不對稱合成反應(yīng)

1、不對稱合成反應(yīng)1手性：指一個(gè)物體與其鏡像不重合 2345手性是自然界的基本屬性宇宙是非對稱的，如果把構(gòu)成太陽系的全部物體置于一面跟隨著它們的鏡子面前，鏡子中的影像不能和實(shí)體重合。生命由非對稱作用所主宰。我能預(yù)見，所有生物物種在其結(jié)構(gòu)上、在其外部形態(tài)上，究其本源都是宇宙非對稱性的產(chǎn)物。 Louis Pasteur6不對稱合成研究是手性物質(zhì)創(chuàng)造的關(guān)鍵方法和手段，是化學(xué)研究最為活躍的領(lǐng)域之一。它在關(guān)乎人類健康的手性醫(yī)藥、農(nóng)藥、香料、香精、食品添加劑以及多種功能材料等相關(guān)領(lǐng)域具有重要的理論意義和應(yīng)用前景。7內(nèi)容一、有關(guān)不對稱合成中常用術(shù)語二、手性的重要性三、手性的發(fā)展歷史四、手性化合物的來源五、催化劑

2、六、不對稱合成方法七、不對稱合成反應(yīng)8不對稱合成Enantioselective synthesis, also calledchiral synthesisorasymmetric synthesis，is defined byIUPACas: a chemical reaction (or reaction sequence) in which one or more new elements ofchiralityare formed in a substrate molecule and which produces thestereoisomeric(enantiomericordi

3、astereoisomeric) products inunequal amounts 9手性分子的費(fèi)歇爾命名規(guī)則為了確定其它手性分子的相對構(gòu)型, 費(fèi)歇爾(E. Fisher) 選擇D-甘油醛作為構(gòu)型聯(lián)系的標(biāo)準(zhǔn)。并且把D-甘油醛所具有的立體結(jié)構(gòu), 即與不對稱碳原子相結(jié)合的氫原子處在費(fèi)歇爾投影式左邊，編號(hào)最小的原子處在頂端，這樣一種結(jié)構(gòu)稱為D-構(gòu)型，其對映體為L-構(gòu)型。10Cahn-Ingold-Prelog命名規(guī)則按x, y, z和w（原子或者基團(tuán)從大到小）的順序，順時(shí)針旋轉(zhuǎn)為R-構(gòu)型，逆時(shí)針旋轉(zhuǎn)為S-構(gòu)型11不對稱和非對稱不對稱性（Asymmetry），手性分子沒有任何對稱元素。非對稱(di

4、ssymmetry), 分子內(nèi)有一些對稱元素，但仍然有手性。12對映體和非對映體對映體，異構(gòu)體互為不能重疊的鏡影系。非對映體，有兩個(gè)以上的不對稱中心，但異構(gòu)體不為鏡影關(guān)系。13(e.e.)和(d.e.) 對映體過量（enantiomer excess, ee.）非對映體過量(diastereomer excess, de.)14潛手性面，Re和Si面在不對稱合成中，底物中要發(fā)生反應(yīng)的原子以及和它緊相連的其它原子在一個(gè)平面上，發(fā)生反應(yīng)后，這個(gè)原子成為不對稱原子。這個(gè)面稱作潛手性面, 這個(gè)原子往往稱作潛不對稱原子。當(dāng)這個(gè)面對著觀察者，手性原子上連接的原子或者原子團(tuán)的大小是順時(shí)針旋轉(zhuǎn)的，這個(gè)面稱作R

