  156 2H), 0.83 (s, 6H); 13  C NMR (50MHz, CDC1 ): 5 169.89 (2), 135.25, 116.97, 52.42, 52.30, 46.07, 39.10, 33.01, 3  26.77 (2), 23.78; LRMS (EI) m/z (relative intensity): 243 (M +l, 1), 242 (M , 3), 201 (87), 169 (37), 145 (25), +  +  137(60), 109 (22), 101 (51), 69 (100), 55 (20); HRMS (EI) m/z calculated for C 1 3 H 2 2 O 4 (M ) 242.1518, found: 242.1517; +  Analysis calculated for C 1 3 H 2 2 O 4 : C, 64.44; H, 9.15. Found: C, 64.72; H, 9.29.  4.3.22 3,3-Dimethyl-5-hexenyl Cyanide (34)  CN  34  Oven dried KCN (2.0 g, 30 mmol) was added into acetonitrile (20 mL) in a 50 mL RB flask. 18-Crown-8 (30 mg) and tosylate 32 (5.64 g, 20.0 mmol) was then added into the flask. The mixture was refluxed for overnight. After cooled to the room temperature, CH2CI2 (100 mL) was added to the mixture. Filtration removed any solid in the mixture. The solution was then washed with saturated ferrous sulfate solution (50 mL), water (100 mL) and brine (50 mL). The mixture was then dried over MgS0 . Filtration removed the drying reagent. 4  The dried solution was concentrated under reduced pressure. Flash column chromatography of the residue with petroleum ether and diethyl ether (v/v = 95/5) as the eluent yielded 2.5 g (80%) of clear liquid.  IR (CHCI3): 3079, 2962, 2934, 2249, 1639, 1465, 1390, 1370, 996, 918 cm" ; 1  157 H NMR (200MHz, CDC1 ): 6 5.65-5.85 (m, IH), 4.95-5.10 (m, 2H), 2.25 (t, J= 8.2 Hz,  l  3  2H), 1.92 (d,J= 7.6 Hz, 2H), 1.58 (t, J= 8.2 Hz, 2H), 0.85 (s, 6H); 13  C NMR (50MHz, C D C I 3 ) : 5 134.19, 117.87, 112.99, 45.87, 36.94, 33.00, 26.23 (2);  LRMS (DCI(+), ammonia) m/z (relative intensity): 155 (M +18, 20), 138 (M +l, 100); +  +  HRMS (DCI(+), ammonia) m/z calculated for C H i N (M +l) 138.1283, +  9  6  found: 138.1284.  4.3.23 4,4-Dimethyl-6-heptenoic Acid (35)  35  O  A mixture of nitrile 34 (0.70 g, 5.0 mmol), KOH (2.24 g, 40.0 mmol) in ethylene glycol (7 mL) was stirred at 150 °C for overnight. After cooled to the room temperature, water (50 mL) was added into the mixture. The mixture was washed with ether (2 x 20 mL). The aqueous layer was acidified using concentrated HC1 and extracted with Et20 (3 x 20 mL). The extractions was then washed by water (40 mL) and brine (40 mL), and dried over MgS04. Filtration removed the drying reagent. The dried solution was concentrated under reduced pressure. Flash column chromatography of the residue with petroleum ether and diethyl ether (v/v = 60/40) as the eluent yielded 0.63 g (80%) of pale yellow oil.  IR(CHC1 ): 3088, 2930, 1708, 1639, 1521, 1470, 1453, 1414, 1389, 1368, 1303, 1132 cm" ; 1  3  *HNMR(200MHz, C D C I 3 ) : 8 11.40 (s, w, IH), 5.70-5.90 (m, IH), 4.95-5.10 (m, 2H), 2.31 (t, J= 8.3 Hz, 2H), 1.95 (d, J= 7.6 Hz, 2H), 1.54 (t,J= 8.3 Hz, 2H), 0.87 (s, 6H);  158 13  C NMR (50MHz, CDC1 ): 8 181.03, 134.94, 117.24, 46.18,36.08, 32.75,29.38,26.50 (2); 3  LRMS (EI) m/z (relative intensity): 157 (M +l, 0.3), 156 (M , 3), 115 (78), 97 (93), 83(21), +  +  73 (37), 69 (100), 55 (51); HRMS (EI) m/z calculated for C H , 0 (M ) 156.1150, found: 156.1151. +  9  6  2  4.3.24 Hexyl Undecanoate (36)  O  36  Undecanoic acid (0.37 g, 2.0 mmol) was dissolved in CH2CI2 (10 mL) in a 50 mL RB flask. DCC (0.48 g, 2.2 mmol) and DMAP (24 mg) were then added into the flask. 1-hexanol (0.204 g, 2 mmol) was added into the mixture in 5 min. The reaction was stirred at room temperature for 48 h. Water (30 mL) was then added into the mixture. The aqueous phase was extracted with Et20 (3 x 20 mL). The combined organic phase was washed with water (2 x 20 mL) and brine (20 mL), and dried over anhydrous MgSCv Filtration removed the drying reagent. The dried solution was concentrated under reduced pressure. Flash column chromatography of the residue with petroleum ether and diethyl ether (v/v = 95/5) as the eluent yielded 0.45 g (83%) of clear liquid.  IR (CHCI3): 2920, 2860, 1723, 1460, 1354, 1305, 1160, 1112, 1067, 994, 907 cm" ; 1  J  H NMR (200MHz, CDC1 ): 5 4.01 (t, J= 6.6 Hz, 2H), 2.26 (t, J= 7.3 Hz, 2H), 3  1.60 (m, 4H), 1.10-1.40 (m, 20H), 0.84 (m, 6H);  159 13  C NMR (50MHz, C D C I 3 ) : 5 173.88, 64.30, 34.35, 31.86, 31.41, 29.52, 29.43, 29.27, 29.24, 29.12, 28.60, 25.57, 24.99, 22.63, 22.50, 14.02, 13.91;  LRMS (DCI(+), ammonia) m/z (relative intensity): 288 (M +18, 100), 271 (M +l, 28), +  +  270 (M , 18); +  HRMS (DCI(+), ammonia) m/z calculated for C17H38O2N (M +l 8) 288.2903, +  found: 288.2903.  4.3.25 10,10-Dimethyl-7-hydroxyl-13-tridecanolide (37) and 10,10-Dimethyl-8-hydroxyl13-tridecanoIide (38)  X 37  X 38  (a) Lactone 14 (48 mg, 0.20 mmol) was dissolved in THF (5 mL) in a 25 mL RB flask. BH -Me2S (10 M , 25 uL) was added into the reaction solution. After 4 h at room 3  temperature, the reaction mixture was cooled down to 0 °C. NaOH solution (3M, 0.23 mL) was added into the flask, followed by H2O2 (dropwise, 30%, 0.4 mL). The reaction was kept at 0 °C for another 30 min, and then diluted with water (20 mL). This mixture was extracted with CH2CI2 (3 x 15 mL). The combined organic layer was dried over anhydrous M g S 0 4 . Filtration removed the drying reagent. The dried solution was concentrated under reduced pressure. Flash column chromatography of the residue with petroleum ether and diethyl ether (v/v = 85/15) as the eluent yielded two products (37, 22.8 mg, 44%; and 38,20.7 mg, 40%).  