河北医科大学药学院2018 Total Synthesis of Strychnine 一别删 Woodward total synthesis of strychnine(1954) Structure and Synthesis of Penicillin 没有结构一切无从谈起 Sir Alexander Fleming.the so rdly changed However.during World War I.the United States government undertook a massive effort to determine the chemical structure of penicillin and to chemically synthesize it in large quantities. treat soldiers on the battlefield.More than a thousand chemists working at thirty-nine laboratories were involved in the project. Despite the huge investment by the government,none proved to be successful in solving this elusive problem. 天然药物化学教研室史清文教授 1
河北医科大学药学院2018 天然药物化学教研室史清文教授 1 81 Total Synthesis of Strychnine Woodward total synthesis of strychnine (1954) Heinrich O. Wieland (1877-1957) 1927 NP 82 Structure and Synthesis of Penicillin • For three decades after the discovery of natural penicillin by Sir Alexander Fleming, the source of the antibiotic hardly changed. Scientists made the drug by natural fermentation of Penicillium mold. However, during World War II, the United States government undertook a massive effort to determine the chemical structure of penicillin and to chemically synthesize it in large quantities. • The scale of this project was compared to the development of the atomic bomb. This stemmed from the dire need for the antibiotic to treat soldiers on the battlefield. More than a thousand chemists working at thirty-nine laboratories were involved in the project. Despite the huge investment by the government, none proved to be successful in solving this elusive problem. 没有结构一切无从谈起
河北医科大学药学院2018 A well-known dispute about the Structure of Penicillin Structure of Penicillin Cn告诉罗氏 天然药物化学教研室史清文教授 2
河北医科大学药学院2018 天然药物化学教研室史清文教授 2 83 C C O NH N S H H H COOH H H O This incident is significant because Robinson refused to give much credence to spectroscopic data, while Woodward was a pioneer in using it for organic structure determination. It displays the generational gap between two of the greatest synthetic organic chemists of the twentieth century. A well-known dispute about the Structure of Penicillin 84 C C O NH N S H H H COOH H H O Penicillin G was proposed by Woodward in 1944 to contain a novel blactam in its structure based on degradation products, reaction profiles, and UV studies. 二战时期，英、美两国合作青霉素计划，化学组由R. Robinson 领导。 但他的结构与伍德沃德的不同。伍德沃德的内酰胺(b-lactam)结构由钱恩 (E. Chain)告诉罗氏，而后者老羞成怒，将桌上墨水瓶向钱恩掷去，幸未 击中。青霉素的分子式，经X光晶体衍射求正，正如伍德沃德所想的一样。 Structure of Penicillin
河北医科大学药学院2018 Structure of Penicillin CO.H Abraham's Woodward 944.27岁 1944.58 Scheme 1.The notional reconstruction of penicillin from its degradation products. Edward Penley Abraham proposed b-lactam but opposed by Robinson Azadirachtin印楝素 The First Complete Structure Ley's Modification198 9能 CO:Me "H A品，co Correct Structure oughton.H.B.Ley.S.V.J. hem.Soc.Chem.Commun.1986.46. X-ray 1986 by Ley 天然药物化学教研室史清文教授 3
河北医科大学药学院2018 天然药物化学教研室史清文教授 3 85 Structure of Penicillin • Scheme 1. The notional reconstruction of penicillin from its degradation products. • R = pent-2-enyl for the penicillin grown by fermentation in Oxford; R = benzyl for that grown in America. The difference was slightly confusing until clarified in 1943, but it did not affect the structural debates. Edward Penley Abraham proposed b-lactam but opposed by Robinson 1944, 27岁 1944, 58岁 CHO H R N O + CO2 + H2N CO2H Me HS Me H R N O S HN CO2H Me Me CO2H N H N O S Me Me CO2H R O OR R N HN S R O Me Me CO2H Abraham' s correct structure Robinson' s incorrect structure Woodward 86 The First Complete Structure MeO2C O AcO H O O H CO2Me OH O O OH O OH O Ley’s Modification 1985 MeO2C O O O O OH O AcO H O O H OH CO2Me OH Correct Structure Azadirachtin印楝素 Broughton, H. B.; Ley, S. V. J. Chem. Soc. Chem. Commun. 1986, 46. Nakanishi’s Azadirachtin 1975 X-ray 1986 by Ley
