Total synthesis of the potent antibiotic platensimycin

TOTAL SYNTHESIS OF THE POTENT ANTIBIOTIC PLATENSIMYCIN EEY TZE CHIANG STANLEY NATIONAL UNIVERSITY OF SINGAPORE 2011 TOTAL SYNTHESIS OF THE POTENT ANTIBIOTIC PLATENSIMYCIN EEY TZE CHIANG STANLEY (B.Sc.(Hons.), NUS A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF CHEMISTRY NATIONAL UNIVERSITY OF SINGAPORE 2011 To my mum and my wife Alicia i ACKNOWLEDGEMENTS I joined the Lear-group in 2005 as an undergraduate, and I was one of the few pioneer members who have stayed and grew with the group. This is the place where I was first introduced to synthetic natural product chemistry, and my interest in this field has deepened over the years. I could still remember the grueling first time I met up with Dr. Lear, and he overwhelmed me with his jargon of name reactions in organic chemistry. He has then been a considerable figure who has greatly influenced me over the years. The phrase “…not for the weak-hearted…” was an advice from Dr. Lear to students applying for his total synthesis projects. Indeed, the completion of this project did not come easy, and I would not have succeeded without the help from several people. I am sincerely grateful to my supervisor Dr. Martin J. Lear who has given me much valuable advice and encouragement throughout my studies. He has always been patient and understanding in giving me time to surmount the difficulties I encountered over the course of my research and personal events. I would also like to thank him for the confidence and freedom he has given me to exercise my creativity and determination in carrying out my research independently. Finally, I could not thank him more for his thoughtful efforts to financially support me as a research assistant in the group during the final year of my Ph.D. study, which also happened to be my toughest period. I would like to express this gratitude to ALL the past and present Leargroup members for their advice and assistance shown to me over the years with special mentioning – Dr. Santosh Kumar, Mr. Shibaji Ghosh, and Mr. Eugene Yang whom have been very generous with their support and friendship. Not forgetting Dr. Patil Basanagoud, Dr. Bastien Reux, Dr. Oliver Simon, Dr. Miao ii Ru, Dr. Song Hongyan, Dr. Ngai Mun-Hong, and Mr. Sandip Pasari whose friendship to me preserved my sanity in the laboratory with their lively companionship and helpful discussions. I would also like to thank my undergraduate students – Miss Toh Qiaoyan, Mr. Jason Tan, Mr. Benjamin Tan, Mrs. Goh-Huang Xinhui, and Miss Tang Shiqing, as I have truly learned and benefitted from every one of them. I want to express my special thanks to Prof. Tan C. H. for his timely concern and encouragement during my Ph.D. study. My earnest appreciation extends to the past and present CMMAC staff, especially Madam Han Yanhui, Mr. Wong Chee Ping, and Madam Lai Hui Ngee for their expertise and kind assistance in the characterization of the compounds in this thesis. I would also like