药用天然产物全合成四川大学博士考试.ppt

1、,课程主要内容： 课程讲授药用天然产物全合成，着重强调天然产物骨架的有效构建方法，如何从小分子片断或从结构相关的、资源丰富的天然产物合成结构复杂的天然药物。授课内容包括如下四个部分：1) 药用吲哚生物碱的合成；2)头孢类抗生素合成及新药研发的一般程序；3) 药用大环多肽的合成；4) 异戊二烯类天然产物的生物合成。,Syntheses of Natural Medicines秦勇教授, 王光明教授，邓金根教授，张国林教授,Syntheses of Natural Medicines秦勇教授, 王光明教授，邓金根教授，张国林教授,课程进度安排: 第一周：药用吲哚生物碱慨述。第二周至第三周：长春花碱

2、的合成。第四周：马钱子碱和利血平的合成。第五周至第八周：头孢类抗生素合成及新药研发的一般程序。第十周：天然环肽的分离、纯化和结构鉴定。第十一周：环肽的合成方法学。第十二周至第十三周：药用天然环肽的合成。第十四周：C5单元的合成及组合。第十五周：单萜、倍半萜和二萜的合成。第十六周至第十七周：二倍半萜、三萜和类胡萝卜素的合成。,Syntheses of Natural Medicines General Introduction of Indole Alkaloids,Structurally most diverse natural product, over 5000 has been ide

3、ntifiedMost from plant kingdom, also from fungi，insects and mammals Long historic usage: Traditional Chinese medicines; Poisons for hunting, murder; euphoriants, psychedelics and stimulants in religious activities; drug abuse-serious social problemHuman interest-Pharmacological activities, lead comp

4、ounds to synthetic analogue-drugs,Isolated in 1958 from Cathrathus roseus:1) Nobel, R. L. et al. Ann. N.Y. Acad. Sci. 1958, 76, 882;2) Svoboda, G.H. et al. J. Am. Pharm. Assoc. Sci. Ed. 1959, 48, 659.,Strong toxicity and side effectsCombined usage with other anticancer reagents: methotrexate, daunom

5、ycin, cyclophosphamide,In the middle of 1960s was used in clinic for treatment of nonmalignant disease and malignant disease: Hodgkins lymphoma, testicular cancer, bladder cancer; melanoma, lung cancer, breast cancer,L1210 RCC-2 Colon Microtuble Leukemia Adenocarcinoma AssemblyIC50 (nM) 0.4 3 300,Sa

6、fe Drug-SAR on Vinblastine Leading to Navalbine,Syntheses of Natural MedicinesStructural Summaries of Medicinal Indole Alkaloids,Anticancer agents,Syntheses of Natural MedicinesStructural Summaries of Medicinal Indole Alkaloids,Antileukemia,0.05%,Syntheses of Natural MedicinesStructural Summaries of

7、 Medicinal Indole Alkaloids,Blood pressure lowing agents,Syntheses of Natural MedicinesStructural Summaries of Medicinal Indole Alkaloids,Syntheses of Natural MedicinesStructural Summaries of Medicinal Indole Alkaloids,Antiaddictive,Syntheses of Natural MedicinesStructural Summaries of Medicinal Ind

8、ole Alkaloids,Synthetic Challenge Molecules,Synthesis of Vinblastine,P. Potier et al. J. Am. Chem. Soc. 1979, 101, 2243；M. E. Kuehne et al. J. Org. Chem. 1991, 66, 1560；P. Magnus et al. J. Am. Soc. Chem. 1992, 114, 10232；T. Fukuyama et al. J. Am. Soc. Chem. 2002, 124, 2137,Synthesis of VinblastineP.

9、 Potier et al. J. Am. Chem. Soc. 1979, 101, 2243,Synthesis of VinblastineP. Potier et al. J. Am. Chem. Soc. 1979, 101, 2243,Synthesis of VinblastineP. Potier et al. J. Am. Chem. Soc. 1979, 101, 2243,Synthesis of VinblastineP. Potier et al. J. Am. Chem. Soc. 1979, 101, 2243,Synthesis of VinblastineCa

10、tharanthine Synthesis,B. M. Trost et al. J. Org. Chem. 1979, 44, 2054;M. Honaoka et al. Tetrahydron Lett. 1980, 21, 3285;G. Buchi et al. J. Am. Chem. Soc. 1970, 92, 999.,Catharanthine Synthesis B. M. Trost et al. J. Org. Chem. 1979, 44, 2054,Catharanthine Synthesis B. M. Trost et al. J. Org. Chem. 1

