combinatorial synthesis of derivatives of bioactive compounds via a sulfone scaffold

Combinatorial Synthesis of Derivatives of Bioactive Compounds via a Sulfone Scaffold GAO YONGNIAN NATIONAL UNIVERSITY OF SINGAPORE 2008 Combinatorial Synthesis of Derivatives of Bioactive Compounds via a Sulfone Scaffold GAO YONGNIAN (B.Sc., Soochow University) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF CHEMISTRY NATIONAL UNIVERSITY OF SINGAPORE 2008 ACKNOWLEDGEMENTS I would like to express my greatest gratitude to my advisor, Associate Professor Lam Yulin, for her patient guidance, stimulating ideas and invaluable advice throughout my study. I am also grateful to her for carrying out the X-ray crystallographic analyses of my crystals. I would also like to express my appreciation to my group members, Fu Han, Makam Raghavendra, He Rongjun, Soh Chai Hoon, Kong Kah Hoe, Gao Yaojun, Che Jun, Ching Shi Min, Fang Zhanxiong, and Wong Ling Kai for their help and encouragement during my research. I appreciate the support of the research laboratory staff Madam Han Yanhui and Mr. Wong Chee Ping from the NMR laboratory, Madam Wong Lai Kwan and Madam Lai Hui Ngee from the MS lab and other members of Chemical & Molecular Analysis Centre. I can always receive help from them when I was facing technical problems. I am also grateful to the National University of Singapore for awarding me the research scholarship. Finally, I thank my wife Ding Lijun and my family for their love, support and motivation. Without which, this thesis would not have been possible. i TABLE OF CONTENTS ACKNOWLEDGEMENTS i SUMMARY v LIST OF TABLES vii LIST OF FIGURES viii LIST OF SCHEMES ix LIST OF ABBREVIATIONS x PUBLICATIONS Chapter 1: Introduction xiii 1.1 Combinatorial chemistry 1.2 Solid-phase synthesis 1.3 Solid supports 1.4 Linkers 12 1.5 Monitoring of Solid-phase reactions 19 1.6 Sulfone chemistry 20 1.7 Objectives of our studies 27 1.8 References 28 Chapter 2: 2.1 Traceless Solid-phase Synthesis of 1,2,3-Triazoles Introduction 33 2.1.1 Importance of 1,2,3-triazoles 33 2.1.2 General synthetic methods in solution-phase chemistry 33 2.1.3 Solid-phase synthesis of 1,2,3-triazoles 35 2.2 Results and discussion 38 2.3 Conclusions 45 2.4 Experimental section 45 2.4.1 General procedures 45 2.4.2 Materials 45 2.4.3 Chromatography 46 2.4.4 Physical data 46 ii 2.4.5 2.5 Experimental procedures References Chapter 3: 47 58 Combinatorial Synthesis of Triazolo[4,5-b]pyridine-5-ones and Pyrrolo[3,4-b]pyridine-2-ones 3.1 Introduction 61 3.2 Results and discussion 61 3.2.1 Synthesis of substituted triazolo[4,5-b]pyridin-5-ones 61 3.2.2 Synthesis of substituted pyrrolo[3,4-b]pyridin-2-ones 69 3.3 Conclusions 74 3.4 Experimental section 74 2.5 3.4.1 General procedures 74 3.4.2 Materials 74 3.4.3 Chromatography 74 3.4.4 Physical data 75 3.4.5 Experimental procedures 75 References Chapter 4: 87 Synthesis and Application of Polymer-supported N-sulfonyloxaziridine (Davis Reagent) 4.1 Introduction 89 4.2 Results and discussion 90 