R-沙美特罗的合成方法

近年来手性沙美特罗的合成方法有微生物催化、不对称氢化、CBS(Corey-Bakshi-Shibata)还原反应及不对称Henry反应、手性(Salen)Co试剂催化的HKR(末端环氧不对称水解动力学)拆分反应等。对这些方法进行比较,结果表明,不对称催化合成由于其反应收率高、反应产物光学纯度高、操作容易控制,在目前手性药物的合成中处于主导地位。此外酶催化不对称合成、手性辅基诱导的对映选择性合成等方法也是有效的途径。     

手性芳基醇的生物催化不对称合成

光学活性芳基醇化合物是一类重要的手性砌块,可用于合成多种手性药物,其制备技术研究是近年来的研究热点。与传统的化学制备方法相比,生物催化方法由于具有选择性高、反应条件温和以及环境危害少等优点更具吸引力。通过生物催化不对称还原芳基酮是合成对映体纯芳基醇最有效的方法之一。本文综述了生物催化不对称还原制备手性芳基醇的研究进展,重点介绍了不同形式的生物催化剂应用于生物不对称还原的研究现状,包括微生物细胞、酶、重组工程菌以及固定化细胞等,概述了有机溶剂、表面活性剂和离子液体等底物助溶剂对生物不对称催化的影响,并对生物催化制备对映体纯芳基醇的研究前景进行了展望。     

由(1S,2S)—伪麻黄碱制备噁唑硼烷催化甲硼烷不对称还原含氟酮

前手性酮的对映选择性还原在不对称合成中占有极其重要的地位。人们对这类反应进行了广泛的研究,其中Ｉｔｓｕｎｏ和Ｃｏｒｙ等发现的用手性硼杂口恶唑烷催化不对称还原的方法,已成为高对映选择性还原羰基化合物最成功的方法之一［１,２］。近年来,国内外许多文献报道...     

面包酵母在催化不对称合成中的应用

介绍了当前国内外在以面包酵母为催化剂不对称催化合成手性化合物的研究情况,重点介绍了面包酵母催化各类潜手性羰基的不对称还原、潜手性碳一碳双键的不对称加成和碳一碳键形成的反应情况,讨论了各种提高酵母催化不对称合成反应立体选择性的方法,对酵母催化不对称合成有关生物学方面的研究进行了简单的介绍。     

手性炔丙醇的不对称催化合成研究进展

手性炔丙醇是一种重要中间体化合物,作为合成多种光学活性化合物的重要合成前体受到学者们广泛关注。目前通过酮的不对称催化反应合成手性炔丙醇的研究开发具有极大发展前景,因此本文围绕酮类化合物的不对称催化反应来进行综述,结合相关反应最新研究进展,全面总结并分类了不对称催化还原、催化不对称加成等反应类型,介绍了合成不同结构手性炔丙醇的新思路,并对酮的不对称催化反应在未来能成为工业化重要生产途径作出展望。     

手性药物的酶催化不对称定向合成

手性药物目前已成为国际上新药研究的热点。手性药物及其中间体的酶催化定向合成与传统的有机合成反应相比,所需条件温和,无需强酸强碱、高温高压等极端条件,可大大降低对设备的要求,同时具备反应速度快、立体选择性高等优势,而且对环境污染小,属于绿色合成技术,因而成为制备手性化合物的最有前景的方法之一。本文主要介绍了手性药物的酶催化不对称定向合成的方式、催化机理及应用,并引入了一些最新进展情况。     

手性亚砜合成

手性亚砜及其衍生物广泛作为重要手性中间体和辅剂、手性配体和催化剂、手性药物。手性亚砜可以采用生物方法和化学方法来合成,化学方法包括手性辅剂诱导、手性氧化剂氧化、手性拆分和不对称催化等。本文简要综述了手性亚砜的各种用途和各种合成方法的研究进展,主要介绍了钛和钒催化的不对称硫醚氧化反应,也介绍了作者最近在钒催化的不对称硫醚氧化反应方面所做的研究工作。     

生物催化不对称合成β-羟基酸衍生物

手性β-羟基酸及其衍生物是应用化工和有机合成的关键中间体.生物催化的不对称合成方法以其绿色环保、简洁高效及高立体选择性已成为一个新兴的研究热点.本文较系统地总结了生物催化不对称合成β-羟基酸及其衍生物的研究工作,重点介绍了脂肪酶、腈代谢酶及还原酶在合成手性β-羟基酸衍生物中的应用.最后,展望了生物催化不对称合成β-羟基酸的发展方向.     