11、979, 44, 2054,Catharanthine Synthesis B. M. Trost et al. J. Org. Chem. 1979, 44, 2054,Racemic,Synthesis of VinblastineM. E. Kuehne et al. J. Org. Chem. 1991, 66, 1560,Synthesis of VinblastineM. E. Kuehne et al. J. Org. Chem. 1991, 66, 1560,Synthesis of VinblastineM. E. Kuehne et al. J. Org. Chem. 19

12、91, 56, 513,Synthesis of VinblastineM. E. Kuehne et al. J. Org. Chem. 1996, 61, 1175,3 ：1,Synthesis of VinblastineM. E. Kuehne et al. J. Org. Chem. 1991, 56, 513,Martin E. Kuehne et al. J. Org. Chem. 2001, 66, 1560,Synthesis of VinblastineM. E. Kuehne et al. J. Org. Chem. 1991, 56, 513,Synthesis of

13、VinblastineM. E. Kuehne et al. J. Org. Chem. 1991, 56, 513,Synthesis of VinblastineM. E. Kuehne et al. J. Org. Chem. 1991, 56, 513,Synthesis of VinblastineM. E. Kuehne et al. J. Org. Chem. 1991, 56, 513,Synthesis of VinblastineP. Magnus et al. J. Am. Soc. Chem. 1992, 114, 10232,Synthesis of Vinblast

14、ineP. Magnus et al. J. Am. Soc. Chem. 1992, 114, 10232,Synthesis of Vinblastine P. Magnus et al. J. Am. Soc. Chem. 1992, 114, 10232,Synthesis of Vinblastine P. Magnus et al. J. Am. Soc. Chem. 1992, 114, 10232,Synthesis of Vinblastine P. Magnus et al. J. Am. Soc. Chem. 1992, 114, 10232,Synthesis of V

15、inblastine P. Magnus et al. J. Am. Soc. Chem. 1992, 114, 10232,Synthesis of VinblastineT. Fukuyama et al. J. Am. Soc. Chem. 2002, 124, 2137,Synthesis of VinblastineT. Fukuyama et al. J. Am. Soc. Chem. 2002, 124, 2137,Synthesis of VinblastineT. Fukuyama et al. J. Am. Soc. Chem. 2002, 124, 2137,Synthe

16、sis of VinblastineT. Fukuyama et al. J. Am. Soc. Chem. 2002, 124, 2137,Synthesis of VinblastineT. Fukuyama et al. J. Am. Soc. Chem. 2002, 124, 2137,Synthesis of VinblastineT. Fukuyama et al. J. Am. Soc. Chem. 2002, 124, 2137,Synthesis of VinblastineT. Fukuyama et al. J. Am. Soc. Chem. 2002, 124, 213

17、7,Synthesis of VinblastineT. Fukuyama et al. J. Am. Soc. Chem. 2002, 124, 2137,Synthesis of VinblastineT. Fukuyama et al. J. Am. Soc. Chem. 2002, 124, 2137,Mitsunobu Reaction,Synthesis of VinblastineT. Fukuyama et al. J. Am. Soc. Chem. 2002, 124, 2137,Synthesis of VinblastineT. Fukuyama et al. J. Am

18、. Soc. Chem. 2002, 124, 2137,Synthesis of Vindole,Albert Padwa et al. Organic Lett. 2004, Aug. ASAPD. Boger et al. J. Am. Chem. Soc. 2002, 124, 11292;T. Fukuyama et al. J. Am. Soc. Chem. 2002, 124, 2137;M. E. Kuehne et al. J. Org. Chem. 1987, 52, 347;H. Repoport et al. J. Am. Chem. Soc.1987, 109, 16

19、03;G. Buchi et al. J. Am. Chem. Soc. 1975, 97, 6880,Synthesis of VindoleAlbert Padwa et al. Organic Lett. 2004, Aug. ASAP,Synthesis of Vindole D. Boger et al. J. Am. Chem. Soc. 2002, 124, 11292,Synthesis of Vindole M. E. Kuehne et al. J. Org. Chem. 1987, 52, 347,Woodward Synthesis of Reserpine Woodw

20、ard, R. B. J. Am. Chem. Soc. 1956, 78, 2023 Woodward, R. B. J. Am. Chem. Soc. 1956, 78, 2657,Retrosynthetic Analysis,Woodward Synthesis of Reserpine Woodward, R. B. et al. J. Am. Chem. Soc. 1956, 78, 2023; 1956, 78, 2657,Diels-Alder Reaction Rule: Electron-deficient diene +electron rich dienophile;E