4.2.1 Synthesis of polymer-supported N-sulfonyloxaziridine 90 4.2.2 Oxidation of sulfides and selenides 92 4.2.3 Oxidation of amines and phosphines 96 4.2.4 Oxidation of enolates and enamines 98 4.2.5 Oxidative rearrangement 100 4.2.6 Recycling of polymer-supported N-sulfonyloxaziridine 101 4.3 Conclusions 103 4.4 Experimental section 103 3.4.1 General procedures 103 3.4.2 Materials 103 iii 4.5 3.4.3 Chromatography 103 3.4.4 Physical data 104 3.4.5 Experimental procedures 105 References 121 Appendix NMR and IR spectral analyses 125 iv Summary This thesis focuses on combinatorial synthesis of derivatives of bioactive compounds via a sulfone scaffold. The first project is to extend the application of polymer-supported sodium benzenesulfinate in solid-phase synthesis. A traceless solid-phase synthesis of trisubstituted and disubstituted 1,2,3-triazoles has been developed. 23 different compounds were obtained by [3+2] cycloaddition of the polymer-supported vinyl sulfones and sodium azide in 37-78% yield. Using microwave irradiation, the total reaction time could be shortened from over day to h. The second project is triazolo[4,5-b]pyridin-5-ones to develop and combinatorial synthesis pyrrolo[3,4-b]pyridin-2-ones. of 22 triazolo[4,5-b]pyridin-5-ones were prepared by [3+2] cycloaddition of heterocyclic vinyl sulfones and azides in good yield (76% to 98%). 10 pyrrolo[3,4-b]pyridin-2-ones were synthesized by [3+2] cycloaddition of heterocylic vinyl sulfones and isocyanides in good yield and regioselectivity. The third project aims to develop soluble polymer-supported Davis reagent and its application in organic synthesis. An efficient synthetic route of synthesizing polymer-supported Davis reagent was devised. The reagent was successfully applied v in the oxidation of the sulfides, amines, selenides, phosphines and enolates as well as the rearrangement of the imidazoles. vi LIST OF TABLES Table 1.1 Nucleophile-labile linkers and their cleavage reagents 15 Table 2.1 Cycloaddition of resin 2-3a to form triazole 2-4a 40 Table 2.1 Cycloaddition of resin 2-3a to form triazole 2-5a 43 Table 3.1 Synthesis of 3-3b 64 Table 3.2 Synthesis of 3-8a 65 Table 3.3 Cycloaddition of Cyclic Vinylsulfones 3-5b and TosMIC 71 Table 4.1 Oxidation of 4-2 91 Table 4.2 Condensation of Polymer 4-5 with Benzenesulfonamide. 92 Table 4.3 Oxidation of sulfide 4-7a to sulfoxide 4-8a 93 Table 4.4 Oxidation of sulfides using 4-1 94 Table 4.5 Oxidation of sulenides using 4-1 95 Table 4.6 Amine oxidation by 4-1 97 Table 4.7 Oxidation of triphenylphosphine 4-13a to triphenylphosphine oxide 4-14a 97 Table 4.8 Phosphine oxidation by 4-1 98 Table 4.9 Oxidation of deoxybenzoin with 4-1 99 Table 4.10 Enolate and enamine oxidation with 4-1 99 Table 4.11 Recycling versus oxidative activity of 4-1 102 vii LIST OF FIGURES Figure 1.1 Difference between traditional synthesis and combinatory chemistry Figure 1.2 Split-pool synthesis Figure 1.3 Split-pool synthesis Figure 1.4 Solid-phase synthesis Figure 1.5 The internal molecular structure of polystyrene Figure 1.6 The precursors used in the preparation of polyacrylamide resins 10 Figure 1.7 TentaGel resin has a polyethylene glycol chain grafted onto a cross-linked polystyrene backbone 11 Figure 1.8 Polymer bound cations after cleavage of the product via SN1 reaction 13 Figure 1.9 Dependence of the cleavage conditions on the aromatic substituents 14 Figure 1.10 β-elimination on the fluorenyl linker. 