PART A: SYNTHESIS OF MANNOSIDE GLYCANS OF PHOSPHATIDYLINOSITOL MANNOSIDES (PIMs) PART B: SYNTHETIC STUDIES TOWARDS BIELSCHOWSKYSIN MACROCYCLES RAVI KUMAR SRIRAMULA NATIONAL UNIVERSITY OF SINGAPORE 2011 PART A: SYNTHESIS OF MANNOSIDE GLYCANS OF PHOSPHATIDYLINOSITOL MANNOSIDES (PIMs) PART B: SYNTHETIC STUDIES TOWARDS BIELSCHOWSKYSIN MACROCYCLES RAVI KUMAR SRIRAMULA (M.Sc., University of Hyderabad, India) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF CHEMISTRY NATIONAL UNIVERSITY OF SINGAPORE 2011 Acknowledgements I would first like to express my sincere gratitude to my thesis supervisor, Asst. Prof. Martin J. Lear. He gave me the opportunity to join his research group. He was always patient and encouraging independent thinking with valuable guidance at critical points not only in research life but also in my personal life. I also want to thank the members and collaborators, particularly, Prof. Markus Wenk on the PIMs project. I would like thank all the members of the bielschowskysin team; Subramanian, Karthik, Eugene, Bastien, Miao Ru for their co-operation and Praveena for her invaluable help in ab initio/DFT calculations and also for her suggestions and comments on my project as well as thesis. I wish to thank Mdm. Han Yanhui and Mr. Chee Peng for their timely assistance for NMR measurements and Mdm. Wong Lai Kwai and Mdm. Lai Hui Ngee for their help with Mass Spectroscopy measurements. I thank Stanley for reading my thesis draft and his valuable comments. I would like to thank all present and past group members of Dr. Lear group, Particularly, Munhong, the person who is approachable at any time without hesitation and Bastien for his suggestions during writing my thesis. It is my great opportunity to thank all my friends for their timely help and understanding to have a wonderful life in Singapore. i Dedication This thesis is dedicated to all my parents and family members particularly, my wife, Praveena for her immense and incredible support and understanding all through my graduate studies and my cute, lovely daughter Krithika, who become a charming relief to me with her smile every time. ii Table of Contents Table of Contents . iii  Summary viii  List of Figures . x  List of Schemes . x  List of Tables . xvi  Abbreviations xvii  Part A: Synthesis of Mannoside Glycans of Phosphatidylinositol Mannosides (PIMs) Background and Introduction 1  1.1 Phosphatidylinositol Mannosides (PIMs) and Tuberculosis . 1  1.2 Previous Synthesis of PIMs: Seeberger 4+3 Coupling . 2  PIMs: 1st Generation Synthetic Plan 4  2.1 Mannoside Glycan Synthetic Plan 1: A Convergent 3+2 Approach 4  2.2 Synthesis of Mannose Building Blocks 5  2.2.1 Schmidt Donor of Mannose . 5  2.2.2 Mannose With Accessible C2-Hydroxyl Group 6  2.3 Glycosylation Attempt Towards Dimannoside . 7  PIMs: 2nd Generation Synthetic Plan . 8  3.1 Seeberger in situ Glycosylation Method . 9  3.2 Synthetic Plan 2: Iterative in situ Coupling of Mannose 1,2-Orthoesters 10  3.3 Synthesis of Mannose Building Blocks 11  iii 3.3.1 Mannose with Accessible 1,6-Hydroxyl Groups . 11  3.3.2 Synthesis of Methoxy-1,2-Orthoester of Mannose 12  3.4 Optimizing in situ Coupling Method; Synthesis of a Model Trimannoside . 13  3.5 Synthesis of Mannoside Glycan Units of PIMs 15  3.5.1 Synthesis of Dimannoside of PIMs . 15  3.5.2 Iterative Glycosylation: Synthesis of Tri-, Tetramannoside Glycan Units of PIMs 15  3.5.3 Synthesis of Petamannosides of PIMs . 17  Conclusion . 19  References for Part A 20  Experimental Procedures (Part A) 22 Appendix 1: Spectra (Part A) 43 Part B: Chapter 1: Background and Introduction 1.1 Bielschowskysin: Isolation, Structural Characterization and Biological Properties 61  1.2 Furanocembrane Family: Related Octocoral Diterpenoids . 63  1.3 Biological Evolution of Diterpene Skeletons: Interrelation Pattern . 64  1.4 Bielschowskysin: Proposed Biosynthesis . 66  1.5 Gorgonian Diterpenes: Established Synthetic Methods . 67  1.5.1 Paquette Methodology towards Cembranoid Skeletons10 67  1.5.2 Marshall Methodology towards Cembrane/Pseudopterane Skeletons11 69  1.5.3 Donohoe RCM Method for Butenolide of Deoxypukalide 71  1.5.4 Pattenden RCM-CM Method for Cembranoids . 73  1.5.5 Trauner Method to Bipinnatin J and Intricarene 74  iv 1.6 Progress towards Bielschowskysin: Synthetic Reports 76  1.6.1 Sulikowski Synthesis of Tetracyclic Core . 76  1.6.2 Lear Synthesis of Tricyclic Core . 77  1.6.3 Nicolaou Synthesis of Tetracyclic Skeleton 78  1.7 Summary: Chapter (Part B) 81  References for Chapter (Part B) . 82  Part B: Chapter 2: Bielschowskysin: Transannular [2+2] Model 2.1 Bielschowskysin: Transannular [2+2] Based Synthetic Plan . 85  2.2 Strategy I: Butenolide Construction Followed by Macrocyclization . 