有机小分子不对称催化Michael加成的研究进展

有机小分子催化成为现在最热门的研究领域之一.不对称Michael加成反应是合成具有一个或多个手性中心合成砌块和药物中间体的重要方法.介绍了近3年来有机小分子伯胺衍生物、吡咯烷衍生物、(硫)脲、手性方酰胺和磷酸等在不对称催化Michael加成中的应用研究进展.对各种小分子结构和催化活性的关系、催化剂诱导活化机理以及各种催化体系在药物和关键中间体合成中的应用也进行详细的评述.     

茚及其衍生物的催化不对称合成

茚及其衍生物广泛存在于自然界中,其中多官能团化的茚类化合物大多具有重要的生物活性,因而非常具有成为药物的先导化合物的潜力。特别是茚类化合物的不对称合成吸引了有机化学家们的广泛关注,最近有许多相应的合成方法研究被报道,包括外消旋体拆分、手性辅基及底物诱导的合成和手性催化合成等。本文总结了茚及其衍生物的催化不对称合成研究进展,重点介绍过渡金属及有机小分子不对称催化反应,并对该领域的研究前景进行了展望。     

Production of enantiopure chiral aryl heteroaryl carbinols using whole‐cell Lactobacillus paracasei biotransformation

Abstract

Aryl and heteroaryl chiral carbinols are useful precursors in the synthesis of drugs. Lactobacillus paracasei BD87E6, which is obtained from a cereal based fermented beverage, was investigated as whole cell biocatalyst for the bioreduction of different ketones (including aromatic, hetero-aromatic and fused bicyclic ketone) into chiral carbinols, which can be used as a pharmaceutical intermediate. The study shows that bioreduction of aryl, heteroaryl and fused bicyclic ketone (1-5) to their corresponding chiral carbinols (1a-5a) in excellent enantioselectivity (>99%) with high yields. This study gave the first example for an enantiopure production of (S)-6-chlorochroman-4-ol (3a), which has many antioxidant activity, by a biological method. For asymmetric bioreduction of other prochiral ketones, these results open way to use of L. paracasei BD87E6 as biocatalysts. Also, the present process shows a hopeful and alternative green synthesis for the production of enantiopure carbinols in a mild, inexpensive and environmentally friendly process.     

Candida zeylanoides as whole-cell biocatalyst to perform asymmetric bioreduction of benzophenone derivatives

Abstract

Candida zeylanoides P1 was investigated as whole cell biocatalyst for the bioreduction of biaryl prochiral ketones into chiral carbinols, which can be used as pharmaceutical intermediate. Bioreduction of different biaryl ketones was carried out to their corresponding chiral biaryl carbinols such as (S)-(4-chlorophenyl) (phenyl) methanol (2a), which can be used in the synthesis of L-cloperastine drug, with antitussive, antiepidemic activity and bronchial musculature relaxant characteristics, in gram scale, enantiopure form (>99%) and excellent yields. The selectivity of C. zeylanoides P1 in enantioselective reduction of biaryl ketones was not affected by the steric and electronic effects of substrates. The current method demonstrates an encouraging green chemistry approach for the production of biaryl secondary chiral alcohols of pharmaceutical importance in mild, inexpensive and environmentally friendly process. The present study has many benefits since this yeast biocatalyst were successfully applied bioreduction of structurally bulky prochiral substrates, which cannot be reducted by chemical catalysis.     

