Reagent Engineering for Group Transfer Biocatalysis

Biocatalysis has become a major driver in the innovation of preparative chemistry. Enzyme discovery, engineering and computational design have matured to reliable strategies in the development of biocatalytic processes. By comparison, substrate engineering has received much less attention. In this Minireview, we highlight the idea that the design of synthetic reagents may be an equally fruitful and complementary approach to develop novel enzyme-catalysed group transfer chemistry. This Minireview discusses key examples from the literature that illustrate how synthetic substrates can be devised to improve the efficiency, scalability and sustainability, as well as the scope of such reactions. We also provide an opinion as to how this concept might be further developed in the future, aspiring to replicate the evolutionary success story of natural group transfer reagents, such as adenosine triphosphate (ATP) and S-adenosyl methionine (SAM).     

Data-Driven Machine Learning for Understanding Surface Structures of Heterogeneous Catalysts

The design of heterogeneous catalysts is necessarily surface-focused, generally achieved via optimization of adsorption energy and microkinetic modelling. A prerequisite is to ensure the adsorption energy is physically meaningful is the stable existence of the conceived active-site structure on the surface. The development of improved understanding of the catalyst surface, however, is challenging practically because of the complex nature of dynamic surface formation and evolution under in-situ reactions. We propose therefore data-driven machine-learning (ML) approaches as a solution. In this Minireview we summarize recent progress in using machine-learning to search and predict (meta)stable structures, assist operando simulation under reaction conditions and micro-environments, and critically analyze experimental characterization data. We conclude that ML will become the new norm to lower costs associated with discovery and design of optimal heterogeneous catalysts.     

Stereoselectivity in a nitroso-ene cyclization: Formal synthesis of rac-manzacidins A and C

Nitroso-ene (NE) reactions have been adapted in the construction of nitrogen-containing motifs in many biologically interesting compounds. The transient and highly reactive “nitroso” species remains a challenge for designing stereocontrolled syntheses. Although chiral auxiliary-based method has been developed to achieve high diastereoselectivity, the use of the inherent chirality of the nitroso compound for stereochemical control remains underdeveloped. We chose the formation of a γ-lactam via a NE cyclization as a basis to study the applicable principles for future asymmetric syntheses. The selected examples presented herein reveal that the intramolecular hydrogen bond would provide conformational restraint to facilitate excellent facial selectivity in the NE reaction via a chair-like transition state. The sterically bulky amino group also provides excellent stereochemical control possibly through steric repulsion. The following transformations led to a key intermediate (Ohfune's lactone) in the preparation of manzacidins A and C and thus constitutes a formal synthesis.     

Promotion Mechanism of H2O for Stereoselectivity in Pd(II)-catalyzed C-H Arylation of Diarylphosphinamides with Arylboronic Acids

On the basis of a series of control experiments and nuclear magnetic resonance analyses, it is discovered that Boc-protected amino acid ligand coordinated to Pd center is partly replaced by N,N-dimethylformamide, and H₂O can inhibit coordination of N,N-dimethylformamide to Pd center. The novel action mechanism perfectly explains H₂O promotion for stereoselectivity in Pd(II)-catalyzed C-H arylation of diarylphosphinamides with arylboronic acids.     

Expanding the Promiscuity of a Copper-Dependent Oxidase for Enantioselective Cross-Coupling of Indoles

Herein, we disclose the highly enantioselective oxidative cross-coupling of 3-hydroxyindole esters with various nucleophilic partners as catalyzed by copper efflux oxidase. The biocatalytic transformation delivers functionalized 2,2-disubstituted indolin-3-ones with excellent optical purity (90–99 % ee), which exhibited anticancer activity against MCF-7 cell lines, as shown by preliminary biological evaluation. Mechanistic studies and molecular docking results suggest the formation of a phenoxyl radical and enantiocontrol facilitated by a suited enzyme chiral pocket. This study is significant with regard to expanding the catalytic repertoire of natural multicopper oxidases as well as enlarging the synthetic toolbox for sustainable asymmetric oxidative coupling.     

