不对称生物还原制备手性药物

近年来手性药物的发展非常迅速,手性合成药物的出现不仅提高了药效,而且有利于克服现行消旋体药物在治疗上的副作用。本文介绍了用生物还原法制备高光学纯度手性醇前体的一些方法。     

环氧化物的生物不对称合成

手性环氧化物是有机化学合成中重要的中间体,与以往化学合成方法相比,手性环氧化物的生物合成有其独特之优点,本文从直接加氧、间接环氧和酶解拆分三个途径全面地介绍该领域的研究成果和最新进展,并对其未来的发展和方向进行了展望。     

环氧化物的生物不对称合成

手性环氧化物是有机化学合成中重要的中间体;与以往化学合成方法相比,手性环氧化物的生物合成有其独特之优点;本文从直接加氧、间接环氧和酶解拆分三个途径全面地介绍该领域的研究成果和最新进展,并对其未来的发展和方向进行了展望 。     

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。     

面包酵母催化羰基不对称还原合成手性醇的研究

以2-辛酮和4-氯乙酰乙酸乙酯(COBE)为模型底物分别考察了酵母细胞对直链甲基酮和陆羰基酯中的羰基不对称还原情况。实验发现不对称还原2-辛酮的产物主要是S型的2-辛醇,且对映体选择性很高。不对称还原COBE生成的主要是S(D)-型产物,反应COBE的转化率、光学选择性都比较高。同时发现COBE的浓度和产物对不对称还原都有一定负面的影响。     

疏水离子液体中生物不对称还原制备手性醇

针对近平滑假丝酵母全细胞不对称还原2-羟基苯乙酮制备光学纯(R)-苯基乙二醇反应中底物的质量浓度、产量及质量平衡低的问题,运用多相萃取生物转化的原理,比较不同非水介质对不对称还原反应效率的影响,构建具有良好生物相容性和高质量平衡的水/疏水离子液体1-丁基-3-乙基咪唑六氟磷酸盐([BEIM]PF6)双相反应体系。考察该体系下辅助底物种类、辅助底物用量、底物质量浓度、催化剂用量、离子液体比例、p H和反应温度对生物催化反应的影响,通过正交试验设计和响应面法优化不对称还原2-羟基苯乙酮的反应条件,在最优反应条件下,产物质量浓度、产率和质量平衡得率分别达到15.35 g/L、76.8%和84.3%,产物的对映消旋值(e.e.值)大于99.9%。     

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。     

羰基生物还原法合成手性醇的研究进展

手性醇是合成许多光学活性药物、农用化学品及其他精细化学品的关键手性砌块。羰基生物还原法理论上可实现100%转化率,且反应条件温和,对环境十分友好,被普遍认为是生产手性醇的绿色、高效途径。综述了近年来利用生物信息学、高通量筛选和蛋白质工程的发展对新型、高效生物催化剂开发的影响,特别是利用相关技术手段开发羰基还原酶的进展。     

转氨酶催化不对称合成芳香族L-氨基酸

芳香族L-氨基酸是合成许多药物、农药、精细化学品和食品添加剂的重要手性砌块(Chiral buildingblocks)。利用酶催化具有高活性和高立体选择性的特点合成手性砌块是目前不对称合成领域重要的研究方向。通过对不同来源转氨酶的进化分析,选择分别源自原核生物大肠杆菌Escherichia coli和真核生物酿酒酵母Saccharomyces cerevisia中的两种具有代表性Ⅰ型芳香族转氨酶TyrB和Aro8,比较研究了两种转氨酶通过平衡逆转不对称氨化催化合成芳香族L-氨基酸的反应过程和催化效率。重组转氨酶TyrB和Aro8都能有效地合成天然芳香族氨基酸苯丙氨酸和酪氨酸以及非天然氨基酸苯甘氨酸。手性HPLC分析表明,合成的氨基酸都是L-构型的,e.e值等于100%。L-丙氨酸是适宜的氨基供体,转氨酶TyrB和Aro8都不能利用D-型氨基酸作为氨基供体。反应体系中氨基供体L-丙氨酸和氨基受体芳香族α-酮酸的最适摩尔比为4∶1。底物芳香族α-酮酸分子结构中芳香环上的取代基以及脂肪酸碳链部分的长度都对酶催化的转氨效率有显著的影响。在制备规模试验中,TyrB催化不对称转氨反应合成L-苯甘氨酸、L-苯丙氨酸和L-酪氨酸的比生产速率为0.28 g/(g.h)、0.31 g/(g.h)和0.60 g/(g.h),Aro8催化上述反应的比生产速率分别为0.61 g/(g.h)、0.48 g/(g.h)和0.59 g/(g.h)。研究结果对利用转氨酶通过平衡逆转不对称催化合成芳香族L-氨基酸的工业化应用具有指导意义。     

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。     

Formation and Degradation of Styrene Oxide Stereoisomers by Different Microorganisms

The formation of optically pure styrene oxides by oxidation of styrene and the isomerisation of styrene oxide to phenylacetaldehyde was investigated with different microorganisms.     