15 Figure 1.11 Aminolysis of ester linker 15 Figure 1.12 The structure of sulfone 20 Figure 1.13 One example of organic sulfonyl compounds 21 Figure 1.14 Preparation and the application of Davis reagent 22 Figure 1.15 Huang and his coworkers’ application of polymer supported sulfinate 24 Figure 1.16 Kurth and his coworkers’ application of polymer supported sulfinate 25 Figure 1.17 Sheng and his coworkers’ application of polymer supported sulfinate 26 Figure 1.18 27 Figure 2.1 Lam and coworkers’ application of polymer supported sulfinate An example of bioactive 1,2,3-triazole Figure 2.2 Library of 4,5-disubsituted-1,2,3-driazoles 40 Figure 2.3 Crystal structures of 2-4b, 2-4c, 2-4f and 2-4i 41 Figure 2.4 HMBC study of 2-5a 43 Figure 2.4 Crystal structures of 2-5a, 2-5e1 and 2-5e2 44 Figure 2.5 Trisubsituted-1,2,3-Triazoles 44 Figure 3.1 Library of 3-3 67 Figure 3.2 NOESY Spectra of 3-3n 68 Figure 3.3 NOESY Spectra of 3-3p 69 Figure 3.4 Library of 3-4 71 Figure 3.5 NOESY spectra of 3-4e 72 Figure 3.6 X-ray diffraction study of 3-4c and 3-4d 73 33 viii 170 160 150 7.2 6.8 140 6.4 130 6.0 120 40.3265 40.0534 39.7730 39.5000 39.2196 38.9392 38.6662 7.6 113.4025 8.0 116.2287 8.4 130.5000 129.4005 126.6555 125.8142 146.3062 8.8 2.9971 2.0000 Integral 2.5000 7.8475 7.8417 7.8348 7.8209 7.8162 7.8069 7.5539 7.5446 7.5388 7.5237 7.5133 7.4982 7.4912 7.4854 7.4773 7.4738 7.4552 7.4506 Appendix 5.6 110 H NMR of 2-4a 5.2 13 4.8 100 4.4 (ppm) 90 4.0 80 3.6 3.2 70 2.8 60 2.4 50 2.0 1.6 40 1.2 30 0.8 20 0.4 10 0.0 C NMR of 2-4a (ppm) 125 170 160 150 1.0002 1.0000 7.2 6.8 140 2.5000 2.4945 6.7606 6.7546 6.7491 6.7431 7.1063 7.0943 7.9988 7.9933 6.4 130 6.0 120 5.6 5.2 13 110 40.3338 40.0534 39.7730 39.5000 39.2196 38.9466 38.6809 7.6 115.1071 112.5760 112.3546 111.3142 8.0 138.6319 8.4 141.4876 145.1182 8.8 0.9665 Integral Appendix H NMR of 2-4b 4.8 100 4.4 (ppm) 4.0 90 3.6 80 3.2 70 2.8 60 2.4 2.0 50 1.6 40 1.2 30 0.8 20 0.4 0.0 C NMR of 2-4b (ppm) 10 126 170 160 150 140 130 2.0000 6.9848 5.8011 7.9777 7.9695 7.4643 7.4567 7.4512 7.4457 7.4353 7.4271 7.3783 7.3729 7.3624 7.3564 7.3455 7.3159 7.2600 5.6 120 5.2 13 110 4.8 100 4.4 90 4.0 80 60.7376 6.0 77.4218 77.0000 76.5782 6.4 114.5578 6.8 119.0816 7.2 123.0745 7.6 133.2421 132.6385 131.0457 130.4129 129.1256 129.0165 128.6238 8.0 146.3699 8.4 151.1119 154.3048 8.8 0.9080 Integral Appendix H NMR of 2-5e1 (ppm) 3.6 3.2 70 2.8 60 2.4 50 2.0 1.6 40 1.2 30 0.8 20 0.4 0.0 C NMR of 2-5e1 (ppm) 10 127 190 180 170 160 150 10.0 140 130 9.0 13 120 8.0 110 7.0 100 6.0 90 80 70 5.0 4.0 60 3.0 50 40 2.0000 1.9952 2.0372 