to thank a group of great support staff – Miss Suriawati Binte Saad, Madam Irene Teo, Madam Lim Nyoon Keow, and Mr. Sim Hang Whatt for their wonderful administrative and technical assistance over the years. I owe a very special and big thank you to my parents whom have made me what I am today with their unrelenting devotion to my education and unconditional support of my personal goals. My mum, in particular, has only little knowledge about my Ph.D. work, but she has always kept her confidence in me, and showed me her greatest support by keeping me healthy and strong throughout my studies. Finally, I would like to thank my wife, Alicia Lock who is also my best friend, from the bottom of my heart for her unwavering patience, confidence, encouragement, and love. Her timely support and sacrifice over the past eight years have been my source of courage and motivation every day. iii TABLE OF CONTENTS TABLE OF CONTENTS iv ABSTRACT ix LIST OF TABLES xi LIST OF FIGURES xiv LIST OF SCHEMES xvii LIST OF SPECTRA xxiii LIST OF ABBREVIATIONS xxv Chapter 1: An Introduction to Platensimycin 1.1 Background of Antibacterial Resistance 1.2 Discovery of Platensimycin 1.3 Unique Mode of Antibacterial Action 1.4 Biosynthesis of Platensimycin 10 1.5 Nicolaou’s Syntheses of Platensimycin 13 1.6 Total & Formal Syntheses of Platensimycin – Key Strategic Steps 19 1.7 Platensimycin Analogues 40 1.8 Conclusion 42 Chapter 2: A Dirhodium(II)-Catalyzed Carbonyl Ylide 44 Cycloaddition Approach to Platensimycin 2.1 First-Generation Retrosynthetic Analysis of (±)-Platensimycin 45 2.2 Carbonyl Ylide Cycloaddition Strategy to the Oxabicyclo[3.2.1] 47 iv Carbon Skeleton 2.3 Radical-Based Cyclization and 1,4-Addition Cascade to the 52 Oxatricyclic Core 2.4 Future Plans for the Assembly of the Oxatricyclic Compact Core 54 2.5 A Second-Generation Carbonyl Ylide Cycloaddition Approach 57 to the Tetracyclic Enone (-)-1-23 2.6 Pursuit of the Quaternary-Substituted Keto-Acid 2-60 via Meyers’ 59 Bicyclic Lactam Auxiliary 2.7 Efforts to Prepare the α-Diazo-Ketone Intermediate 63 2.8 Other Methods to Prepare the α-Diazo-Ketone Intermediate 67 2.9 Summary 71 Appendix – Experimental Details for Chapter 73 Chapter 3: An Oxirane Rearrangement Carbonyl Ylide 103 Cycloaddition Approach to Platensimycin 3.1 Epoxy Ketone 3-7 as Carbonyl Ylide Precursor 104 3.2 Photo-Induced Carbonyl Ylide Cycloaddition to the Compact 106 Core 3.3 Eun Lee’s Formal Synthesis of (-)-Platensimycin via the Carbonyl 108 Ylide Cycloaddition Strategy 3.4 Designing a Photo-Labile Precursor for the Synthesis of the 109 Tetracyclic Enone 1-23 3.5 Efforts toward a Modified Second-Generation Synthesis of the 111 Oxabicyclo[3.2.1] Carbon Skeleton v 3.6 Efforts to Study the Regioselectivity of the Photo-Induced 115 Carbonyl Ylide Cycloaddition 3.7 Exploration of a Lewis Acid-Promoted Carbonyl Ylide 122 Cycloaddition with the α,β-Epoxy-1,1-Diester 3-12 3.8 Summary 127 Appendix – Experimental Details for Chapter 129 Chapter 4: Early Studies