有机合成0第一章-绪论.ppt

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,专业任选课,有机合成化学,ORGANIC SYNTHESIS CHEMISTRY,2014,1,导言,Chemistry is a central science since“its methods,concepts,and practitioners are penetrating virtually every nook and cranny of science and technology”,-Amato,I.,Science,1991,253,12121213.,合成则又是化学的中心。合成不仅是认识世界的一种重要手段，更是人类改造世界和创造全新物质世界的专门学科。合成化学对人类物质文明发展显然起到不可替代的重要作用。,Designer Molecules,Advanced Formulations&Materials,2,导言,化学是一门实验科学，化学家们必须不停地继续寻找新的分子，并且试着合成他们，这是化学家们永远不应当放弃的基础科学。,没有合成化学和合成化学家，就不会有新的分子来捕捉我们的幻想和想象，就不能为化学研究的创造性能量开辟释放的出路。没有合成化学，难以想象化学是一门有生命力的知识领域。,合成化学是分子科学的最具创造性的分枝。,Topology in Chemistry:Designing Mbius Molecules,R.Herges,Chem.Rev.,2006,106,4820,3,Joys of Molecules.1.Campaigns in Total Synthesis -K.C.Nicolaou.,J.Org.Chem.,2005,70,7007-7027,The joys of molecules manifest themselves in many ways.These include beautiful colors,exquisite aromas,distinct tastes,psychological ups and downs,and intellectual inspirations,among other forms of stimulation,material or spiritual.,For us privileged scientists,there are,joys,of yet another kind that can be experienced from molecules,especially those designed and produced so elegantly by Nature.,Inspirations,new knowledge,challenges,and,conquests,by synthesis are but some of these joys that we,in particular,as practitioners of the art of total synthesis,can enjoy from molecules.,4,第一章,绪论1.1有机合成化学概貌,1.1.1 有机合成及其作用,一般说来，有机合成是指从原料（单质、无机物或简单的有机物）经由一系列化学反应制备结构更为复杂的有机物的过程。,当然，一些特殊情况下，由结构较为复杂的有机物经讲解（Degradation）反应生成结构相对更为简单的有机物的过程亦属此列。,有机合成化学是研究有机合成反应的基本规律，以及将其应用于有机合成实践中的基本规律为主要内容的一门科学。,6,有机合成作用,a)Structural verification(结构验证),For the final determination of the structure,the total synthesis of all reasonable diastereomers and comoarison with an authentic sample remains an important method,though we have today very powerful tools,which were often borrowed from Physical Chemistry,such as NMR,MS,IR,X-ray crystallography,etc.,b)Important biological activity(重要生物活性),An obvious reason for total synthesis is the importance of the target in medicine,agricuture,or other commercial ventures.If the molecule is to undergo further biological screening or be used clinically,total synthesis may be the only means to obtain sufficient material.,High anticancer activity,Isolated yields nature sources below 0.039%,Many total syntheses,7,c)Analog generation and studies(类似物研究）,Subsequent studies often show that the structural modification to the basic skeleton gives a molecue with interesting or commercially attractive properties.Therefore,synthetic modification of a known structure,as well as the further studies on the structure-activity pro a molecule with known biological screening,often serve as impetus for designating a new synthetic target.,The modification to Chlorexolone resulted in improved hypotensive action and diuretic action,but no increase of urinary pH,8,Topology in Chemistry:Designing Mbius Molecules,R.Herges,Chem.Rev.,2006,106,4820,Determination the topological symmetry of