对映异构体的拆分

1、A collection containing equal amounts of the two enantiomeric forms of a chiral molecule is called a: racemic mixture or racemate.,Resolution of enantiomers,Molecules with 2 or more chiral centers have more isomers.,A mixture containing predominantly one enantiomer is termed as: Enantiomerically Enr

2、iched, or Enantioenriched.,Quantitating Enantiopurity (对映纯度） Enantiomeric Excess (%e.e.) : Enantiopurity is usually reported in terms of “enantiomeric excess”,Most of chiral compounds are unavailable in enantioenriched form,Most of the important molecules to living systems are enantioenriched. Examp

3、les include: amino acids; sugars; proteins; nucleic acids; vitamins; terpenoids; alkaloids; and steroids.,Methods for obtaining enantioenriched compounds 1. Directly from chiral pool(手性源) 2. Synthesis from enantioenriched chiral pool starting products. 3. Synthesis using enantioenriched chiral pool

4、auxiliaries(辅助物). 4. Enantioselective catalysts(催化剂). 5. Classical resolution 或与一种异构体比与另外一种形成包合物稳定。 手性宿主腔穴 （ Chiral host cavity ）,手性冠醚（ chiral crown ether ） 54和53水溶液：混和均匀，平衡。 氯仿层中，R型54浓度是S型的两倍。 水层情况如何？,54,53,其它手性冠醚、穴状配体( cryptand) 环糊精类（cyclodextrins ，、型） 胆酸（cholic acid ） 酶：具极好的手性识别能力。,4生物化学处理（ Bioch

5、emical processes ） 微生物：有的可能只对对映体中一个异构体发生作用。 寻找适合的微生物是问题关键。,5 机械分离（ Mechanical separation ，手工分离） Pasteur 首创 Racemic acid（）和（）tartaric acid Racemic solution ammonium tartrate （外消旋酒石酸胺钠） （）成一种晶体；（）成一种晶体 非重叠晶体. The seeding of a racemic solution with something that will cause only one enantiomer to cryst

6、allize引入晶种,例2：heptahelicene，其一异构体具 =+1200，在苯中易结晶。 例3：Polycrystalic racemic samples of () 1,1-binaphthyl （双萘）加热到 76150C发生晶型转化，从一种晶型转化成另外一种晶型光学活性晶体产生。,例4在手性添加物（chiral additive）存在下，对映选择性结晶。,升华（ Sublimation ）拆分 例：,6动力学拆分（ Kinetic resolution ） 对映体与手性化合物以不同速度进行反应，可在完全反应前中止反应，达到部分分离。 例1：对映体烯烃与光学活性diisopino

7、campheylborane（二异松蒎醇硼烷）反应。,例2：allylic alcohols （烯丙基醇）与手性环氧化试剂（对映体之一）反应,获得另外一个对映体或相应产物方法： （1）选用另外一个对映体试剂 （2）保持立体化学中心构型不变情况下，从产物转化为起始物。,手性环氧化试剂,7. 去外消旋化(Deracemization)：将对映体之一转化成另一异构体，得到单一对映体纯或相对含量多的产物 例： 去外消旋化的两个条件： （1）对映体与不同光学活性物形成复合物 （2）在实验条件下须能互为转化,racemer,产物,Optical Purity Percent optical purity=

8、 与化合物浓度一般成线性关系。 Optical purity= percent enantiomeric excess = 100 =%(R)-%(S),obs,max, 100,?,max如何测定? %(R)或%(S)如何测定? (R)+(S)=100% NMR方法测定：（请阅读 Ref 167。） R 和 S 对映异构体的非外消旋混合物( Nonracemic mixture)mixture of diastereomer with an optically pure reagent测NMR谱（对映体结构中R、S某些峰已分离）,对映体测NMR：R、S所有对映体信号重叠 对映体： 在一般非手

9、极性溶剂中,具相同的NMR谱图， 在手性溶剂或添加手性试剂环境下，具不同的NMR谱图，混合物中哪个信号属哪个对映体？,Chiral solvent(手性溶剂) 镧位移试剂（ Chiral lanthanide shift reagent ） 例: tris 3-trifluoroacetyl-d-camphorato europium () lanthanide shift reagent: spreading NMR peak of compound with which they can form coordination compounds （配位化合物）, for example al

10、cohols, carbonyl compounds, amines, etc. Chiral lanthanide shift reagents shift the peeks of the two enantiomers of many such compounds to different extents,（3）GC（手性涂层和手性固定相）,Nickle (II) bis 3-(heptafluorobutanoyl)-1(R )-camphorate,Example 1: gas chromatography separation on chirasil Val Column,Comp

