动态动力学拆分制备(R)-1-氨基茚满

首次采用动态动力学方法成功制备光学纯(R)-1-氨基茚满.以十二烷基磺酸根离子改性的层状双氢氧化物(LDH)为载体负载金属钯制备了新型消旋催化剂Pd/LDH-DS,对其消旋化(S)-1-氨基茚满的反应条件进行了研究,发现其具有优越的反应性能;在此基础上结合脂肪酶Novozym 435的反应条件,最终确定以甲苯为反应溶剂,戊酸对氯苯酯为酰基供体,底物浓度为82.5 mmol/L,55℃条件下反应15 h后制备得到(R)-1-氨基茚满戊酸酯,产物转化率>99%,产物光学纯度eeP>99%.     

有机相酶催化氨解反应拆分制备(R)-4-氯-3-羟基丁酸乙酯

通过脂肪酶催化的氨解反应拆分4-氯-3-羟基丁酸乙酯. 经过对脂肪酶及反应溶剂的筛选, 确定最佳脂肪酶及溶剂分别为Novozym435和二氧六环; 并在该反应体系中考察了温度、底物浓度、酶浓度与摇床转速对反应的影响. 综合考虑反应的反应速度和对映体选择率, 确定较佳的反应条件为: 温度30 ℃、底物浓度0.5 mol/L、酶量10 mg/mL、摇床转速200 n/min. 反应35 h后, ee可以达到99%以上, 此时转化率为57.7%.     

华根霉菌丝体结合脂肪酶催化酯合成动力学拆分2-辛醇

研究了华根霉CCTCC M201021菌丝体结合脂肪酶(RCL)在非水相中催化酯合成动力学拆分外消旋2-辛醇的能力.发现RCL对该反应具有较好的光学选择性(E>100),辛酸和异辛烷分别是最佳的酰基供体和反应溶剂,体系水活度的减少对反应的光学选择性没有明显影响,但能显著提高反应初速度.在相同转化率下,通过添加3A分子筛降低体系水含量可使反应初始速度提高7.3倍.当底物浓度提高到0.230 mol/L,反应40 h时转化率达44.4%,产物酯的ee值为94.7%.与三种商品化脂肪酶进行了比较,发现在相同条件下RCL对2-辛醇的拆分不但具有较好的光学选择性(E=103.1),而且也表现出较高的反应初速度和转化率.     

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.     

离子液体中脂肪酶催化拆分外消旋烯丙酮醇反应

 以离子液体为溶剂,考察了溶剂类型、水活度、温度、 pH值和共溶剂等因素对脂肪酶催化拆分外消旋烯丙酮醇(R,S)-4-羟基-3-甲基-2-(2-丙烯基)-2-环戊烯-1-酮反应的影响,并与常用于外消旋烯丙酮醇拆分的有机溶剂乙酸乙烯酯进行了比较. 结果表明,在离子液体［bmim］PF6中脂肪酶的催化性能较好,酶初始反应速率为18.48 μmol/(g·min), 半衰期为74.53 h, 高于在乙酸乙烯酯中的相应值(9.18 μmol/(g·min)和64.29 h). 但离子液体中拆分反应的转化率低于在乙酸乙烯酯中的转化率,可以通过向离子液体中补加酰基供体来提高外消旋烯丙酮醇的转化率. 两种反应介质中最佳酶反应条件均为水活度0.17, 温度40 ℃和pH=7, 但加入共溶剂后,离子液体中脂肪酶催化拆分外消旋烯丙酮醇的效率降低,而在乙酸乙烯酯中则有所提高.     

脂肪酶-酸性树脂耦合催化1-苯乙醇的动态动力学拆分

发现了一种催化效率较高的消旋催化剂——CD550树脂,其与脂肪酶耦合可成功催化1-苯乙醇的动态动力学拆分(DKR).该树脂60℃下可将100 mmol/L(S)-1-苯乙醇于1.5 h内完全消旋.当其应用于1-苯乙醇的DKR反应时,通过采用结构较复杂的邻苯二酚二乙酸酯、间苯二酚二乙酸酯、3,5-二甲基苯酸乙酸酯作为酰基供体,可有效抑制树脂催化的底物无选择性转酯化,极大提高底物转化率和产物ee值.以邻苯二酚二乙酸酯参与的DKR反应为例,反应10 h,转化率大于99%,eeP为90.5%.     

