手性化合物制备的方法

手性是自然界最重要的属性之一,分子手性识别在生命活动中起着极为重要的作用。同一化合物的两个对映体之间不仅具有不同的光学性质和物理化学性质,而且它们具有不同的生物活性,比如在药理上,药物作用包括酶的抑制、膜的传递、受体结合等均和药物的立体化学有关;手性药物的对映体的生物学活性、毒性、代谢和药物素质完全不同。手性化合物的制备已成为当前国内外较热门的研究课题之一。本文从非生物法和生物法两个方面较全面地综述了手性化合物的制备方法,希望为相关研究者提供参考。     

植物与手性化合物的对映体选择性相互作用

植物与手性化合物存在着非常密切的联系.一方面,植物分泌、合成的一些手性化合物,如糖甙、酶、萜类化合物、有机酸及植物激素等,在植物的生理生化过程中起着重要的作用;另一方面,人工合成的手性化合物尤其是农药等环境污染物与植物具有对映体选择性相互作用,它们或是选择性地抑制植物的生长和生理过程,或是被植物选择性地吸收和代谢.因此,在开发、生产和使用手性化合物时需要考虑植物与对映体之间的选择性因素;同时,合理利用植物对手性污染物进行环境修复也具有重要意义.本文对植物与手性化合物相互作用中的对映体选择性进行了综述,并对手性污染物的植物修复进行了展望.     

二氢吡啶类钙通道阻滞剂及其药物手性研究

人体是一种高度复杂的手性环境.手性药物用于机体后.两对映体与体内的大分子物质结合,呈现作用机制和结合力的差别,从而导致手性药物的体内立体选择性特征,产生药理学上的差别.二氢吡啶类钙通道阻滞剂具有舒张血管等重要作用,在临床上对治疗高血压等心脑血管痰病具有很好的临床应用价值.本文就以手性药物和钙通道阻滞剂的药效学立体选择性作一综述.     

羰基还原酶及其催化不对称合成大基团手性羟基类化合物的研究进展

手性羟基化合物以其独特的光、热和化学性质广泛应用于医药、农药、精细化工、功能材料等行业.立体专一性羰基还原酶能够直接针对关键手性位点催化不对称还原潜手性底物获得目的手性产物.基于羰基还原酶的底物多样性,具有不同化学结构和功能的醇类、酯类、氨基酸、环氧化合物等重要手性中间体能够通过不对称还原途径实现单一光学活性对映体的高效制备.然而,针对具有应用价值的含有大基团、结构复杂的潜手性羰基化合物,已知的羰基还原酶通常催化活性较低.本文综述了生物催化不对称氧化还原反应的特点和规律及其关键立体选择性羰基还原酶的性质和结构特征,并在此基础上,重点针对大基团手性羟基化合物的不对称合成,总结了羰基还原酶及其催化系统开发和应用的研究进展,并进一步提出解决该关键问题的主要发展策略.     

手性技术与生物催化

简要介绍了手性,手性技术与生物催化的基本概念。手性,是指一个有机分子具有不对称性,形成两种空间排布方式不同的对映异构体。手性技术即生产手性化合物的技术,手性化合物的制备方法主要有手性源、外消旋体拆分、不对称合成等几种。生物催化,即利用酶或微生物等生物材料催化进行某种化学反应,被认为是手性化合物生产取得突破的关健技术。文章还介绍了生物催化外消旋体拆分、生物催化不对称合成等几种生产手性化合物的应用实例。     

生物催化不对称还原制备氟代手性醇

由于氟原子的特殊性质，化合物中引入氟原子可显著改变其物理化学性质。因此，氟原子在药物中的应用越来越广。此外，80%药物分子结构属于手性分子。其中，氟代手性醇常见于手性药物结构中，该类结构的合成方法研究具有重要的意义。不对称还原含氟酮是合成此结构的常见方法。与化学还原方法相比，生物催化还原具有对映选择性强、产率高和易于分离纯化等优点。生物催化，特别是酶催化还原含氟酮类化合物成为手性药物合成领域的研究热点。本文从纯化酶催化和全细胞催化两个方面，综述了近年来含氟酮生物催化还原合成氟代手性醇的研究进展，并分析总结了氟代对酮生物催化还原的影响，最后对生物催化还原法未来的发展进行了展望。     

生物制造:手性化学品的绿色制造之路

<正>手性化学品广泛应用于医药、农业、食品、材料等领域,在国计民生中占据极其重要的地位。例如人们服用消旋体药物,在摄入活性对映体的同时,也摄取了大量无效甚至有毒有害的对映体,对人体的健康构成了直接或潜在的威胁;农药在以外消旋体形式使用时,在施用活性对映体的同时,也施用了大量     

假丝酵母C-5的不对称生物还原作用研究

生命与手性密切相关,凡涉及到生命现象和生理活性物质几乎都离不开有关分子的空间立体构型问题,不同构型的手性分子具有不同的生理活性。利用酶反应的立体专一性,用生物转化法取代部分传统的化学方法,可以很方便地制备具有所需手性中心的化合物。因此,近年来生物转化...     

