薄层色谱法在制备光学戊醇中的应用

光学戊醇是合成手性药物、手性材料的重要中间体,可通过酶法以三丁酸甘油酯为底物进行拆分制备。本文用猪胰脂肪酶(PPL)为催化剂,三丁酸甘油酯(TBT)为底物兼有机相对DL-2-甲基-1-丁醇拆分。用TLC法对反应过程中的各种戊酯进行分离并得出定量分析结果。     

脂肪酶催化酯化拆分与水解拆分2-甲基丁酸及其酯

2-甲基丁酸手件中心碳原子上的基团差异较小,是一种典型的酶法动力学拆分较为困难的风味化合物.本文分别在不同体系中比较了几种商品化脂肪酶和华根霉脂肪酶(RCL)催化酯化和水解反应对2-甲基丁酸及其酯的拆分,结果表明,RCL不仅在非水相中具有一定的选择性酯化能力,而且在水相中具有更强的选择性水解2-甲基丁酸乙酯的能力,在40℃下优先水解(S-型底物,反应10h后(R)-2-甲基丁酸乙酯的ee值为92.4%.进一步考察了温度对RCL催化酯化拆分与水解拆分的影响,结果表明,低温下反应的对映体选择性较高,在4℃下通过水解拆分获得的(R)-2-甲基丁酸乙酯的ee值町提高至95.0%.     

固定化嗜热酯酶催化拆分(R,S)-2-甲基-1-丁醇

利用帆布固定化嗜热酯酶APE1547(3)在非水介质中催化转酯化反应进行酶促拆分(R,S)-2-甲基-1-丁醇制备(S)-2-甲基-1-丁醇(4).初步探讨了溶剂、酰基供体、温度及底物配比对3的催化活力(EA3)′与4对映选择性比率(E4)的影响.在最佳拆分条件下,EA3 =0.53 μmol·min-1·mg-1,E4=15.4.3套用8次后仍然保持较高的催化活性.     

微水相中改性Ultrastable-Y分子筛固定化脂肪酶拆分(R,S)-2-辛醇

采用改性Ultrastable-Y分子筛固定化P. expansum PED-03脂肪酶(PEL), 利用固定化PEL在微水相中对(R,S)-2-辛醇进行拆分. 结果表明, 改性Ultrastable-Y分子筛固定化PEL所催化的拆分反应的转化率(c)和对映体过量值(e.e.)以及对映体选择性(E)均得到大幅度提高. 介质类型和体系含水量对酶促拆分反应有较大的影响. 在以正己烷为溶剂, 含水量为0.8%的体系中, 于50 ℃反应24 h的转化率(c)可达到理论值的97.68%, 对映体过量值(e.e.)可达到98.75%. 改性Ultrastable-Y分子筛固定化PEL催化效率高、立体选择性强, 且催化性能稳定, 在(R,S)-2-辛醇的酶法拆分方面具有良好的应用前景.     

不对称加氢催化剂[Ru(BINAP)(OAc)2]的合成及其固载化研究

对文献报道的实验反应条件进行优化改进后,合成了不对称加氢催化剂[Ru((S)-BINAP)(OAc)2]和[Ru((R)-BINAP)(OAc)2]。将合成的催化剂应用于惕各酸的不对称催化氢化,(S)-2-甲基丁酸得率为88%,立体选择性可达85%e.e.。为了提高催化剂的利用率,将催化剂[Ru(BINAP)(OAc)2]负载在新型介孔分子筛SBA-15上,用于惕各酸的不对称催化氢化,循环应用3次后,(S)-2-甲基丁酸得率仍可达到59%,立体选择性达57%e.e.。     

高效液相色谱-旋光检测器联用实时检测对映体过量

在手性合成或拆分过程中,实时监测反应产物的对映体过量(e.e.)对于确定产物光学纯度至关重要。根据在一定测定条件下,单一对映体旋光度仅与其浓度成正比,利用高效液相色谱与旋光检测器联用,提出了一种实时测定e.e.的新方法。并在猪胰脂肪酶催化酯交换反应制备(S)-2-甲基-1-丁醇的过程中,比较了该方法与常规测定方法,证实了该方法简单,快速,有望作为一种手性技术中e.e.在线测定通用方法。     