Chiral porphyrin imine manganese complex as catalyst for asymmetric epoxidation of styrene derivatives

New chiral porphyrin imine was synthesized from (S)‐3‐benzyl‐2‐methyl‐4‐phenylbutanal according to dipyrromethane method using trifluoroacetic acid, BF₃ etherate, and p‐chloranil. Manganese complex of this chiral porphyrin imine ligand was used as catalyst in the asymmetric epoxidation of styrene derivatives possessing different substituents. Styrene derivatives possessing electron withdrawing groups gave the corresponding chiral epoxides in high yield up to 98% and ee up to 99%. The mechanism for the catalytic asymmetric epoxidation was also discussed based on transfer of oxygen.     

植物体内一氧化氮合成途径研究进展

一氧化氮(NO)作为一种气体信号分子,在植物生理过程中发挥重要作用,它参与调节植物的生长、发育及对外界环境的应激反应.植物体内主要通过酶催化途径和非酶催化途径合成NO.酶催化途径合成NO的主要酶包括一氧化氮合酶(nitric oxide synthase,NOS)和硝酸还原酶(nitrate reductase,NR),以及在某些植物的特定组织或器官或在特殊环境条件下存在的一氧化氮氧化还原酶(nitric oxide oxidoreductase,Ni-NOR)和黄嘌呤氧化还原酶(xanthine oxidoreductase,XOR).非酶催化合成途径主要是在酸性和还原剂存在条件下将亚硝酸盐还原成NO.该文主要结合研究方法,综述了植物体内NO合成途径的研究进展,为植物体内NO信号的作用机理的深入研究提供信息资料.     

Biosynthesis of trichothecene mycotoxins: cell-free epoxidation of a trichodiene derivative

A cell-free enzyme system from cultures of Fusarium culmorum catalyses the 12,13-epoxidation of semi-synthetic 9 beta,10 beta-epoxytrichodiene to 9 beta,10 beta;12,13-diepoxytrichodiene. This enzyme activity may be involved in the biosynthesis of trichothecene mycotoxins and since the 12,13-epoxide is known to be essential for toxicity, the enzyme activity probably confers the toxic properties associated with this group of mycotoxins. The epoxidase requires NADPH and molecular oxygen, is inhibited by carbon monoxide, and thus appears to be a cytochrome P-450-dependent mono-oxygenase. Whole cell cultures of the fungus carry out the same biotransformation, and in addition hydroxylate the diepoxide product at position 3, yielding 3 alpha-hydroxy-9 beta,10 beta;12,13-diepoxytrichodiene.     

Carbon Anionic Chiral Initiators for Asymmetric Anionic Polymerization of Achiral Isocyanates

Novel optically active carbon anionic initiators bearing a chiral oxazole substituent on fluorene ring, (S)‐1‐(9H‐fluoren‐2‐yl)‐4‐isopropyl‐4, 5‐dihydrooxazole lithium ((S)‐1‐FIDD‐Li) and (S)‐2‐(9H‐fluoren‐2‐yl)‐4‐isopropyl‐4, 5‐dihydrooxazole lithium ((S)‐2‐FIDD‐Li), were synthesized. Anionic polymerizations of achiral polyisocyanates with the chiral initiators were investigated and optical rotation of the obtained polymers were attributed to asymmetric induction of the chiral initiators. The crowded substituent of initiator ((S)‐2‐FIDD‐Li) seems to reduce the polymerizability of isocyanates and yet enhances the chiral induced ability in polymerization. Chirality 27:449–453, 2015. © 2015 Wiley Periodicals, Inc.     

Chiral nanotechnology

A review of chiral, nanoscale science and technology is presented, with the subject divided into two topics. The first discusses nanotechnology in the service of asymmetric synthesis, chiral separations, and analysis. The second topic concerns broader research in the nanotechnology realm, where molecular chirality plays a role in the properties of materials, including molecular devices, chiral supramolecules, chiral nanotubes, chiral fullerenes, and DNA nanotechnology.     

Double Asymmetric Induction During the Addition of (RP)‐Menthyl Phenyl Phosphine Oxide to Chiral Aldimines

P,C‐Stereogenic α‐amino phosphine oxides were prepared from the addition of (R_P)‐menthyl phenyl phosphine oxide to chiral aldimines under neat condition at 80 °C in up to 91:9 dr_C and 99% yields. The diastereoselectivity was mainly induced by chiral phosphorus that showed matched or mismatched induction with (S)‐ or (R)‐aldimines, respectively. Chirality 28:132–135, 2016. © 2015 Wiley Periodicals, Inc.     

Chiral ionic liquids: a compendium of syntheses and applications (2005-2012)

In recent years, the field of chiral ionic liquids (CILs) has undergone exponential growth. As the technology has advanced, new ways of synthesizing stable and structurally diverse ionic liquids have been established. This has led to heretofore unknown applications of CILs as well as in improving efficiency of previously identified applications. In this review article we have compiled a comprehensive database containing structures and physical properties of notable CILs that have been synthesized during the last 6 years. Their applications in the fields of asymmetric organic synthesis, spectroscopy, and chromatography are also illustrated. This is an expansion of our previous review, which covered the literature before 2005.