反柄紫芝中的二个新化合物

采用色谱法从反柄紫芝的子实体中分离得到4个化合物,波谱学方法鉴定了它们的结构,分别为:cochlearol E(1)、cochlearol F(2)、ganocin A(3)和ganocin B(4)。其中化合物1和2是新化合物,化合物3和4系文献已报道的源自本菌子实体的多环芳香杂萜。化合物1、3和4均是外消旋体,对新化合物1进行了手性拆分并通过量子化学计算方法确定了其对映体的绝对构型。     

利用微生物重组技术促进羰基不对称还原研究进展

手性醇是许多手性药物合成的关键手性砌块,利用微生物细胞催化相应前手性羰基化合物不对称还原,是合成手性醇的重要方法之一。但应用野生微生物催化时,反应的时空产率、立体选择性较低。详细介绍了利用微生物重组技术以促进前手性羰基化合物不对称还原反应合成手性醇的国内外研究进展。从酶的种类、表达系统以及辅酶再生系统3个方面对重组细胞催化反应体系的构建进行了概述。同时按照反应底物的类型,对重组微生物在催化不同类型羰基化合物不对称还原合成手性醇中的应用分别进行了归纳和介绍。     

地尔硫卓手性中间体合成进展

地尔硫卓是重要的心血管药物,在其分子结构中含有2个手性中心,可产生4个立体异构体,其中只有（2s,3s）-异构体具有药理活性,因此其立体选择性合成具有很大的挑战性。研究人员采用多种方法合成单一构型的地尔硫卓手性中间体,其中包括化学拆分、化学不对称合成以及化学-酶法合成等方法。对地尔硫卓手性中间体的制备方法进行了综述。     

Enantiomeric separation and determination of absolute stereochemistry of asymmetric molecules in drug discovery: building chiral technology toolboxes

The application of Chiral Technology, or the (extensive) use of techniques or tools for the determination of absolute stereochemistry and the enantiomeric or chiral separation of racemic small molecule potential lead compounds, has been critical to successfully discovering and developing chiral drugs in the pharmaceutical industry. This has been due to the rapid increase over the past 10-15 years in potential drug candidates containing one or more asymmetric centers. Based on the experiences of one pharmaceutical company, a summary of the establishment of a Chiral Technology toolbox, including the implementation of known tools as well as the design, development, and implementation of new Chiral Technology tools, is provided.     

Functional characterization of salt‐tolerant microbial esterase WDEst17 and its use in the generation of optically pure ethyl (R)‐3‐hydroxybutyrate

The two enantiomers of ethyl 3‐hydroxybutyrate are important intermediates for the synthesis of a great variety of valuable chiral drugs. The preparation of chiral drug intermediates through kinetic resolution reactions catalyzed by esterases/lipases has been demonstrated to be an efficient and environmentally friendly method. We previously functionally characterized microbial esterase PHE21 and used PHE21 as a biocatalyst to generate optically pure ethyl (S)‐3‐hydroxybutyrate. Herein, we also functionally characterized one novel salt‐tolerant microbial esterase WDEst17 from the genome of Dactylosporangium aurantiacum subsp. Hamdenensis NRRL 18085. Esterase WDEst17 was further developed as an efficient biocatalyst to generate (R)‐3‐hydroxybutyrate, an important chiral drug intermediate, with the enantiomeric excess being 99% and the conversion rate being 65.05%, respectively, after process optimization. Notably, the enantio‐selectivity of esterase WDEst17 was opposite than that of esterase PHE21. The identification of esterases WDEst17 and PHE21 through genome mining of microorganisms provides useful biocatalysts for the preparation of valuable chiral drug intermediates.     

Indirect Chiral Separation of New Recreational Drugs by Gas Chromatography‐Mass Spectrometry Using Trifluoroacetyl‐L‐Prolyl Chloride as Chiral Derivatization Reagent

New recreational drugs such as amphetamine‐, cathinone, and benzofury derivatives gained high popularity on the drug market in recent years. They can be purchased via the Internet from different providers and online portals. Most of these compounds are chiral, which makes the development of chiral separation methods necessary. Besides this, it is useful to find out if the compounds were sold as racemic mixtures. Also, it is important to check whether the new psychoactive compounds contain further ingredients or impurities. The aim of this research was the continuation of the application of a method for indirect chiral separation of 24 new psychoactive compounds recently purchased via the Internet. After derivatization with the chiral derivatization reagent trifluoroacetyl‐L‐prolyl chloride, chromatographic separation of diastereomers was achieved using a 30 m HP5‐MS capillary column. As carrier gas, helium was used with a constant flow of 1.0 ml/min. Three different column temperature programs were tested. Under optimum conditions 13 out of 24 compounds were successfully resolved into their enantiomers obtaining Rs values up to 7.0. The use of a single quadrupole mass spectrometer as the detector allowed the identification of the compounds in multicomponent samples. Chirality 27:211–215, 2015. © 2014 Wiley Periodicals, Inc.     