一个具有相反光学选择性的新颖海洋 GDSL脂肪酶MT6用于（S）-1-苯基乙醇制备

1-苯乙醇是一种重要的手性药物中间体,并且(S)-1-苯乙醇和(R)-1-苯乙醇均具有应用价值.怎样获得光学醇的1-苯乙醇是药物合成中的重要问题.传统的化学合成手段不仅反应过程复杂,而且反应条件剧烈,对环境污染严重,因此生物催化方法越来越受到重视.脂肪酶和酯酶以其出色的立体选择性和温和的反应条件而被广泛用于手性药物的拆分制备.但是之前的一些研究发现脂肪酶和酯酶大都对(R)-1-苯乙醇及其衍生物有选择性,而我们发现并鉴定的脂肪酶 MT6的立体选择性则与这些脂肪酶/酯酶完全相反,具体体现在以下两个方面：(1) MT6能够特异地催化(S)-1-苯乙醇和乙酸异丙烯酯的转酯反应,生成(R)-1-苯乙醇;(2) MT6能够选择性地水解(S)-乙酸苏合香酯,生成(S)-1-苯乙醇.可见,利用 MT6催化的转酯反应和水解反应可以巧妙地进行(S)-1-苯乙醇和(R)-1-苯乙醇的制备. MT6来源于深海放线菌Marinactinospora thermotolerans SCSIO 00652,属于 GDSL家族脂肪酶第 II类群,这一类群的脂肪酶绝大多数来自微生物.有关 GDSL家族脂肪酶在手性拆分中的应用研究非常少.我们之前报道了 MT6的克隆、表达、纯化及转酯拆分反应,本文重点考察了 MT6通过水解反应制备(S)-1-苯乙醇的条件,优化了酶促水解拆分反应温度、有机共溶剂、pH、离子强度、酶用量、底物浓度、反应时间以及底物侧链长度等参数.研究发现,在反应体系中加入一定量的有机共溶剂能够大大提高产物(S)-1-苯乙醇的光学纯度,其中添加二氯甲烷获得的结果最为理想,可以将产物光学纯度从43%提高到89%,E值从2.84提高至22.82.经过优化,最佳反应温度为40°C,共溶剂二氯甲烷浓度为5%(体积分数),反应缓冲液为0.1 mol/L Tris-HCl (pH =7.0),酶用量为150 mg/mL,底物为15 mmol/L乙酸苏合香酯,反应时间控制在12 h.在此条件下,制备的(S)-1-苯乙醇的光学纯度可达97%,转化率可达28.5%,E值为95.9.此外,还比较了侧链长度不同的1-苯基乙醇酯对水解反应的影响,结果表明1-苯基乙醇酯的侧链长度可极大影响光学选择性和产率.在反应条件相同时, MT6催化侧链长度为4个碳的丁酸-1-苯乙酯水解,生成(S)-1-苯乙醇的光学纯度仅为50%.利用 AutoDock软件进行分子对接,结果显示长侧链的1-苯基乙醇酯离活性中心 His230的咪唑基较远,可能是导致酶立体选择性低的重要原因.值得注意的是,海洋微生物来源的 GDSL脂肪酶 MT6在水解反应和转酯反应中均表现出与一些已知脂肪酶/酯酶相反的立体选择性,因而具备进一步开发和应用价值.所制备的(S)-1-苯乙醇的光学纯度为97%,可以通过和转酯反应相结合的方式进一步提高产物的光学纯度和转化率.     