on a Friedel-Crafts Cyclization Strategy 150 to Platensimycin 4.1 Third-Generation Retrosynthetic Analysis of (±)-Platensimycin 151 via a Friedel-Crafts Cyclization Approach 4.2 Efforts to Prepare the Friedel-Crafts Precursor 4-3 via a 155 Conjugate Reduction Approach 4.3 Synthesis of the Friedel-Crafts Precursor 4-3 via a Claisen-type 159 [3,3]-Sigmatropic Rearrangement Approach 4.4 Friedel-Crafts Cyclization via Marson-type Oxocarbenium 165 Chemistry 4.5 Towards Tetracyclic Dienone 4-1 via Alkylative 168 Cyclodearomatization under Mitsunobu Activation 4.6 Stereoselective Preparation of the Iodo-Benzotetrahydrofurans 172 4-67/68 4.7 Deprotection Strategies for Iodo-Benzotetrahydrofurans 176 4-67/68 4.8 Application of Aryl Mesylate as Protecting Group in the 183 vi Synthesis of the Tetracyclic Dienone 4-1 4.9 Optimization of Synthetic Sequence 187 4.10 SnCl4-Mediated Friedel-Crafts Cyclization of the Free Lactol 190 of Aryl Allyl Ethers 4-84/85 4.11 Completion of the Tetracyclic Dienone (±)-4-1 193 4.12 Summary 195 Appendix – Experimental Details for Chapter 197 Chapter 5: An Asymmetric Total Synthesis of (-)-Platensimycin 243 5.1 Retrosynthetic Analysis of (-)-Platensimycin 245 5.2 Synthesis of the Tetracyclic Dienone (-)-4-1 via SnCl4-Mediated 246 Stereoselective Friedel-Crafts Cyclization 5.3 Synthesis of the Tetracyclic Dienone (-)-4-1 via Bromohydrin 5-10 249 5.4 Development of a New Catalytic Friedel-Crafts Cyclization with 251 Bromo-Lactol 5-11 5.5 Discovery of a New Bi(OTf)3-LiClO4 Combination for Catalytic 255 Friedel-Crafts Cyclization of Tosyl-Lactol 5-3 5.6 TBAF-Promoted Intramolecular Alkylative Dearomatization to the 257 Tetracyclic Dienone 4-1 5.7 Conjugate Reduction of the Tetracyclic Dienone 4-1 260 5.8 Stereocontrolled Organocatalytic Conjugate Reduction of the 266 Tetracyclic Dienone 4-1 5.9 Synthesis of the 6-Methoxyplatensinoate Esters 272 5.10 Efforts to Deprotect the C6-Methyl Enol Ether 274 vii 5.11 Formal Synthesis of (-)-Platensimycin 280 5.12 A Michael Addition Strategy to (-)-Platensic Acid 1-14 282 5.13 A Concise and High-Yielding Route to the Aromatic Fragment 283 of (-)-Platensimycin 5.14 Completion of the Total Synthesis of (-)-Platensimycin 285 5.15 Future Work – Explorations into C2-Symmetry-Based 287 Organocatalytic 1,4-Reduction of the Tetracyclic Dienone 4-1 5.16 Future Work – Acyl-Transfer Method in a More Convergent 290 Total Synthesis Approach to (-)-Platensimycin 5.17 Conclusion 292 Appendix – Experimental Details for Chapter 295 List of References 346 Appendix – NMR Spectra for Selected Compounds 367 viii O OBn O 3-7 H NMR spectrum (300 MHz, CDCl3) 13 C NMR spectrum of 3-7 (125 MHz, CDCl3) 373 O O O MeO2C CO2Me 3-12 H NMR spectrum (500 MHz, CDCl3) 13 C NMR spectrum of 3-12 (125 MHz, CDCl3) 374 O O H O MeO2 C MeO2C H 3-17 H NMR spectrum (500 MHz, CDCl3) 13 C NMR spectrum of 3-17 (125 MHz, CDCl3) 375 O O O MeO2C CO2Me CO2Me 3-21 H NMR spectrum (500 MHz, CDCl3) 13 C NMR spectrum of 3-21 (125 MHz, CDCl3) 376 O O