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1、1复杂分子的合成化学 合成设计与战略实践姚祝军 中国科学院上海有机化学研究所2005年2月22005 YZJ-SIOC课程内容安排1.有机合成的目的、使命与发展历史2.复杂分子合成的基本概念3.目标分子的考察4.反合成分析5.合成原料、砌块与手性源6.合成计划的考察与选择7.实例分析（包括利用有机所电子数据库辅助的合成 设计）8.复杂分子多样性与类天然产物化学32005 YZJ-SIOC课程考试与成绩计算?上课出席率（每次1分，共计10分）?Quiz （3次，每次10分，共计30分）?期末考试笔试（40分）?期末考试开卷设计（20分）42005 YZJ-SIOC联系方式联系方式?姚祝军?电话分
2、机：4 5133?电子邮件：?办公室：新大楼321室52005 YZJ-SIOC第一部分有机合成的目的、使命与发展历史62005 YZJ-SIOC有机合成是在一个真实的世界旁边创造 着一个新的世界。有机合成是在一个真实的世界旁边创造 着一个新的世界。R. B. Woodward，1965Chart Title天然产物材料用途分子生物活性分子理论研究分子医学用途分子设计分子目标导向试剂催化剂合成战略合成方法方法导向有机合成72005 YZJ-SIOC有机合成：挑战、奋斗与创造的轨迹挑战、奋斗与创造的轨迹1. 复杂分子结构的挑战性2. 激发新的合成方法学的发展? Shorter time? Mor
3、e efficient? Previously undreamed complexity3. 产生新的有机化学理论4. 创造新的功能性物质82005 YZJ-SIOC历史回顾（1828-1944） -天然产物与生命现象OH2NNH2Urea (Wohler, 1828)OOHAcetic Acid (Koble, 1845)OOHHOHO HOOHGlucose (Fischer, 1890)MeMe OHa-Terpineol (Perkin, 1904)OMeMeMeCamphor (Komppa, 1903; Perkin, 1904)NMeOTropinone (Robinson, 1
4、917)NNMeMeNNMeMeHOOCCOOHFeHaemin (Fischer, 1929)MeHHOOEquilenin (Backmann, 1939)NOHOHOHMe HClPyridoxine HCl (Folker, 1939)NMeOHOHHHQuinine (Woodward 100g30% H2O2: 607g (4.4 equiv, 10% excess)Na2WO4-2H2O: 4.01gQ+HSO4- (Olefin: W: PTC = 100: 1: 1)75oC to 90oC for 8hrs161 of adipic acid was obtained.Pr
5、oducts in crystalline is filtered and the aqueous phase can be re-used with a renewed PTC and 30% H2O2.44基础研究的重要性452005 YZJ-SIOC “通过科学发现创造经济繁荣” -美国经济发展委员会（1998）?基础研究是美国的巨大资产之一；我们未来的 经济繁荣也将取决于我们现在在国家基础研究 的历史性和根本性承诺方面做出的努力。?基础研究是技术、生产水准和生活方式得以改 善的一个主要因素。基础研究及其相关的创新 不会马上显现，通常在几十年后才发生。?基础研究的社会回报率远高于私营回报
6、率。?例子：激光器、X射线、半导体、GPS、HIV病 毒和艾滋病治疗、因特网等。462005 YZJ-SIOC簇集与“解簇集”Tim Clackson, et al. Science 2000, 287, 826.In Ariads RAPID technique, a therapeutic protein such as insulin (red) is linked to a protein (blue) that forms aggregates in a cells endoplasmic reticulum. Addition of a small- molecule drug (
7、green) breaks up the aggregates, resulting in release of the therapeutic protein.472005 YZJ-SIOC48第二部分复杂分子合成的基本概念492005 YZJ-SIOC参考文献?合成设计1.Corey “The logic of chemical synthesis”, Wiley, New York, 1989.2.Warren “Organic synthesis: the disconnection approach”, Wiley, New York, 1982.3.Fuhrhop, Penzlin
8、 “Organic synthesis: concepts, methods, starting materials”, VCH, Weinhein, 1994.502005 YZJ-SIOC参考文献?全合成1.Nicolaou, Sorensen “Classics in total synthesis”, VCH, Weinheim, 1996.2.Hanessian “Total synthesis of natural products: the chiron approach”, Pergamon, Oxford, 1983.3.Bindra “Art in organic synt
9、hesis”, Wiley, New York, 1988.4.Koshinen “Asymmetric synthesis of natural products”, Wiley, New York, 1993.512005 YZJ-SIOC参考文献?重要的综述/评述1.Corey, Science 1969, 166, 178; 1985, 228, 408.2.Corey, Chem. Soc. Rev. 1988, 17, 111.3.Corey, Pure Appl. Chem. 1967, 14, 19; 1971, 18, 45; 1990, 62, 1209.4.Corey,
10、Angew. Chem. Int. 1991, 30, 455.522005 YZJ-SIOC参考文献?官能团保护1.Greene, Wuts “Protecting groups in organic synthesis”, 3rd Ed., Wiley, New York, 1999.2.Kocienski, P. “Protecting Groups”; Thieme: Stuttgart, 1994.3.Kunz, H.; Waldmann, H. “Protecting Groups in Comprehensive Organic Synthesis”; Trost, B. M.,
11、 Fleming, I., Eds; Pergamon Press: Oxford, 1991; pp 631-701.4.Giovanni Sartori, Roberto Ballini, Franca Bigi, Giovanna Bosica, Raimondo Maggi, and Paolo Righi. Chem. Rev. 2004, 104, 199-250. and references cited therein.532005 YZJ-SIOC参考文献?计算机辅助的合成设计1.Corey, Wipke, Science 1969, 166, 178.2.Corey, Lo
12、ng, J. Org. Chem. 1978, 43, 2208.3.Jorgensen, Pure Appl. Chem. 1990, 62, 1921.4.Hendrickson, J. Chem. Inf. Comput. Sci. 1992, 32, 209.5.Hendrickson, Acc. Chem. Res. 1986, 19, 274.54合成的分类552005 YZJ-SIOC1. 线性合成（Linear Synthesis）?The target compound is made through a series of linear transformations.AB
13、5 stepsOverall yield 90%/step 59% 70%/step 17%562005 YZJ-SIOC2. 汇聚式合成(Convergent Synthesis)?Individually prepared compounds are convergently brought together to make the target compound.CDEFB5 stepsoverall yield90%/step 73% 70%/step 34%Advantages of a convergent synthesis1. Shorter; 2. Simpler to ex
14、ecute; 3. Higher overall yields; 4. Better material balance and supply.572005 YZJ-SIOC汇聚式合成(Convergent Synthesis)?Triply Convergent Synthesis?Three major components are brought together in a single step to make the target compound.CDEFGHI582005 YZJ-SIOC3. 发散性合成(Divergent Synthesis)?For a class of co
15、mpounds, it is advantageous to prepare a common intermediate and use this common intermediate to prepare all members of the class of agents.?Examples: prostaglandinsOCHOROOROR1R2OHOHPGF1 PGF2 PGF33592005 YZJ-SIOC发散性合成(Divergent Synthesis)?Prepare the structurally related products.?Good strategy for
16、the structure-activity studies.?The basis of most combinational chemistry methods.NOOMe MeOMeONOMe MeOMeOR1ORNOMe MeOMeOO OMeImerubrineR=CH3, R1=H Rufescine R=H, R1=H Norrafescine R=CH3, R1=OCH3 ImeluteineJACS 1995, 117, 12452.JOC 1984, 49, 4050.602005 YZJ-SIOC4. 全合成(Total Synthesis) Start with readily available ma