Efficient Enantioselective Biocatalytic Production of a Chiral Intermediate of Sitagliptin by a Newly Filamentous Fungus Isolate

(S)-3-Hydroxy-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-1-one ((S)-HTPP) is a crucial intermediate for the synthesis of Sitagliptin. A fungal strain ZJPH1308, capable of the biocatalysis of ketoamide 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-one (OTPP) to (S)-HTPP with excellent enantioselectivity, was isolated from a soil sample and identified as Rhizopus microsporus var. rhizopodiformis ZJPH1308 based on its morphological characteristics and internal transcribed spacer (ITS) sequence. Some key reaction parameters involved in the bioreduction catalyzed by isolate ZJPH1308 were then optimized. It demonstrated that the bioreduction of OTPP was effective conducted at relative high temperature (45 °C), along with distilled water as reaction medium and glycerol-coupling approach for cofactor regeneration. Under the optimal conditions, the preparative-scale bioreduction gave a 93.2 % yield (with >99.9 % of enantiomeric excess (ee)) at 15 mM of OTPP and 45 °C, reaction for 24 h. The results indicated that fungal isolate ZJPH1308 can afford a thermostable carbonyl reductase and is a promising biocatalyst for clean and efficient production of valuable chiral intermediate.     

Enantioselective Reduction of 2-Ketoalkanephosphonate by Baker's Yeast

Bioreduction of 2-oxo-3-halo (or azido) alkanephosphonates and 4-ethoxy-4,2-dioxobutanephosphonates by baker's yeast afforded 3-substituted 2-hydroxyalkanephosphonates in moderate to good yields and ee value. Moreover, a regio- and stereoselective bioreduction of 2,3-dioxoalkanephosphonates and 2,4-dioxoalkanephosphonates by baker's yeast was studied also. The resulting chiral hydroxy compounds can be used as chirons for the stereoselective synthesis of biologically active molecules.     

Novel cinchona alkaloid carbamate C9-dimers as chiral anion-exchange type selectors for high-performance liquid chromatography

Nine new quinine (QN) carbamate C9-dimers (QN-X-QN), with different aliphatic and cyclic spacers (X), have been synthesized and immobilized onto porous silica gel for HPLC. The chiral discriminating behavior of these "dimeric" anion-exchange type chiral stationary phases (CSPs) has been investigated in detail, to elucidate the role of the presence of a second QN subunit on the chiral selector (SO), as well as the influence of the structure and length of the spacer, on the overall chiral recognition of a set of N-derivatized amino acids and other acidic drugs. The bulkiness of the intermediate spacer tuned the chiral recognition abilities of these SOs, with the 1,3-adamantylen-derived CSP being the one that led to the best separations. Shorter spacers reduced the chiral discrimination abilities of the "dimeric" selectors, with the n-hexylen bridge being the most favorable distance to allow a nearly independent interaction of the two QN subunits with the racemic analytes. The comparison to five "monomeric" CSPs showed that the "dimeric" ones usually retain the chiral analytes more strongly, though the enantioseparation is not improved. Nevertheless, the exceptional resolution abilities of dimeric SOs with a trans- 1,2-diaminocyclohexylen-bridge for the separation of DNP-derivatives of amino acids and certain acidic drugs of therapeutical interest (e.g., profens) seemed to be superior to most of the other CSPs.     

Biocatalytic preparation of optically active 4-(N,N-dimethylamino)pyridines for application in chemical asymmetric catalysis

4-Chloro-2-(1-hydroxybenzyl)pyridine and 4-chloro-2-(1-hydroxyalkyl)pyridines were obtained with moderate to excellent enantiomeric excesses and high isolated yields by bioreduction with Baker’s yeast of the corresponding ketones. The resulting optically active alcohols were transformed into adequate DMAP derivatives, which have been applied in asymmetric catalytic processes as nucleophilic catalysts in the stereoselective chemical alkoxycarbonylation of 1-phenylethanol or as chiral ligands in the enantioselective addition of diethylzinc to benzaldehyde.     

Immobilized penicillin G acylase as reactor and chiral selector in liquid chromatography

In this paper, the use of penicillin G acylase (PGA) as a biocatalyst and as a chiral selector is described. Penicillin G-acylase is an interesting enzyme used in the manufacture of semisynthetic antibiotics and, in particular, in the production of 6-APA by hydrolysis of penicillin G. Five PGA-based HPLC columns have been prepared by using two different silica supports by employing two immobilization methods, namely "in situ" and "in batch". The effects of the immobilization techniques and of different silica pore size on the catalytic properties of the enzyme as well as the applicability of the PGA-bonded stationary phases as chiral selectors for a number of chiral drugs have been investigated. The HPLC columns based on immobilized PGA combine the hydrolytic activity and the chiral recognition properties of PGA, therefore they have been used for the development of a combined reaction-separation system for chiral and achiral substrates.     