4.9055 2.9652 2.9488 2.9337 2.8278 2.8139 2.7988 2.5076 2.5038 2.5000 2.4975 2.4937 3.3195 4.9382 7.3147 7.3122 7.3021 7.2971 7.2946 7.2870 7.2769 7.2441 7.2366 7.2265 7.2227 7.2189 7.2164 14.1718 30 16.7197 11.0 44.8344 40.0028 39.8352 39.6676 39.5073 39.3397 39.1721 39.0045 31.4402 12.0 128.2747 127.7355 127.3201 127.0067 13.0 137.1216 14.0 146.4130 168.2241 0.9045 Integral Appendix H NMR of 3-3a (ppm) 2.0 1.0 20 0.0 C NMR of 3-3a (ppm) 10 128 190 180 170 160 150 140 130 6.0 13 120 5.5 110 5.0 100 4.5 90 4.0 80 3.5 3.0 70 2.5 60 2.0 50 1.5 40 30 18.7520 6.5 24.8662 7.0 40.6360 7.5 45.7153 8.0 3.0832 0.9923 1.0000 0.9579 2.0244 2.0138 9.7801 -0.0000 3.1543 3.1405 3.1354 3.1279 3.1216 3.1140 3.1090 3.1014 3.0951 3.0812 2.8064 2.7938 2.7749 2.7623 2.4572 2.4370 2.4244 2.4055 1.2393 1.2254 5.3606 5.3316 5.3266 5.2963 4.9559 4.9244 4.8941 7.3021 7.2580 7.2542 7.2517 7.2479 7.2404 7.2366 7.2303 7.2265 7.2227 7.2152 7.2126 7.2013 7.1962 7.1925 7.1836 7.1799 7.1748 7.1685 7.1647 7.1609 7.1534 7.1483 7.1408 7.1332 58.3589 8.5 77.2551 77.0000 76.7449 9.0 136.7856 135.9986 135.5540 128.6019 128.5727 128.2958 128.0991 127.7857 127.3995 9.5 146.3321 168.3618 Integral Appendix H NMR of 3-3m (ppm) 1.0 0.5 20 0.0 C NMR of 3-3m (ppm) 10 129 190 180 170 160 150 140 130 120 110 100 90 4.0 80 3.5 70 3.0 60 2.5 2.0 50 1.5 40 1.0 30 20 14.3213 4.5 20.3261 18.8103 5.0 29.7122 13 5.5 36.7300 36.0523 6.0 47.0416 6.5 60.3994 7.0 77.2551 77.0000 76.7449 7.5 3.0255 3.0335 3.1976 1.0000 2.9921 1.9693 1.9874 0.9689 4.8475 0.8795 1.6314 1.6175 1.6049 1.5910 1.2040 1.1901 1.1763 0.8132 0.7993 0.7464 0.7337 2.6084 2.5908 2.5795 2.5668 2.5530 2.5000 2.4874 2.4748 2.4622 4.1831 4.1692 4.1554 4.1415 5.4627 6.4499 6.4436 7.1017 7.0941 7.0853 7.0651 7.0563 7.0475 7.0386 8.9108 109.1519 8.0 117.5542 117.1388 8.5 132.1581 127.9169 127.5744 126.6197 9.0 138.2212 9.5 159.4347 171.3277 Integral Appendix H NMR of 3-4d (ppm) 0.5 0.0 C NMR of 3-4d (ppm) 10 130 10.8 10.2 9.6 9.0 8.4 7.8 7.2 6.6 6.0 5.4 23.149 4.8 4.2 3.6 3.0 2.4 1.8 1.2 0.8858 1.1291 1.3875 1.5640 1.7746 5.4017 6.4960 7.0482 7.7403 7.6307 8.0807 1.0000 21.535 3.1410 2.0141 Integral Appendix H NMR of 4-1 (ppm) 0.6 0.0 ( FTIR of 4-1 131 210 200 190 180 170 160 7.2 150 13 140 130 1.0815 1.0441 1.0810 6.6 120 30.2674 30.0165 29.7583 29.5000 29.2417 28.9908 28.7326 7.8 117.4156 8.4 127.3185 9.0 2.0866 2.0752 1.0000 6.0 5.4 110 4.8 100 4.2 90 3.6 80 3.0 70 60 2.0651 2.0570 2.0500 2.0430 2.0361 2.8405 5.4626 5.4254 6.0511 5.9919 6.9135 6.8775 6.8555 6.8183 7.9106 7.8827 7.7005 7.6738 10.0232 130.3366 9.6 136.7048 136.6089 10.2 143.8331 10.8 191.9749 205.7666 Integral Appendix H NMR Spectra of 4-3 (ppm) 2.4 50 1.8 40 1.2 30 0.6 20 0.0 C NMR Spectra of 4-3 (ppm) 10 132 Appendix 11.4 10.8 10.2 9.6 9.0 8.4 7.8 7.2 6.6 1.5519 1.4188 1.8176 14.438 6.5588 7.0518 19.131 7.5208 H NMR Spectra of 4-4 2.0216 1.0000 Integral 9.8930 6.0 5.4 4.8 4.2 3.6 3.0 2.4 1.8 1.2 0.6 0.0 (ppm) FTIR of 4-4 133 Appendix 11.4 10.8 10.2 9.6 9.0 8.4 7.8 7.2 6.6 1.3870 1.5569 1.7787 