化学-酶催化动态动力学拆分工艺中多相催化剂的研究进展

利用外消旋体进行化学-酶催化动态动力学拆分是制备单一手性化合物的有效手段之一。论述了近几年用于动态动力学拆分工艺中的固定化脂肪酶和固相外消旋化多相催化剂的研究进展,介绍了过渡金属配合物、酸性β-沸石和酸性树脂等固相外旋消化催化剂与固定化脂肪酶配伍,用于化学-酶催化动态动力学拆分工艺的催化效果。     

动态动力学拆分在手性药物合成中的应用

动态动力学拆分是合成手性化合物最方便和最有效的方法之一,该方法的主要特征是用酶催化拆分和金属催化原位外消旋化未反应的底物,克服了经典动力学拆分最高产率只有50%的缺陷,理论上可以达到100%的收率。本文概述了动态动力学拆分技术在手性药物合成中的应用。     

酶催化的动态动力学拆分和去消旋化反应的研究进展

最近,在外消旋化合物的动态动力学拆分以及去消旋化反应方面,新型催化剂的发现以及反应条件的优化都得到了很大的发展。一些特殊功能团使得它们的化合物可以发生动态动力学拆分或是去消旋反应,如仲醇、α-氨基酸、胺及羧酸。在催化反应过程中,一般都是对映体选择性酶与化学试剂的相结合,化学试剂一般常用于催化非活性对映体发生去消旋反应或是回收去消旋化过程中的中间体。在一些动态动力学拆分中,消旋酶还可以催化对映异构体之间发生互变。     

动态动力学拆分方法在不对称催化中的应用与进展

不对称催化在有机合成中具有广阔的应用前景。传统的动力学拆分方法的缺点是最大产率仅为 5 0 %。而采用动态动力学拆分方法 ,所有外消旋底物都能转化成单一的对映体 ,产率为 10 0 %。主要论述了酶催化的动力学拆分、金属催化的外消旋作用及两者相结合的动态动力学拆分方法的原理和应用     

酶催化外消旋体的动态动力学拆分反应研究进展

外消旋体的动态动力学拆分（DKR）是制备手性化合物的重要方法之一,过去多用化学催化剂进行反应,近年来生物催化剂的引入大大提高了DKR的效率和收率。系统地介绍了DKR的原理及酶催化外消旋体的动力学拆分反应的最新进展。     

生物催化轴手性化合物的不对称合成进展

轴手性化合物是许多天然产物、药物中间体、手性配体的核心骨架,在手性化合物中占有重要地位。与金属催化剂催化的不对称化学偶联反应等化学方法相比,生物催化方法具有选择性高、反应条件温和、环保等优势。随着酶的改造等关键技术的快速发展,酶催化轴手性化合物的合成成为新的研究热点与难点。从动力学拆分(kinetic resolution,KR)、动态动力学拆分(dynamic kinetic resolution,DKR)以及去对称化(desymmetrization)等不对称合成方法入手,综述了生物催化轴手性化合物的合成领域的主要研究成就,并阐述了此方向的发展前景、应用及存在的问题。     

酰基供体对动态动力学拆分1-四氢萘胺的影响

采用新型消旋催化剂耦合Novozym 435成功构建1-四氢萘胺的动态动力学拆分体系用于制备光学纯(R)-1-四氢萘胺。该反应存在着自催化酰胺化反应,会降低反应的对映体选择性。从改变酰基供体结构的角度出发来抑制这种自催化酰胺化反应,考察了不同酸部以及不同醇部的酰基供体对1-四氢萘胺动态动力学拆分反应的影响,发现随着酰基供体结构变得复杂,1-四氢萘胺动态动力学拆分反应结果也相应变得越好,当采用戊酸对氯苯酯作为酰基供体时,动态动力学拆分反应结果就可达到最佳,即转化率>99%,光学纯度eeP>99%。     