87  2.2.1 Butenolide Construction Studies 88  2.2.1.1 Background: Reductive Hydroalumination-Addition onto Aldehydes . 88  2.2.1.2 Synthesis of γ-Hydroxy Propiolate . 90  2.2.1.3 Hydroalumination-Addition onto Aldehyde Studies 90  2.3 Strategy II: RCM of allylic Acrylates Followed by Macrocyclization . 92  2.3.1 Synthesis of Allylic Alcohol Building Block 93  2.3.2. Synthesis of Alkynal Synthons . 93  2.3.3 Synthesis of RCM Precursor 94  2.3.4 RCM Study to Butenolide 96  2.4 Strategy III: Allene Making Followed by Macrocyclization 98  2.4.1 Synthesis of Chiral Allylic Alcohol . 99  2.4.2 Assembly of Fragments, Allene Formation and Baylis Hillman Homologation103  2.4.3 Macrocyclization: RCM Attempts in the Presence of Allene 105  2.4.4 Macrolactonization: Synthesis of Macrolactone 107  v 2.4.5 Butenolide Installation: RCM Study of Macrolactone 108  2.5 Summary: Chapter (Part B) . 110  References for Chapter (Part B) . 111  Part B: Chapter 3: RCM Methods Towards Bielschowskysin Macrocycles: Synthesis of Building Blocks 3.1 Towards Bielschowskysin 114  3.1.1 Bielschowskysin: Retrosynthesis I 114  3.1.2 Alkyne Synthon: 1st Generation Synthesis 116  3.1.3 Alkyne Synthon: 2nd Generation Synthesis 121  3.1.4 Conjugated Aldehyde Synthon: 1st Generation Synthesis . 123  3.2 Assembly of Building Blocks: Alkyne Addition onto Aldehyde . 126  3.2.1 Carreira Asymmetric Addition Study 126  3.2.2 Base Mediated Methods . 129  3.3 Summary: Chapter (Part B) . 131  References for Chapter (Part B) . 132  Part B: Chapter 4: Allene Formation and Photochemical Cycloaddition Studies 4.1 Allene Formation Studies . 135  4.1.1 Bielschowskysin: Synthetic Plan . 135  4.1.2 Allenes: Introduction . 136  4.1.3 Synthesis of Propargylic Alcohol and Allene Formation Studies . 138  4.1.4 Allene Formation by Keck Conditions 140  4.1.5 Keck Conditions with Stereodefined Propargylic Alcohols 142  4.2 Allene Formation and Photochemical [2+2] Cycloaddition Studies 145  vi 4.2.1 Allene Formation Studies on Allyl Terminated Propargylic Alcohol . 145  4.2.2 Photochemical [2+2] Cycloaddition Attempt 147  4.3 Summary: Chapter (Part B) . 149  References for Chapter (Part B) . 150  Part B: Chapter 5: RCM Methods Towards Macrocyclic Framework of Bielschowskysin 5.1 Convergent Synthetic Plan to Macrocyclic Framework of Bielschowskysin . 152  5.1.1 Bielschowskysin: Retrosynthesis II . 152  5.2 ‘Modified Conjugated Aldehyde’ Synthon . 153  5.2.2 ‘Modified Conjugated Aldehyde’ Synthon: 1st Generation Synthesis . 153  5.2.4 ‘Modified Conjugated Aldehyde’ Synthon: 2nd Generation Synthesis 158  5.2.5 ‘Modified Conjugated Aldehyde’ Synthon: 3rd Generation Synthesis 160  5.3 Synthesis of Macrocyclic Framework of Bielschowskysin 163  5.3.1 Assembly of Building Blocks: RMgX Mediated Addition of Alkyne 163  5.3.1 RCM Study 164  5.3.2 Prediction of Stereochemistry at C5-Propargylic Ether . 167  5.4 Summary: Chapter (Part B) . 170  References for Chapter 172  Experimental Procedures (Part A) 174 Appendix 2: Spectra (Part A) 246 vii 180   170 160 150 140 5.6 5.4 130 5.2 5.0 120 4.8 4.6 110 4.4 4.2 100 4.0 3.8 90 3.6 80 3.4 3.2 70 3.0 2.8 60 2.6 2.4 50 2.2 2.0 40 1.8 1.6 30 1.4 20 1.2 3.2337 5.8 13.4141 6.0 28.3824 26.5897 26.2108 6.2 52.0226 50.7473 6.4 3.3064 3.3000 1.1016 3.1738 1.1106 1.1089 1.0854 1.0864 3.0845 1.0476 4.65 79.7802 77.2588 77.0037 76.7487 6.6 1.0565 6.56 105.3006 6.8 1.0057 1.0000 (ppm) 111.8301 7.0 131.7975 7.2 137.3723 167.7315 Integral 1.0476 1.0565 1.0000 4.5885 4.6074 4.6263 4.6742 4.6667 4.6579 6.5628 6.5603 6.5805 6.5779 2.1377 2.1288 2.1238 2.1175 2.1150 2.1087 2.1036 2.0961 2.0935 2.0897 2.0809 2.0759 2.0671 2.0318 2.0242 2.0128 2.0040 1.9952 1.9838 1.9750 1.8981 1.8956 1.7910 1.7821 1.7746 1.7645 1.7569 1.7544 1.7481 1.7393 1.7304 1.7216 1.5237 1.3232 3.7476 3.3240 3.3139 3.3089 3.3038 3.2988 3.2950 3.2887 3.2799 3.1916 3.1778 3.1740 3.1601 3.1551 3.1412 4.6742 4.6667 4.6579 4.6263 4.6074 4.5885 5.8694 5.8619 6.5805 6.5779 6.5628 6.5603 7.2600 Appendix 2: Spectra (Part B) 1H AMX500 RK 4090_iodination (rk0603 exp 11) (ppm) 4.60 (ppm) 1.0 10 0.8 0.6 13C AMX500 RK 4090_iodination (rk0603 exp 12) (ppm) 304 305   155 150 145 140 135 130 125 120 115 110 105 5.2 100 4.8 95 90 4.4 85 4.0 (ppm) 80 75 70 26.5860 26.5277 26.1706 24.8589 21.6014 5.6 67.0527 6.0 3.6 3.2 65 60 2.8 55 2.4 50 45 2.0 40 1.6 35 30 25 2.9212 3.0583 4.78 2.9798 (ppm) 3.0270 2.9578 1.0099 4.80 3.0982 1.0174 4.82 1.0099 0.9796 0.9765 5.91 0.9796 1.0174 0.9765 2.0000 1.9690 (ppm) 71.7531 6.4 83.2671 82.0356 79.8275 77.2551 77.0000 76.7449 6.8 105.0710 7.2 109.0207 7.6 112.4676 8.0 129.6367 128.3978 8.4 132.6828 145.0568 Integral 3.8901 3.8838 3.9077 3.9002 4.7852 4.7814 4.8243 4.8180 5.9085 5.9148 1.1871 1.1404 1.2993 1.4682 2.4440 4.0577 4.0514 4.0414 4.0351 4.0237 4.0161 4.0086 3.9960 3.9859 3.9808 3.9783 3.9682 