16.101 6.5056 7.0326 20.677 7.2600 7.4939 7.7788 H NMR Spectra of 4-5 6.5191 1.0000 Integral 8.6570 6.0 5.4 4.8 4.2 3.6 3.0 2.4 1.8 1.2 0.6 0.0 (ppm) FTIR of 4-5 134 190 180 8.4 170 8.0 160 7.6 150 7.2 6.8 13 140 6.4 130 6.0 120 5.6 5.2 110 4.8 O 100 4.4 S O 8k 90 4.0 80 2.2933 S O 8k 3.3803 2.3025 O 54.2721 52.7889 50.7006 8.8 2.1109 1.0000 3.7720 3.6965 3.6501 3.5874 3.5410 4.3164 4.2699 4.2038 4.1562 6.4475 6.4370 6.3952 6.3883 6.3790 7.2600 7.4306 7.4260 77.4280 77.0000 76.5794 9.2 111.9773 111.1951 9.6 143.8111 143.2429 165.5207 Integral Appendix H NMR Spectra of 4-8k O O (ppm) 3.6 3.2 70 2.8 60 2.4 50 2.0 1.6 40 1.2 30 0.8 20 0.4 10 0.0 C NMR Spectra of 4-8k O O (ppm) 135 190 180 170 160 150 7.2 6.8 140 6.4 13 130 6.0 120 5.6 5.2 110 4.8 100 4.4 90 4.0 3.6 80 3.2 70 2.8 60 2.4 50 2.0 1.6 40 1.2 30 20 17.4330 7.6 25.9957 24.9390 23.9698 8.0 42.2975 8.4 46.1307 8.8 4.1014 2.0681 3.0000 4.1507 0.9706 0.9254 1.6107 1.6069 1.5968 1.5930 1.4153 1.4127 1.4039 1.4014 1.3976 1.3913 1.3800 1.3749 1.3686 1.3144 1.3018 1.2930 3.3177 3.2307 6.5779 6.5641 6.5502 6.5351 6.5212 6.5073 6.0535 6.0497 6.0472 6.0434 6.0232 6.0194 6.0169 6.0131 77.2551 77.0000 76.7376 9.2 121.4165 9.6 139.8171 164.7108 Integral Appendix H NMR Spectra of 4-10b (ppm) 0.8 0.4 10 0.0 C NMR Spectra of 4-10b (ppm) 136 210 200 8.8 8.4 190 8.0 180 7.6 170 7.2 160 6.8 6.4 13 150 140 6.0 5.6 130 5.2 120 4.8 110 4.4 100 4.0 90 3.6 80 3.2 2.8 70 30.2637 30.0091 29.7546 29.5000 29.2382 28.9836 28.7291 9.2 2.0000 7.6407 0.9796 1.8754 2.0648 2.0571 2.0500 2.0423 2.0352 2.8181 5.1114 8.3141 8.2999 8.2884 8.2813 7.9257 7.5773 7.5680 7.5636 7.5603 7.5575 7.5510 7.5455 7.4189 7.4135 7.4063 7.4009 7.3899 7.3833 7.3768 7.3718 7.3691 7.3647 7.3548 7.3472 7.3253 71.3416 9.6 135.5405 133.2495 132.2240 130.1512 129.5766 128.9511 128.8638 128.7620 128.5220 205.7759 Integral Appendix H NMR Spectra of 4-12d (ppm) 2.4 60 2.0 50 1.6 40 1.2 30 0.8 20 0.4 0.0 C NMR Spectra of 4-12d (ppm) 10 137 190 180 170 160 150 140 130 120 5.6 5.2 110 4.8 100 4.4 90 4.0 3.6 80 3.2 70 2.8 60 2.4 50 2.0 1.6 40 1.2 30 13.9715 13 6.0 24.9390 22.5196 6.4 31.4248 6.8 34.2013 7.2 37.5243 7.6 55.5533 8.0 66.9143 8.4 3.1836 4.2248 2.3527 0.6072 1.0325 1.0578 1.0486 0.9819 2.0711 0.9986 1.0000 2.0368 3.0271 5.0134 5.0058 4.9970 4.9894 4.9806 4.9730 4.6906 4.6856 4.6768 4.6705 4.6667 4.6604 4.6579 4.6516 4.6452 4.2998 4.2809 4.2658 4.2607 4.2544 4.2418 4.2368 3.4312 3.4148 3.3353 3.3290 3.3076 3.3013 2.8664 2.8474 2.8399 2.8210 1.8426 1.8351 1.8300 1.8237 1.8162 1.8099 1.8036 1.7935 1.7834 1.7771 1.6044 1.5993 1.5867 1.5804 1.5350 1.5275 1.5186 1.5086 1.4997 1.4934 1.4884 1.3648 1.3510 1.3459 1.3421 1.3384 1.3333 1.3283 1.3220 1.3157 1.2980 1.2841 0.9084 0.8946 0.8807 7.3596 7.3571 7.3457 7.3432 7.3306 7.3041 7.2940 7.2890 7.2840 7.2739 7.2600 7.2247 7.2222 7.2083 77.2551 77.0000 76.7449 70.8786 8.8 129.4472 129.0464 127.5161 9.2 134.8180 9.6 153.1822 175.0953 Integral Appendix H NMR Spectra of 4-16c (ppm) 0.8 20 0.4 10 0.0 C NMR Spectra of 4-16c (ppm) 