有机催化靛红亚胺与1,2,4-三氮唑衍生物的不对称aza-Mannich反应北大核心CSCD

将Takemoto型(硫)脲衍生物用于催化靛红亚胺与1,2,4-三氮唑的不对称aza-Mannich反应.筛选出最佳催化剂体系为:10%(摩尔分数)的1-[3,5-双(三氟甲基)苯基]-3-[(1R,2R)-2-(吡咯烷-1-基)环己基]硫脲催化剂1e,1 mL乙醚为溶剂,室温反应.以77%～90%的产率和最高达99%的对映选择性获得手性3-N,N’-缩酮-2-吲哚酮衍生物.     

非手性PNNP型钌配合物催化仲醇的外消旋化研究

制备了两种非手性PNNP型钌配合物Ru(BF4)2P2N2(3a,P2N2=N,N'-双-[邻-(二苯基膦)苯哑甲基]乙二胺)和Ru(BF4)2P2H4(3b,P2N2H4=N,N'-双-[邻-(二苯基膦)苯甲基]乙二胺),并以(R)-苯乙醇的消旋化为探针反应,分别考察了添加剂、溶剂、催化剂用量及温度等对两种钌配合物催化反应的影响,得到了较理想的反应条件,即4%3a,2 mL甲苯,lequiv.Ag2O,70℃下,在氮气保护下反应12 h.反应结果发现钌配合物3a可以较好地催化仲醇的消旋化,其中(R)-和(S)-苯乙醇消旋化反应后,ee都为58%;另外(S)-对甲基苯乙醇和(S)-对氟苯乙醇消旋化反应后,ee值分别为85%和71%.并初步试探了以苯乙醇为探针底物,钌配合物结合脂肪酶Candida antarctica催化的动态动力学拆分.     

(+)-1R,3R(3S),5S-2,4,3-二氮磷杂二环[3.2.1]辛烷衍生物的不对称合成

用(+)-顺式-1R,3S-1,2,2-三甲基-1,3-环戊二胺1为手性诱导试剂分别和几类硫代磷酰二氯2a—k反应,合成了11个新型的含手性磷原子的(+)-1R,3RS,5S-2,4,3-二氮磷杂二环[3.2.1]辛烷的衍生物3a-k.3(1R,3Rs,5S)由两个不等量的非对映异构体3’(1R,3R,5S)和 3"(1R,3S,5S)组成,d.e.值对 3’为 6.2—83.6％,对3"为50.4—100％,表明3的合成是经过不对称反应实现的.苯氧基硫代磷酰二氯2e和1的反应具较高的光学选择性,产物中R磷原子异构体3’e的含量占90％;N,N-二烷基胺基硫代磷酰二氯2h,2i和1反应时,只得到含S磷原子的异构体3"h和3"i,为立体专一性反应.     

Kinetic Resolution of (R,S)-2-Butanol Using Enzymatic Synthesis of Esters

Kinetic resolution of (R,S)-2-butanol using enzymatic synthesis of esters has been studied. (R,S)-2-Butanol is commonly found as a racemic mixture, and the products of its esterification are racemic mixtures too. This work is of great significance in the field of the enzymatic kinetic resolution due to the little information found in literature about the resolution of (R,S)-2-butanol as pure compound. So, this article is a contribution about the enzymatic resolution of (R,S)-2-butanol. The reaction here studied is the esterification/transesterification of (R,S)-2-butanol in organic media (n-hexane) using as biocatalyst the lipase Novozym 435?. The main target of this study is to analyze the influence of certain variables in this reaction. Some of these variables are acyl donor (acids and esters), concentration of substrates, enzyme/substrate ratio, and temperature. The main conclusions of this study are the positive effect of higher substrates concentration (1.5 M) and larger amount of enzyme (13.8 g mol(-1) substrate) on kinetic resolution rate but not a very noticeable effect on enantiomeric excesses. The longer the carboxylic acid chain is, the better results are obtained. Besides to achieve a satisfactory kinetic resolution, it is recommendable to select reaction times (180 min) at which the highest substrate enantiomeric excess is reached (~60%). The temperature has not an appreciable influence on the resolution in the range studied (40-60 °C). When an ester (vinyl acetate) is used as acyl donor, the resolution shows better results than when using a carboxylic acid as acyl donor (ee(s)?~90% at 90 min). Moreover, Michaelis-Menten parameters, v(max) and K(M), were determined, 0.04 mol l(-1) min(-1) and 0.41 mol l(-1), respectively.     