3.9077 3.9002 3.8901 3.8838 4.8243 4.8180 4.7852 4.7814 5.9148 5.9085 7.3356 7.3193 7.2600 7.8324 7.8160 Appendix 2: Spectra (Part B) 1H AMX500 4093_recrystallized (rk0618 exp 21) (ppm) 3.88 (ppm) 1.2 0.8 20 15 0.4 13C AMX500 4093_recrystallized (rk0618, exp 22) 10 Appendix 2: Spectra (Part B) 1H AMX500 SRK 4102_iodination 1.5451 1.4745 1.3560 4.5898 4.5822 4.5734 4.3175 4.3099 4.3049 4.2973 4.2922 4.2834 4.2569 4.2494 4.2368 4.2292 4.1208 4.1094 4.1044 4.0918 4.0615 4.0477 4.0300 3.7640 3.7552 3.7438 3.7350 5.8039 5.7963 7.2600 *** Current Data Parameters *** NAME : EXPNO : rk0722 PROCNO : 3.7640 3.7552 3.7438 3.7350 4.1208 4.1094 4.1044 4.0918 4.0615 4.0477 4.0300 4.3175 4.3099 4.3049 4.2973 4.2922 4.2834 4.2569 4.2494 4.2368 4.2292 4.5898 4.5822 4.5734 *** Acquisition Parameters *** BF1 : 500.1300000 MHz LOCNUC : NS : O1 : 2H 3088.51 Hz PULPROG : SFO1 zg30 : 500.1330885 MHz SOLVENT : SW CDCl3 : 20.6557 ppm *** Processing Parameters *** 4.6 4.5 4.4 4.3 4.2 4.1 4.0 3.9 3.8 (ppm) LB : 0.30 Hz PHC0 : 166.704 degree PHC1 : -1.518 degree O O O O 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 5.19 6.4427 3.2381 3.1587 1.0366 1.0816 1.0944 1.0372 1.0353 1.0332 1.0000 Integral I 7.5 1.5 O 1.0 (ppm) 13C AMX500 SRK 4102_iodination 19.1893 26.5932 26.5349 26.3965 25.1722 65.7556 77.2551 77.0000 76.7449 75.4769 81.7368 81.4672 103.1179 111.6660 109.9899 *** Current Data Parameters *** NAME : EXPNO : rk0722 PROCNO : *** Acquisition Parameters *** BF1 : 125.7577890 MHz LOCNUC : NS : O1 : PULPROG : O O O SFO1 SW 66 13204.57 Hz zgpg30 : 125.7709936 MHz SOLVENT : O 2H : CDCl3 238.7675 ppm *** Processing Parameters *** O I 5.19 115 110 105 100 95 90 85 80 75 70 65 60 55 50 45 40 35 30 25 20 LB : PHC0 : 74.653 degree 1.00 Hz PHC1 : 41.704 degree 15 (ppm) 306   120 307   116 112 108 104 100 96 78 92 88 84 5.2 80 4.8 76 72 4.4 68 4.0 77 64 (ppm) 60 56 3.6 (ppm) 52 3.2 2.8 O O 48 44 2.4 40 36 2.0 32 28 1.6 24 3.3035 3.2421 3.1855 3.1660 3.8 2.2767 1.1492 1.1094 1.0935 1.0325 1.1110 1.0325 1.1110 1.0767 1.1065 Integral 1.0502 1.0000 O 4.6874 5.6 O 26.7536 26.6151 26.3965 25.2378 6.0 3.9 1.0767 (ppm) 29.0782 6.4 4.0 1.1065 4.1 48.8707 6.8 1.0502 1.0000 (ppm) 67.4681 7.2 81.3578 80.6874 77.5830 77.2551 77.0000 76.7449 7.6 77.2551 77.0000 76.7449 77.5830 (ppm) 104.9106 8.0 109.6474 111.9211 Integral 3.7703 3.8031 3.7892 3.7854 3.9241 3.9140 3.9077 3.8976 4.0994 4.0867 4.0830 4.0704 4.0313 4.0174 4.0073 3.9935 4.6679 4.6591 4.6516 5.7761 5.7686 2.2637 2.2574 2.2423 2.2373 2.2310 2.2234 2.2183 2.2120 2.2045 2.1856 2.1414 2.1326 2.1288 2.1213 2.1124 2.1087 2.0998 2.0923 2.0860 2.0834 2.0771 2.0734 2.0645 2.0532 2.0444 2.0381 1.4959 1.4165 1.3434 1.3144 5.7761 5.7686 4.6679 4.6591 4.6516 4.0994 4.0867 4.0830 4.0704 4.0313 4.0174 4.0073 3.9935 3.9241 3.9140 3.9077 3.8976 3.8031 3.7892 3.7854 3.7703 3.4274 3.4198 3.4135 3.4085 3.4047 3.3996 3.3946 3.3858 3.2799 3.2736 3.2673 3.2622 3.2496 3.2433 3.2294 7.2600 Appendix 2: Spectra (Part B) 1H AMX500 SRK 4111-Iodination (rk0811 exp.11; y.2010) O O I O 5.21 (ppm) 1.2 20 0.8 16 0.4 12 0.0 -0.4 13C AMX500 SRK 4111-Iodine (rk0811, exp 12; year 2010) O O I O 5.21 Appendix 2: Spectra (Part B) 1H AMX500 4112_Fe rxn_spot below SM 1.5142 1.4121 1.3276 1.2974 2.6199 2.6098 2.6010 2.5909 2.5821 2.5720 4.6093 4.6005 4.5929 4.2513 4.2437 4.2387 4.2311 4.2248 4.2172 4.0987 4.0912 4.0785 4.0710 3.9815 3.9689 3.9651 3.9525 3.8869 3.8730 3.8705 3.8567 5.8890 5.8713 5.8688 5.8537 5.8499 5.8360 5.8335 5.8158 5.8007 5.7931 5.2762 5.2737 5.2397 5.2119 5.2082 5.1918 5.1880 6.7425 7.2606 *** Current Data Parameters *** NAME : rk0813 EXPNO : 11 PROCNO : *** Acquisition Parameters *** BF1 : 500.1300000 MHz LOCNUC : NS : O1 : PULPROG : SFO1 3088.51 Hz zg30 : 500.1330885 MHz SOLVENT : SW 2H : CDCl3 20.6557 ppm 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 LB : 0.30 Hz PHC0 : 138.766 degree PHC1 : -0.213 degree 3.1034 3.1635 3.0491 3.0232 1.0066 1.0264 1.0194 0.9981 0.9930 0.9869 2.0508 0.9709 1.0000 Integral *** Processing Parameters *** 1.5 1.0 (ppm) 13C AMX500 4112_Fe rxn 26.6516 26.3382 26.1633 25.1576 50.5031 65.2673 83.6752 79.7692 77.2551 77.0000 76.7449 76.0454 104.6774 109.5090 111.8336 119.0263 132.3039 *** Current Data Parameters *** NAME : rk0813 EXPNO : 12 PROCNO : 76.0454 76.7449 77.0000 77.2551 *** Acquisition Parameters *** BF1 : 125.7577890 MHz LOCNUC : 2H NS : 130 O1 : PULPROG : SFO1 zgpg30 : 125.7709936 MHz SOLVENT : SW 13204.57 Hz : CDCl3 238.7675 ppm *** Processing Parameters *** 77.0 76.5 LB : 1.00 Hz PHC0 : 163.135 degree PHC1 : 39.863 degree 76.0 (ppm) 135 130 125 120 115 110 105 100 95 90 85 80 75 70 65 60 55 50 45 40 35 30 25 20 (ppm) 308   Appendix 2: Spectra (Part B) 1H AMX500 4114_top spot 5.8379 5.8354 5.8291 5.8228 5.8152 5.8026 5.7950 5.7887 5.7812 5.7686 5.7471 