H O MeO2C MeO2C H CO2 Me 3-22 H NMR spectrum (500 MHz, CDCl3) 13 C NMR spectrum of 3-22 (125 MHz, CDCl3) 377 13 170 160 150 140 130 120 110 100 90 80 70 60 2.5 50 2.0 40 30 21.5978 3.0 25.3071 3.5 31.6252 4.0 34.8462 4.5 41.2956 5.0 55.9796 5.5 77.7251 77.2587 77.0037 76.7486 73.4329 6.0 81.8352 6.5 113.1490 110.8973 7.0 124.9400 7.5 H NMR spectrum (500 MHz, CDCl3) 3.8365 3.8188 3.6852 3.6663 4.6522 4.6421 5.4616 6.5471 6.4575 7.3010 7.2846 7.2606 7.7132 7.6968 1.0962 1.1727 3.2057 1.0820 1.1238 1.1953 5-8 3.1577 OMe 2.9552 2.9477 2.9199 2.9124 2.8720 2.8367 2.4661 2.4346 2.4081 2.3967 2.3867 2.3740 2.3652 1.9378 1.9151 OH 1.0810 1.0961 4.3902 1.0245 0.9661 1.0294 1.0145 OTs 133.2039 132.4314 129.7351 128.0590 146.5252 144.7252 143.4499 8.0 2.0169 2.0000 Integral O (ppm) 1.5 20 1.0 C NMR spectrum of 5-8 (125 MHz, CDCl3) (ppm) 10 378 13 190 180 170 160 150 140 130 120 110 100 90 3.0 80 70 2.5 60 2.0 50 40 22.2446 3.5 44.1213 42.4671 4.0 (ppm) 49.8054 49.7180 4.5 55.8685 54.9212 5.0 86.7524 79.6618 77.2715 77.0165 76.7614 5.5 117.8768 6.0 121.4039 6.5 4.5895 1.1710 2.2542 2.2771 1.0720 3.3507 1.0458 1.0658 1.0000 O 152.2003 7.0 160.6172 181.9765 Integral O OMe 4-1 H NMR spectrum (500 MHz, CDCl3) 1.5 30 1.0 C NMR spectrum of 4-1 (125 MHz, CDCl3) (ppm) 20 10 379 3.6701 2.5695 2.5569 2.5443 2.2379 2.2291 2.2228 2.2139 2.1988 2.1938 2.1862 2.1812 2.1761 2.1711 2.1635 2.1585 1.9984 1.9757 1.9441 1.9378 1.9215 1.9151 1.7626 1.7399 1.6252 1.5256 1.5193 1.5004 4.7266 4.7177 5.5536 6.1550 7.2606 13 200 180 6.0 160 5.6 5.2 140 4.8 4.4 (ppm) 120 4.0 100 3.6 80 51.7166 46.2365 44.2033 42.7459 42.2649 37.9435 37.4625 29.6942 23.1137 6.4 87.0385 79.0151 77.2589 77.0038 76.7487 6.8 128.8972 7.2 155.1244 199.0381 3.2 2.8 60 2.4 40 2.0 3.1674 2.1451 1.5667 3.3078 4.2533 1.0000 0.9369 0.9657 Integral O O 1-23 H NMR spectrum (500 MHz, CDCl3) 1.6 C NMR spectrum of 1-23 (125 MHz, CDCl3) (ppm) 20 380 2.4232 2.4018 2.3942 2.3879 2.3791 2.3551 2.3463 2.3413 2.3299 2.3186 2.3123 2.3085 1.9555 1.9492 1.9340 1.9277 1.8987 1.8761 1.7588 1.6655 1.6441 1.4449 4.1655 4.1592 4.1517 5.9469 5.9268 6.6202 6.6000 7.2606 13 210 200 190 180 170 160 5.0 150 140 4.5 130 120 4.0 110 3.5 100 90 3.0 80 2.5 70 60 2.0 50 40 30 10.9227 5.5 23.0613 6.0 51.7837 48.4999 46.7576 44.3629 42.5489 41.2153 37.1572 6.5 77.6596 77.4230 77.0000 76.5770 7.0 3.0219 3.3645 2.1419 3.6599 1.5087 1.2534 0.1115 2.0368 0.8976 0.1327 1.0000 1.0314 H 128.1497 7.5 154.1332 201.6478 Integral Me O O 2-1 H NMR spectrum (300 MHz, CDCl3) (ppm) 1.5 1.0 C NMR spectrum of 2-1 (75 MHz, CDCl3) (ppm) 20 10 381 2.3960 2.3736 2.3512 2.3298 2.3084 2.0893 2.0474 1.9734 1.9509 1.9285 1.9169 1.8799 1.8409 1.8302 1.7902 1.7795 1.7552 1.7347 1.6305 1.5935 1.4348 1.2458 1.1367 1.1143 4.4667 4.4511 4.3479 5.9344 5.9013 6.5471 6.5139 7.2600 210 13 200 190 180 170 5.5 160 150 5.0 140 4.5 130 4.0 120 110 3.5 100 90 3.0 80 2.5 70 60 2.0 50 40 30.7873 30.3355 28.0982 24.5566 23.0117 6.0 54.9668 46.2001 46.0252 45.9596 44.6843 43.1831 40.5669 6.5 