160 (b) Lactone 14 (48 mg, 0.20 mmol) was dissolved in THF (5 mL) in a 25 mL round bottom flask. Disiamyl borane/THF solution (1 M , 0.25 mL) was added into the reaction solution. After 48 h at room temperature, the reaction mixture was cooled down to 0 °C. NaOH solution (3  M ,  0.23 mL) was added into the flask, followed by H 2 O 2 (dropwise, 30%,  0.4 mL). The reaction was kept at 0 °C for another 30 min, and then diluted with water (20 mL). This mixture was extracted with C H 2 C I 2 (3x15 mL). The combined organic layer was dried over anhydrous M g S 0 4 . Filtration removed the drying reagent. The dried solution was concentrated on rotovap. Flash column chromatography of the residue with petroleum ether and diethyl ether (v/v = 85/15) as the eluent yielded two products (37, 23 mg, 45%>; and 38, 19 mg, 37%). (c) Lactone 14 (48 mg, 0.20 mmol) was dissolved in THF (5 mL) in a 25 mL round bottom flask. 9BBN/THF solution (0.50 M , 0.50 mL) was added into the reaction solution. After 72 h at room temperature, the reaction mixture was cooled down to 0 °C. NaOH solution (3  M ,  0.23 mL) was added into the flask, followed by H 2 O 2 (dropwise, 30%>,  0.4 mL). The reaction was kept at 0 °C for another 30 min, and then diluted with water (20 mL). This mixture was extracted with C H 2 C I 2 (3x15 mL). The combined organic layer was dried over anhydrous M g S 0 4 . Filtration removed the drying reagent. The dried solution was concentrated under reduced pressure. Flash column chromatography of the residue with petroleum ether and diethyl ether (v/v = 85/15) as the eluent yielded two products (37, 24 mg, 46%; and 38, 16 mg, 32%).  Compound 37 IR(CHC1 ): 3612, 2945,2864, 1722, 1446, 1352, 1260, 1200, 1153, 1029 cm"'; 3  161 'HNMR (200MHZ, CDC1 ): 5 4.58 (m, 1H), 3.52-3.73 (m, 2H), 2.18-2.45 (m, 2H), 3  1.10-1.90 (m, 17H), 0.84 (s, 6H); , 3  C NMR (50MHz, CDC1 ): 5 173.52, 71.46, 64.19, 35.80, 35.66, 34.89, 32.54, 32.26, 28.77, 3  28.72, 28.67, 25.77, 24.61, 24.34, 23.48; LRMS (DCI(+), ammonia) m/z (relative intensity): 274 (M +18, 100), 257 (M +l, 3), +  +  256 (M , 14); +  HRMS (DCI(+), ammonia) m/z calculated for C15H32O3N (M +l 8) 274.2382, +  found: 274.2385;  Analysis calculated for C ^ s C b : C, 70.27; H, 11.01. Found: C, 70.42; H, 11.08.  Compound 38 IR(CHC1 ): 3613, 2942, 2864, 1721, 1447, 1255, 1245, 1045, 834 cm" ; 1  3  H NMR (200MHz, C D C I 3 ) : 5 4.66 (m, 1H), 3.58-3.88 (m, 2H), 2.19-2.52 (m, 2H),  l  1.09-1.80 (m, 16H), 1.03 (s, 3H), 0.84 (s, 3H); 13  C NMR (50MHz, CDC1 ): 5 173.50, 66.72, 64.16,48.23, 36.58, 35.92, 33.42, 32.36, 29.26, 3  29.16, 25.66, 24.95, 24.18, 24.16, 23.29; LRMS (DCI(+), ammonia) m/z (relative intensity): 274 (M +18, 100), 257 (M +l, 5), +  +  256 (M , 28), 239 (41), 127 (53); +  HRMS (DCI(+), ammonia) m/z calculated for C15H32O3N (M +18) 274.2382, +  found: 274.2378; Analysis calculated for C 1 5 H 2 8 O 3 : C, 70.27; H, 11.01. Found: C, 70.10; H, 11.01.  162  4.3.26 10,10-Dimethyl-8-hydroxyl-13-tridecanolide (38)  38 A solution of lactone 57 (25.4 mg, 0.100 mmol) in THF (10 mL) was stirred at -15 °C. THF solution of K-selectride (1.0 M, 0.20 mL) was added into the reaction flask by syringe. The reaction was stirred at -15 °C for 3 h. HC1 (1 M, 0.10 mL) and H 0 (30%, 0.10 2  2  mL) were then added into the reaction mixture. The mixture was warmed up to room temperature and diluted with Et 0 (50 mL). This solution was washed with saturated 2  NaHCC>3 solution (30 mL) and brine (30 mL), and was dried over anhydrous MgS04. Filtration removed the drying reagent. The dried solution was concentrated under reduced pressure. Flash column chromatography of the residue with petroleum ether and diethyl ether (v/v = 75/25) as the eluent yielded 21 mg (84%) colorless liquid. The spectral data of the product is the same as those of compound 38.  163  4.3.27 (25*, 7/c*)-7-hydroxyl-2,10,10-Trimethyl-13-tridecanoIide (39) and (25*, 75*)-7-hydroxyl-2,10,10-Trimethyl-13-tridecanolide (40)  39  40  A solution of diisopropylamine (44 mg, 0.44 mmol) in THF (10 mL) was stirred at -78 °C. A solution of n-BuLi in hexane (1.3 M, 0.34 mL) was added into the reaction flask. After 10 minutes, a solution of compound 60 (131 mg, 0.40 mmol) in THF (5 mL) was added into the reaction mixture. After another 10 min, Mel (54.5 uL, 0.44 mmol) was added into the reaction flask. A THF solution of TBAF (1.0 M, 0.50 mL) was added into the reaction mixture in 15 min, and this mixture was stirred at room temperature for 2 h. Water (50 mL) was then added into the reaction solution. This aqueous solution was extracted with Et20 (3 x 20 mL). The combined organic solution was dried over anhydrous MgSO*4. Filtration removed the drying reagent. The dried solution was concentrated under reduced pressure. Flash column chromatography of the residue with petroleum ether and diethyl ether (v/v = 75/25) as the eluent yielded two products (39, 49 mg, 44%; and 40, 35 mg, 32%) and 23 mg of 37 was recovered.  Compound 39 IR(CHC1 ): 3613,2941,2864, 1718,1461,1387, 1365,1284, 1164,1083, 1039, 881 cm" ; 1  3  l  H N M R (500MHz, CDC1 ): 8 4.29 (m, IH), 4.09 (m, IH), 3.71 (m, IH), 2.49 (m, IH), 3  164 1.18-1.64 (m, 16H), 1.17 (s, 3H), 1.16 (d, J = 6.9 Hz, 3H), 0.89 (s, 3H); 13  C NMR (50MHz, CDC1 ): 8 176.45, 71.59, 64.05, 39.67, 35.91, 35.07, 34.34, 33.00, 32.31, 3  28.67, 28.58, 28.45, 26.42, 24.98, 24.50, 18.52; LRMS (DCI(+), ammonia) m/z (relative intensity): 288 (M +18, 89), 271 (M +l, 13), +  +  270 (M , 42), 253 (100), 176 (25), 158 (22), 141 (68), 123 (30), 112 (61), 83 (23); +  HRMS (DCI(+), ammonia) m/z calculated for C16H34O3N (M +18) 288.2539, +  found: 288.2537;  Analysis calculated for Ci H o0 : C, 71.07; H, 11.18. Found: C, 71.29; H, 11.10. 