138 190 8.8 180 8.4 170 8.0 160 7.6 150 7.2 6.8 140 6.4 13 130 6.0 120 5.6 5.2 110 4.8 100 4.4 90 4.0 80 3.6 3.2 70 2.8 60 23.1318 9.2 52.6165 9.6 2.4 50 4.0000 2.0142 2.0852 0.9563 5.3581 2.9092 1.8352 Integral 2.0 1.6 40 1.2 30 0.8 20 0.4 10 -0.0000 2.6274 2.6148 2.6097 2.6047 2.5971 2.5908 2.5832 2.4017 2.3954 2.3866 2.3815 2.3765 2.3689 2.3588 1.7801 1.7713 1.7675 1.7575 1.7474 1.7436 1.7335 1.7222 1.7095 1.7007 1.6969 4.8273 7.9565 7.9413 7.9388 7.4093 7.4017 7.3942 7.3879 7.3803 7.3097 7.2946 7.2832 7.2794 7.2378 7.2341 7.2240 7.2076 7.1899 7.1824 7.1799 7.1698 7.1647 77.2551 77.0000 76.7449 76.0964 136.6763 136.0933 132.7703 129.7606 129.0245 128.6602 128.3031 127.9897 197.1396 Appendix H NMR Spectra of 4-16e (ppm) 0.0 C NMR Spectra of 4-16e (ppm) 139 190 180 170 160 150 7.2 6.8 140 6.4 13 130 6.0 120 5.6 5.2 110 4.8 100 4.4 90 4.0 3.6 80 3.2 70 2.8 60 2.4 50 2.0 1.6 40 25.7544 7.6 37.1730 8.0 44.4969 8.4 2.2910 6.0923 2.0000 5.0727 0.8675 1.9580 1.9476 1.9405 1.9235 1.9021 1.8917 1.8737 1.8638 1.7493 1.7246 1.7120 4.5548 7.4524 7.3056 7.2848 7.2793 7.2607 7.2541 7.2486 7.2327 7.2125 7.2021 7.1621 7.1560 7.1358 77.8219 77.4218 77.0000 76.5782 8.8 128.9802 128.0929 127.4819 9.2 135.6277 9.6 151.0101 184.9896 Integral Appendix H NMR Spectra of 4-18a (ppm) 1.2 30 0.8 20 0.4 0.0 C NMR Spectra of 4-18a (ppm) 10 140 [...]... 3 A1 B 4 A1 B5 A 2 B1 A2 B2 A2 B 3 A2 B 4 A2 B5 A3 B1 Split and react A3 B2 A3 B3 A3 B4 A3 B5 A 1 B1 A2 B3 A3 B 2 A 3 B3 A 1B 4 A3 B 4 A 2B 5 A 2B 4 C1 A 2B 2 A 3B 1 Split and react A1 B3 A 2 B1 Pool A 1B 2 A1 B 5 15 Products A 3B 5 C2 4 Reactions C4 C3 A1 B1 C 1 A1 B 2 C 1 A 1 B1 C 2 A 1B 2C 2 A 1B 1C 3 A1 B2C3 A 1 B1 C 4 A 1 B2 C 4 A2 B1 C 1 A2 B 2 C 1 A 2 B1 C 2 A 2B 2C 2 A 2B 1C 3 A2 B2C3 A 2 B1 C 4 A. .. collection of compounds is referred to as a combinatorial library In addition, because combinatorial synthesis discards the traditional concepts of organic synthesis that all compounds and intermediates need to be fully purified and characterized, combinatorial synthesis is much faster and more economical Generally, two different strategies are used in combinatorial synthesis: plit-pool synthesis and parallel... general, combinatorial libraries comprising of hundreds to thousands of compounds are synthesized by parallel synthesis, often in an automated fashion Unlike split-pool synthesis, which requires a solidsupported, parallel synthesis can be done either on solid-phase or in solution 3 Chapter 1 A3 A1 A2 Split and react A1 3 Reactions A3 A2 3 Products A1 A2 Pool A3 B1 B2 B3 5 Reactions B5 B4 A 1 B1 A1 B2 A1 ... that might benefit from the combinatorial chemistry, as the principles are being applied increasingly in the search for new materials1, 2 and better catalysts3-9 Combinatorial chemistry is a technique by which large numbers of structurally distinct molecules may be synthesized in a time and submitted for pharmacological assay The key of combinatorial chemistry is that a large range of analogues are... biologically active components