11、lexation gas chromatography on chiral column Example 2 Z- and E-2-ethyl 1,6-dioxaspiro4,4nonane,Complexation gas chromatography on chiral column Example 3,Complexation gas chromatography on chiral column Example 4,Complexation gas chromatography on chiral column Example 5,Complexation gas chromatogr

12、aphy on chiral column Example 6,Complexation gas chromatography on chiral column Example 7,Complexation gas chromatography on chiral column Example 8,（4）HPLC（High-pressure/ performance liquid chromatography), SFC 转化成差向异构体测定 利用手性柱测定 加入手性试剂形成水溶性包合物进行测定 利用手性溶剂测定（原则上可以）,Supercritical fluid Chromatograph

13、y on chiral stationary phases Example 1,Supercritical fluid Chromatography on chiral stationary phases Example 2,Supercritical fluid Chromatography on chiral stationary phases Example 3,Supercritical fluid Chromatography on chiral stationary phases Example 4,Supercritical fluid Chromatography on chi

14、ral stationary phases Example 5,Ion pair HPLC on chiral column Examples 1 and 2,Ion pair HPLC on chiral column Examples 3 and 4,环糊精柱,Enantiomeric HPLC Separation,CSP:手性固定相,Enantiomer separation on CSPs（手性固定相） depends upon formation of transient diastereomeric adsorbates （吸附物） of differing free energ

15、y. Stability differences as small as 10 calories/mole molecule can result in detectable HPLC separation. The above illustrates are the use of a stationary phase containing an immobilized enantioenriched selector molecule.,An alternative approach utilizes an enantioenriched selector molecule which is

16、 added to the mobile phase.,Prof. William Pirkle, of the University of Illinois was an early pioneer in the development of chiral stationary phases. Research in his group entails the use of chromatographic and spectroscopic (especially NMR) techniques to study the details of how one enantiomer of a

17、substance discriminates between the enantiomers of other substances,/chem/faculty/William_Pirkle.html,His rationale for the development of the Pirkle Chiral Stationary Phase was based on the following: If a chiral molecule is to have different affinities for enantiomers, it mus

18、t have a minimum of three points of interaction- at least one of these being stereochemically dependent.,Chiral Columns,With Pirkle CSPs, chiral recognition occurs at binding sites. Major binding sites are classified as - basic or - acidic aromatic rings, acidic sites, basic sites, and steric intera

19、ction sites. Aromatic rings are potential for - interactions. Acidic sites supply hydrogens for potential intermolecular hydrogen bonds. Basic sites, such as electrons may also form hydrogen bonds. Steric interactions may also occur between large groups.,Pirkle CSPs generally fall into three classes

20、: -electron acceptors -electron donors -electron acceptors and -electron donors,Enantiomer Separation The Pirkle CSPs manufactured by Regis Technologies can separate a wide variety of enantiomers in numerous compound groups. Examples include: Aryl Propionic Acid Non-Steroidal Anti-Inflammatory Drugs

21、. Agricultural Compounds. Natural Products. -Blockers. Many Pharmaceuticals.,Ability to Invert Elution Order An important advantage of the Pirkle Chiral Stationary Phase is the ability to invert elution order by using the same type of CSP, but with the opposite absolute configuration. As a result it

22、 is possible to have the trace enantiomer elute before the major a desirable feature for enantiomeric purity determinations. For preparative separations it is beneficial to elute the desired component first.,preparative separation,enantiomeric purity determination,Recommended Column Selection Sequen

23、ce For Compound Types,Resolution of Enantiomers,Baseline Resolution (Rs 1.5) allows for convenient quantitation of e.e.,Resolution 1.5 (overlapping peaks) complicates e.e. determinations,Resolution 1.5 may also complicate e.e. determination, but is useful for preparative separations.,where: t1 = ret

24、ention time of 1st eluted peak t2 = retention time of 2nd eluted peak w1 = peak width at baseline of 1st eluted peak w2 = peak width at baseline of 2nd eluted peak,Other Types of CSPs Modified Polysaccharides: Chemically modified polysaccharides (starch or cellulose) are absorbed on silica. Advantages： Resolve a wide variety of enantiomers Reasonably good efficiency Reasonably good capacity Disadvantages： The CSP has poor stability/ durability Poor solvent compatability Cannot invert elution order Often unpredictable structure resolution properties.,Cyc