5.7408 5.0689 5.0663 5.0348 5.0310 4.9907 4.9705 4.6314 4.6238 4.6150 3.9090 3.9014 3.8888 3.8812 3.7249 3.7047 3.6947 2.8727 2.6205 2.3091 2.2978 2.2801 2.2688 2.2587 2.2511 2.2398 1.9750 1.9586 1.9511 1.9372 1.9296 1.9208 1.9170 1.9082 1.8994 1.7758 1.7645 1.7582 1.7531 1.7481 1.7430 1.7380 1.7317 1.7267 1.7216 1.7166 1.7103 1.6989 1.6334 1.6258 1.6182 1.6082 1.6006 1.5930 1.5842 1.5754 1.5678 1.4934 1.3157 *** Current Data Parameters *** NAME : rk0818 EXPNO : 11 PROCNO : *** Acquisition Parameters *** BF1 : 500.1300000 MHz LOCNUC : NS : O1 : PULPROG : HO O HO 2H 3088.51 Hz zg30 SFO1 : 500.1330885 MHz SOLVENT : SW : CDCl3 20.6557 ppm *** Processing Parameters *** O O LB : 0.30 Hz PHC0 : 253.471 degree PHC1 : -1.561 degree 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 3.2386 3.2416 1.1420 1.0991 1.5049 1.1041 1.0639 0.9922 0.9695 3.2711 1.0466 1.0279 0.9971 0.9952 1.0172 1.0000 Integral 5.26 1.5 1.0 (ppm) 13C AMX500 26.7317 26.3673 24.2321 31.7600 45.5987 63.3216 82.8372 81.0591 77.2551 77.0000 76.7449 72.7660 *** Current Data Parameters *** 104.6410 111.7680 115.0109 138.2358 4114_top spot NAME : rk0818 EXPNO : 12 PROCNO : *** Acquisition Parameters *** BF1 : 125.7577890 MHz LOCNUC : 2H NS : 112 O1 : PULPROG : HO O HO O 5.26 140 135 130 125 120 115 110 105 100 95 90 85 80 (ppm) 309   zgpg30 SFO1 : 125.7709936 MHz SOLVENT : SW : CDCl3 238.7675 ppm *** Processing Parameters *** O 145 13204.57 Hz 75 70 65 60 55 50 45 40 35 30 25 20 LB : 1.00 Hz PHC0 : 162.833 degree PHC1 : 53.761 degree   175 170 165 160 155 150 145 140 135 130 125 120 115 110 105 2.5 100 95 90 MeO 85 2.0 O 80 1.5 75 4.6153 3.4726 1.1834 1.2137 3.0901 4.5267 4.5456 4.5658 4.6200 4.6125 4.6036 5.8064 5.7988 5.7837 5.7698 5.7610 5.7496 5.7358 5.7295 5.7232 5.7156 5.7030 PULPROG : SOLVENT : SW 1.0 70 0.5 65 60 55 50 45 40 : 4.60 (ppm) 35 30 25 13.3084 3.0 1.0954 1.0209 3.0143 1.0478 1.0117 1.1513 1.0244 SFO1 26.6005 26.1779 23.3650 3.5 31.6070 4.0 51.8221 49.7161 4.5 80.5417 77.4445 77.2551 77.0000 76.7449 5.0 105.2896 5.5 111.5203 6.0 1.0478 5.70 1.0117 (ppm) 114.9891 6.5 2.0516 5.75 1.1513 1.0244 1.0000 5.80 131.2399 7.0 138.1921 137.9370 167.8298 Integral 2.2322 2.2196 2.2032 2.1906 2.1742 2.1629 2.0595 2.0456 2.0292 2.0154 2.0002 1.9864 1.8792 1.8099 1.8010 1.7897 1.7796 1.7708 1.7594 1.7506 1.7040 1.6926 1.6863 1.6762 1.6661 1.6598 1.6485 1.6397 1.6283 1.5048 1.3220 1.3031 1.2816 1.2728 1.2564 3.7136 5.0096 4.9756 4.9491 4.9289 4.6200 4.6125 4.6036 4.5658 4.5456 4.5267 6.5376 6.5200 5.8064 5.7988 5.7837 5.7698 5.7610 5.7496 5.7358 5.7295 5.7232 5.7156 5.7030 7.2600 Appendix 2: Spectra (Part B) 1H AMX500 4116_TT *** Current Data Parameters *** NAME : rk0821 EXPNO : 11 PROCNO : *** Acquisition Parameters *** BF1 : 500.1300000 MHz LOCNUC : NS : O1 : 3088.51 Hz 2H : 500.1330885 MHz zg30 20.6557 ppm CDCl3 *** Processing Parameters *** LB : 0.30 Hz PHC0 : 135.313 degree PHC1 : -0.788 degree O MeO O 20 15 O O 0.0 5.30 (ppm) 13C AMX500 4116_TT (rk0821, exp. 12; year 2010) O O O 5.30 (ppm) 10 310 200 311   190 180 170 160 150 140 130 120 4.4 110 4.0 (ppm) 100 3.6 90 3.2 80 2.8 2.4 70 2.0 60 1.6 50 1.2 40 0.8 0.4 30 10.1529 4.8 26.6661 26.2362 23.4160 5.2 31.6143 5.6 49.9493 6.0 76.7522 6.4 77.0000 77.3425 77.2551 6.8 1.2561 3.0217 3.0803 1.1746 3.0004 1.0591 1.0211 0.9876 0.9830 1.0018 1.9353 0.9409 4.72 80.5344 77.3425 77.2551 77.0000 76.7522 7.2 105.4718 7.6 0.9453 1.0000 4.76 111.8701 8.0 115.2951 8.4 137.7913 8.8 141.1799 9.2 149.0794 194.6765 0.9443 0.9830 1.0018 4.6843 4.6768 4.6679 4.7158 4.7335 4.7537 2.2726 2.2612 2.2436 2.2322 2.2234 2.2146 2.2032 2.0935 2.0784 2.0620 2.0494 2.0469 2.0330 2.0179 1.8969 1.8880 1.8767 1.8679 1.8590 1.8464 1.8389 1.8099 1.8073 1.7796 1.7695 1.7632 1.7582 1.7531 1.7481 1.7418 1.7367 1.7317 1.7254 1.7216 1.7153 1.7040 1.5476 1.3459 1.3283 1.3194 1.3144 1.3106 1.3018 1.2955 1.2879 1.2791 1.2703 1.2615 7.2600 6.3044 6.3018 6.2880 6.2855 5.8719 5.8656 5.8001 5.7875 5.7799 5.7736 5.7660 5.7534 5.7459 5.7396 5.7333 5.7194 5.0399 5.0361 5.0058 5.0020 4.9894 4.9869 4.9693 4.9667 4.7537 4.7335 4.7158 4.6843 4.6768 4.6679 9.4600 Appendix 2: Spectra (Part B) 1H AMX500 SRK 4097= right fragment (rk0610 exp 11) (ppm) 4.68 (ppm) -0.0 20 -0.4 10 -0.8 13C AMX500 SRK 4097=right fragment (rk0610 exp 12) (ppm) 150   140 130 77.4 120 110 77.0000 77.2 100 90 80 70 60 4.0 50 3.6 40 3.2 30 2.8 20 2.4 10 2.0 1.6 SFO1 SW NAME 8.8994 3.4639 3.0464 3.2432 3.0172 3.8348 1.1041 0.7729 1.3744 1.0823 1.0598 4.50 1.9255 4.4 1.0469 4.60 13.5999 4.8 1.0452 1.1004 1.0062 0.9848 4.70 26.6953 26.2945 23.4524 5.2 0.9986 (ppm) 31.7819 31.2353 5.6 1.0505 2.1725 7.4 50.2626 49.7817 6.0 77.4664 77.2769 77.2551 77.0000 76.7449 69.9385 67.8835 67.1985 6.4 1.0000 3.1648 (ppm) 82.5238 80.6655 90.7513 6.8 104.9981 7.2 111.3454 116.4830 