水解动力学拆分3-(1-萘氧基)-1,2-环氧丙烷

研究了3-(1-萘氧基)-1,2-环氧丙烷[(R,S)-1]在Salen Co(Ⅲ)催化下的水解动力学拆分(HKR)。以转化率和ee值为指标,考察了催化剂用量、底物用量、反应温度、反应时间、溶剂种类等对HKR反应的影响。最佳HKR条件为:(R,S)-1 10 mmol,w[Salen Co(Ⅲ)]=0.75%,THF 1 mL,水0.5 eq,于25℃水解40 h,(R,S)-1的转化率为49.5%,(S)-1的ee为99.5%。     

非水相中微生物脂肪酶催化转酯化拆分(R,S)-α-苯乙醇

研究了非水有机溶剂体系中脂肪酶不对称转酯化拆分(R,S)-α-苯乙醇反应,比较了15种不同微生物来源的脂肪酶,从中优选出催化活性及对映选择性较高的脂肪酶Lipase PS,系统考察了影响该酶催化不对称转酯化反应的关键因素,获得了优化的催化拆分工艺条件.结果表明,脂肪酶Lipase PS在非水反应体系中,以正己烷为反应介...     

羰基还原酶CR2重组酶体系不对称合成(S)-N,N-二甲基-3-羟基-3-(2-噻吩)-1-丙胺

构建了羰基还原酶CR2重组酶体系,并优化了相关的酶促催化反应条件.通过在催化体系中添加辅酶NADP+(0.1 mmol/L)和辅底物葡萄糖(120 g/L),在30℃及p H=8.0的条件下反应4 h,CR2重组酶体系不对称还原N,N-二甲基-3-酮-3-(2-噻吩)-1-丙胺(DKTP,10 g/L),合成了高光学纯度(S)-N,N-二甲基-3-羟基-3-(2-噻吩)-1-丙胺[(S)-DHTP,e.e.值99.9%],产率为62%.在酶促催化过程中,由于辅酶循环生成葡萄糖酸导致反应体系p H值下降而影响催化效率.通过调控反应体系p H值,(S)-DHTP的产率提高到68%.不同浓度底物的反应过程表明底物对CR2酶促反应具有抑制作用,且在10 g/L底物浓度下反应的时空产率可达1.3 g·L-1·h-1.     

有机相酶催化转酯化反应拆分西酞普兰中间体

利用脂肪酶催化的不对称转酯反应成功远程拆分具有季碳手性中心的西酞普兰中间体4-[4-(二甲基氨基)-1-(4’-氟苯基)-1-羟基丁基]-3-(羟基甲基)苄腈(1). 以乙酸乙烯酯作为酰基供体, 通过筛选酶和溶剂, 确定最佳脂肪酶及溶剂分别为Candida antarctica lipase B (Novozym 435)和乙腈; 并在该反应体系中考察了反应温度、二醇1与酰基供体的比例、酶浓度和摇床转速等对反应的影响, 确定优化的反应条件为: 温度30 ℃, 二醇1与酰基供体的物质的量比为1∶5, 酶浓度为10 mg/mL, 摇床转速200 r/min. 分别考察二醇1浓度为60和180 mmol/L的反应情况, 均具有较高的选择性和反应速度. 实验结果表明酶能够多次重复利用.     

有机相酶催化拆分制备(S)-2-氯-1-(2-噻吩)-乙醇

首次在有机相中对酶催化条件下的2-氯-1-(2-噻吩)-乙醇的反应进行了研究. 通过对不同来源酶的筛选, 找到了Novozym 435和Alcaligenes sp两种选择性较好的酶, 它们均对该反应具有较高的选择性和较快的反应速度, 在此基础上进一步通过对溶剂、温度、摇床转速以及酶用量的筛选, 确定了能够有效拆分2-氯-1-(2-噻吩)-乙醇的较佳反应条件. 当温度35 ℃, 酶量10 mg/mL, 反应72.5 h, 产物的ee值为98.5%时收率为48.6%.     

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.     

有机相中利用脂肪酶催化的醇解反应拆分炔丙醇酮乙酸酯

 研究了有机相中脂肪酶催化的炔丙醇酮乙酸酯的立体选择性醇解反应, 考察了碱的种类、酰基受体和溶剂等对反应的影响. 结果表明, 以四氢呋喃为溶剂, CH3OH 为酰基受体, Lipase PLG 脂肪酶为催化剂, Na2CO3 为碱性添加剂, 高底物浓度下 40 oC 反应 96 h 后, 底物转化率和产物 ee 值分别达到 49.5% 和 99.5%. 碱的添加极大地提高了反应速度.     