86.9511 80.1811 77.2516 77.0038 76.7487 76.5010 7.0 127.3231 7.5 153.3609 172.5631 203.3085 30 3.0562 9.6491 3.9093 3.3555 0.4206 0.7902 1.2784 1.2744 2.4443 2.4337 2.0076 1.0727 1.1798 0.9809 0.0532 1.0316 1.0000 0.0981 Integral O t BuO O O 5-56 H NMR spectrum (500 MHz, CDCl3) (ppm) 1.5 C NMR spectrum of 5-56 (125 MHz, CDCl3) (ppm) 20 382 2.4094 2.3955 2.3829 2.3438 2.2429 2.2379 2.2240 2.2127 2.1433 2.1383 2.1156 2.1017 2.0929 2.0727 2.0627 2.0286 2.0097 1.9971 1.9870 1.8546 1.8483 1.8332 1.8256 1.7714 1.7576 1.7336 1.6857 1.6693 1.6441 1.6378 1.6101 1.6000 1.5886 1.4361 1.4298 1.4172 1.2167 4.4416 4.3937 5.8915 5.8789 5.8713 5.8587 6.5092 6.4891 6.4576 6.4374 7.2606 200 13 190 180 7.0 170 6.5 160 150 6.0 140 5.5 130 5.0 120 4.5 110 100 4.0 90 3.5 80 70 30.0657 7.5 79.5178 77.2588 77.0037 76.7486 71.4070 8.0 109.3305 153.6231 150.9559 135.0403 134.7488 132.5335 128.8825 128.8533 128.7149 128.6202 128.5910 127.0752 126.9295 196.8372 H NMR spectrum (500 MHz, CDCl3) 7.7662 7.7473 7.3943 7.3892 7.3829 7.3779 7.3703 7.3640 7.3464 7.2606 6.8976 6.8786 3.0701 3.0 60 50 1.5495 2.5430 5.0329 5-58 5.2523 BnO 2.0846 OBn O 2.1139 1.0287 9.9237 1.0000 Integral O2N (ppm) 2.5 2.0 40 1.5 C NMR spectrum of 5-58 (125 MHz, CDCl3) (ppm) 30 20 383 200 180 160 6.0 140 5.5 5.0 4.5 (ppm) 120 100 4.0 3.5 13 80 52.2484 6.5 78.6724 77.2587 77.0036 76.7485 71.2247 7.0 108.9369 7.5 117.7546 164.2116 153.6813 151.9032 138.2248 135.7835 134.6540 134.2313 128.7002 128.4306 128.4160 126.9804 8.0 3.1454 2.1147 2.1281 1.0490 10.277 1.0000 Integral O2N OBn O 60 OMe BnO 5-59 H NMR spectrum (500 MHz, CDCl3) 3.0 2.5 40 2.0 1.5 C NMR spectrum of 5-59 (125 MHz, CDCl3) (ppm) 20 384 3.8756 5.2132 5.1476 7.9868 7.4813 7.4674 7.4132 7.3993 7.3854 7.3741 7.3577 7.3413 7.3338 7.3287 7.2606 6.8774 6.8597 3.3025 3.3000 3.2962 3.8711 4.8179 6.3560 6.3384 7.1982 7.1805 OH O H2N OMe HO 1-151 8.0 7.8 7.6 7.4 7.2 7.0 6.8 6.6 6.4 3.4983 1.0138 1.0000 Integral H NMR spectrum (500 MHz, CD3OD) 6.2 6.0 5.8 5.6 5.4 5.2 5.0 4.8 4.6 4.4 4.2 4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 (ppm) 385 210 13 200 190 180 9.5 170 9.0 8.5 160 8.0 150 7.5 140 130 6.0 120 110 (ppm) C NMR spectrum of 5-62 (125 MHz, CDCl3) 5.5 5.0 100 90 80 4.0 70 3.5 60 3.0 50 46.6882 46.2145 46.0979 44.6550 43.1393 40.5814 32.1353 31.6471 29.6868 24.2140 22.9897 4.5 2.5 40 2.0 30 3.5504 3.0293 2.1270 1.9587 2.5491 4.5900 3.3493 1.3732 1.1373 0.6344 3.4497 0.9960 1.0000 6.5 54.8938 52.1829 5-62 H NMR spectrum (500 MHz, CDCl3) 11.0655 11.6391 7.2606 6.5155 6.4979 6.4941 5.9381 5.9180 4.4429 3.9197 2.8027 2.5568 2.5468 2.5329 2.5279 2.5228 2.5178 2.5052 2.4926 2.4421 2.4295 2.4156 2.4081 2.3854 2.3703 2.3564 2.3488 2.3236 2.1131 2.1017 2.0752 2.0689 2.0513 2.0450 2.0261 2.0021 1.9265 1.9151 1.9025 1.8975 1.8912 1.8685 1.8622 1.8055 1.7916 1.7815 1.7676 1.6441 1.6214 1.4512 1.2734 7.5657 7.5481 O 1.1334 O 8.1041 2.1234 7.0 87.0457 77.2587 77.0037 76.7486 76.4207 10.0 104.0617 10.5 114.3879 111.2616 11.0 127.3740 127.1481 OH N H 1.0076 