114.9672 7.6 1.5077 4.3225 Integral (ppm) 77.2769 77.2551 77.4664 8.0 128.2594 127.7347 127.3412 124.7541 139.8609 139.1977 138.6876 138.2576 1.0598 1.0452 1.1004 4.0880 4.0754 4.0628 4.0502 4.5557 4.5330 4.5192 4.5003 4.4814 4.6238 4.6150 4.6074 4.7272 0.9848 1.0062 4.9793 4.9768 4.9592 4.9566 5.0184 5.0146 5.0525 5.0487 5.5189 5.5366 7.3445 7.3344 7.3281 7.3218 0.9986 1.0505 1.0000 4.3225 Integral 2.2713 2.2562 2.2385 2.2272 2.2158 2.1187 2.1061 2.0897 2.0771 2.0645 2.0507 2.0355 2.0229 1.9359 1.9271 1.9082 1.8981 1.7985 1.7430 1.7342 1.7216 1.7141 1.7052 1.7027 1.6939 1.6876 1.6813 1.6724 1.6636 1.6573 1.6460 1.6359 1.6245 1.5413 1.5048 1.3358 0.1545 4.0880 4.0754 4.0628 4.0502 4.3666 4.3439 7.3344 7.3281 7.3218 7.3054 7.2739 7.2688 7.2600 7.2499 7.2449 7.2398 5.8303 5.8253 5.8152 5.8102 5.8039 5.7963 5.7786 5.7761 5.7711 5.7648 5.7597 5.7446 5.5366 5.5189 5.2504 5.2164 5.1974 5.0525 5.0487 5.0184 5.0146 4.9793 4.9768 4.9592 4.9566 4.7272 4.6238 4.6150 4.6074 4.5557 4.5330 4.5192 4.5003 4.4814 Appendix 2: Spectra (Part B) 1H AMX500 SRK 4100_Coupling_spot (top) (rk0618 exp 1) (ppm) 4.08 (ppm) (ppm) 1.2 0.8 : PULPROG : SOLVENT : : 0.4 0.0 13C AMX500 SRK 4100_Coupling_spot (top) *** Current Data Parameters *** EXPNO : PROCNO : rk0618 *** Acquisition Parameters *** BF1 : 125.7577890 MHz LOCNUC : 2H NS : 2272 O1 : 13204.57 Hz : 125.7709936 MHz zgpg30 238.7675 ppm CDCl3 *** Processing Parameters *** LB : 1.00 Hz PHC0 : 353.182 degree 77.0 PHC1 : 26.677 degree (ppm) (ppm) 312 150 313   140 130 120 110 77.4 100 77.2 90 80 3.5 (ppm) 70 3.0 60 2.5 50 2.0 40 1.5 30 20 1.9182 4.0 13.2136 4.5 31.7746 31.2645 30.3171 29.6831 26.7026 26.3018 23.4597 5.0 8.8263 3.5894 3.0591 3.0616 2.5120 3.2318 3.0889 1.1701 2.2278 1.0881 1.0596 1.0555 1.0324 1.0819 1.0005 5.04 50.2335 49.7962 5.5 0.9801 2.0105 7.20 82.5457 80.6801 77.5247 77.2842 77.2551 77.0000 76.7449 69.9458 67.8908 67.4317 90.7513 6.0 2.1496 1.0000 3.0810 (ppm) 77.0000 6.5 105.0054 7.0 111.3745 7.5 7.30 77.2842 77.2551 77.5247 2.5698 4.0258 7.40 116.4830 114.9891 8.0 128.2739 127.7420 127.3557 125.4975 125.0967 140.0212 139.2269 138.7022 138.2358 Integral 2.0105 Integral 2.5698 4.0258 Integral 4.9793 4.9768 4.9592 4.9554 5.0512 5.0474 5.0449 5.0411 5.0172 5.0134 5.0109 5.0071 7.3457 7.3344 7.3293 7.3218 7.3054 7.2739 7.2701 7.2600 7.2499 7.2449 7.2398 5.7723 5.7673 5.7585 5.7522 5.7383 5.4975 5.4798 5.2517 5.2176 5.1962 5.1937 5.0512 5.0474 5.0449 5.0411 5.0172 5.0134 5.0109 5.0071 4.9793 4.9768 4.9592 4.9554 4.7638 4.7537 4.6200 4.6112 4.6036 4.5570 4.5343 4.5192 4.5015 4.4826 4.3717 4.3477 4.0918 4.0792 4.0666 4.0540 2.2713 2.2587 2.2473 2.2297 2.2171 2.2070 2.1692 2.1263 2.1137 2.0973 2.0847 2.0771 2.0608 2.0456 2.0318 1.9410 1.9322 1.9132 1.9032 1.8111 1.7279 1.7204 1.7077 1.7014 1.6901 1.6813 1.6750 1.6649 1.6586 1.6548 1.6485 1.6384 1.6271 1.5552 1.5401 1.5048 1.3371 0.1533 Appendix 2: Spectra (Part B) 1H AMX500 4100_btm_pure *** Current Data Parameters *** 1.0 0.5 77.0 (ppm) 10 NAME : EXPNO : PROCNO : PULPROG : SFO1 SOLVENT : SW SFO1 SW : PULPROG : SOLVENT : : rk0831 *** Acquisition Parameters *** BF1 : 500.1300000 MHz LOCNUC : NS : O1 : 2H 3088.51 Hz : 500.1330885 MHz CDCl3 zg30 *** Processing Parameters *** 20.6557 ppm LB : PHC0 : 10.958 degree PHC1 : 0.482 degree 0.30 Hz (ppm) 4.96 (ppm) 0.0 13C AMX500 SRK 4100_Coupling_spot (bottom) *** Current Data Parameters *** NAME : rk0621 EXPNO : 12 PROCNO : *** Acquisition Parameters *** BF1 : 125.7577890 MHz LOCNUC : 2H NS : 1415 O1 : 13204.57 Hz : 125.7709936 MHz zgpg30 238.7675 ppm CDCl3 *** Processing Parameters *** LB : 1.00 Hz PHC0 : 351.820 degree PHC1 : 25.583 degree   8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 7.9144 6.3215 9.7418 3.4283 3.1091 3.2071 2.5707 2.0100 3.0958 1.0735 2.1354 0.5343 5.10 1.0787 0.9320 5.20 0.9784 (ppm) 2.1017 1.0000 0.9977 1.9995 2.1038 (ppm) 0.9919 3.0165 2.2046 3.9557 Integral 1.9995 2.1038 0.9919 2.2046 3.9557 4.9693 4.9491 5.0436 5.0399 5.0096 5.0058 5.2403 5.2378 5.2050 5.1937 5.1911 5.1735 5.1710 5.4244 5.4055 7.3407 7.3281 7.3142 7.2991 7.2600 7.2487 7.2360 2.2713 2.2499 2.2335 2.2234 2.2108 2.1692 2.0847 2.0721 2.0557 2.0431 2.0154 1.9284 1.9183 1.8994 1.8906 1.7708 1.7683 1.6977 1.6888 1.6712 1.6561 1.6460 1.5527 1.5375 1.4959 1.3346 0.9727 0.9564 0.9400 0.6500 0.6462 0.6349 0.6311 0.6197 0.6147 0.6033 0.5983 0.1470 5.7736 5.7648 5.7585 5.7509 5.7446 5.7307 5.4244 5.4055 5.2403 5.2378 5.2050 5.1937 5.1911 5.1735 5.1710 5.0436 5.0399 5.0096 5.0058 4.9693 4.9491 4.7297 4.6112 4.6036 4.5948 4.5419 4.5192 4.5129 4.4940 4.4750 4.3717 4.3578 4.3490 4.3351 4.1057 4.0930 4.0817 4.0691 Appendix 2: Spectra (Part B) 1H AMX500 4121_TES Of top *** Current Data Parameters *** (ppm) 5.00 0.0 NAME : EXPNO : PROCNO : PULPROG : SFO1 SOLVENT : SW : rk0906 *** Acquisition