6  3  3  Compound 40 IR(CHC1 ): 3613,2941,2865, 1722, 1461, 1387, 1365, 1273, 1155, 1115, 1039, 908 cm- ; 1  3  U NMR (200MHz, C D C I 3 ) : 5 4.83 (m, 1H), 3.60 (m, 1H), 3.49 (t, 1H), 2.58 (m, 1H),  l  1.04-1.80 (m, 17H), 1.10 (d, J= 6.9 Hz, 3H), 0.86 (s, 3H), 0.85 (s, 3H); 13  C N M R (50MHz, CDC1 ): 8 176.83, 71.74, 64.05, 37.54, 36.13, 35.73, 35.60, 34.41, 32.27, 3  28.80,28.73, 28.70, 25.15, 24.51, 23.63, 18.43; LRMS (DCI(+), ammonia) m/z (relative intensity): 288 (M +18, 100), 271 (M +l, 9), +  +  270 (M , 39), 253 (88), 141 (66), 123 (30), 112 (60), 83 (23); +  HRMS (DCI(+), ammonia) m/z calculated for C16H34O3N (M +18) 288.2539, +  found: 288.2534; Analysis calculated for C 1 6 H 3 0 O 3 : C, 71.07; H, 11.18. Found: C, 71.18; H, 11.12.  165  4.3.28 (25*, 85*)-8-hydroxyl-2,10,10-Trimethyl-13-tridecanolide (41) and (25*, 8i?*)-8-hydroxyl-2,10,10-Trimethyl-13-tridecanolide (42)  41  42  A solution of diisopropylamine (44 mg, 0.44 mmol) in THF (10 mL) was stirred at -78 °C. A solution of n-BuLi in hexane (1.3 M, 0.34 mL) was added into the reaction flask. After 10 minutes, a solution of compound 61 (131 mg, 0.40 mmol) in THF (5 mL) was added into the reaction. After another 10 min, Mel (54.5 uL, 0.44 mmol) was added into the reaction flask. A THF solution of TBAF (1 M, 0.5 mL) was added into the reaction mixture in 15 minutes, and this mixture was stirred at room temperature for 2 hours. Water (50 mL) was then added into the reaction solution. This aqueous solution was extracted with E12O (3 x 20 mL). The combined organic solution was dried over anhydrous MgSC>4. Filtration removed the drying reagent. The dried solution was concentrated under reduced pressure. Flash column chromatography of the residue with petroleum ether and diethyl ether (v/v = 75/25) as the eluent yielded two products (41, 80 mg, 68%; and 42, 8 mg, 7%) and 15 mg of 38 was recovered.  Compound 41 IR(CHC1 ): 3612, 2936, 2862,1716,1460, 1387,1366, 1280,1152, 1083,1044, 996, 3  896 cm" ; 1  166 'H NMR (500MHz, CDCI3): 8 4.54 (m, 1H), 3.79 (m, 1H), 3.66 (m, 1H), 2.43 (m, 1H), 1.10-1.60 (m, 17H), 1.17 (d, J=7.1 Hz, 3H), 1.01 (s, 3H), 0.84 (s, 3H); 13  C NMR (50MHz, CDC1 ): 8 176.22, 67.42, 64.32, 49.28, 41.36, 37.04, 35.89, 33.48, 32.41, 3  29.07,28.58,26.13,25.03,24.15,22.72,18.56; LRMS (DCI(+), ammonia) m/z (relative intensity): 288 (M +18, 83), 271 (M +l, 5), +  +  270 (M , 27), 253 (68), 172 (26), 127 (100), 126 (23), 109 (24), 83 (27); +  HRMS (DCI(+), ammonia) m/z calculated for C i H 0 N (M +18) 288.2539, +  6  34  3  found: 288.2538;  Analysis calculated for Ci H o0 :C, 71.07; H, 11.18. Found: C, 70.79; H, 11.16. 6  3  3  Compound 4 2 IR(CHC1 ): 3612,2938,2862, 1721, 1460, 1387, 1363, 1161, 1064,992,887 cm- ; 1  3  K NMR (200MHz, CDC1 ): 8 4.76 (m, 1H), 3.74 (m, 1H), 3.56 (m, 1H), 2.60 (m, 1H),  l  3  1.13-1.71 (m, 17H), 1.11 (d, J=6.9 Hz, 3H), 1.04 (s, 3H), 0.86 (s, 3H); 13  C NMR (50MHz, C D C I 3 ) : 8 176.75, 66.33, 63.86, 47.63, 37.68, 36.61, 36.14, 33.92, 32.33, 29.39, 29.11, 25.18, 24.97, 24.33, 23.81, 17.80;  LRMS (DCI(+), ammonia) m/z (relative intensity): 288 (M +18, 96), 271 (M +l, 5), +  +  270 (M , 26), 253 (65), 172 (26), 127 (100), 126 (24), 109 (25), 83 (27); +  Analysis calculated for Ci6H o0calculated :C, 71.07;for H,C16H34O3N 11.18. Found: H, 11.09. HRMS (DCI(+), ammonia) m/z (M C, +l 71.11; 8) 288.2539, +  3  found: 288.2538;  3  167  4.3.29 (25*, 7i?*)-7-hydroxyl-2,10,10-Trimethyl-13-tridecanolide (39), (25*, 75*)-7-hydroxyl-2,10,10-Trimethyl-13-tridecanolide (40), (25*, 85*)-8-hydroxyl-2,10,10-Trimethyl-13-tridecanolide (41), and (25*, 8if*)-8-hydroxyl-2,10,10-Trimethyl-13-tridecanolide (42)  Lactone 43 (51 mg, 0.20 mmol) was dissolved in THF (5 mL) in a 25 mL round bottom flask. BHa-M^S (10 M , 25 uL) was added into the reaction solution. After 4 h at room temperature, the reaction mixture was cooled down to 0 °C. A NaOH solution (3 M , 0.23 mL) was added into the flask, followed by H 2 O 2 (dropwise, 30%, 0.4 mL). The reaction was kept at 0 °C for another 30 min, and then diluted with water (20 mL). This mixture was extracted with C H 2 C I 2 (3x15 mL). The combined organic layer was dried over anhydrous MgS04. Filtration removed the drying reagent. The dried solution was concentrated under reduced pressure. Flash column chromatography of the residue with petroleum ether and diethyl ether (v/v = 85/15) as the eluent yielded four products (39, 8.5 mg, 16%; 40, 11.3 mg,  21%; 41, 8.7 mg, 16%; and 42,15.7 mg, 29%).  168  4.3.30 (£)-2,10,10-Trimethyl-13-tridec-7-enolide (43)  43 A solution of diisopropylamine (22 mg, 0.22 mmol) in THF (10 mL) was stirred at -78 °C. A solution of n-BuLi in hexane (1.3 M, 0.17 mL) was added into the reaction flask. After 10 min, a solution of compound 14 (47.6 mg, 0.20 mmol) in THF (5 mL) was added into the reaction mixture. After another 10 min, Mel (27.5 pL, 0.20 mmol) was added into the reaction flask. A THF solution of TBAF (1.0 M, 0.30 mL) was added into the reaction mixture in 15 min, and this mixture was stirred at room temperature for 2 h. Water (50 mL) was then added into the reaction solution. This aqueous solution was extracted with Et^O (3 x 20 mL). The combined organic solution was dried over anhydrous MgSC>4. Filtration removed the drying reagent. The dried solution was concentrated under reduced pressure. Flash column chromatography of the residue with petroleum ether and diethyl ether (v/v = 95/5) as the eluent yielded 43 mg (85%) colorless liquid.  