酶法动态动力学拆分制备R-(-)-乙酰基邻氯扁桃酸

采用假单胞菌脂肪酶Pseudomonas sp. ECU1011催化乙酰基邻氯扁桃酸进行不对称水解,利用突变后的扁桃酸消旋酶(V29I)对拆分后的产物S-(-)-邻氯扁桃酸进行消旋,消旋后的邻氯扁桃酸经过酰化重新被利用到水解反应中,实现了酶法动态动力学拆分制备R-(-)-乙酰基邻氯扁桃酸。通过对拆分反应、拆分混合物的分离回收以及消旋反应的工艺优化,最终获得光学纯度ee>99.9%的R-(-)-乙酰基邻氯扁桃酸,其收率达80%。本研究建立的R-(-)-乙酰基邻氯扁桃酸的动态动力学拆分工艺,对其工业化应用具有重要的指导意义。     

化学-酶法耦合制备拆分β-萘乙醇

通过化学-酶相耦合的方法,成功制备出e.e.值〉99%的S-β-萘乙醇,使其光学纯度达到了制备R-2-萘乙胺的要求。研究中以β-萘乙酮为原料,经硼氢化钠还原得到外消旋的β-萘乙醇。经过酶催化动力学拆分,β-萘乙醇中R型底物100%全转化为酯,S构型底物型被保留,这样体系中S构型底物的e.e.值达到近100%。本文还考察了若干因素对酶催化动力学拆分过程的影响,并最终确定了酶催化动力学拆分β-萘乙醇制备S-β-萘乙醇的最适条件：反应温度45℃,溶液为甲苯,底物浓度为100 mmol/L。     

手性反应控制进展

现在越来越多的方法应用到用酶高效催化手性非外消旋化合物的对映性选择反应中来.对于不对称性合成反应或者动力学拆分的替代反应有动态动力学拆分、去消旋化和对映会聚转化等.另外,人们对影响反应生成的立体化学产物的参数(如溶剂、底物设计、固定化、定向进化等)有了进一步的了解.     

利用工程酶改进有机合成的研究进展

修饰酶用于有机合成已经涉及了许多领域。它包括改变酶反应机制来催化新的反应,改变底物专一性、扩大底物专一性、改善底物专一性,例如动力学拆分中的对映选择性。酶修饰可以通过理性设计或随机突变方法来实现,前者需要知道酶的结构,后者则需要进行筛选。两种策略的酶工程都能成功,并且对于改进在催化中应用的酶非常有意义。最近,有例子表明这两种策略已经应用于许多酶中。     

Mechanisms of Enhanced Catalysis in Enzyme–DNA Nanostructures Revealed through Molecular Simulations and Experimental Analysis

Understanding and controlling the molecular interactions between enzyme substrates and DNA nanostructures has important implications in the advancement of enzyme–DNA technologies as solutions in biocatalysis. Such hybrid nanostructures can be used to create enzyme systems with enhanced catalysis by controlling the local chemical and physical environments and the spatial organization of enzymes. Here we have used molecular simulations with corresponding experiments to describe a mechanism of enhanced catalysis due to locally increased substrate concentrations. With a series of DNA nanostructures conjugated to horseradish peroxidase, we show that binding interactions between substrates and the DNA structures can increase local substrate concentrations. Increased local substrate concentrations in HRP(DNA) nanostructures resulted in 2.9‐ and 2.4‐fold decreases in the apparent Michaelis constants of tetramethylbenzidine and 4‐aminophenol, substrates of HRP with tunable binding interactions to DNA nanostructures with dissociation constants in the micromolar range. Molecular simulations and kinetic analysis also revealed that increased local substrate concentrations enhanced the rates of substrate association. Identification of the mechanism of increased local concentration of substrates in close proximity to enzymes and their active sites adds to our understanding of nanostructured biocatalysis from which we can develop guidelines for enhancing catalysis in rationally designed systems.     

动态动力学拆分制备手性化合物的研究进展

综述了固体酸、固体碱和金属配合物在动态动力学拆分制备光学纯手性化合物进行外消旋化的催化机理,讨论了均相外消旋催化剂和多相外消旋催化剂在动态动力学拆分工艺中的应用,重点介绍了过渡金属配合物催化剂和生物酶配伍进行动态动力学拆分制备手性化合物的研究进展和发展趋势。     

Heterogeneous Catalysts for Racemization and Dynamic Kinetic Resolution of Amines and Secondary Alcohols