Parameters *** BF1 : 500.1300000 MHz LOCNUC : NS : O1 : 2H 3088.51 Hz zg30 : 500.1330885 MHz 20.6557 ppm CDCl3 *** Processing Parameters *** LB : PHC0 : 3.758 degree PHC1 : 0.271 degree 0.30 Hz (ppm) -0.5 314 315   150 140 130 120 110 100 90 80 (ppm) 70 77.6 60 50 77.2 40 30 2.8 20 2.4 10 1.8745 3.2 6.7862 4.7749 3.6 12.9003 4.0 26.6953 26.3163 23.4232 4.4 31.8256 31.2426 4.8 76.7449 5.2 77.0000 5.6 50.2116 49.9274 6.0 2.0 (ppm) 76.8 1.6 SFO1 SW NAME 1.2 PULPROG : SOLVENT : : 0.8 7.8279 6.6717 9.3397 4.0115 2.9142 3.0453 1.3051 2.0226 3.0376 1.0114 1.8352 0.9639 0.9163 0.9581 2.0231 0.9604 0.9674 1.9166 5.10 2.0570 (ppm) 77.3206 77.2551 77.1822 77.6559 6.4 1.0001 5.20 83.6679 80.6218 77.6559 77.3206 77.2551 77.1822 77.0000 76.7449 70.0333 67.9418 67.6867 (ppm) 88.9076 2.9348 7.2 105.0127 6.8 111.2652 7.2 116.0968 114.9308 7.6 1.4736 3.8660 7.4 123.9380 8.0 128.2448 127.7055 127.2902 140.8009 139.2779 138.7823 138.2868 Integral Integral 0.9674 1.9166 2.0570 1.4736 3.8660 4.7411 4.7486 5.0071 5.0033 4.9667 4.9478 5.0411 5.0373 5.2454 5.2113 5.1974 5.1949 5.1748 7.3419 7.3293 7.3256 7.3003 7.2688 7.2600 7.2512 2.2549 2.2448 2.2158 2.1856 2.0897 2.0771 2.0620 2.0494 2.0255 2.0091 1.9359 1.9259 1.9069 1.8969 1.7821 1.7796 1.6989 1.6762 1.6674 1.6611 1.6523 1.5539 1.5401 1.4959 1.3497 1.3346 1.3169 0.9677 0.9513 0.9248 0.6727 0.6576 0.6412 0.6260 0.6235 0.6109 0.6071 0.5945 0.5907 0.5781 0.1444 4.1157 4.1031 4.0918 4.0792 7.3419 7.3293 7.3256 7.3003 7.2688 7.2600 7.2512 5.8379 5.8228 5.8177 5.8076 5.8001 5.7887 5.7824 5.7749 5.7686 5.7623 5.7547 5.7484 5.7421 5.7282 5.4080 5.3903 5.2454 5.2113 5.1974 5.1949 5.1748 5.0411 5.0373 5.0071 5.0033 4.9667 4.9478 4.7486 4.7411 4.6112 4.6036 4.5961 4.5469 4.5230 4.5141 4.4952 4.4776 4.3755 4.3528 Appendix 2: Spectra (Part B) 1H AMX500 4119_TES protection of btm diasteromer 5.00 (ppm) (ppm) 0.4 13C AMX500 4119_TES protection of btm diasteromer *** Current Data Parameters *** : rk0831 EXPNO : 12 PROCNO : *** Acquisition Parameters *** BF1 : 125.7577890 MHz LOCNUC : 2H NS : 630 O1 : 13204.57 Hz : 125.7709936 MHz zgpg30 238.7675 ppm CDCl3 *** Processing Parameters *** LB : 1.00 Hz PHC0 : 166.637 degree PHC1 : 32.388 degree 0.0 150   140 130 120 110 100 77.0 90 80 70 60 2.5 50 2.0 40 1.5 30 1.0 20 1.8672 3.0 13.5561 3.5 26.7026 26.3018 23.4524 4.0 31.7819 31.3811 4.5 50.3719 49.8108 5.0 8.8126 3.3056 2.9657 2.9901 2.3050 3.0297 1.0422 2.1542 1.0525 2.9382 1.0200 2.0512 2.0660 0.9828 5.8 55.5095 5.5 0.9644 1.0314 5.9 80.6218 77.4955 77.3425 77.2551 77.0000 76.7449 75.8923 69.9895 67.9709 91.5966 6.0 2.1187 (ppm) 75.8923 6.5 1.0000 3.0647 6.0 76.7449 7.0 105.0272 7.5 111.3308 7.2 77.0000 77.4955 77.3425 77.2551 1.5442 4.0925 7.4 116.3591 114.9453 8.0 128.2448 127.7201 127.2902 126.3647 139.1467 138.7459 138.2795 137.7402 Integral Integral 3.0647 Integral 1.5442 4.0925 5.8266 5.8190 5.8114 5.8026 5.7950 5.7849 5.7774 5.7723 5.7635 5.7572 5.7509 5.7370 7.3293 7.3243 7.3167 7.3016 7.2688 7.2600 7.2512 7.2398 5.8026 5.7950 5.7849 5.7774 5.7723 5.7635 5.7572 5.7509 5.7370 5.5013 5.4836 5.2454 5.2088 5.1874 5.0462 5.0424 5.0109 5.0083 4.9743 4.9541 4.6188 4.6112 4.6036 4.5482 4.5305 4.5255 4.5129 4.4940 4.3691 4.3540 4.3465 4.1057 4.0930 4.0817 4.0678 3.2975 2.2700 2.2587 2.2410 2.2297 2.2183 2.1213 2.1087 2.0923 2.0797 2.0645 2.0494 2.0355 2.0217 1.9561 1.9473 1.9284 1.9183 1.7607 1.7292 1.7166 1.7077 1.7002 1.6964 1.6888 1.6762 1.6661 1.6598 1.6548 1.6498 1.5817 1.5401 1.5237 1.3346 0.1533 Appendix 2: Spectra (Part B) 1H AMX500 SRK 4101_NaH/MeI 0.5 10 *** Current Data Parameters *** NAME : EXPNO : PROCNO : PULPROG : SFO1 SOLVENT : SW : PULPROG : rk0622 *** Acquisition Parameters *** BF1 : 500.1300000 MHz LOCNUC : NS : O1 : 2H 3088.51 Hz : 500.1330885 MHz zg30 20.6557 ppm CDCl3 *** Processing Parameters *** LB : PHC0 : 71.934 degree PHC1 : 1.690 degree 0.30 Hz (ppm) 5.7 (ppm) 0.0 13C AMX500 SRK 4101_NaH/MeI *** Current Data Parameters *** NAME : EXPNO : PROCNO : rk0622 *** Acquisition Parameters *** BF1 : 125.7577890 MHz LOCNUC : 2H NS : 1144 O1 SFO1 : : 125.7709936 MHz 13204.57 Hz zgpg30 SOLVENT : SW : 238.7675 ppm CDCl3 *** Processing Parameters *** LB : 1.00 Hz PHC0 : 341.465 degree PHC1 : 42.258 degree (ppm) 76.0 (ppm) 316 29.6977 29.5884 129.0318 128.3104 127.9897 127.6837 127.3995 140 317   130 120 110 100 90 80 (ppm) 70 60 3.6 50 3.2 40 2.8 30 2.4 20 2.0 10 1.6 2.8578 3.1916 1.4167 2.2861 Integral 2.1397 3.7407 Integral 1.6372 0.5222 1.0000 Integral 2.0872 2.0696 2.0570 2.0406 1.9574 1.9473 1.9385 1.9284 1.9170 1.9006 1.8906 1.8729 1.8414 1.8389 4.5053 4.4864 4.4675 4.4435 4.5973 4.5683 4.5620 4.5532 4.5444 5.7963 5.7887 5.8404 5.8228 5.8127 5.8581 TMSO Me BnO H 12 1.2 SFO1 SW (ppm) H 12 10 H 11 13 0.8 NAME : EXPNO : PROCNO : PULPROG : SOLVENT : : TMSO Me BnO 10 