河北医科大学药学院2018 Azadirachtin sees first total synthesis 10 August 2007 "OH 印 A complex natural product has finally succumbed to its first total ynthesis after 22 of attempts by eminent organic chemists. 87 Me Me HO Heinrich O.Wieland Structure for Ergsterol 1932 朱子浦 Me Et、 MeH○ M Me OH Structure for Cholesterol 1932 Bemal,J.D.Nature,1932.19,7 天然药物化学教研室史清文教授 4
河北医科大学药学院2018 天然药物化学教研室史清文教授 4 87 Azadirachtin sees first total synthesis 10 August 2007 A complex natural product has finally succumbed to its first total synthesis after 22 years of attempts by eminent organic chemists. 印楝素 88 Me Me Me Me OH Et Me Me Me Me Me HO H H Me Me Me Me Me HO H H H Structure for Cholesterol Wieland/Windaus 1927 NP Structure for Ergsterol 1932 Structure for Cholesterol 1932 Heinrich O. Wieland 汪猷 Bernal, J. D. Nature, 1932, 129, 721. 朱子清
河北医科大学药学院2018 0a -eo Heinrich Otto Wieland 了yTt 7.mt乡 89 朱子 H.O.Wieland 27 NP Fritz Pregl 23NP 1929年 美国伊利诺大学研究院求学 士学位 (A 1)学习微量分析 0年生 清学成回国。1955年首先确定了该类植物碱的基本骨架为变型体 天然药物化学教研室史清文教授 5
河北医科大学药学院2018 天然药物化学教研室史清文教授 5 89 Heinrich Otto Wieland 90 朱 子 清 １９２９年在美国伊利诺大学研究院求学。１９３３年他获哲学博士学位。 同年由伊利诺大学研究院化学系主任亚当斯（Ｒ・Ａｄａｍｓ）推荐，赴 德国明兴大学从名师维兰德（Ｈ・Ｗｉｅｌａｎｄ）继续进行有机化学研 究。１９３４年转赴奥地利格拉兹大学，跟随微量化学的首创人、诺贝尔 奖金获得者普雷格尔（Ｆ・Ｐｒｅｇｌ）学习微量分析。１９３５年朱子 清学成回国。１９５５年首先确定了该类植物碱的基本骨架为变型甾体。 H. O. Wieland 27 NP Fritz Pregl 23NP
河北医科大学药学院2018 波谱学 What we will learn? How to use them? An Historical Glance Before 60's Chemistry 广Degradation gram quantities Derivatization CUV,IR Between 60-80's Spectra MS H-NMR mg 13C-NMR NOE,DEPT H-H COSY After 80's 2D NMR HMQC (HSQC) mg-ug HMBC NOESY (ROESY) INADEQUATE 92 天然药物化学教研室史清文教授 6
河北医科大学药学院2018 天然药物化学教研室史清文教授 6 波 谱 学 What we will learn? How to use them? 91 An Historical Glance Before 60’s Between 60-80’s After 80’s 2D NMR Chemistry Degradation Derivatization UV, IR MS 1H-NMR 13C-NMR NOE, DEPT Spectra gram quantities 1H-1H COSY HMQC (HSQC) HMBC NOESY (ROESY) INADEQUATE mg mg-µg 92
河北医科大学药学院2018 Strategy of Structure Elucidation 化合物类型和共轭体系 官能田 HR-MS 分子式：双健，环数，杂原子 CH-NMR H的个教和相互关系 ID NMR 3C-NMR◆ NOE ,SP2,Spo L DEPT H的空 ]关 C的种类C,CH,CH,CH H-H COSY H-C-C-H HMQC H-C 2D NMR HMBC H-C-C,H-C-C-C,H-C-C=C-C NOESY(ROESY)H-H conformation INADEQUATE C-C What Differences Between Them CgHaoO 天然药物化学教研室史清文教授 7
河北医科大学药学院2018 天然药物化学教研室史清文教授 7 Strategy of Structure Elucidation 1H-NMR 13C-NMR NOE DEPT 1H-1H COSY H-C-C-H HMQC H-C HMBC H-C-C, H-C-C-C, H-C-C=C-C NOESY (ROESY) H-H conformation INADEQUATE C-C 1D NMR 2D NMR UV IR HR-MS 化合物类型和共轭体系 官能团 分子式:双键,环数,杂原子 H的个数和相互关系 C的个数和SP, SP2, SP3 H的空间关系 C的种类C, CH, CH2, CH3 93 94 What Differences Between Them O OH C8H10O 1 2
河北医科大学药学院2018 What Differences Between Them 95 What Differences Between Them CgH10O2 COOH 天然药物化学教研室史清文教授 8
河北医科大学药学院2018 天然药物化学教研室史清文教授 8 95 What Differences Between Them CHO O C8H8O 1 2 96 What Differences Between Them O O 1 2 COOH O O 3 O 4 O C9H10O2
河北医科大学药学院2018 Structure Elucidation OH HaCo C10HgO4 3 Difference of IR,'H-NMR,13C-NMR 1.How to Distinguish the Structures of A and B? OH 天然药物化学教研室史清文教授 9
河北医科大学药学院2018 天然药物化学教研室史清文教授 9 97 Structure Elucidation OH O O O O O H3CO OH 1 2 Difference of IR, 1H-NMR, 13C-NMR C10H8O4 98 1. How to Distinguish the Structures of A and B? O O OH O OH A B
河北医科大学药学院2018 2.How to Distinguish the Structures of 1 and 2? 》OH OH OH OH O H-NMR? 3.How to Distinguish the Structures of 1 and 2? HO. HO. 100 天然药物化学教研室史清文教授 10
河北医科大学药学院2018 天然药物化学教研室史清文教授 10 99 2. How to Distinguish the Structures of 1 and 2? O O OH OH HO OH O O OH OH HO 1 2 OH 1H-NMR? 100 3. How to Distinguish the Structures of 1 and 2? O O OH OH HO OCH3 O O OCH3 OH HO OH 1 2