21、lectron-deficient dienophile +electron rich diene.,Diels-Alder Reaction Rule,Woodward Synthesis of Reserpine Woodward, R. B. et al. J. Am. Chem. Soc. 1956, 78, 2023; 1956, 78, 2657,Woodward Synthesis of ReserpineWoodward, R. B. et al. J. Am. Chem. Soc. 1956, 78, 2023; 1956, 78, 2657,Woodward Synthes

22、is of ReserpineWoodward, R. B. et al. J. Am. Chem. Soc. 1956, 78, 2023; 1956, 78, 2657,Woodward Synthesis of ReserpineWoodward, R. B. et al. J. Am. Chem. Soc. 1956, 78, 2023; 1956, 78, 2657,Woodward Synthesis of ReserpineWoodward, R. B. et al. J. Am. Chem. Soc. 1956, 78, 2023; 1956, 78, 2657,Woodwar

23、d Synthesis of ReserpineWoodward, R. B. et al. J. Am. Chem. Soc. 1956, 78, 2023; 1956, 78, 2657,Activation of Carbonic Acid,Woodward Synthesis of ReserpineWoodward, R. B. et al. J. Am. Chem. Soc. 1956, 78, 2023; 1956, 78, 2657,Woodward Synthesis of ReserpineWoodward, R. B. et al. J. Am. Chem. Soc. 1

24、956, 78, 2023; 1956, 78, 2657,Synthesis of Reserpine,Sparks, S. M.; Gutierrez, A. J.; Shea, K. J. J. Org. Chem. 2003; 68 (13), 5274-5285;Sparks, S. M.; Shea, K. J.; Org. Lett.2001; 3(15), 2265-2267,Woodward Synthesis of Strychnine Woodward, R. B. et al. J. Am. Chem. Soc. 1954, 76, 4749,Woodward Synt

25、hesis of Strychnine Woodward, R. B. et al. J. Am. Chem. Soc. 1954, 76, 4749,Woodward Synthesis of Strychnine Woodward, R. B. et al. J. Am. Chem. Soc. 1954, 76, 4749,Woodward Synthesis of Strychnine Woodward, R. B. et al. J. Am. Chem. Soc. 1954, 76, 4749,Woodward Synthesis of Strychnine Woodward, R.

26、B. et al. J. Am. Chem. Soc. 1954, 76, 4749,Woodward Synthesis of Strychnine Woodward, R. B. et al. J. Am. Chem. Soc. 1954, 76, 4749,Woodward Synthesis of Strychnine Woodward, R. B. et al. J. Am. Chem. Soc. 1954, 76, 4749,Woodward Synthesis of Strychnine Woodward, R. B. et al. J. Am. Chem. Soc. 1954,

27、 76, 4749,Woodward Synthesis of Strychnine Woodward, R. B. et al. J. Am. Chem. Soc. 1954, 76, 4749,Woodward Synthesis of Strychnine Woodward, R. B. et al. J. Am. Chem. Soc. 1954, 76, 4749,Woodward Synthesis of Strychnine Woodward, R. B. et al. J. Am. Chem. Soc. 1954, 76, 4749,Woodward Synthesis of S

28、trychnine Woodward, R. B. et al. J. Am. Chem. Soc. 1954, 76, 4749,Woodward Synthesis of Strychnine Woodward, R. B. et al. J. Am. Chem. Soc. 1954, 76, 4749,28-Step, overall yield 0.006%,Magnus Synthesis of Strychnine Magnus, P. et al. J. Am. Chem. Soc. 1992, 114, 4403,Magnus Synthesis of Strychnine M

29、agnus, P. et al. J. Am. Chem. Soc. 1992, 114, 4403,Magnus Synthesis of Strychnine Magnus, P. et al. J. Am. Chem. Soc. 1992, 114, 4403,Magnus Synthesis of Strychnine Magnus, P. et al. J. Am. Chem. Soc. 1992, 114, 4403,Magnus Synthesis of Strychnine Magnus, P. et al. J. Am. Chem. Soc. 1992, 114, 4403,

30、Magnus Synthesis of Strychnine Magnus, P. et al. J. Am. Chem. Soc. 1992, 114, 4403,Magnus Synthesis of Strychnine Magnus, P. et al. J. Am. Chem. Soc. 1992, 114, 4403,Magnus Synthesis of Strychnine Magnus, P. et al. J. Am. Chem. Soc. 1992, 114, 4403,Magnus Synthesis of Strychnine Magnus, P. et al. J.