5、e面，如果是反時(shí)針旋轉(zhuǎn)則稱作Si面。15二、手性的重要性手性與生命現(xiàn)象：氨基酸、糖、蛋白質(zhì)、DNA都是手性的；手性與人類健康：“反應(yīng)?！笔录cFDA手性藥物指導(dǎo)原則，藥物中近50%具有手性，開發(fā)中的有2/3以上是手性的；手性與環(huán)境：手性技術(shù)與手性產(chǎn)品符合綠色化學(xué)原則；手性與材料和信息科學(xué)：手性液晶顯示、手性傳感、手性分離等16手性藥物含有手性的藥物，其藥效與分子的立體構(gòu)型有密切關(guān)系1、兩種對映異構(gòu)體的藥理作用相同，但藥效差別很大17 2、兩種對映體藥性相反巴比妥酸鹽通常用作催眠鎮(zhèn)痛藥，一般（S)-（-）-的異構(gòu)體具有抑制神經(jīng)活動(dòng)的作用，而（R）-（+）-異構(gòu)體具有興奮作用18 3、其中一種有毒

6、或引起嚴(yán)重副反應(yīng)反應(yīng)停是一種緩解婦女懷孕初期反應(yīng)的鎮(zhèn)痛劑，它的副作用曾經(jīng)使歐洲2萬多孕婦產(chǎn)生災(zāi)難性后果胎兒發(fā)生畸變19手性農(nóng)藥 多效唑含兩個(gè)手性中心，其中（2R,3R)-異構(gòu)體具有強(qiáng)的殺菌活性和弱的植物生長調(diào)節(jié)活性，因此用作殺菌劑；(2S,3S)-異構(gòu)體有強(qiáng)的植物生長調(diào)節(jié)活性和弱的殺菌活性，用作植物生長調(diào)節(jié)劑手性農(nóng)藥主要有以下幾大類：擬除蟲菊酯、有機(jī)膦殺蟲劑；三唑類、N-?；桨奉悮⒕鷦槐窖趸?，芳氧苯氧丙酸酯類、酰胺類、二苯醚類、氨基甲酸鹽類、咪唑啉酮類、三嗪類除草劑。20其他領(lǐng)域手性不僅在醫(yī)藥和農(nóng)藥上有重要的作用，在香料、香精、食品添加劑開發(fā)，以及在包括如手性開關(guān)、手性液晶顯示器、手性傳

7、感等在內(nèi)的功能材料及其他相關(guān)領(lǐng)域也具有重要的應(yīng)用前景。21?？舅?2三、手性的發(fā)展歷史 18151905 In 1815 the French physicistJean-Baptiste Biotshowed that certain chemicals could rotate the plane of a beam of polarised light, a property called optical activity. Until 1848, whenLouis Pasteurproposed that it had a molecular basis originating f

8、rom some form ofdissymmetry, The origin of chirality itself was finally determined in 1874, whenJacobus Henricus van t HoffandJoseph Le Belindependently proposed thetetrahedralgeometry of carbon(models up until this time had been 2D) and theorised that the arrangement of groups around this tetrahedr

9、on could dictate the optical activity of the resulting compound. 23In 1894，Hermann Emil Fischeroutlined the concept ofasymmetric induction;in which he correctly ascribed selective the formation ofD-glucose by plants to be due to the influence of optically active substances within chlorophyll. Fische

10、r also successfully performed what would now be regarded as the first example of enantioselective synthesis, by enantioselectively elongating sugars via a process which would eventually become theKilianiFischer synthesis. 24However, the first enantioselective synthesis is often attributed to Willy M

11、arckwald; who in 1904 described the enantioselective decarboxylationof themalonic acid2-ethyl-2-methylmalonic acid, mediated bybrucine.2519051965The development of enantioselective synthesis was initially slow, largely due to the limited range of techniques available for their separation and analysi

12、s. Diastereomers possess different physical properties, allowing separation by conventional means, however at the time enantiomers could only be separated byspontaneous resolution(where enantiomers separate upon crystallisation) orkinetic resolution(where one enantiomer is selectively destroyed). Th

13、e only tool for analysing enantiomers wasoptical activityusing apolarimeter, a method which provides no structural data. 26It was not until the 1950s that major progress really began. Driven in part by chemists such asR. B. WoodwardandVladimir Prelogbut also by the development of new techniques. The

14、 first of these wasXray Crystallography, which was used to determine theabsolute configurationof an organic compound byJohannes Bijvoetin 1951.Chiral chromatography was introduced a year later by Dalgliesh, who usedpaper chromatographyto separate chiral amino acids.Although Dalgliesh was not the fir