Kinetic study on enantioselective resolution of (R,S)-2-phenylpropionic acid through Novozyme 435–catalyzed esterification

2-Phenylpropionic acid (2-PPA) is a very important chiral intermediate in the synthesis of aryl propionic acid drugs with anti-inflammatory and analgesic effects. Enzymatic kinetic resolution of (R,S)-2-PPA using n-hexanol as an acyl donor was carried out in n-hexane. Lipases from different sources were used to catalyze the esterification of 2-PPA, among which Novozyme 435 had the highest catalytic efficiency. The effects of reaction conditions on conversion (c) and enantiomeric excess (ee), involving temperature, substrate concentrations, enzyme loading, and reaction time were investigated. The kinetic model based on the Ping-Pong bi-bi mechanism was established to simulate the enzymatic esterification process. The experimental values of initial rates of various 2-PPA concentrations were consistent with the simulated values.     

Lipase-mediated kinetic resolution of (RS)-1-bromo-3-[4-(2-methoxy-ethyl)-phenoxy]-propan-2-ol to (R)-1-bromo-3-(4-(2-methoxyethyl) phenoxy) propan-2-yl acetate

A novel biocatalytic method for the enantioselective synthesis of (R)-bromo-3-[4-(2-methoxy-ethyl) phenoxy]-2-propanol [(R)-BMEPP], a precursor for the synthesis of (S)-metoprolol, an anti hypertensive drug is described. We have developed kinetic resolution of rac-BMEPP by transesterification using Candida rugosa lipase and vinyl acetate as the acyl donor affording the product with excellent conversion (49%) and ee (>99%). Various reaction parameters (source of enzyme, reaction media, and concentration of substrate and acylating agent) for the enzymatic kinetic resolution have been reported.     

(R)-(+)-N-methylbenzoguanidine ((R)-NMBG) catalyzed kinetic resolution of racemic secondary benzylic alcohols with free carboxylic acids by asymmetric esterification

(R)-(+)-N-Methylbenzoguanidine ((R)-NMBG) was found to function as an efficient acyl-transfer catalyst for the kinetic resolution of racemic secondary benzylic alcohols in the presence of achiral carboxylic acids and pivalic anhydride. The use of a tertiary amine in this reaction is not necessary to attain good chemical yields of the products. It was determined that diphenylacetic acid could be employed as the most suitable acyl donor for achieving a high enantioselectivity for the kinetic resolution of the racemic secondary benzylic alcohols having normal aliphatic alkyl chains at the C-1 positions. On the other hand, a less-hindered carboxylic acid, such as 3-phenylpropanoic acid, functioned as a better acyl donor for the kinetic resolution of racemic secondary benzylic alcohols having branched aliphatic alkyl chains at the C-1 positions.     

An alternative stereoselective total synthesis of (-)-pyrenophorol

The total synthesis of 16-membered C₂–Symmetric dilactone (-)-Pyrenophorol was accomplished starting from commercially available (S)-epoxide prepared by hydrolytic kinetic resolution of (±) – epoxide with key steps of Grignard reaction, Swern oxidation, Wittig reaction and cyclization was achieved by intermolecular Mitsunobu cyclization. The synthesis of (-)-Pyrenophorol accomplished from cheaply available starting material, easily work-up procedures and reduction of cost in industrial process were major advantages of this route.     

Lipase-catalyzed kinetic resolution approach toward enantiomerically enriched 1-(β-hydroxypropyl)indoles

In a route towards enantiomerically enriched 1-(β-hydroxypropyl)indoles, which are potentially useful building blocks for high value-added chemicals synthesis, a kinetic resolution approach by means of lipase-catalyzed enantioselective acylation as well as hydrolysis/methanolysis has been elaborated for the first time. The enzymatic resolution of chiral N-substituted indole-based sec-alcohols was successfully accomplished, yielding both enantiomeric forms of the employed derivatives with up to >99% enantiomeric purity via an enantioselective transesterification under mild reaction conditions. The most selective resolutions were obtained using fungal (CAL-B and TLL) and bacterial (PFL and BCL) lipases and vinyl acetate as the acyl?group donor. The synthetic protocol described herein is very simple, user-friendly and efficient, thus paving the way for future access towards more complex compounds of this type. The absolute configurations of novel enantiomeric derivatives, and thus stereoselectivity of the described enzymatic reactions were confirmed by application of CDA-based NMR methodology and single-crystal X-ray diffraction analysis.