the,“,Mbius ladders,”,There is only one sharp 13C NMR signal for all six olefinic carbon atoms,because they are rapidly interconverted by the fast motion of the twist,10,f）Development of new reactions or reagents(新反应,新试剂发展),During a total synthesis,completion of a key transformation may be impossible via known chemical reaction.However,the target often is complex,so that development of new methodology or modification of existing reactions must be accomplished to give the desired transformation and complete the synthesis.,Examples here include the Diels-Alder reaction,the Wittig reaction,the hydroboration reaction,the Corey dithiane reaction,the Sharpless asymmetric epoxidation reaction,the various palladium-catalyzed coupling reactions,the olefin metathesis reaction,and last but not least,the multitude of protecting groups available to the synthetic chemists.,11,基本有机合成工业,（,Heavy Organic Synthesis Industry）,利用化学方法将廉价易得的天然资源（如煤、石油、天然气、农副产品等）及其初步加工品和服产品（如电石、煤焦油等）加工为最基本的有机原料（如三烯、三苯B.T.X.、一炔、一萘），然后再合成为重要的有机原料（如乙醇、甲醛、乙酸、丙酮等）。,Wacker Process,13,精细有机工业合成,（Fine Organic Synthesis Industry）,利用重有机合成工业的产品进一步合成具有特殊性能而且直接用到实际中的产品。,如医药、农药、染料、涂料、香料、食品添加剂、合成洗涤剂、石油添加剂、感光材料、化妆品、粘合剂、浮选剂、饲料添加剂、催化剂、汽车用化学品、增塑剂、炸药等等。,特点：,a.,经济规模比较小；,b.,投资比较少；,c.,产品量较小；,d.,品种繁多；,e.,产品利润较高；,f.,反应步骤多；,g.,技术要求高；,h.,产品质量要求高,15,1-2 有机合成简要发展历史,(1)有机合成的形成初期,1845年柯尔伯（H.Kolbe）合成了醋酸，首次使用,“,synthesis,”,1854年柏赛罗（M.Berthelot）合成了油脂等。,“,生命力,”,说才彻底被打破。,有机合成开始形成雏形，并逐渐受到人类的重视。,注：1857年凯库勒（F.A.Kekul)提出碳四价及CC链学说,F.W,hler,1828,年韦勒偶然由加热氰酸铵得到尿素，被认为是有机合成的第一人。,16,(+)-Glucose synthesis,But perhaps,after urea,the most spectacular total,synthesis of the nineteenth century was that of(+)-glucose,by E.Fischer.This total synthesis is remarkable,not only for the complexity of the target,which included,for,the first time,stereochemical elements,but also for the,considerable stereochemical control that accompanied it.,With its oxygen-containing monocyclic structure(pyranose,吡喃糖,)and five stereogenic centers(four controllable),glucose represented the state-of-the-art in terms of target molecules at the end of the nineteenth century.E.Fischer became the second winner of the Nobel Prize for chemistry(1902).,18,(3)Synthesis in the Twentieth Century,The twentieth century has been an age of enormous scientific advancement and technological progress.,Chemistry has played a central and decisive role in shaping the twentieth century.,Synthetic organic chemistry is perhaps,the most expressive branch(,影响最大的分枝,)of the science,of chemistry in view of its creative power and unlimited scope.To appreciate its impact on modern humanity one only has to look around and recognize that this science is a pillar behind pharmaceuticals,high-tech materials,polymers,fertilizers,pesticides,cosmetics,and clothing.,19,(3-1)The Pre-World War II Era,This Era began with impressive strides and with increasing,molecular complexity and sophistication in strategy design,.,Particularly impressive,were one-step synthesis of tropinone and synthesis of