0.9293 MeO 2C 154.8547 153.8709 153.8345 11.5 173.6270 170.6756 203.6436 0.9932 OH O 1.5 (ppm) 20 386 11.0 10.5 10.0 9.5 9.0 8.5 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 3.3603 3.3355 1.1248 1.1560 1.1338 2.1853 1.1718 1.3932 1.1306 OH 1.1189 HO2C 3.4696 1.0797 1.8728 2.6170 1.5278 1.0950 1.0000 Integral OH O N H O O (-)-1-4 H NMR spectrum of synthetic platensimycin (500 MHz, C5D5N) (ppm) 1.0 H NMR spectrum of natural platensimycin[17] (500 MHz, C5D5N) C5D5N 387 4.4749 2.8574 2.8284 2.8044 2.7944 2.7717 2.7616 2.7402 2.7086 2.6809 2.6721 2.6569 2.6481 2.4313 2.1943 2.1817 2.1690 2.0606 2.0518 2.0341 2.0127 1.9976 1.8942 1.8841 1.8060 1.7820 1.7253 1.7051 1.5702 1.5563 1.5336 1.4756 1.4542 1.3836 1.1302 5.9374 5.9184 6.3610 6.3408 6.8741 6.8564 7.2031 7.5700 8.1146 8.0970 8.7248 10.5188 OH O HO2C OH 13 210 200 13 190 180 170 160 150 140 130 120 110 100 90 80 N H 70 O O (-)-1-4 C NMR spectrum of synthetic platensimycin (125 MHz, C5D5N) (ppm) 60 50 40 30 20 C NMR spectrum of natural platensimycin[17] (125 MHz, C5D5N) 388 46.7023 46.5857 46.1266 45.0262 43.0368 40.7631 32.1276 31.7559 30.4879 24.4176 23.2151 54.9443 76.4493 86.7828 109.9712 107.1146 115.2910 135.7029 135.5062 135.3094 129.3702 127.2277 123.7006 123.5039 123.2998 158.2500 153.9213 150.1100 149.8914 149.6801 174.7340 203.1912 [...]... Synthesis of the alkyl 6-methoxyplatensinoates 5-35 and 273 5-37 Scheme 5.6 Synthesis of the tetracyclic enone (-)-1-23 281 Scheme 5.7 Synthesis of the (-)-platensic acid 1-14 283 Scheme 5.8 A high-yielding synthesis of the aromatic unit (1-151) of 284 platensimycin Scheme 5.9 Preparation of the C6-methoxy analog (5-60) of (-)- 286 platensimycin Scheme 5.10 Completion of the total synthesis of (-) -platensimycin. .. iodo-benzotetrahydrofuran 4-102 xxi Chapter 5 Scheme 5.1 Retrosynthetic analysis of the tetracyclic dienone 4-1 of 245 (-) -platensimycin via a stereoselective Friedel-Crafts cyclization approach Scheme 5.2 Synthesis of (-)-dienone 4-1 via the tosyl lactol 5-3 246 Scheme 5.3 Synthesis of (-)-dienone 4-1 via the bromo lactol 5-11 250 Scheme 5.4 Synthesis of the TFA salts of amino acid tert-butyl 267 esters Scheme 5.5 Synthesis. .. Scheme 1.5 Nicolaou’s formal synthesis of (-) -platensimycin via an 19 enantioselective enyne cycloisomerization for terminal alkynes Scheme 1.6 A Synthesis of aniline 1-114 from Giannis’ methyl 38 ester B Giannis’ concise synthesis of the aromatic sub-unit (1-151) of platensimycin Chapter 2 Scheme 2.1 Retrosynthetic analysis of (±) -platensimycin (1-4) 46 Scheme 2.2 Synthesis of a key oxabicyclo[3.2.1]octane... platensic acid 1-14 via the enol forms of alkyl 274 6-methoxyplatensinoate esters xvi LIST OF SCHEMES Chapter 1 Scheme 1.1 Nicolaou’s racemic synthesis of platensic acid 1-14 14 Scheme 1.2 Nicolaou’s completion of (±) -platensimycin 15 Scheme 1.3 Nicolaou’s formal synthesis of (-) -platensimycin via an 17 enantionselective enyne cycloisomerization Scheme 1.4 Nicolaou’s formal synthesis of (-) -platensimycin