This paper gives an overview of the available heterogeneous catalysts for racemization of chirally stable secondary alcohols and amines, and of the combination of these catalysts with immobilized enzymes in dynamic kinetic resolution (DKR) for production of enantiopure esters or amides. For the one-pot DKR process, compatibility of enzyme and heterogeneous catalyst is a major issue, and in some cases the combination fails because of (mutual) deactivation. Heterogeneous catalysts of various types, such as zeolites or oxides effect alcohol racemization; they function either via acid catalysis and carbenium chemistry, or via a redox pathway via the ketone. Dynamic kinetic resolution of aliphatic alcohols using a heterogeneous catalyst in mild conditions is however an open challenge. Heterogeneous amine racemization catalysts invariably operate using a redox mechanism via the imine. In this case, the scope encompasses benzylic and aliphatic amines. The practicality of the approach is illustrated with the production of enantiopure N-acylated homoserine lactones, which are signalling compounds in microbial communities.     

Asymmetric catalysis of epoxide ring-opening reactions

The discovery of the metal salen-catalyzed asymmetric ring-opening (ARO) of epoxides is chronicled. A screening approach was adopted for the identification of catalysts for the addition of TMSN(3) to meso-epoxides, and the chiral (salen)CrN(3) complex was identified as optimal. Kinetic and structural studies served to elucidate the mechanism of catalysis, which involves cooperative activation of both epoxide and azide by two different metal centers. Covalently linked bimetallic complexes were constructed on the basis of this insight, and shown to catalyze the ARO with identical enantioselectivity but 1-2 orders of magnitude greater reactivity than the monomeric analogues. Extraordinarily high selectivity is observed in the kinetic resolution of terminal epoxides using the (salen)CrN(3)/TMSN(3) system. A search for a practical method for the kinetic resolution reaction led to the discovery of highly enantiomer-selective hydrolytic ring-opening using the corresponding (salen)Co(III) catalyst. This system displays extraordinary substrate generality, and allows practical access to enantiopure terminal epoxides on both laboratory and industrial scales.     

Confinement of metal complexes within porous hosts: development of functional materials for gas binding and catalysis

The development of porous functional materials, using template copolymerization, that function in gas binding/release and catalysis is described. Using substitutionally inert metal complexes as templates, materials were prepared with immobilized sites that retained structural properties of the template; this allows for tunable functional properties. Chemical modification of the immobilized sites led to coordinatively unsaturated metal centers that reversibly bind either O2 or NO. Materials have also been prepared that exhibit varying degrees of catalytic activity in the hydrolytic kinetic resolution of epoxides as a function of the template concentration used to prepare the polymers.     

Lipolysis and heterogeneous catalysis. A new concept for expressing the substrate concentration

A new concept is proposed for quantifying the substrate concentration during heterogeneous catalysis of the kind which occurs during lipolysis. The number of molecules of protein (enzyme) adsorbable to the lipid substrate interface per unit of volume was evaluated and defined as a volumetric concentration of protein (enzyme) binding site (PEBS). Using porcine pancreatic lipase (EC 3.1.1.3) as a model enzyme, the maximal PEBS concentration was measured under various assay conditions by determining the saturation of the lipid substrate with the enzyme. Abacuses correlating the lipid substrate concentration (M) with the PEBS concentration (M) under each experimental conditions were used to express the kinetic data in terms of a volumetric concentration of PEBS. Comparisons could thus be made between data obtained with various enzymes and lipid interfaces because they were expressed with the same unit. In the case of pancreatic lipase, using triolein and tributyrylglycerol as substrates,K _m values of 2.7 and 7.5 nM PEBS were obtained, respectively, andK _D values ranging around 9 nM PEBS were also obtained from Scatchard plots. In addition, the average superficial density of PEBS was found to be 10×10¹¹ molecules·cm⁻², which is a value commonly obtained with structural proteins and enzymes adsorbed to an acylglyceride-water interface, this finding supports the idea that the PEBS concept represents the room in which the protein molecule adsorbs at the lipidic interface.     

金属催化和生物催化在对映体拆分中的联合应用

随着对单一对映体化合物需求的日益增长，外消旋体向单一对映体的转化(去外消旋化过程)成为研究的主要方面之一，最近在去外消旋化过程中的生物催化和金属催化的联合作用被证明是非常有效的。动态动力学拆分和循环去外消旋化已经对这方面的研究有很大的推动作用。