IR(CHC1 ): 2943, 2861, 1720, 1453, 1248, 1182, 975 cm' ; 1  3  *H NMR (200MHz, CDCI3): 5 5.18-5.43 (m, 2H), 4.43 (m, IH), 3.89 (m, IH), 2.45 (m, IH), 2.01 (m, 2H), 1.86 (m, 2H), 1.11-1.55 (m, 10H), 1.10 (d, J= 6.8 Hz, 3H), 0.88 (s, 3H), 0.87 (s, 3H);  169 13  C NMR (50MHz, CDC1 ): 6 176.96, 132.38, 128.12, 64.38, 44.76, 39.65, 37.09, 34.55, 3  32.81, 31.83, 28.40, 28.27, 27.67, 25.82, 23.68, 17.87; LRMS (DCI(+), ammonia) m/z (relative intensity): 270 (M +18, 100), 253 (M +l, 41), +  +  252 (M , 18), 251(33), 127 (19), 109 (20), 83 (86), 82 (29); +  HRMS (DCI(+), ammonia) m/z calculated for CJ6H32O2N (M +18) 270.2433, +  found: 270.2433.  4.3.31 (25*, IR*, (25*, IS*,  8/?*)-7,8-epoxy-2,10,10-Trimethyl-13-tridecanolide (44) and 8S*)-7,8-epoxy-2,10,10-Trimethyl-13-tridecanolide (45)  44  45  Lactone 43 (76 mg, 0.30 mmol) and M C P B A (258 mg, 1.50 mmol) was dissolved in  C H 2 C I 2 (12 mL). The mixture was stirred at room temperature for 24 h. This reaction solution was washed with saturated NaHCCb solution (2 x 10 mL), Saturated NaHSC>3 solution (10 mL),  saturated NaHCC>3 solution (10 mL), and brine (10 mL). The organic layer was then  dried over M g S G v  Filtration removed the drying reagent. The dried solution was  concentrated under reduced pressure. Reverse phase column chromatography of the residue with methanol and water (v/v = 90/10) as the eluent yielded two products (44, 26.8 mg, 33%; and 45, 45.6 mg, 57%).  170 Compound 44 IR (CHCI3): 2946, 2861, 1720, 1455, 1284, 1247, 1179, 1072 cm" ; 1  !  H NMR (500MHz, CDCI3): 5 4.30 (m, 1H), 4.04 (m, 1H), 2.68 (m, 2H), 2.45 (m, 1H), 2.05 (m, 1H), 1.85 (m, 1H), 0.96-1.69 (m, 12H), 1.14 (d,J= 7.1 Hz, 3H), 0.99 (s, 3H), 0.90 (s, 3H);  13  C NMR (50MHz, CDC1 ): 5 176.34, 64.53, 59.27, 55.98, 45.03, 40.29, 37.69, 34.60, 32.39, 3  31.28, 28.72, 27.29, 26.76, 25.81, 23.80, 18.22; LRMS (DCI(+), ammonia) m/z (relative intensity): 286 (M +l8, 87), 269 (M +l, 100), +  +  268 (M , 16), 251 (73), 139 (22), 127 (66), 126 (21), 111 (20), 95 (31), 83 (36); +  HRMS (DCI(+), ammonia) m/z calculated for C 1 6 H 2 9 O 3 (M +l) 269.2117, +  found: 269.2118;  Analysis calculated for Ci6H 80 : C, 71.60; H, 10.52. Found: C, 71.47; H, 10.71. 2  3  Compound 45 IR(CHC1 ): 2946, 2861, 1721, 1453, 1390, 1360, 1254, 1184, 1053, 1006, 825 cm" ; 1  3  !  H NMR (500MHz, CDCI3): 5 4.51 (m, 1H), 3.78 (m, 1H), 2.62 (m, 2H), 2.50 (m, 1H), 2.02 (m, 1H), 1.80 (m, 1H), 0.98-1.66 (m, 12H), 1.12 (d, J= 6.9 Hz, 3H), 1.00 (s,3H), 0.89 (s,3H);  13  C NMR (50MHz, CDC1 ): 6 176.94, 64.33, 59.50, 56.61,45.45, 38.44, 37.76, 35.26, 32.40, 3  32.31,28.66,27.11,26.32,25.45,23.62,17.77; LRMS (DCI(+), ammonia) m/z (relative intensity): 286 (M +18,100), 269 (M +1, 77), +  +  268 (M , 17), 251 (69), 139 (20), 127 (56), 126 (19), 95 (25), 83 (31); +  HRMS (DCI(+), ammonia) m/z calculated for C 1 6 H 2 9 O 3 (M +l) 269.2117, +  171 found: 269.2115;  Analysis calculated for Ci H 80 : C, 71.60; H, 10.52. Found: C, 71.52; H, 10.63. 6  2  3  4.3.32 2-(7'-Hydroxyl heptoxyl) Tetrahydropyran (47)  Heptane-1,7-diol (13.2 g, 0.100 mol) was added into toluene (150 mL) in a 250 mL Erlenmeyer flask. Acidic resin Amberlite IR-120 (10 g) and 3,4-dihydropyran (DHP, 8.4 g, 0.1 mol) was then added. After being stirred at room temperature for 3 h, the mixture was fdtered to remove the resin. The organic solution was washed with saturated NaHC0  3  solution (2 x 50 mL) and water (2 x 50 mL), then dried over M g S 0 4 . The dried solution was fdtered to remove the drying reagent and was concentrated under reduced pressure. Flash column chromatography of the residue with petroleum ether and ethyl acetate (v/v = 60/40) as the eluent yielded 18 g (85%) of clear liquid.  IR(CHC1 ): 3623, 3463, 2935, 2862, 1456, 1360, 1323, 1126, 1074, 1034, 988, 905 cm" ; 1  3  'H NMR (200MHz, CDC1 ): 5 4.52 (dd, J= 3.1, 4.4 Hz, IH), 3.29-3.88 (m, 6H), 3  1.99 (s, IH), 1.23-1.87 (m, 16H); 13  C NMR (50MHz, CDC1 ): 5 98.72, 67.53, 62.69, 62.20, 32.56, 30.65, 29.56, 29.15, 26.09, 3  25.67,25.38,19.55; LRMS (DCI(+), ammonia) m/z (relative intensity): 234 (M +18, 55), 217 (M +l, 28), +  150(64), 102 (44), 85 (100);  +  172 HRMS (DCI(+), ammonia) m/z calculated for C12H28O3N (M +18) 234.2069, +  found: 234.2067.  4.3.33 2-(7'-Oxoheptoxyl) Tetrahydropyran (48)  Oxalyl chloride (1.04 mL, 11.5 mmol) and C H 2 C I 2 (25 mL) were added into a 100 mL RB flask. The mixture was stirred at -78 °C for 5 min. DMSO (1.82 mL, 26 mmol) was added slowly to the reaction mixture, and stirred for another 15 min. Compound 47 (2.16 g, 10.0 mmol) was then added in dropwise into the flask during 15 min. The solution was stirred for another 30 min, and Et3N (6.9 mL, 50 mmol) was added. The cold bath was removed after 10 more minutes and water (20 mL) was added into the mixture. The two phases were separated and the aqueous phase was extracted with C H 2 C I 2 (2 x 20 mL). The extraction was combined with the organic phase, and the combined phase was washed with water (30 mL) and brine (30 mL) and dried over anhydrous MgSC<4. Filtration removed the drying reagent. The dried solution was concentrated under reduced pressure. Flash column chromatography of the residue with petroleum ether and ethyl acetate (v/v = 90/10) as the eluent yielded 1.6 g (82%) of clear liquid.  