多步骤有机合成路线设计

1、第第1212章章 多步骤多步骤有机合成路线设计有机合成路线设计212.1 12.1 有机合成的概念及其意义有机合成的概念及其意义有机合成是利用天然资源或工业生产中形成的简单有机分子，通过一系列化学反应合成得到各种复杂结构的天然或非天然的有机化合物的过程。Organic synthesis is a special branch of chemical synthesis and is concerned with the construction of organic compounds via organic reactions. Organic molecules can often co

2、ntain a higher level of complexity compared to purely inorganic compounds, so the synthesis of organic compounds has developed into one of the most important branches of organic chemistry. There are two main areas of research fields within the general area of organic synthesis: total synthesis and m

3、ethodology.3Vitamin B124Palytoxin, C130H229N3O53 5有机合成的应用有机合成的应用： 1、提供医药、农药、染料等有机材料； 2、合成天然产物探讨活性，或确定结构； 3、合成探讨机理用的化合物或中间体，探讨化学或生物功能。6反合成设计基于仿生的反合成设计基于化学反应的反合成设计Elias James Corey12 July 1928Harvard Nobel Prize in Chemistry (1990)Robert Robinson1886-1975Cambridge Nobel Prize in Chemistry (1947)12.2 1

4、2.2 逆合成分析法（逆合成分析法（retrosynthesisretrosynthesis）7ABCDABCD逆向合成分析法逆向合成分析法是设计复杂化合物的常用方法。它是将目标化合物倒退一步寻找上一步反应的中间体，而这个中间体，又可由上一步的中间体得到，以此类推，最后确定最适合的基础原料和最终的合成路线。 Retrosynthesis is the art of taking a product and working itbackwards into simple starting materials which we know how to combine. You start by d

5、isconnecting bonds which look like they should give plausible starting materials.8OHOOHOOOOCOOEtOBrBr+OOdis dis OClO+BrOO9在逆合成分析中，有时需将化合物中碳原子上的电荷发生变化，这一过程为极性转换（极性转换（umpolung）。）。OHRSSHRHSSHn-BuLiSSRRXSSRRORRH2OAny process by which the normal alternating donor and acceptor reactivity pattern of a chai

6、n, which is due to the presence of O or N heteroatoms, is interchanged. Reactivity umpolung is most often achieved by temporary exchange of heteroatoms (N, O) by others, such as P, S and Se. 10在逆合成分析中，要讲究切断策略：1、一般在目标分子中有官能团的地方切断；2、在带支链的地方切断；3、切断后得到的合成子应是合理的；4、一个好的切断，应同时满足合理的反应机理、 最大可能的简化、给出认可的原料三大条件

7、。11H3COH3COHNOOCH3OCH3H3COH3CONH2H3COH3COCOOH+FGIH3COOCH3CNFGIH3COOCH3ClOCH3OCH3+ HCHO + HCl + ZnCl212在含有两个以上官能团的目标分子中，两个官能团之间的距离距离是帮助选择切断的指南。1，2-二官能团OHOOCOOBuOHCOOBuCOOBuCOOBuCOOBuHOHHOH131，3-二官能团PhOOPhCHO +OOOO+OOOEtOOEtOCOOEt141，4-二官能团OOOOCOOEtOEtOO+BrOOOOOEtOOOHOEtOOO+151，5-二官能团+OOOMichaelAdditi

8、onO1，6-二官能团PhOHOOPhOHPhO+ PhMgBr16汇总合成：汇总合成：一条线合成：一条线合成：A + BCDE +FGHG-HG-H-IIA + BCDGEFHE-FG-HG-H-I1712.3 12.3 导向基导向基作用：活化作用 钝化作用 利用封闭特定位置来导向 BrBrBrBrBrBrNH2NH2NO218NH2BrNHCOCH3BrNHCOCH3NH2CH3ClCH3ClSO3HCH3SO3HCH31912.4 12.4 保护基保护基在多官能团化合物的合成中，如果要使几个活性相近的官能团中的一个发生反应，或使活性相对较弱的官能团发生反应，则需使用保护基团。A prot

9、ecting group or protective group is introduced into a molecule by chemical modification of a functional group in order to obtain chemoselectivity in a subsequent chemical reaction. It plays an important role in multistep organic synthesis. 20HOH2CCHOHOOCCHOHOOHH+HOH2COOKMnO4HOOCOOH+/H2O+HOOH将转化为HOOC

10、CHOHOH2CCHO2112.5 12.5 合成问题简化合成问题简化1 1、利用分子的对称性、利用分子的对称性O OOOHOHOO+ 22 2、模型化合物的应用、模型化合物的应用H3CCH3CH3OHCH3OHpinacolrearrangementOCH3CH3CH3CH3OHOOHHOO22烯烃的复分解反应（烯烃的复分解反应（Olefin Metathesis）Grubbs 1st Cat.NBocHOGrubbs Cat.NOHBocLnMRRRLnMRRRMLnRRRRuPCy3PCy3HPhClCl23“For olefin metathesis in organic synthe

11、sis”Yves Chauvinthe Institut franais du ptroleFranceRobert H. GrubbsCalifornia Institute of TechnologyPasadena, CA, USARichard R. SchrockMassachusetts Institute of TechnologyCambridge, MA, USAThe Nobel Prize in Chemistry 200524RuPCy3PhClClNNGrubbs 2nd Cat.RuClClNNHoveyda-Grubbs Cat.O25Richard F. Hec

12、k Ei-ichi Negishi Akira Suzuki University of Delaware Purdue University Hokkaido UniversityNewark, DE, USA WestLafayette, IN, USA Sapporo, Japan“For palladium-catalyzed cross coupling in organic synthesis”The Nobel Prize in Chemistry 201026R1X +R2HR4R3Pd(0) (catalytic)ligand, base, solvent, heatR2R1R4R3Arylated or alkenylated olefinR1X + R2Zn XNiLn or PdLn (catalytic)solvent/L (ligand)R1R2coupled productR2X+R1B(R)2Pd(