Investigation of the Enantioseparation of Basic Drugs with Erythromycin Lactobionate as a Chiral Selector in CE

The macrocyclic antibiotics including ansamycins, glycopeptides, aminoglycosides and polypeptides have been demonstrated to exhibit powerful enantioselectivity towards numerous chiral compounds. By comparison with the four classes of antibiotics, macrolides are another type of macrocyclic antibiotics. In this study erythromycin lactobionate belonging to the group of macrolides is first used as a chiral selector in CE for the enantiomeric separations of basic drugs. As observed, erythromycin lactobionate allowed excellent separation of the enantiomers of N,N-dimethyl-3-(2-methoxyphenoxy)-3-propylamine, propranolol and duloxetine, as well as partial enantioresolution of primaquine, chloroquine and nefopam. In addition, erythromycin lactobionate possesses advantages such as high solubility and low viscosity in the solvent and very weak UV absorption. Among several experimental factors including buffer pH, BGE and erythromycin lactobionate concentrations, capillary temperature and applied voltage, we found that the enantioseparations of basic drugs above-mentioned strongly depended on the pH of BGE and the concentration of the chiral additive. The optimum pH was in the neutral or weak basic region but varied among drugs. An erythromycin lactobionate concentration of about 10% (w/v) and a low capillary temperature of 16 °C were recommended for the practical analysis.     

分子印迹聚合物在毛细管电色谱拆分手性药物中的研究进展

手性药物通过与生物体内生物大分子之间的手性匹配与分子识别来发挥药理作用。两个对映体与体内手性环境相互作用的不同导致每个对映体表现出不同的药理活性、代谢过程、代谢速率及毒性等药代动力学特征。因此发展手性药物的拆分方法,对于手性药物的开发和生产过程的质量监控具有重要意义。分子印迹聚合物（MIPs）是以目标分子作为模板而制备的高分子聚合物,它具有特定的空间分子结构和官能团,对目标分子具有高度的特异性识别能力。基于该特点,MIPs非常适合于手性药物的拆分和纯化。毛细管电色谱（CEC）可同时基于毛细管电泳和液相色谱的分离机理对目标物进行分离,因此具有高分离效率和高选择性的特点。将MIPs材料作为CEC的固定相,可将这两种技术的优势结合,从而实现对手性药物的高效拆分。MIPs材料在1994年首次应用于CEC手性拆分,此后该研究领域开始获得关注和发展。MIPs材料主要通过4种模式在CEC中实现手性拆分,分别是作为开管柱、填充柱和整体柱的固定相以及分离介质中的准固定相。该综述以这4种模式作为分类基准,根据MIPs制备所需的材料和分离对象对其在CEC手性拆分中的应用进行了总结,揭示了MIPs在CEC手性拆分中的潜力,同时评述了这4种模式各自的优势与不足,并对将来MIPs在CEC手性拆分中的发展进行了展望。     

Highly Efficient Synthesis of Optically Pure (S)-1-phenyl-1,2-ethanediol by a Self-Sufficient Whole Cell Biocatalyst

Terminal vicinal diols are important chiral building blocks and intermediates in organic synthesis. Reduction of α-hydroxy ketones provides a straightforward approach to access these important compounds. In this study, it has been found that asymmetric reduction of a series of α-hydroxy aromatic ketones and 1-hydroxy-2-pentanone, catalyzed by Candida magnolia carbonyl reductase (CMCR) with glucose dehydrogenase (GDH) from Bacillus subtilis for cofactor regeneration, afforded 1-aryl-1,2-ethanediols and pentane-1,2-diol, respectively, in up to 99 % ee. In order to evaluate the efficiency of the bioreduction, lyophilized recombinant Escherichia coli whole cells coexpressing CMCR and GDH genes were used as the biocatalyst and α-hydroxy acetophenone as the model substrate, and the reaction conditions, such as pH, cosolvent, the amount of biocatalyst and the presences of a cofactor (i.e., NADP⁺), were optimized. Under the optimized conditions (pH 6, 16 h), the bioreduction proceeded smoothly at 1.0 m substrate concentration without the external addition of cofactor, and the product (S)-1-phenyl-1,2-ethanediol was isolated with 90 % yield and 99 % ee. This offers a practical biocatalytic method for the preparation of these important vicinal diols.