15、st to observe such separations, he correctly attributed the separation of enantiomers to differential retention by the chiral cellulose. This was expanded upon in 1960, when Klem and Reed first reported the use of chirally-modified silica gel for chiralHPLCchromatographic separation. 27ThalidomideFi

16、rst synthesized in 1953, thalidomide was widely prescribed for morning sickness from 1957 to 1962, but was soon found to be seriouslyteratogenic,eventually causing birth defects in more than 10,000 babies. The disaster prompted many counties to introduce tougher rules for the testing and licensing o

17、f drugs, such as theKefauver-Harris Amendment(U.S.) andDirective 65/65/EEC1(E.U.). 28since 1965The CahnIngoldPrelog priority rules (often abbreviated as theCIP system) were first published in 1966; allowing enantiomers to be more easily and accurately described.The same year saw first successful ena

18、ntiomeric separation bygas chromatographyan important development as the technology was in common use at the time. 29Metal catalysed enantioselective synthesis was pioneered byWilliam S. Knowles,Ryji NoyoriandK. Barry Sharpless; for which they would receive the 2001Nobel Prize in Chemistry.Knowles a

19、nd Noyori began with the development ofasymmetric hydrogenation, which they developed independently in 1968. Knowles replaced the achiraltriphenylphosphineligands inWilkinsons catalystwith chiralphosphine ligands. This experimental catalyst was employed in an asymmetric hydrogenation with a modest 1

20、5%enantiomeric excess. Knowles was also the first to apply enantioselective metal catalysis to industrial-scale synthesis; while working for theMonsanto Companyhe developed an enantioselective hydrogenation step for the production ofL-DOPA, utilising theDIPAMPligand. 3031Noyori devised a copper comp

21、lex using a chiralSchiff baseligand, which he used for themetal-carbenoid cyclopropanationofstyrene.In common with Knowles findings, Noyoris results for the enantiomeric excess for this first-generation ligand were disappointingly low: 6%. However continued research eventually led to the development

22、 of theNoyori asymmetric hydrogenationreaction. 32Sharpless complemented these reduction reactions by developing a range of asymmetric oxidations (Sharpless epoxidation,Sharpless asymmetric dihydroxylation,Sharpless oxyamination) during the 1970s to 1980s. With the asymmetric oxyamination reaction,

23、usingosmium tetroxide, being the earliest. 33During the same period, methods were developed to allow the analysis of chiral compounds byNMR; either using chiral derivatizing agents, such asMoshers acid,oreuropiumbased shift reagents, of which Eu(DPM)3was the earliest. 34Chiral auxiliaries were intro

24、duced byE.J. Coreyin 1978and featured prominently in the work ofDieter Enders. Around the same enantioselective organocatalysis was developed, with pioneering work including theHajosParrishEderSauerWiechert reaction. Enzyme-catalyzed enantioselective reactions became more and more common during the

25、1980s,particularly in industry,with their applications includingasymmetric ester hydrolysis with pig-liver esterase. The emerging technology ofgenetic engineeringhas allowed the tailoring of enzymes to specific processes, permitting an increased range of selective transformations. For example in the

26、 asymmetric hydrogenation ofstatinprecursors. 35363738從國際上看，美國、日本和德國是不對稱合成研究的強(qiáng)國，其原創(chuàng)性研究工作在世界上有重大的影響，引領(lǐng)著不對稱合成研究發(fā)展的方向和趨勢。例如，史一安發(fā)展的以天然糖為原料的手性酮催化劑及“史環(huán)氧化反應(yīng)”、美國的List和Barbas研究小組報(bào)道的脯氨酸催化劑、Jacobsen發(fā)展的手性硫脲催化劑、日本的Akiyama和Terada發(fā)展的手性磷酸催化劑，使得手性有機(jī)小分子催化成為近10年不對稱合成研究的一個(gè)新熱點(diǎn)。在不對稱合成的新概念和新策略方面，日本的Noyori等提出的“不對稱放大”、Mikam