31、 Am. Chem. Soc. 1992, 114, 4403,Second Total Synthesis (Racemic),27-Step, overall yield 0.03%,Rawal Synthesis of Strychnine Rawal, V. H. et al. J. Org. Chem. 1994, 59, 2685,Reto-synthetic analysis,Rawal Synthesis of Strychnine Rawal, V. H. et al. J. Org. Chem. 1994, 59, 2685,Rawal Synthesis of Stryc

32、hnine Rawal, V. H. et al. J. Org. Chem. 1994, 59, 2685,Rawal Synthesis of Strychnine Rawal, V. H. et al. J. Org. Chem. 1994, 59, 2685,Rawal Synthesis of Strychnine Rawal, V. H. et al. J. Org. Chem. 1994, 59, 2685,Woodward Procedure,Fourth synthesis of racemic strychnine15-Step, overall yield 10%,Thi

33、rd synthesis of racemic strychnine17-Step, overall yield 2%. See Kuehne et al. J. Org. Chem. 1993, 58, 7482,Overman Synthesis of (-)-StrychnineOverman, L. E. et al. J. Am. Chem. Soc. 1995, 117, 5775;Overman, L. E. et al. J. Am. Chem. Soc. 1993, 115, 9293.,Retro-analysis,Overman Synthesis of (-)-Stry

34、chnineOverman, L. E. et al. J. Am. Chem. Soc. 1995, 117, 5775;Overman, L. E. et al. J. Am. Chem. Soc. 1993, 115, 9293.,(+),Overman Synthesis of (-)-StrychnineOverman, L. E. et al. J. Am. Chem. Soc. 1995, 117, 5775;Overman, L. E. et al. J. Am. Chem. Soc. 1993, 115, 9293.,Overman Synthesis of (-)-Stry

35、chnineOverman, L. E. et al. J. Am. Chem. Soc. 1995, 117, 5775;Overman, L. E. et al. J. Am. Chem. Soc. 1993, 115, 9293.,Overman Synthesis of (-)-StrychnineOverman, L. E. et al. J. Am. Chem. Soc. 1995, 117, 5775;Overman, L. E. et al. J. Am. Chem. Soc. 1993, 115, 9293.,Overman Synthesis of (-)-Strychni

36、neOverman, L. E. et al. J. Am. Chem. Soc. 1995, 117, 5775;Overman, L. E. et al. J. Am. Chem. Soc. 1993, 115, 9293.,Overman Synthesis of (-)-StrychnineOverman, L. E. et al. J. Am. Chem. Soc. 1995, 117, 5775;Overman, L. E. et al. J. Am. Chem. Soc. 1993, 115, 9293.,-Ester,-Ester,Overman Synthesis of (-

37、)-StrychnineOverman, L. E. et al. J. Am. Chem. Soc. 1995, 117, 5775;Overman, L. E. et al. J. Am. Chem. Soc. 1993, 115, 9293.,Overman Synthesis of (-)-StrychnineOverman, L. E. et al. J. Am. Chem. Soc. 1995, 117, 5775;Overman, L. E. et al. J. Am. Chem. Soc. 1993, 115, 9293.,Magnus Synthesis,(-)-Strych

38、nine,24-Step, overall yield 0.03%,Kuehne Synthesis of (-)-StrychnineKuehne, M. E. et al. J. Org. Chem. 1998, 63, 9427,Racemic synthesis see: Kuehne, M. E. et al. J. Org. Chem. 1993, 58, 7490,Kuehne Synthesis of (-)-StrychnineKuehne, M. E. et al. J. Org. Chem. 1998, 63, 9427,Kuehne Synthesis of (-)-S

39、trychnineKuehne, M. E. et al. J. Org. Chem. 1998, 63, 9427,Kuehne Synthesis of (-)-StrychnineKuehne, M. E. et al. J. Org. Chem. 1998, 63, 9427,Kuehne Synthesis of (-)-StrychnineKuehne, M. E. et al. J. Org. Chem. 1998, 63, 9427,Kuehne Synthesis of (-)-StrychnineKuehne, M. E. et al. J. Org. Chem. 1998

40、, 63, 9427,Overman Reduction,Kuehne Synthesis of (-)-StrychnineKuehne, M. E. et al. J. Org. Chem. 1998, 63, 942,14-Step, overall yield 5.3%. The shortest rout to (-)-StrychnineRacemic 17-step, 2% overall yield, J. Org. Chem. 1993, 58, 7490,(-)-Strychnine,Shibasaki Synthesis of (-)-StrychnineShibasaki, M. et al. J. Am. Chem. Soc. 2002, 124, 14546,31-Step, longer than Woodward routeOverall yield 0.6%,G. Stork Synthesis of (-)-Strychnine(Unpublished Result)See: Ischia Advanced School of organic ChemistryIschia Porto, Italy, Sept. 21, 1992,