IR(CHC1 ): 2940,2867,1724, 1441, 1410,1351,1322,1267, 1201, 1185, 1133,1046, 3  812 cm" ; 1  'H NMR (200MHz, CDCI3): 5 9.73 (t, J= 1.8 Hz, IH), 4.58 (dd, J= 2.9,4.4 Hz, IH),  173 3.30-3.89 (m, 4H), 2,41 (m, 2H), 1.19-1.91 (m, 14H); 13  C NMR (50MHz, CDC1 ): 5 203.07, 91.94, 67.44, 62.37, 43.82, 30.77, 29.52, 28.98, 26.02, 3  25.48,22.01,19.69; LRMS (DCI(+), ammonia) m/z (relative intensity): 232 (M +18, 38), 215 (M +l, 30), +  +  102 (56), 85 (100); HRMS (DCI(+), ammonia) m/z calculated for C12H26O3N (M +18) 232.1913, +  found: 232.1913.  4.3.34 2-(7'-Heptenoxyl) Tetrahydropyran (49)  Methyl triphenylphosphonium bromide (9.31 g, 26.1 mmol) was added into THF (75 mL) in a 250 mL RB flask. The mixture was cooled to 0 °C. Hexane solution of BuLi (1.0 M, 32.5 mL) was added to the mixture during 15 min. It was stirred for another 30 min. Aldehyde 48 (2.8 g, 13 mmol) was then added to the flask in dropwise. The reaction was stirred at 0 °C for another 90 min. Water (100 mL) was then added to the reaction. After the separation of the two phases, the aqueous phase was extracted with  Et20  (4 x 50 mL). The  extraction was combined with the organic phase, and the combined phase was washed with brine (2 x 100 mL) and dried oyer anhydrous MgSC»4. Filtration removed the drying reagent. The dried solution was concentrated under reduced pressure. Flash column chromatography of the residue with petroleum ether and ethyl acetate (v/v = 97/3) as the eluent yielded 2.1 g (80%) of clear liquid.  174  IR (CHCI3): 3078, 2930, 2860, 1639, 1454, 1358, 1323, 1280, 1127, 1073, 1032, 990, 908, 867 cm- ; 1  !  H NMR (200MHz, CDCI3): 8 5.69-5.89 (m, 1H), 4.83-5.01 (m, 2H), 4.52 (dd, J= 2.9, 4.5 Hz, 1H), 3.30-3.89 (m, 4H), 2.03 (m, 2H), 1.22-1.83 (m, 14H);  13  C NMR (50MHz, CDCI3): 5 139.03, 114.14, 98.78, 67.57, 62.24, 33.69, 30.75, 29.67, 28.92, 28.82, 26.07, 25.49, 19.64;  LRMS (DCI(+), ammonia) m/z (relative intensity): 230 (M +18, 18), 213 (M +l, 6), +  +  212 (M , 4), 102 (66), 101 (23), 85 (100); +  HRMS (DCI(+), ammonia) m/z calculated for Ci H 80 N (M +l 8) 230.2120, +  3  2  2  found: 230.2120.  4.3.35 7-Octen-l-ol (50)  OH  50  Pyridinium toluene-4-sulfonate (0.67 g, 2.7 mmol) was added into MeOH (200 mL) in a 500 mL RB flask. Compound 49 (9.0 g, 42 mmol) was then added. The mixture was stirred at room temperature for 24 h. The solvent was removed under reduced pressure, and Et 0 (200 mL) was then added to the residue. The solution was washed by water (100 mL), 2  saturated NaHC03 solution (100 mL) and brine (100 mL), and dried over MgS0 . . Filtration 4  removed the drying reagent. The dried solution was concentrated under reduced pressure.  175 Flash column chromatography of the residue with petroleum ether and ethyl acetate (v/v = 65/35) as the eluent yielded 5.0 g (95%) of clear liquid.  IR(CHC1 ): 3623, 3461, 3078, 2930, 2858, 1639, 1460, 1390, 1050, 997, 913 cm" ; 1  3  'H NMR (200MHz, CDC1 ): 5 5.66-5.90 (m, IH), 4.87-5.01 (m, 2H), 3.59 (t, J= 6.4 Hz, 3  2H), 2.04 (q, 2H), 1.20-1.70 (m, 9H); 13  C NMR (50MHz, CDC1 ): 5 139.02, 114.21, 62.90, 33.68, 32.68, 28.86, 28.84, 25.57; 3  LRMS (DCI(+), ammonia) m/z (relative intensity): 146 (M +18, 100), 129 (M +l, 5), +  +  128 (M , 3), 110 (33), 109 (24), 95 (42), 82 (42), 81 (61), 71 (21); +  HRMS (DCI(+), ammonia) m/z calculated for C H O N (M +18) 146.1545, +  8  20  found: 146.1544.  4.3.36 5-Hexenyl Tosylate (52) OTs  52  p-Toluene sulfonyl chloride (2.3 g, 12 mmol) was added to a solution of 5-hexen-l-ol (1.0 g, 10 mmol) in pyridine (5 mL), which was stirred at 0 °C in a 20 mL RB flask. The reaction was left for overnight. The mixture was then poured into water (50 mL). This aqueous mixture was extracted by Et 0 (3 x 20 mL). The extraction was washed with water 2  (2 x 30 mL) and brine (40 mL), then dried over MgSOv. Filtration removed the drying reagent. The dried solution was concentrated under reduced pressure. Flash column  176 chromatography of the residue with petroleum ether and diethyl ether (v/v = 80/20) as the eluent yielded 2.4 g (90%) of clear liquid.  IR(CHC1 ): 3071,2936, 2864, 1641, 1599, 1495, 1456, 1358, 1308, 1290, 1172, 1098, 3  1020,993,959,913 cm" ; 1  'H NMR (200MHz, CDC1 ): 5 7.74 (m, 2H), 7.31 (m, 2H), 5.59-5.79 (m, 1H), 3  4.85-4.96 (m, 2H), 3.99 (t, J= 6.3 Hz, 2H), 2.42 (s, 3H), 1.97 (m, 2H), 1.32-1.69 (m,4H); 13  C NMR (50MHz, CDC1 ): 5 144.69, 137.88, 133.17, 129.82, 127.85, 115.03, 70.44, 32.89, 3  28.18,24.52,21.60; LRMS (DCI(+), ammonia) m/z (relative intensity): 272 (M +18, 100), 82 (69); +  HRMS (DCI(+), ammonia) m/z calculated for C13H22O3NS (M +18) 272.1321, +  found: 272.1324.  