27、i提出的“不對稱活化”、Shibasaki提出的“協(xié)同催化”、美國的Yamamoto與Faller提出的“不對稱毒化”等概念為設(shè)計(jì)手性催化劑提供了全新的思路。此外，日本的Soai等提出的“不對稱自催化”和美國的Sharpless等提出的“配體加速催化反應(yīng)”等策略也是不對稱合成研究的新領(lǐng)域。39目前我國具有較大影響的工作包括：陳新滋等合成的阻轉(zhuǎn)異構(gòu)的聯(lián)吡啶膦配體，已轉(zhuǎn)移到國際工業(yè)界進(jìn)行應(yīng)用開發(fā)；周其林等發(fā)展的手性螺環(huán)骨架的配體已經(jīng)引起國際知名公司的關(guān)注，多個(gè)配體被國內(nèi)外同行廣泛應(yīng)用，并被列入Aldrich和Strem等試劑目錄；林國強(qiáng)小組發(fā)明的新型手性雙烯配體，合成方便，被列入Aldrich試劑

28、目錄。圍繞手性催化中催化劑的選擇性和效率等難題，旨在尋找高選擇性高效率的手性催化劑、實(shí)現(xiàn)催化劑的回收和循環(huán)利用、探討不對稱誘導(dǎo)機(jī)理以及發(fā)展不對稱反應(yīng)新方法和新策略等研究，是當(dāng)前不對稱合成研究的關(guān)鍵內(nèi)容。40四、手性化合物的來源天然產(chǎn)物外消旋體的拆分不對稱合成41直接從天然來源獲得天然存在的手性化合物品種很多，其中含量較大的那些天然手性化合物常稱為“手性源”化合物 D-（+）-葡萄糖 D-（-）-果糖 L-谷氨酸 （+）-酒石酸 （-）-薄荷醇 （1R,2S)-麻黃堿42五、催化劑有機(jī)配體金屬絡(luò)合物 常見的一些配體結(jié)構(gòu)：43有機(jī)小分子催化劑氨基酸和胺類 銨鹽、唑鹽類 有機(jī)磷 硫脲類44酶催化45

29、六、不對稱合成的基本方法以手性天然產(chǎn)物為原料合成手性底物控制的不對稱合成手性輔基控制的不對稱合成手性試劑控制的不對稱合成手性催化劑控制的不對稱合成雙不對稱合成46Enantiomers possess identical energies and hence should be produced in equal amounts by an undirected process, leading to aracemic mixture. A common solution is to introduce a chiral feature which will promote the forma

30、tion of one enantiomer over another, via interactions at thetransition state. This is known asasymmetric inductionand can involve chiral features in thesubstrate,reagent,catalystor environment and works by making theactivation energy required to form one enantiomer lower than that of the opposing en

31、antiomer.47以手性天然產(chǎn)物為原料合成自然界形成的天然產(chǎn)物許多是對映純的化合物，如氨基酸是L-型的，碳水化合物是D-型的，還有天然萜類化合物、甾族化合物及天然羥基酸都可以作為合成手性化合物的起始原料48用L-蘇氨酸可以制備手性元，-環(huán)氧丁酸，用于合成抗菌藥物49手性底物控制的不對稱合成反應(yīng)物的反應(yīng)中心一般與已存在的手性單元相鄰，在手性單元誘導(dǎo)下，與反應(yīng)試劑作用后生成新的手性單元50用含手性結(jié)構(gòu)的丙酸酯作為烯醇化試劑與醛反應(yīng)，可高選擇性的生成syn-醛醇縮合產(chǎn)物51手性輔基控制的不對稱合成在反應(yīng)底物分子中引入含手性單元的輔基，由于在輔基手性的誘導(dǎo)下，臨近的反應(yīng)中心與反應(yīng)試劑作用生成新的手