Use of a microemulsion system to incorporate a lipophilic chiral selector in electrokinetic capillary chromatography

Summary The separation of (1R, 2S) and (1S, 2R)-ephedrine using microemulsion electrokinetic capillary chromatography is reported. The lipophilic chiral selector, (2R, 3R)-di-n-butyl tartrate (0.5% w/w), was introduced into the electrophoretic buffer consisting of 0.6% (w/w) sodium dodecyl sulfate (SDS) and 1.2% (w/w) 1-butanol in 15 mM tris-hydroxyaminomethane buffer (pH 8.1). The two isomers of ephedrine were separated with excellent resolution.     

Chiral recognition between 1-(4-fluorophenyl)ethanol and 2-butanol: higher binding energy of homochiral complexes in the gas phase

Diastereomeric adducts between (S)-1-(4-fluorophenyl)-ethanol and R and S 2-butanol, formed by supersonic expansion, have been investigated by means of a combination of mass selected resonant two-photon ionization-spectroscopy and infrared depletion spectroscopy. Chiral recognition is evidenced by the specific spectroscopic signatures of the S(1)← S(0) electronic transition as well as different frequencies and intensities of the OH stretch vibrational mode in the ground state. D-DFT calculations have been performed to assist in the analysis of the spectra and the determination of the structures. The homochiral and heterochiral complexes show slight structural differences, in particular in the interaction of the alkyl groups of 2-butanol with the aromatic ring. The experimental results show that the homochiral [FE(S)·B(S)] complex is more stable than the heterochiral [FE(S)·B(R)] diastereomer in both the ground and excited states. The binding energy difference has been evaluated to be greater than 0.60 kcal mol(-1).     

Modelling neurotransmitter functions: a laser spectroscopic study of (1S,2S)-N-methyl pseudoephedrine and its complexes with achiral and chiral molecules

Wavelength and mass resolved resonance-enhanced two photon ionization (R2PI) excitation spectra of (1S,2S)-N-methyl pseudoephedrine (MPE) and its complexes with several achiral and chiral solvent molecules, including water (W), methyl (R)-lactate (L(R)), methyl (S)-lactate (L(S)), (R)-2-butanol (B(R)), and (S)-2-butanol (B(S)), have been recorded after a supersonic molecular beam expansion and examined in the light of ab initio calculations. The spectral patterns of the selected complexes have been interpreted in terms of the specific hydrogen-bond interactions operating in the diastereomeric complexes, whose nature in turn depends on the structure and the configuration of the solvent molecule. The obtained results confirm the view that a representative neurotransmitter molecule, like MPE, "communicates" with the enantiomers of a chiral substrate through different, specific interactions. These findings can be regarded as a further contribution to modelling neurotransmitter functions in biological systems.     

Short-range interactions within molecular complexes formed in supersonic beams: structural effects and chiral discrimination

One- and two-color, mass-selected R2PI spectra of the S1<--S0 transitions in the bare chiral chromophore R-(+)-1-phenyl-1-propanol (R) and its complexes with a variety of alcoholic solvent molecules (solv), namely methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, S-(+)-2-butanol, R-(-)-2-butanol, 1-pentanol, S-(+)-2-pentanol, R-(-)-2-pentanol, and 3-pentanol, were recorded after a supersonic molecular beam expansion. Spectral analysis, coupled with theoretical calculations, indicate that several hydrogen-bonded [R.solv] conformers are present in the beam. The R2PI excitation spectra of [R.solv] are characterized by significant shifts of their band origin relative to that of bare R. The extent and direction of these spectral shifts depend on the structure and configuration of solv and are attributed to different short-range interactions in the ground and excited [R.solv] complexes. Measurement of the binding energies of [R.solv] in their neutral and ionic states points to a subtle balance between attractive (electrostatic and dispersive) and repulsive (steric) forces, which control the spectral features of the complexes and allow enantiomeric discrimination of chiral solv molecules.     