haemin,20,(3-2)The Woodward Era -有机合成艺术时代,Selected syntheses by the Woodward Group(1944-1981).,21,(3-2)The Woodward Era -有机合成艺术时代,“,The synthesis of a complicated molecule is,however,a very difficult task;every group,every atom must be placed,in its proper position and this should be taken in its most,literal sense.It is sometimes said that organic synthesis,is at the same time an exact science and a fine art.Here,nature is the uncontested master,but I dare say that,the prize-winner of this year,Professor Woodward,is a good second.,”,-Introduction for Woodward at the Nobel ceremonies in 1965,the year in which Woodward received the prize for the art of organic synthesis.,22,(3-3)The Corey Era -,有机合成技术性时代,.Corey has thus been awarded with the Prize for three intimately connected contributions,which form a whole.Through retrosynthetic analysis and introduction of new synthetic reactions,he has succeeded in preparing biologically important natural products,previously thought impossible to,achieve.,Coreys contributions have turned the art of synthesis into a science.,-The introduction of E.J.Corey at the Nobel ceremonies in 1990,Elias James Corey,24,(4)The Facilitated synthesis Era？,Synthesizing our future,Synthesis must pursue practical elegance that is,it must be,logically,elegant but must at the same time lead to practical applications.,Ideally,we should aim at synthesizing target compounds with a 100%yield and 100%selectivity and avoid the production of waste.This process must be economical,safe,resource-efficient,energy-efficient and environmentally benign.In this regard,the atom economy and the E-factor should be taken into account.The 3Rs(reduction,recycling and reuse)of resources are particularly important.,Chemistry has a central role in science,and synthesis has a central role in chemistry.,25,Chemistry goes green,These challenges can only be embraced with a combination of pure,discovery-oriented research and translational,application-focused research,26,Nobel Prize彰示着有机合成的发展和成就,葛君,图书馆理论与实践,2004,(2),55.,王智民,化学通报,2004,67,w008.,包括,2005,年的获奖者伊夫,肖万,(Yves Chauvin),、罗伯特,格拉布,(Robert H.Grubbs),、理查德,施罗克,(Richard R.Schrock),，有机化学学科共,43,人获奖,27,次，获奖频率,27.5%,。,2010,年诺贝尔化学奖授予,Richard F.Heck,Ei-ichi Negishi,和,Akira Suzuki,。,大多数获奖者都是因为或者主要因为杰出的合成工作而获奖的，所以说，从,Noble,化学奖可以清楚地看到有机合成发展轨迹。,28,1.有机合成成就从开始授奖就非常受重视。,Hermann Emil Fischer,（德）,1902,年，制出糖及嘌呤衍生物,奠定了生物化学发展的基础,.,Johann Friedrich Wilhelm Adolf von Baeyer,（德）,1905,年，对有机染料和芳香族化合物的研究，,1882,年合成靛蓝。,Otto Wallach,（德）,1910,年，对脂环,(,族,),化学的研究,既研究萜烯,包括樟脑以及香精油的其它成份，化学工业的先驱。,29,2.天然复杂具有生物功能化合物的合成,Adolf Friedrich Johann Butenandt,（德）,Leopold Ruzicka,（瑞士）,1939,年，分别以雌素酮、孕甾酮和雄甾酮等性激素的分离和雄甾酮和睾丸激素的合成。,Sir Robert Robinson,（英）,(1886,1975),1947,年，生物碱的研究,类固醇激素合成。,31,2.天然复杂具有生物功能化合物的合成,Vincent du Vigneaud,（美,),1955,年，合成了后叶加,(,血,),压素和后叶催产素这两个多肽激素。,Lord(Alexander R.)Todd,（英）,1957,年，合成了活细胞中的主要能量载体,ATP,和,ADP,。,32,2.