32、性單元，然后除去手性輔基得到手性產(chǎn)物。常用的手性輔基有手性胺、肼、脯氨醇、惡唑烷、噁唑啉、亞砜和Evans試劑52手性肼與醛酮反應(yīng)可以生成手性腙，后者在強(qiáng)堿下在-碳上不對稱烴化，除去手性輔基后得到-手性的羰基化合物53手性試劑控制的不對稱合成用手性試劑直接將無手性的反應(yīng)底物轉(zhuǎn)化為手性產(chǎn)物。缺點(diǎn)是要使用化學(xué)計(jì)量的對映純手性試劑，手性試劑沒法回收54金屬氫化物如氫化鋁鋰在手性二胺或手性氨基醇存在下能不對稱的還原羰基化合物得到相應(yīng)的手性醇55手性催化劑控制的不對稱合成僅使用催化量的手性催化劑，使無手性的反應(yīng)物直接轉(zhuǎn)化為手性物。這一方法是最經(jīng)濟(jì)有效且對環(huán)境友好的不對稱合成方法56Jacobsen環(huán)氧化

33、反應(yīng)57雙不對稱合成在手性反應(yīng)底物和手性試劑或手性催化劑雙重手性因子控制下的不對稱合成，對同時(shí)形成兩個(gè)新的手性單元特別有價(jià)值58七、不對稱合成反應(yīng)烯鍵的立體選擇性反應(yīng)羰基化合物的立體選擇性反應(yīng)59烯鍵的立體選擇性反應(yīng)不對稱氫化反應(yīng)不對稱環(huán)氧化反應(yīng)不對稱雙羥基化反應(yīng)不對稱氨基羥基化反應(yīng)不對稱環(huán)丙烷化反應(yīng)不對稱Diels-Alder反應(yīng)60不對稱氫化反應(yīng)催化氫化反應(yīng)產(chǎn)率高，產(chǎn)物后處理簡單，是工業(yè)上廣泛應(yīng)用的合成反應(yīng)。不對稱催化加氫是研究最早、最有成效的不對稱反應(yīng)之一。不對稱氫化反應(yīng)主要包括以下三類不飽和鍵的不對稱加成6162Novartis公司開發(fā)的不對稱催化氫化合成S-異丙甲草胺的技術(shù)這可以看作

34、是不對稱合成中的一個(gè)里程碑。63Sharpless環(huán)氧化（AE)反應(yīng)烯丙式醇的不對稱環(huán)氧化反應(yīng)是美國化學(xué)家Sharpless發(fā)現(xiàn)的不對稱合成新方法，特點(diǎn)有（1）很高的選擇性，（2）底物適用面寬，不管烯丙醇雙鍵上有什么取代基，基本都能反應(yīng)（3）產(chǎn)物絕對構(gòu)型可以預(yù)測紫杉醇是一種從紅豆杉樹皮中分離得到的具有很強(qiáng)的抗腫瘤活性的化合物，對轉(zhuǎn)移性卵巢癌和乳腺癌有顯著療效，對肺癌也確定有療效，是迄今三種最重要的植物來源的抗癌藥之一64不對稱雙羥基化（AD)反應(yīng)AD反應(yīng)在合成上的成功應(yīng)用已有很多報(bào)道，如一種從西紅柿中分離提出重要生物活性化合物secosyrin的全合成的關(guān)鍵步驟便用了AD反應(yīng)喜樹堿是從我國珙桐科植物喜樹中提取出來的具有很強(qiáng)抗癌活性的化合物65不對稱氨基羥基化（AA）反應(yīng)許多天然存在或合成的有重要生物活性化合物都含有-氨基醇的結(jié)構(gòu)單元，因此在碳碳雙鍵上同時(shí)加上氨基和羥基在合成上有很重要的意義66不對稱環(huán)丙烷化反應(yīng)許多藥物含有手性環(huán)丙烷結(jié)構(gòu)，如 -內(nèi)酰胺類抗生素西司他丁，高效低毒農(nóng)藥除蟲菊酯，具有抗癌活性的分子curac