4.3.37 Methyl 2-methylcarboxylatyl-7-octenoate (53)  COOMe COOMe 53  Dimethyl malonate (1.45 g, 11.0 mmol) and KI (1.83 g, 11.0 mmol) were added to a solution of tosylate 52 (2.62 g, 10.0 mmol) in THF/DMF (8.5 mL/8.5 mL). The mixture was cooled to 0 °C and stirred for 15 min, and then warm up to 60°C. The reaction mixture was cooled to room temperature after 24 h. The mixture was diluted with ethyl acetate (100 mL),  177 and washed with water (50 mL) and 1M HC1 (50 mL). The combined aqueous layer was neutralized with saturated N a H C 0 3 solution, and extracted with ethyl acetate (3 x 30 mL). The combined organic phase was washed with NaHC03 solution (50 mL) and brine (100 mL), then dried over MgS04. Filtration removed the drying reagent. The dried solution was concentrated under reduced pressure. Flash column chromatography of the residue with petroleum ether and diethyl ether (v/v = 90/10) as the eluent yielded 1.9 g (87%) of clear liquid.  IR(CHC1 ): 3076, 2931, 2859, 1738, 1640, 1455, 1328, 1133, 1061, 996, 908 cm" ; 1  3  'H NMR (200MHz, CDC1 ): 5 5.65-5.87 (m, IH), 4.86-5.02 (m, 2H), 3.70 (s, 6H), 3.32 (t, 3  .7=7.6 Hz, IH), 2.01 (q, J=6.8Hz, 2H), 1.89 (q, J=7.7Hz, 2H), 1.34 (m, 4H); 1 3  C NMR (50MHz, CDC1 ): 5 169.87(2), 138.47, 114.58, 52.40 (2), 51.63, 33.33, 28.65, 3  28.38,26.73; LRMS (DCI(+), ammonia) m/z (relative intensity): 232 (M +18, 52), 215 (M +l, 100), +  +  214 (M , 1), 145(21); +  HRMS (DCI(+), ammonia) m/z calculated for C 1 1 H 1 9 O 4 (M +l) 215.1283, +  found: 215.1283.  178  4.3.38 10,10-Dimethyl-7,8-epoxy-13-tridecanolide (54)  54 Lactone 14 (70 mg, 0.30 mmol) and MCPBA (258 mg, 1.50 mmol) was dissolved in  C H 2 C I 2 (12 mL). The mixture was stirred at room temperature for 24 h. This reaction solution was washed with saturated NaHC0 solution (2x10 mL), Saturated NaHS03 solution (10 3  mL), saturated NaHCC>3 solution (10 mL), and brine (10 mL). The organic layer was then dried over MgSO*4. Filtration removed the drying reagent. The dried solution was concentrated under reduced pressure. Flash column chromatography of the residue with petroleum ether and diethyl ether (v/v = 90/10) as the eluent yielded 70 mg (92%) colorless liquid.  IR(CHC1 ): 2945,2863, 1722, 1445, 1341, 1252, 1156, 1052, 829 cm" ; 1  3  !  H NMR (500MHz, CDC1 ): 8 4.44 (m, IH), 3.93 (m, IH), 2.67 (m, 2H), 2.34 (m, 2H), 3  2.02 (m, IH), 1.85 (dd, J= 3.0, 14.0 Hz, IH), 1.38-1.72 (m, 8H), 1.06-1.29 (m, 4H), 1.00 (s,3H), 0.89 (s,3H); 13  C NMR (50MHz, CDCI3): 5 173.64, 64.36, 59.32, 56.24,45.22, 37.52, 33.76, 32.32, 31.78, 28.67, 28.02, 26.46, 25.50, 25.05, 23.60;  LRMS (DCI(+), ammonia) m/z (relative intensity): 272 (M +18,100), 255 (M +l, 24), +  +  179 254 (M , 10); +  HRMS (DCI(+), ammonia) m/z calculated for C H3o0 N (M +18) 272.2226, +  15  3  found: 272.2222;  Analysis calculated for C 1 5 H 2 6 O 3 : C, 70.83; H, 10.30. Found: C, 70.70; H, 10.35.  4.3.39 7-Chloro-10,10-dimethyl-8-hydroxyl-13-tridecanolide(55)  55  Epoxide 54 (102 mg, 0.40 mmol) was dissolved in THF (10 mL). The solution was stirred at room temperature. Concentrated HC1 (0.10 mL) was added into the solution in dropwise. The mixture was stirred for another 15 min, and then diluted with Et20 (40 mL). The solution was washed with saturated NaHC03 solution (20 mL) and brine (20 mL), dried over anhydrous MgS0 . Filtration removed the drying reagent. The dried solution was 4  concentrated under reduced pressure. Flash column chromatography of the residue with petroleum ether and diethyl ether (v/v = 85/15) as the eluent yielded 110 mg (95%) colorless liquid.  IR(CHC1 ): 3578, 2950, 2866, 1725, 1449, 1246, 1152, 1065, 1042, 828 cm ; -1  3  'H NMR (200MHz, CDC1 ): 8 4,64 (m, 1H), 4.17 (m, 1H), 3.97 (m, 1H), 3.69 (m, 1H), 3  180 2.37 (m, 2H), 1.11-2.00 (m, 15H), 1.05 (s, 3H), 0.91 (s, 3H); 13  C NMR (50MHz, CDC1 ): 8 173.34, 70.04, 69.19, 63.68, 41.92, 37.12, 35.90, 32.51, 31.94, 3  29.23, 28.37, 27.25, 24.60, 24.64, 24.15; LRMS (DCI(+), ammonia) m/z (relative intensity): 310 ( C1, M +18, 34), 37  +  308 ( C1, M +18, 100), 291 (M +l, 1), 290 (M , 1), 272 (21), 127 (36); 35  +  +  +  HRMS (DCI(+), ammonia) m/z calculated for C i H i 0 C l N (M +18) 310.1963, 37  5  3  +  3  found: 310.1960; calculated for C H i 0 ]5  3  35 3  C l N (M +18) 308.1993, +  found: 308.1987;  Analysis calculated for C i H 0 : C, 61.95; H, 9.36. Found: C, 62.11; H, 9.42. 5  28  3  4.3.40 7-Chloro-10,10-dimethyl-8-oxo-13-tridecanolide (56)  56  A mixture of compound 55 (87 mg, 0.30 mmol) and PCC (215 mg, 1.00 mmol) in  C H 2 C I 2 (20 mL) was stirred at room temperature for 48 h. The solvent was then removed under reduced pressure. The residue was extracted with 20% Et20 in petroleum ether (3x15 mL). The combined organic layer was washed with water (30 mL), brine (30 mL),  181 and dried over anhydrous MgSGv Filtration removed the drying reagent. The dried solution was concentrated under reduced pressure. Flash column chromatography of the residue with petroleum ether and diethyl ether (v/v = 90/10) as the eluent yielded 74 mg (85%) colorless liquid.  IR(CHC1 ): 2949, 2868, 1722, 1445, 1248, 1149, 1113, 1049, 829 cm" ; 1  3  'H NMR (200MHz, CDC1 ): 5 4.20-4.41 (m, 2H), 3.94 (m, IH), 2.28 (d, J= 14.9 Hz,lH), 3  2.32 (d, J = 14.9 Hz, IH), 1.12-2.49 (m, 14H), 1.07 (s, 3H), 1.01 (s, 3H); 13  C NMR (50MHz, CDC1 ): 5 203.53, 64.09, 61.03, 49.35, 36.94, 34.12, 33.71, 31.59, 28.68, 3  27.84, 26.72, 24.34, 24.04, 23.99; LRMS (DCI(+), ammonia) m/z (relative intensity): 308 (M +18, 34), 306 (M +18, 100), +  +  289 (M +l, 7), 288 (M , 2), 272 (27), 143 (54); +  +  HRMS (DCI(+), ammonia) m/z calculated for  C H 2 903 15  37  C1N (M +18) 308.1806,  found: 308.1808; calculated for C i H i 0 C l N (M +18) 306.1836, 35  5  3  +  3  found: 306.1842.  