H 13 5.38a 8.0576 1.0752 1.8800 3.7710 31.348 2.8578 3.1916 2.2 1.4167 4.50 1.8235 4.0 2.2861 2.7826 1.0014 (ppm) 15.2833 4.4 29.6977 29.5884 26.8483 26.3382 23.2192 4.8 33.1883 5.2 2.1397 4.60 47.4716 5.6 3.7407 1.0946 1.6372 (ppm) 53.9282 52.9371 6.0 0.5222 1.0000 5.1451 Integral 5.84 67.2422 6.4 82.8226 80.9498 77.2551 77.0000 76.7522 75.7101 74.1652 70.7329 6.8 93.4768 7.2 104.9544 7.6 111.3891 138.8406 137.0188 132.8504 129.0318 128.3104 127.9897 127.6837 127.3995 0.1886 0.1684 2.2461 2.2410 2.2196 2.2146 2.1957 2.1843 2.1704 2.1049 2.0872 2.0696 2.0570 2.0406 1.9574 1.9473 1.9385 1.9284 1.9170 1.9006 1.8906 1.8729 1.8414 1.8389 1.5464 1.3371 3.2748 4.1271 4.1120 4.0994 4.5973 4.5683 4.5620 4.5532 4.5444 4.5053 4.4864 4.4675 4.4435 5.8581 5.8404 5.8228 5.8127 5.7963 5.7887 5.5782 5.5694 5.5656 5.5631 5.5555 5.5530 5.5404 5.5378 5.5341 5.5315 5.5240 5.5215 7.3546 7.3419 7.3281 7.3117 7.2600 Appendix 2: Spectra (Part B) 1H AMX500 GH-II_new spot (rk0728_expt 1) OMe 14 O 15 0.4 BF1 : 125.7577890 MHz LOCNUC : 2H NS : 33205 O1 : 13204.57 Hz 16 O O 5.38a (ppm) 2.0 (ppm) 0.0 13C AMX500 *** Current Data Parameters *** rk0921~1 *** Acquisition Parameters *** : 125.7709936 MHz zgpg30 *** Processing Parameters *** 238.7675 ppm CDCl3 LB : 1.00 Hz PHC0 : 276.474 degree PHC1 : 44.726 degree (ppm) 128 OMe 11 14 O 15 O 16 O Appendix 2: Spectra (Part B) DEPT135 AMX500 11 H O 14 129 H 128 12 130 125 120 29.0 115 110 105 100 95 90 1.8307 15.2978 23.2192 O 28.0 27.0 26.0 (ppm) 5.38a 135 26.3382 26.8483 16 O 15 13 (ppm) 140 29.6977 29.5956 26.8483 26.3382 33.1883 47.4570 53.9282 52.9298 29.6977 29.5956 10 70.7328 OMe 77.2186 75.7028 74.1579 82.8226 104.9471 TMSO Me BnO 127.4067 127.6909 127.9752 128.3177 129.0318 132.8431 129.0318 128.3177 127.9752 127.6909 127.4067 RCM product of Biels (rk0921_2 nights scanned exp 3) 85 80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 (ppm) ppm 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm Current Data Parameters NAME rk0922 EXPNO PROCNO F2 - Acquisition Parameters Date_ 20100922 Time 14.52 INSTRUM spect PROBHD mm TXI 1H-13 PULPROG cosygs TD 2048 SOLVENT C6D6 NS 80 DS 16 SWH 5122.951 Hz FIDRES 2.501441 Hz AQ 0.2000324 sec RG 256 DW 97.600 usec DE 6.00 usec TE 298.0 K D0 0.00000300 sec D1 1.00000000 sec D13 0.00000300 sec D16 0.00020000 sec IN0 0.00019520 sec ======== CHANNEL f1 ======== NUC1 1H P0 8.20 usec P1 8.20 usec PL1 -2.00 dB SFO1 500.2320200 MHz ====== GRADIENT CHANNEL ===== P16 1500.00 usec F1 - Acquisition parameters ND0 TD 256 SFO1 500.232 MHz FIDRES 20.011526 Hz SW 10.241 ppm FnMODE QF F2 - Processing parameters SI 512 SF 500.2300028 MHz WDW SINE SSB LB 0.00 Hz GB PC 1.40 F1 - Processing parameters SI 512 MC2 QF SF 500.2300045 MHz WDW SINE SSB LB 0.00 Hz GB 318   Appendix 2: Spectra (Part B) ppm 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm Current Data Parameters NAME rk0924 EXPNO PROCNO F2 - Acquisition Parameters Date_ 20100924 Time 17.03 INSTRUM spect PROBHD mm TXI 1H-13 PULPROG noesygptp TD 2048 SOLVENT CDCl3 NS 64 DS 16 SWH 4251.701 Hz FIDRES 2.076026 Hz AQ 0.2410124 sec RG 812.7 DW 117.600 usec DE 6.00 usec TE 298.2 K D0 0.00000300 sec D1 2.00000000 sec D8 0.50000000 sec D16 0.00020000 sec d20 0.24830000 sec IN0 0.00011760 sec ======== CHANNEL f1 ======== NUC1 1H P1 8.40 usec P2 16.80 usec PL1 -2.00 dB SFO1 500.2318490 MHz ====== GRADIENT CHANNEL ===== GPNAM1 SINE.100 GPNAM2 SINE.100 GPX1 0.00 % GPX2 0.00 % GPY1 0.00 % GPY2 0.00 % GPZ1 40.00 % GPZ2 -40.00 % P16 1500.00 usec F1 - Acquisition parameters ND0 TD 300 SFO1 500.2318 MHz FIDRES 14.172336 Hz SW 8.499 ppm FnMODE TPPI F2 - Processing parameters SI 512 SF 500.2300071 MHz WDW QSINE SSB LB 0.00 Hz GB PC 1.00 F1 - Processing parameters SI 512 MC2 TPPI SF 500.2300060 MHz WDW QSINE SSB LB 0.00 Hz GB ppm 20 40 60 TMSO Me BnO 10 11 H O 14 H 12 13 ======== CHANNEL f1 ======== NUC1 1H P1 8.40 usec P2 16.80 usec PL1 -2.00 dB SFO1 500.2318490 MHz 100 ======== CHANNEL f2 ======== CPDPRG2 garp NUC2 13C P3 13.20 usec P4 26.40 usec PCPD2 70.00 usec PL2 -2.00 dB PL12 12.49 dB SFO2 125.7942545 MHz 120 16 ====== GRADIENT CHANNEL ===== P16 1500.00 usec O 15 O 140 5.38a 160 HMQC 180 319   F2 - Acquisition Parameters Date_ 20100925 Time 7.46 INSTRUM spect PROBHD mm TXI 1H-13 PULPROG inv4gstp TD 512 SOLVENT MeOH NS 96 DS 16 SWH 4251.701 Hz FIDRES 8.304103 Hz AQ 0.0603788 sec RG 32768 DW 117.600 usec DE 6.00 usec TE 298.7 K D0 0.00000300 sec D1 1.00000000 sec D2 0.00345000 sec d4 0.00172500 sec D11 0.03000000 sec D13 0.00000300 sec D16 0.00020000 sec d20 0.00002500 sec d21 0.00174600 sec IN0 0.00000994 sec 80 OMe Current Data Parameters NAME rk0924 EXPNO PROCNO ppm F1 - Acquisition parameters ND0 TD 256 SFO1 125.7943 MHz FIDRES 98.270439 Hz SW 199.987 ppm FnMODE TPPI F2 - Processing parameters SI 512 SF 500.2300066 MHz WDW QSINE SSB LB 0.00 Hz GB PC 1.40 F1 - Processing parameters SI 512 MC2 TPPI SF 125.7828923 MHz WDW QSINE SSB LB 0.00 Hz GB [...]