(R)-3-氨基丁醇的合成研究进展

(R)-3-氨基丁醇是合成抗艾滋病整合酶抑制剂度鲁特韦的重要中间体,其品质的好坏以及价格的高低对于度鲁特韦的品质及生产成本有着很重要的影响。本文从化学拆分法、手性原料合成、化学诱导法、制备色谱法和生物酶法五个方面对合成(R)-3-氨基丁醇的方法进行了综述。     

淀粉衍生物固定相对马拉硫磷和氟虫腈对映体的手性拆分

淀粉衍生物固定相对马拉硫磷和氟虫腈对映体的手性拆分;马拉硫磷;氟虫腈;手性拆分;直链淀粉-三（（S）-苯基乙基氨基甲酸酯）     

Enantioselective chemisorption on a chirally modified surface in ultrahigh vacuum: adsorption of propylene oxide on 2-butoxide-covered palladium(111)

The enantioselective chemisorption of (S)- and (R)-propylene oxide is measured on a Pd(111) surface chirally modified using (S)- and (R)-2-butanol. Reflection-absorption infrared spectroscopic (RAIRS) data suggest that adsorbed 2-butanol forms 2-butoxide species when heated to approximately 150 K and converts to a ketone with a concomitant loss in chirality at 200 K. Methyl ethyl ketone, ethylene, methane, CO, and hydrogen are found as products in temperature-programmed desorption (TPD). Propylene oxide adsorbs reversibly on Pd(111) at 80 K without undergoing any thermal decomposition, thus providing an ideal probe of surface chirality. The coverage of (R)-propylene oxide adsorbing on an (R)-2-butoxide-covered surface, ratioed to that on one covered by (S)-2-butoxide, reaches a maximum value of approximately 2 at a relative 2-butoxide coverage of approximately 25% of saturation and decreases to unity at a coverage of approximately 50% of saturation. This implies that the enantioselectivity depends critically on coverage and arises due to chiral "pockets" formed on the surface.     

Enantioselective oxidation of secondary alcohols at a quinohaemoprotein alcohol dehydrogenase electrode

Quinohaemoprotein alcohol dehydrogenase fromComamonas testosteroni was co-immobilized with a redox polymer (a poly(vinylpyridine) complex functionalized with osmium bis(bipyridine) chloride) on an electrode. The enzyme electrode readily oxidizes primary alcohols and secondary alcohols with maximum current densities varying between 0.43 and 0.98 A m^-2 depending on the substrate and the operation temperature. The affinity of the enzyme for aliphatic alcohols increases with the chain length of the substrate (i.e., 1-pentano1 [K_m = 0.006 mM] is a much better substrate than ethanol [K_m= 2.2 mM]). The same property is observed for secondary alcohols in the series 2-propanol (K_m = 22 mM) to 2-octano1 (K_m = 0.05 mM). The enzyme electrode is enantioselective in the oxidation of secondary alcohols. A strong preference is observed for the S-2-alcohols; the enantioselectivity increases with increasing chain length. The enantiomeric ratio (E) increases from 13 for (R,S)-2-butanol to approximately 80 for (R,S)-2-heptanol and (R,S)-2-octanol. This makes the enzyme electrode, potentially, a powerful tool for the preparation of a large range of alkanones and/or for the (kinetic) resolution of racemic alcohols.     

Synthesis of C 2-Symmetric Chiral Amino Alcohols: Their Usage as Organocatalysts for Enantioselective Opening of Epoxide Ring

A series of β-amino alcohols derivatives were synthesized from (R)-2-amino-1-butanol and (S)-1,2-propanediol, and they have been used as organocatalaysts in the racemic ring opening of epoxide in good yields with high enantiomeric excess (up to 97%).