4.3.41 10,10-Dimethyl-8-oxo-13-tridecanolide (57)  57  +  182 A mixture of compound 56 (29 mg, 0.10 mmol), Zn (65 mg, 1.0 mmol), and acetic acid (0.2 mL) in THF (20 mL) was stirred at room temperature for 24 h. The solvent was then removed by rotovap. The residue was extracted with 20% Et20 in petroleum ether (3x15 mL). The combined organic layer was washed with water (30 mL) and brine (30 mL), and was dried over anhydrous  MgSGv  Filtration removed the drying reagent. The dried  solution was concentrated under reduced pressure. Flash column chromatography of the residue with petroleum ether and diethyl ether (v/v = 90/10) as the eluent yielded 23 mg (90%) colorless liquid.  IR(CHC1 ): 2943,2865, 1715, 1460, 1359, 1270, 1152, 1101, 1079, 1048, 996, 908 cm" ; 1  3  •H NMR (200MHz, CDC1 ): 6 4.11 (t, J= 5.2 Hz, 2H), 2.39 (t, J= 6.4 Hz, 2H), 3  2.29 (t, J= 6.2Hz, 2H), 2.21 (s, 2H), 1.10-1.63 (m, 12H), 0.95 (s, 6H); 13  C NMR (50MHz, CDC1 ): 5 210.37, 173.37, 64.00, 42.49, 36.89, 33.88, 33.74, 28.14 (2), 3  26.44, 26.40, 24.10, 23.88, 20.74; LRMS (DCI(+), ammonia) m/z (relative intensity): 272 (M +18, 100), 255 (M +l, 36), +  +  254 (M , 2), 83 (27), 82 (24); +  HRMS (DCI(+), ammonia) m/z calculated for C i H O N (M +18) 272.2226, +  5  found: 272.2220.  30  3  183  4.3.42 10,10-Dimethyl-7-trimethylsilyloxyl-13-tridecanolide (60)  TMSO  60 A mixture of compound 37 (26 mg, 0.10 mmol), TMSC1 (25 pL, 0.20 mmol), and Et3N (27.5 pL, 0.20 mmol) in THF (5 mL) was stirred at room temperature for 48 h. The solvent was removed under reduced pressure. Flash column chromatography of the residue with petroleum ether and diethyl ether (v/v = 95/5) as the eluent yielded 30 mg (90%) colorless liquid.  IR(CHC1 ): 2946, 2865, 1722, 1445, 1355, 1253, 1204, 1157, 1050, 841 cm" ; 1  3  !  H NMR (200MHz, CDC1 ): 5 4.63 (m, 1H), 3.55-3.72 (m, 2H), 2.23-2.53 (m, 2H), 3  1.83 (m, 1H), 1.01-1.64 (m, 15H), 0.85 (s, 3H), 0.84 (s, 3H), 0.10 (s, 9H); 13  C NMR (50MHz, CDC1 ): 8 173.61, 72.24, 64.18, 36.30, 35.81, 35.34, 32.39, 32.14, 3  28.80 (2), 28.60, 25.84, 24.90, 24.42, 23.60, 0.02 (3); ' LRMS (DCI(+), ammonia) m/z (relative intensity): 346 (M +l 8, 100), 328 (M +l, 11); +  +  HRMS (DCI(+), ammonia) m/z calculated for Ci H O NSi (M +l 8) 346.2778, +  8  found: 346.2777.  40  3  184  4.3.43 10,10-Dimethyl-8-trimethylsilyloxyl-13-tridecanoIide (61)  61 A mixture of compound 38 (26 mg, 0.10 mmol), TMSC1 (25 uL, 0.20 mmol), and Et N (27.5 uL, 0.20 mmol) in THF (5 mL) was stirred at room temperature for 48 h. The 3  solvent was removed under reduced pressure. Flash column chromatography of the residue with petroleum ether and diethyl ether (v/v = 95/5) as the eluent yielded 30 mg (90%) colorless liquid.  IR(CHC1 ): 2940, 2862, 1722, 1445, 1355, 1253, 1204, 1157, 1050 cm ; -1  3  U NMR (200MHz, CDCI3): 8 4.50 (m, IH), 3.61-3.80 (m, 2H), 2.20-2.55 (m, 2H),  l  1.06-1.70 (m, 16H), 0.99 (s, 3H), 0.83 (s, 3H), 0.10 (s, 9H); 13  C NMR (50MHz, CDCI3): 8 173.32, 69.08, 64.29, 49.22, 36.84, 36.38, 34.15, 32.29, 29.47, 28.98,27.30,26.09,25.67,23.73,23.35,2.03 (3);  LRMS (DCI(+), ammonia) m/z (relative intensity): 346 (M +18,100), 328 (M +l, 21); +  +  HRMS (DCI(+), ammonia) m/z calculated for Ci H4o0 NSi (M +18) 346.2778, +  8  3  found: 346.2777; Analysis calculated for Ci H 0 Si: C, 65.80; H, 11.04. Found: C, 65.78; H, 11.08. 8  36  3  185  4.3.44 Benzyl Undecanoate (66)  Undecanoic acid (0.37 g, 2.0 mmol) was dissolved in CH2CI2 (10 mL) in a 50 mL RB flask. DCC (0.48 g, 2.2 mmol) and DMAP (24 mg) were then added into the flask. Benzoyl alcohol (0.22 g, 2.0 mmol) was added into the mixture in 5 min. The reaction was stirred at room temperature for 48 h. Water (30 mL) was then added into the mixture. The aqueous phase was extracted with Et20 (3 x 20 mL). The combined organic phase was washed with water (2 x 20 mL) and brine (20 mL), and dried over anhydrous MgSC»4. Filtration removed the drying reagent. The dried solution was concentrated under reduced pressure. Flash column chromatography of the residue with petroleum ether and diethyl ether (v/v = 95/5) as the eluent yielded 0.45 g (82%) of clear liquid.  IR(CHC1 ): 2930, 2858, 1721, 1658, 1460, 1341, 1162, 1111, 1054, 885 cm" ; 1  3  *H NMR (200MHz, CDCI3): 5 7.35 (s, 5H), 5.10 (s, 2H), 2.35 (t, J= 7.3 Hz, 2H), 1.62 (m, 2H), 1.20-1.40 (2, 14H), 0.92 (t, J= 6.7 Hz, 3H); 13  C NMR (50MHz, CDC1 ): 5 173.61, 136.20, 128.51 (2), 128.15 (2), 128.14, 66.02, 34.33, 3  31.91,29.56,29.47,29.32,29.26,29.15,24.98,22.69, 14.11; LRMS (DCI(+), ammonia) m/z (relative intensity): 294 (M +l 8, 100), 277 (M +l, 3), +  +  276 (M , 4), 185(18); +  HRMS (DCI(+), ammonia) m/z calculated for Ci H 20 N (M +l) 294.2433, +  8  found: 294.2434.  3  2  186  References (1) Ruzicka, L. Helv. Chim. Acta 1926, 9, 715. (2) Ruzicka, L. Helv. Chim. Acta 1926, 9, 1008. (3) Ruzicka, L.; Stoll, M.; Muyser, H. W.; Boekenoogen, H. A. Helv. Chim. Acta 1930,13, 1152. (4) Ruzicka, L; Plattner, P. A.; Wild, H. Helv. Chim. Acta 1946, 29, 1611. (5) Kobelt, M.; Barman, P.; Prelog, V.; Ruzicka, L. Helv. Chim. Acta 1949, 32, 356. (6) Prelog, V. J. Chem. Soc. 1950, 420. (7) Omura, S. 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Soc. 1989, 111, 8551.  193  Appendix I * H N M R and I R Spectra  194  195  196  197  198  CM O  CO  A  *f  r-  (O ro  > k (O A C(OO h-  CM  CM  CM CM  CO o CO  4 0 (> p m)  1 OO 9 0 S O CD  O d  H  7 0 6 0  'E Ul  cz o  5 0 4 0  H  3 0 2 0  1  o o  H 3 2 0 Q  2 4 0 0 W a v e '  n u m b e r  1 6 0 0 ( c m  —  1)  8 0 0  199  200  11618  2 364 7  17  7 5  7 0  6 0  5 5  5 0  4 0  35  30  25  20  15  10  ppm)  1 OO 90 80 QJ) O CZ o  CO  cz o  70 60 50 4-0  H  30 20 1 O O 3200  2400 Wave  number  1600 (cm.