天然复杂具有生物功能化合物的合成,Robert Burns Woodward,（美）（,1917,1979,）,1965,年，,for his outstanding achievements in the art of organic synthesis,Woodward,被看作是现代有机合成艺术的创始人,他设计并全合成了许多复杂的天然产物,如番木鳖碱,(strychnine),、,青霉素,(Penicillin),、利血平,(reserpine),、胆固醇、叶绿素和维生素,B12,等。从中，独创许多新的成键方法和策略，对于极其困难的合成问题的解决方法和对其生物合成方法的考虑和推测，以及发现了,Woodward,和,Hoffman,定律。,33,有机合成的里程碑-VB12的全合成,维生素,B12,氰钴胺素,分子式,C,63,H,90,N,14,O,14,PCo,含有,9,个,C*,，具有,512,个立体异构体。存在于动物肝脏中，是治疗抗恶性贫血的药物。,1948,年才分出了纯的暗红色,B12,晶体，,1954,年确定结构。,Woodward,、瑞士埃申莫塞（,A.Escheni11oser,）率领,14,个国家的,110,位化学家开始了,VB12,全合成工作，历时,11,年，终于在他谢世前几年的,1972,年完成了复杂的,VB12,的合成工作。,Rarely before has a synthetic project yielded so much knowledge,including:novel bond-forming reactions and strategies,ingenious solutions to formidable synthetic problems,biogenetic considerations and hypotheses,and the seeds of the principles of orbital symmetry conservation known as the Woodward and Hoffmann rules.,of organic synthesis at the time of the accomplishment.,One of the most notable of the many elegant maneuvers of,synthesis of vitamin B12 is the photoinduced ring closure of the corrin ring from a preorganized linear system wrapped around a metal template.,34,2.天然复杂具有生物功能化合物的合成,复杂天然分子的全合成是有机合成化学中最传统也是最具挑战性的分支之一。这化学工作者们提供了一个展示聪明才智、胆略魄力和合成技巧的理想舞台。,伍贻康 吴毓林,有机合成新世纪,-,有机合成近年进展鉴赏,化学进展,2007,19(1),6-34,35,3.新型结构并具有特殊功能化合物的合成,Ernst Otto Fischer,（德）,Geoffrey Wilkinson,（英）,1973,年，全新金属有机夹心化合物，二茂铁。,Donald J.Cram,（美）,Jean-Marie Lehn,（法）,Charles J.Pedersen,（美）,1987,年，,“,洞状,”,和,“,笼状,”,有机化合物，冠醚。,36,3.新型结构并具有特殊功能化合物的合成,Robert F.Curl,（美）,1996,年，富勒烯（,Fullerene,C60),的发现。,Hideki Shirakawa,（日）,2000年，有机导电材料,Richard E.Smalley,（美）,Jr.,Sir Harold W.Kroto,（英）,Alan J.Heeger,（美）,Alan G.MacDiarmid,（美）,37,富勒烯研究,A wide variety of chemically modified fullerenes have been synthesized and outstanding structural,magnetic,superconducting,electrochemical,and photophysical properties reported.,A new interdisciplinary field in which C60-based polymers should furnish unprecedented materials in which the integration of fullerenes as a photo-and electroactive building blocks into the polymer structure should result in new properties for development of realistic applications.In this regard,20 years after the discovery of fullerenes,the scientific community is looking for real applications of the new carbon allotropes.,-F.Giacalone,N.Martn,Fullerene Polymers:Synthesis and Properties.,Chem.Rev.,2006,106,5136-5190.,38,2010年诺贝尔物理奖：石墨烯,石墨烯及其构建的零维富勒烯、一维碳纳米管和三维的石墨,石墨烯结构,曹阳，,大学生化学通讯,，,2010,1,4,39,4.新合成方法 A.金属参与的有机反应 -格式反应和催化氢化,Victor Grignard(,法）,1912,年，格式试剂及参与的反应。,Paul Sabatier,（法）,1912,年，在金属催化剂存在下使有机化合物氢化的方法。,合成方法是进行有机合成的工具，新的、能够有效、特效促进有机反应的方法，历来是有机化学的重要研究领域。,二人是第一次因在有机合成方法学中的先驱工作而获得化学奖，同时也开辟了金属化合物参与有机反应的新领域，也是金属有机化学的开辟者。,40,4.新合成方法 A.金属参与的有机反应 -聚合反应,Karl Ziegler,（,德）,Giulio Natta,（意）,有机金属化合物(Ziegler,-Natta,催化剂)引发聚合反应和证明能产生高度规整的三维结构高分子而获化学奖。,这项技术使高分子合成材料进入新的发展阶段，同时也开辟了金属化合物催化有机反应的新领域。,1963,年，高聚物技术。,41,4.新合成方法 A.金属参与的有机反应 -不对称合成-1,John Warcup Cornforth(,英）,）,Vladimir Prelog,（瑞士）,立体选择性、专一性反应的开创性工作，为认识酶催化反应和不对称合成技术的开发奠定了理论基础。,1975,年，酶促反应和不对称反应。,Prelog,规律：,42,4.新合成方法 A.金属参与的有机反应 -不对称合成-2,开创了手性有机金属化合物催化高对映选择性的不对称合成技术，并且实现了工业应用，使手性工业进入一个新的发展阶段。