纳米混悬药物传递系统研究进展

在新药研发过程中,约有40%的药物存在溶解性差的问题,限制了药物的开发与应用。纳米混悬剂是20世纪末发展起来的一种纳米药物传递系统,可增加难溶性药物的溶解度和溶出速率、改变药物的体内药物动力学特征、提高口服生物利用度、安全性和有效性。纳米混悬剂不但适用于水溶性差的药物,而且适用于水溶性、脂溶性均较差的药物,其制备方法主要包括"bottom up"和"top down"两种。本文从纳米混悬剂的特点、理论基础、专利技术及应用等方面对纳米混悬剂的研究进展进行了综述。纳米混悬剂对改善难溶性药物的溶出、吸收,提高难溶性药物的有效性、安全性等方面具有显著优势,且适合工业化生产,已有越来越多的产品问世。纳米混悬技术是未来药物传递系统的发展方向之一,将具有良好的应用前景。     

Implications of chirality and geometric isomerism in some psychoactive drugs and their metabolites

Many drugs contain a chiral centre, or such a centre is introduced during metabolism of the drug in man and in animals. If a single chiral centre is present, the drug will normally exist as a mixture of two enantiomers, of which one may have quite different pharmacologic and/or toxic effects than the other. Chiral drugs that are used in psychiatry, and some other pharmacologically related drugs are identified, and the implications of the presence of one or two chiral centres in these drugs are discussed. Differences in pharmacologic properties of drug and metabolite enantiomers are identified and discussed. Also reviewed are the properties of some drugs used in psychiatry that both are chiral and display geometric isomerism.     

Separation methods for anthraquinone related anti-cancer drugs

The quinoid anthracycline-related anti-cancer agents represent an important group of anti-tumour drugs with a wide spectrum of activity. We review here some of the separation techniques used for the analysis of anthracyclines and related compounds. In this review we have covered a range of compounds from the early anthracycline antibiotics such as doxorubicin to the more recent anthracenediones and anthrapyrazoles such as mitoxantrone and losoxantrone, respectively. We also include novel compounds such as AQ4N and C1311, both awaiting clinical trial. Separations of the anthraquinone related anti-cancer agents are predominantly by HPLC. These separation techniques have been used for a variety of applications including drug stability, protein binding and therapeutic drug monitoring as well as detailed pharmacokinetic and metabolic studies. Pharmacokinetics, and therefore drug analysis, plays a central role in both the development of new agents and also leads to a better understanding of clinically established agents in this class. Sample preparation and extraction methods including solid-phase and liquid–liquid extraction have also been highlighted. Many anthraquinone related compounds are highly coloured and fluoresce. They are suitable for a range of detection methods including UV–Vis, electrochemical and fluorescence. The methods described are used for sometimes complex separations that are needed for the evaluation of such compounds in biological samples.     

Evaluation of the macrocyclic antibiotic vancomycin as a chiral selector for capillary electrophoresis

Vancomycin is one of a family of related macrocyclic glycopeptide antibiotics that were discovered by scientists at the Eli Lilly Company in the 1950s. It has been used to treat severe staphylococcal infections, particularly when bacterial resistance to other antibiotics has developed. Vancomycin is a naturally occurring chiral compound and has a number of stereogenic centers. Furthermore, it contains a variety of functionalities that are known to be useful for enantioselective interactions (e.g., hydrogen bonding groups, hydrophobic pockets, aromatic groups, amide linkages, etc.). The physicochemical properties of vancomycin, including its stability in solution, are discussed as they pertain to capillary electrophoresis. Over 100 racemates were resolved including many nonsteroidal antiinflammatory drugs, antineoplastic compounds and N-derivatized amino acids. Many of these compounds had very high resolution factors. Optimization and the effect of different experimental parameters on the enantioselective separations are discussed. © 1994 Wiley-Liss, Inc.     

基于噁唑烷酮的不对称催化合成构建多官能化手性氨基酸类化合物

多官能化手性氨基酸及其衍生物是一类重要的手性药物以及合成手性药的关键中间体,如现在大量用于临床的左甲状腺素、赖诺普利、阿莫西林、缬沙坦、头孢氨苄以及青霉素等。进行多官能化手性氨基酸类化合物的不对称催化合成,可为新型化学药的设计与发现开辟新的视野。噁唑烷酮(Azlactone)被证明是合成四取代氨基酸衍生物的优秀底物。可通过不对称催化手段向其中引入需要的基团,再经多取代的噁唑烷酮直接开环得到一系列的目标化合物。本文主要综述了近年来基于恶唑烷酮的不对称催化反应构建四取代氨基酸类化合物的研究。