... dimannoside, followed by 2   Part A: Synthesis of Mannoside Glycans of Phosphatidylinositol Mannosides (PIMs) deprotection of the acetyl group and subsequent iterative glycosylation with the same unit 4 until reaching the tetramannoside (Scheme 1)   Scheme 1: Seeberger Approach to PIM-66c       3 Part A: Synthesis of Mannoside Glycans of Phosphatidylinositol Mannosides (PIMs) 2 PIMs: 1st Generation Synthetic... Part A: Synthesis of Mannoside Glycans of Phosphatidylinositol Mannosides (PIMs) converted to a trichloroacetimidate 11, a Schmidt donor, in good yield by CCl3CN in the presence of DBU.7   Scheme 4: Synthesis of Mannose as a Protected Schmidt Donor 11     2.2.2 Mannose With Accessible C2-Hydroxyl Group Scheme 5: Synthesis of C2-Hydroxyl Mannose 12 6   Part A: Synthesis of Mannoside Glycans of Phosphatidylinositol. .. consumption of the donor forming the dimannoside 18 (Scheme 6) Scheme 6: Glycosylation to Make Dimannoside 18 7 Part A: Synthesis of Mannoside Glycans of Phosphatidylinositol Mannosides (PIMs) All attempts to purify the dimannoside, however, led to elution of both the dimannoside and acceptor compounds during silica gel column chromatography Separation at the dimannoside stage and further removal of the... tetrahydrofuran THP 2-tetrahydropyranyl TIPS triisopropylsilyl TLC thin layer chromatography TLR toll-like receptor TMEDA tetramethylethylenediamine TMS trimethylsilyl TMSOTf trimethylsilyl trifluoromethanesulfonate Tr trityl (triphenylmethyl) Ts p-toluenesulfonyl uv ultraviolet xx PART A SYNTHESIS OF MANNOSIDE GLYCANS OF PHOSPHATIDYLINOSITOL MANNOSIDES (PIMs) Part A: Synthesis of Mannoside Glycans of Phosphatidylinositol. .. Mannoside Glycan of PIMs 10  Scheme 10: Synthesis of Mannose Intermediates 11  Scheme 11: Synthesis of Mannose 1,2-Orthoester10 12  Scheme 12: Optimizing in situ Glycosylation 14  Scheme 13: Synthesis of Dimannosides 15  Scheme 14: Synthesis of Tri- and Tetramannosides 16  Scheme 15: Synthesis of Diversified Pentamannosides 17 Part B: Chapter 1 Scheme... Seeberger in situ Glycosylation Method9 9 Part A: Synthesis of Mannoside Glycans of Phosphatidylinositol Mannosides (PIMs) 3.2 Synthetic Plan 2: Iterative in situ Coupling of Mannose 1,2-Orthoesters Due to practical difficulties in the purification of dimannosides, a new synthetic plan for all variations of PIMs was formulated as depicted in Scheme 9 Here, the dimannoside would be made by regular Schmidt... presence of the acid sensitive benzylidene acetal ring hampered synthetic progress towards the desired pentamannoside 3 PIMs: 2nd Generation Synthetic Plan 1-2 8 7 Scheme 7: PIMs: 2nd Generation Synthetic Plan 8   Part A: Synthesis of Mannoside Glycans of Phosphatidylinositol Mannosides (PIMs) In the meantime, we were planning to study the immunogenic roles of PIMs immunogenic roles of all homologues of. .. 1.9: Pattenden Synthesis of (+)-(Z)-Deoxypukalide (1.54b) 73  Scheme 1.10: Trauner Synthesis of Bipinnatin J (1.2) and Conversion to Intricarene (1.11) 75  Scheme 1.11: Sulikowski Synthesis of Tetracyclic Core of Bielschowskysin 76  Scheme 1.12: Lear Synthesis of Tricyclic Core of Bielschowskysin 78  Scheme 1.13: Nicolaou Synthesis of Tetracyclic Skeleton of Bielschowskysin... 6 of PIMs has linear α1→2, α1→2, α1→6, α1→6 glycosidic linkages between monomeric pyrano-mannoses Thus, the pentamannoside was 4   Part A: Synthesis of Mannoside Glycans of Phosphatidylinositol Mannosides (PIMs) envisioned to be built-up via the convergent assembly of trimannoside 9 and dimannoside 10 through α1→6 glycosylation (Scheme 3).7 The 9 and 10 intermediates could be prepared independently... range of immune responses and act as agonists of toll-like receptor 2 (TLR2) that are involved in innate immunity.3 They are also known to 1 Part A: Synthesis of Mannoside Glycans of Phosphatidylinositol Mannosides (PIMs) recruit natural killer T-cells3b,4 and cause T-cell expansion via binding to the lipid presentation molecule, CD1b.3b,5 Fig 1: Structural Features of PIMs, LM, and LAM 1.2 Previous Synthesis . Synthesis of a Model Trimannoside 13 3.5 Synthesis of Mannoside Glycan Units of PIMs 15 3.5.1 Synthesis of Dimannoside of PIMs 15 3.5.2 Iterative Glycosylation: Synthesis of Tri-, Tetramannoside. situ Glycosylation 14 Scheme 13: Synthesis of Dimannosides 15 Scheme 14: Synthesis of Tri- and Tetramannosides 16 Scheme 15: Synthesis of Diversified Pentamannosides 17 Part B: Chapter 1 Scheme. Table of Contents Table of Contents iii  Summary viii List of Figures x List of Schemes x List of Tables xvi Abbreviations xvii Part A: Synthesis of Mannoside Glycans of Phosphatidylinositol