,2001,年，不对称催化加氢和氧化方法。,William S.Knowles,（美）,Ryoji Noyori,（日）,K.Barry Sharpless,（美）,43,4.新合成方法 A.金属参与的有机反应 -烯烃的复分解反应,“,人类如今每天都在化工生产中应用这一成果，主要是在药物和先进塑料材料的研发上。,”,2005,年，烯烃的复分解反应,(olefin metathesis),。,Yves Chauvin,（法）,Robert H.Grubbs,（美）,Richard R.Schrock,（美）,44,4.新合成方法 A.金属参与的有机反应 -钯催化交叉偶联反应,Richard F.Heck(,理查德,-,赫克，美）,Ei-ichi Negishi(,根岸英一，日）,Akira Suzuki,(,铃木章，,日）,45,4.新合成方法 B.元素有机化合物参与的有机反应,1979,年，分别发现了有机合成的有机硼和有机磷试剂及其应用。,左：,Herbert C.Brown,（美）,右：,Georg Wittig,（德）,46,4.新合成方法 C.环和反应,1950,年，发现和发展了双烯合成方法。,左：,Otto Paul Hermann Diels,（德）,右：,Kurt Alder,（德）,47,4.新合成方法 D.固相合成技术,1984,年，发展了固相合成技术。,原理：每一步反应产物都是以固相存在，原料以液相存在。,特点：产物最终从固相基体上解脱，易提纯，易自动化。特别适合多肽合成。,是多肽合成化学的重要突破。,“,蛋白质自动合成仪,”,既是从此技术发展起来的。,Robert Bruce Merrifield,（美）,48,5.合成理论-逆合成分析法（Restrosynthetic Analysis),Elias James Corey,（美）,20,世纪,Woodward,以外另一位化学合成大师,Corey,对有机合成理论做了精辟的分析，于,20,世纪,60,年代，提出了逆合成分析法，使合成工作达到到理论指导、逻辑推理的高度，有力地推动了这一学科向前发展。,他合成了上百种化合物：银杏毒素,B,，前列腺素，,ecteinascidin 743,，,aspidophytine,，,brevetoxin B,，,B-,内酰胺（重要的抗生素），,erythrolide,，大环内酯（另外一种重要抗生素）等等。,The Logic of Chemical Synthesis,John Wiley&Sons,Inc.1989.,49,世纪工程-海葵毒素,C,129,H,223,N,3,O,54,FW 2680,64,个手性中心,7,个骨架内双键,一百多个官能团,1989,1994,年，哈佛大学,Kishi,的杰作。,The synthesis of palitoxin holds a special place in the history of total synthesis in that palitoxin is the largest secondary metabolite to be synthesized in the laboratory,both in terms of molecular weight and number of stereocenters.,50,1.4 有机合成的研究领域,天然产物、生物物质的合成,新反应的研究。有机金属催化,不对称合成,有机物催化,串联反应,Chemists have developed numerous methods to address these challenges and facilitate natural product syntheses.Major advances in catalytic applications have been made.Ru these processes have become prominent.,新的合成方法,生物合成，仿生合成，微波合成，光合成,Directed evolution of enzymes for synthesis and the combination of metal-catalyzed reactions with enzymes are also very promising developments.,51,1.4 有机合成的研究领域,新型结构化合物的合成,新合成策略的研究。组合化学，点击化学与多样性导向，极性反转，原子经济性,Combinatorial approaches and high throughput experimentation are also firmly established.,精细化学品合成的应用研究。绿色化学，多相催化有机合成,The need for cleaner,more sustainable chemical practices also poses new challenges.Environmentally benign chemistry and sustainable processes require new ways of carrying out synthesis.Hence,in addition to the development of new reactions,reagents,and catalysts,novel ways to assemble molecules are an important driver for organic synthesis.,52,The automated sequence that produces racemic oxomaritidine from readily available starting materials in less than a day is the first multistep flow-through preparation of a natural product.As such,this represents a milestone in method development.,The syntheses required the construction of a fully automated continuous-flow reactor system,with immobilized reagents packed in columns to effect the synthesis steps efficiently.Once set up,the new techniques allow the rapid and scalable automated syntheses of sophisticated molecules.,-Peter K,ndig,science,2006,314(20),430-43