from the mixture Three approaches are generally used for the structural deconvolution of bioactive compounds from assay data: iterative deconvolution11, position scanning deconvolution method12 and tagging13 2 Combinatorial libraries can also be prepared by parallel synthesis1 4 Here, compounds are synthesized in parallel using ordered arrays of spatially separated reaction... A 3 B1 C 1 A 3B 2C 1 A3 B1C2 A3 B2C2 A 3B 1C 3 A 3B 2C 3 A 3B 1C 4 A 3B 2C 4 A1 B 3 C 1 A1 B4C1 A1 B 3 C 2 A1 B 4 C 2 A1 B3C3 A 1 B4 C 3 A 1 B3 C 4 A 1B 4C 4 A2 B 3 C 1 A2 B4C1 A2 B 3 C 2 A2 B 4 C 2 A2 B3C3 A 2 B4 C 3 A 2 B3 C 4 A 2B 4C 4 A3 B 3 C 1 A3 B 4 C 1 A3 B 3 C 2 A3 B4 C 2 A3 B3C3 A 3 B4 C 3 A 3 B3 C 4 A 3 B4 C 4 A1 B 5 C 1 A3 B 5 C 1 A1 B 5 C 2 A3 B 5 C 2 A1 B5C3 A3 B 5 C 3 A 1 B5 C 4 A3 B 5 C 4 A2 ... Acid-Labile Linkers Acid-labile linkers are the most commonly used linkers in both peptide and combinatorial chemistry Chemicals such as TFMSA, HF, HBr, TFA, PPTS, acetic acid and HFIP can be employed as cleavage reagents The greatest part of acid-labile linkers can be subdivided into two categories The first subgroup is characterized by an acid labile acetal group, which is obtained following addition of. .. sensitivity and speed This analysis offers a lot of information required for the reaction optimization such as qualitative ‘yes-orno’ answers and quantitative percentage of conversion 2 Gel-phase NMR The largest obstacle to NMR analysis of compounds on a resin is the broad line in solid state NMR spectra, particularly in proton spectra, which arise from restricted molecular motion and heterogeneity of the sample... antibacterial, antimalarial, antihelmintic, antilepral, antineoplastic, antiinflammatory and antidiabetic acitivities52 Compound 1-3 (Figure 1.13) is an example of an organic sulfone compound which exhibits anticoccidial activity in chicken (Eimeria tenella) with an MIC (minimum inhibitory concentration) of 8 ppm O N N HN Br O S O O 1-3 Figure 1.13 One example of organic sulfonyl compounds Furthermore, sulfone. .. A2 B 5 C 2 A2 B5C3 60 Products A 2 B5 C 4 Figure 1.2 Split-pool synthesis (Sphere represent resin beads, A, B, C, represent the sets of building blocks, borders represent the reaction vessels.) 4 Chapter 1 Couple A 2 Reactions 2 Products A1 A1 A1 A1 A2 A2 A2 A2 Couple B 4 Reactions 4 Products A1 B1 A1 B1 A1 B2 A1 B2 A2 B1 A2 B1 A2 B2 A2 B2 Couple C 8 Reactions 8 Products A1 B1C1 A1 B1C2 A1 B2C1 A1 B2C2 A2 B1C1 A2 B1C2 . Combinatorial Synthesis of Derivatives of Bioactive Compounds via a Sulfone Scaffold GAO YONGNIAN NATIONAL UNIVERSITY OF SINGAPORE 2008 Combinatorial Synthesis. encouragement during my research. I appreciate the support of the research laboratory staff Madam Han Yanhui and Mr. Wong Chee Ping from the NMR laboratory, Madam Wong Lai Kwan and Madam Lai. In addition, because combinatorial synthesis discards the traditional concepts of organic synthesis that all compounds and intermediates need to be fully purified and characterized, combinatorial