—  1)  800  202  203  J&z)  k:  6 0  5 5  40 ppm)  /rl  It  204  1 o o -  1  1  1  T  1  3200  1  1  1  2400 Wave  number  1  1  1  .1 6 0 0 (cm—1)  1  1  1  1 800  206  {  2 596 8  ; 7 5 70 65 60 55  2947  50 J2 7 7 5 4  |2 6 7 4 6  11  2 6600  4 5  J  40 (> p m) 35 30 2 5 20  J2 80 7 5  |2 7 7 3 3  40985  A  15  |5 5 8 2 6  207  ,OTs  26  ) 1 0 0 5  208  27  40 ppm)  CD CD  cr o  'E to cr o  I—  . 1 600 W a v e  n u m b e r  ( c m —  1)  800  209  o ^ o ^ o 28  4 0 ppm)  210  29  JLA  40 ppm)  211  * 0  ^OH  30  4  0  0 pm)  CJ  cr p  3200  240 0 Wave  n u m b e r  1600 ( c m — 1 )  800  212  213  214  215  216  COOH  —  -  k  J  °  o  \  CO cn  CM  (O  00 CM  ;  CD  CD  M  CM  CM  r-  60 ppm)  CD CJ  CO  c: o I—  3200  2400 Wave  number  1600 (cm—1)  80.0  217  218  HO.  37  CO  CO  m  <D  CD  CM  1^  <D  ^ ' _ in  CM  75  70  65  60  55  50  45  40 ppm)  CO CO GO  m  CM  35  30  25  20  15  10  05  1 OO 90 80 CU  cu cr o " i  CI o I—  70  H  6 0 50 4-0 30 20  1O O  l  r  3200  2400 W a v e  n u m b e r  1600 ( c im — 1 )  800  219  cu cz o  CO  cz o  I—  3200  .2400 Wave  number  1 600 (cm—1)  800  220 2  70  65  1 OO 90 SO CU  cu cz o — [  E  cn  cz o L_  70 60 — 50 40  -  30 — 20  -  1O -  o  _ 3200  •• Wave  2400 n u m b e r  1 600 ( c m — 1)  221  223  224  f  43  k  m 4 0 ppm)  o  44  75  70  65  60  55  50  4 5  40 ppm)  35  30  20  1 5  1 0  05  227  47  u> o*> TT O  ^• I--  *-  75  70  65  60  55  2 0  50  W a v e  n u m b e r  ( c m  — 1 )  1 5  10  05  228  48  to o  105  1  100  95  90  15  80  75  70  65  60  55 50 (> p m)  45  o o CM O C  40  A hCM-  CM "<* CM '  35  CM CM  30  25  CO *-  20  15  10  05  OO H 90 SO  CD CD CZ  o  00  cz o  70 60 50  AO 30 20 1O H O 3200  2400 Wave  number  1600 ( c m — 1 )  iOO  229  49  ca  O CM  «  CO  ) CM  CO  CO »»• CO  CM  . • 1 . ,• 40 ppm)  A, J rt O)  rCM  \  CM CD CM  CO f-  co  • 1 ,,  230  1 OO 90 80 cu CJ  cz  "E cn cz o  I—  70 60 50 40 30 20 H 1 o  o 2400  3200 W a v e  n u m b e r  1 ( c m —  600 1)  T  r  800  231  52  /"A 4 0 ppm)  CU o  c:  J 3  'E 00  d o  i —  3200  '2400 • Wave  number-  1600 (cm—1)'  232  COOMe  53  7 5  70  65  60  COOMe  55  50  45  40 ppm)  35  30  25  20  15  10  05  OJ o err o  "EE cn cr o  I—  3200  2400 Wave  number  1600 ( c m — 1 )  800  233  CD CD CZ  jz> " i  cn cz o ^_  2400 Wave  number  ( c m.—  1 )  234  235  236  1  O  r  O 24-00 Wave  number  1600 (cm.— 1 )  800  237  TMSCX  60  1 •  CM  *  c n Ol  JD  CO  CM  75  70  CO  •<*  m  CM  40  k CinM 2 CM  M  \ CoO o  C O "•"  CO  s  CO  3 5 ppm)  1 OO -4 90 80 H CD CD CZ O  'E CO cz o  70 60 50 40  H  30 2  0  1O o H 2400  3200  Wave  n u m b e r  1600  ( c m — 1)  ;oo  239  240  Appendix II Second Set of Data for the Hydrolysis of 11,12 and 36  241  i. Base Mediated Hydrolysis of 11,12 and 36  Hydrolysis of 11,12 and 36 under basic conditions (T=20 °C) 3.00  50  100  •  Lactone 11  *  Lactone 12  •  150  250  200  300  Time (minute)  Ester 36 Lactone 11, y=0.011 lx-0.011, R2=0.9951 Lactone 12, y=0.0063x+0.0596, R2=0.9677 Ester 36, y=0.0082x+0.0376, R2=0.9887  Figure i. Linear relationships between ln([a]o/[a]) and time for the base mediated hydrolysis of lactones 11 and 12, and ester 36.  Table i. Rate constants for the base mediated hydrolysis of 11,12 and 36. Compound  "OH concentration ["OH] (M)  Observed constant kbase (s") 1  Rate constant k (MS" ) 1  lb  11  0.1367  1.9 xlO"  4  1.4 xlO"  12  0.1952  1.1 xlO"  4  0.54 xlO"  36  0.1091  1.4x 10"*  1.3 xlO"  3  3  3  242  ii. Acid Catalyzed Hydrolysis of 11,12 and 36 Hydrolysis of 11,12 and 36 under acidic conditions (T=58 °C) 3 2.5 2  §  0  1.51 0.5 01 100  200  300  500  400  600  700  Time (minute) •  Lactone 11  *  Lactone 12  •  Ester 36 Lactone 11, y=0.0040x+0.0202, R2=0.9841 Lactone 12, y=0.0013x+0.0132, R2=0.9894 Ester36, y=00038x-0.0116, R2=0.9953  Figure ii. Linear relationships between ln([a]o/[a]) and time for the acid catalyzed hydrolysis of lactones 11 and 12, and ester 36.  Table ii. Relative rate constants for the acid catalyzed hydrolysis of 11,12 and 36. Compound  Concentration of H & H20(M) +  Observed constant k id (s") 1  ac  Relative rate constant #2a*  11  0.390 & 18.5  6.7 xlO"  5  3.0  12  0.390 & 18.5  2.2 xlO"  5  1.0  36  0.390 & 18.5  6.3 x 10"  2.9  5  * obtained under the assumption that the basicities of the carbonyl oxygens are the same among the three compounds.  243  iii. Lactone Ring-openning with MeSNa Reactions between MesNa and 11,12 and 36 (T=20 °C) 3.50 3.00 2.50 2.00  % £  1.50 1.00 0.50 0.00 1  50  100  Time (minute)  •  150  200  Lactone 11  m Lactone 12 A  Ester 36 Lactone 11, y=0.0203x+0.0314, R2=0.9888 Lactone 12, y=0.0152x+O.0214, R2=0.9935 Ester 36, y=0.0073x+0.0031, R2=0.9837  Figure iii. Linear relationships between ln([a]o/[a]) and time for the reactions between MeSNa and lactones 11 and 12, and ester 36.  Table iii. Rate constants for the reactions of MeS with 11,12 and 36. -  Compound  MeS" concentration [MeS"] (M)  Observed rate constant ^Mes" (s")  Rate constant * s (M'V ) 1  11  0.500  3.4 x 10"  6.8 x 10"  12  0.500  2.5 x 10"  5.1 x 10"  36  0.500  1.2 x 10"  2.5 x 10"  

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