多步驟有機(jī)合成路線設(shè)計(jì)

1、第第1212章章 多步驟多步驟有機(jī)合成路線設(shè)計(jì)有機(jī)合成路線設(shè)計(jì)212.1 12.1 有機(jī)合成的概念及其意義有機(jī)合成的概念及其意義有機(jī)合成是利用天然資源或工業(yè)生產(chǎn)中形成的簡單有機(jī)分子，通過一系列化學(xué)反應(yīng)合成得到各種復(fù)雜結(jié)構(gòu)的天然或非天然的有機(jī)化合物的過程。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有機(jī)合成的應(yīng)用有機(jī)合成的應(yīng)用： 1、提供醫(yī)藥、農(nóng)藥、染料等有機(jī)材料； 2、合成天然產(chǎn)物探討活性，或確定結(jié)構(gòu)； 3、合成探討機(jī)理用的化合物或中間體，探討化學(xué)或生物功能。6反合成設(shè)計(jì)基于仿生的反合成設(shè)計(jì)基于化學(xué)反應(yīng)的反合成設(shè)計(jì)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設(shè)計(jì)復(fù)雜化合物的常用方法。它是將目標(biāo)化合物倒退一步尋找上一步反應(yīng)的中間體，而這個(gè)中間體，又可由上一步的中間體得到，以此類推，最后確定最適合的基礎(chǔ)原料和最終的合成路線。 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，有時(shí)需將化合物中碳原子上的電荷發(fā)生變化，這一過程為極性轉(zhuǎn)換（極性轉(zhuǎn)換（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，要講究切斷策略：1、一般在目標(biāo)分子中有官能團(tuán)的地方切斷；2、在帶支鏈的地方切斷；3、切斷后得到的合成子應(yīng)是合理的；4、一個(gè)好的切斷，應(yīng)同時(shí)滿足合理的反應(yīng)機(jī)理、 最大可能的簡化、給出認(rèn)可的原料三大條件

7、。11H3COH3COHNOOCH3OCH3H3COH3CONH2H3COH3COCOOH+FGIH3COOCH3CNFGIH3COOCH3ClOCH3OCH3+ HCHO + HCl + ZnCl212在含有兩個(gè)以上官能團(tuán)的目標(biāo)分子中，兩個(gè)官能團(tuán)之間的距離距離是幫助選擇切斷的指南。1，2-二官能團(tuán)OHOOCOOBuOHCOOBuCOOBuCOOBuCOOBuHOHHOH131，3-二官能團(tuán)PhOOPhCHO +OOOO+OOOEtOOEtOCOOEt141，4-二官能團(tuán)OOOOCOOEtOEtOO+BrOOOOOEtOOOHOEtOOO+151，5-二官能團(tuán)+OOOMichaelAdditi

8、onO1，6-二官能團(tuán)PhOHOOPhOHPhO+ PhMgBr16匯總合成：匯總合成：一條線合成：一條線合成：A + BCDE +FGHG-HG-H-IIA + BCDGEFHE-FG-HG-H-I1712.3 12.3 導(dǎo)向基導(dǎo)向基作用：活化作用 鈍化作用 利用封閉特定位置來導(dǎo)向 BrBrBrBrBrBrNH2NH2NO218NH2BrNHCOCH3BrNHCOCH3NH2CH3ClCH3ClSO3HCH3SO3HCH31912.4 12.4 保護(hù)基保護(hù)基在多官能團(tuán)化合物的合成中，如果要使幾個(gè)活性相近的官能團(tuán)中的一個(gè)發(fā)生反應(yīng)，或使活性相對(duì)較弱的官能團(tuán)發(fā)生反應(yīng)，則需使用保護(hù)基團(tuán)。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將轉(zhuǎn)化為HOOC

10、CHOHOH2CCHO2112.5 12.5 合成問題簡化合成問題簡化1 1、利用分子的對(duì)稱性、利用分子的對(duì)稱性O(shè) OOOHOHOO+ 22 2、模型化合物的應(yīng)用、模型化合物的應(yīng)用H3CCH3CH3OHCH3OHpinacolrearrangementOCH3CH3CH3CH3OHOOHHOO22烯烴的復(fù)分解反應(yīng)（烯烴的復(fù)分解反應(yīng)（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(