via... precursors Scheme 4.16 Synthesis of the iodo-phenols 4-88/89 via aryl mesylate 183 protection Scheme 4.17 Improved synthesis to the Ms-protected cis-/trans- 186 iodolactones 4-78/79 Scheme 4.18 Cross-metathesis to prepare the α,β-unsaturated Me 188 ester 4-96 Scheme 4.19 Improved synthesis to the deBn-iodolactones 4-72/73 189 from the Bn-protected eugenol 4-94 Scheme 4.20 Synthesis towards the tetracyclic... studies of platensimycin and 9 ecFabF(C163Q) B Interactions between the benzoic acid and the four critical amino acid residues Figure 1.6 Biosynthesis of platensimycin (1-4) 11 Figure 1.7 Some synthetic analogs of (-) -platensimycin 42 Chapter 2 Figure 2.1 Some totally synthetic natural products prepared via the 47 carbonyl ylide cycloaddition approach Figure 2.2 Possible fragmentation pathways for the. .. acid with the anilide unit was achieved by treatment with HATU, and a final hydrolysis subsequently completed the total synthesis of platensimycin The exploration of C2-symmetrical amine-based organocatalysts to further improve the desired chemo- and stereoselectivity of the conjugate reduction step is currently ongoing in our laboratory x LIST OF TABLES Chapter 1 Table 1.1 Classification of commercially... available antibiotics Table 1.2 Radical-based approaches to the tetracyclic enone 1-23 4 20 of platensimycin Table 1.3 Enantioselective approaches to the tetracyclic enone 26 1-23 of platensimycin Table 1.4 Total and formal syntheses of (±)/(-) -platensimycin 32 Chapter 2 Table 2.1 Selective reduction of the carboxylic acid in 2-17 50 Chapter 3 Table 3.1 Screening of conditions to promote the carbonyl... in the 1940s and 1950s, and newer versions are simply variations of their predecessors based on similar modes of actions.[7,8] Most antibiotics used today generally work on specific bacterial biochemical processes, such as blocking the synthesis of the cell wall, deformation of the cell membrane, and inhibition of their DNA replication or protein production (Table 1.1) 3 Table 1.1 Classification of. .. Antibacterial Resistance The discovery of penicillin (1-1, Figure 1.1) by Alexander Fleming in 1928 represents a milestone in the modern era of antibiotics discovery.[1] Penicillins continue to help millions around the world to fight off deadly infections, and inspired the development of various types of antibiotics against different pathogens However, the effectiveness of available antibiotics has diminished . TOTAL SYNTHESIS OF THE POTENT ANTIBIOTIC PLATENSIMYCIN EEY TZE CHIANG STANLEY NATIONAL UNIVERSITY OF SINGAPORE 2011 TOTAL SYNTHESIS OF THE POTENT ANTIBIOTIC. Retrosynthetic Analysis of (-) -Platensimycin 245 5.2 Synthesis of the Tetracyclic Dienone (-)- 4 - 1 via SnCl 4 -Mediated Stereoselective Friedel-Crafts Cyclization 246 5.3 Synthesis of the. vii Synthesis of the Tetracyclic Dienone 4 - 1 4.9 Optimization of Synthetic Sequence 187 4.10 SnCl 4 -Mediated Friedel-Crafts Cyclization of the Free Lactol of Aryl Allyl Ethers 4-84/85