Analysis of Enzyme Structure and Activity by Protein Engineering

Structure-activity relationships of enzymes can now be analyzed for the first time by the systematic alteration of protein structure. Recent developments in the chemical synthesis of DNA fragments and recombinant DNA technology enable the facile modification of proteins by highly specific mutagenesis of their genes. Kinetic analysis of the mutant enzymes combined with high-resolution structural data from protein X-ray crystallography allow direct measurements on the relationships between structure and function. In particular, the strength and nature of enzyme-substrate interactions and their detailed roles in catalysis and specificity can now be studied. We have developed such analysis of enzyme structure-function by site-directed mutagenesis of the tyrosyl-tRNA synthetase from Bacillus stearothermophilus, concentrating so far on the subtle role of hydrogen bonding in both substrate specificity and catalysis. We find that the energetics of tyrosine and ATP binding must be analyzed in terms of an exchange reaction with solvent water. Based on this idea and structural data, we have engineered an enzyme of improved enzyme-substrate affinity, and there thus appear to be real prospects of engineering proteins of new specificities, activities, and structural properties. We are also using protein engineering to gather direct information on the nature of enzyme catalysis. For example, we find the catalysis of formation of Tyr-AMP from Tyr and ATP is due largely to electrostatic and hydrogen bonding interactions that are stronger in the transition state than in the ground state—a “strain” mechanism rather than acid-base or covalent catalysis.     

离子型有机锡化合物的合成及其生物活性

利用有机锡卤化物与有机酸在有机胺存在下反应合成了一系列离子型有机锡化合物,分子通式为[HNR3][(PhCH2)3Sn(μ2-SCH2COO)Cl]、[HNR3][Ph3Sn)3(O2CCH2CO2)2]·CH3CH2OH和[HNR3] [MeCy2ClSnO2CCH2CO2SnClCy2Me]。化合物的体外抗肿瘤、杀菌和杀螨活性测试结果表明,部分化合物具有很好的生物活性。[HNR3][(Ph3Sn)3(O2CCH2CO2)2]·CH3CH2OH和[HNR3] [MeCy2ClSnO2CCH2CO2SnClCy2Me]配合物对人肺癌细胞株A-549、结肠癌细胞株HCT-8和肝癌细胞株Bel-7402的抑制率约为90%,[HNR3][MeCy2ClSnO2CCH2CO2SnClCy2Me]配合物对小麦赤霉、番茄早疫、芦笋茎枯、苹果轮纹、花生褐斑的杀死率都为100%,配合物[HNR3] [MeCy2ClSnO2CCH2CO2SnClCy2Me]的杀螨活性致死率大于90%。     

Cu(I) catalysed cyclopropanation of olefins: Stereoselectivity studies with Arylid-Box and Isbut-Box ligands

In our quest to find new ligands for highly stereoselective reactions, we tested a variety of chiral non-racemic pseudo-C₂ symmetric bis-oxazolines derived from malonic acid containing an arylidene bridge unit (and appropriately termed Arylid-Box) in the catalytic asymmetric cyclopropanation (CAP) reaction of styrene and ethyl diazoacetate using between only 1-2 mol% of a Cu(I) pre-catalyst. Some very good e.e.s (up to 86%), were obtained. It was possible to isolate 10a′-[Cu(CH₃CN)₄]PF₆ which existed as a bench stable solid that proved to be more efficient than the catalyst prepared in situ. Cu(I) pre-catalysts were used for the first time in the CAP reaction with the Isbut-Box ligands 13a and 13b and, although, the e.e.s were better for ligand 13a using these pre-catalysts, in the case of ligand 11b this was not the case. Spectroscopic studies (UV-Vis and ¹H NMR) were carried out to gain an insight into the nature of the catalytic species at work so that the conditions could be optimised giving better results. Some theoretical studies were conducted to try to explain the better enantioselectivities obtained using Evans’ tert-Box-Cu(I) complex over our complex.     

Application of Laser Induced Breakdown Spectroscopy as a Novel Approach for Monitoring of the Activity of Nano Palladium Catalyst as Compared to Two Well-known Methods

Catalyst deactivation is an unavoidable process that occurs in catalytic chemical reactions. Laser Induced Breakdown Spectroscopy (LIBS) is used here as a novel approach to investigate the activity of palladium supported with carbon catalyst (Pd/C) over the hydrogenation of cinnamic acid with tetralin. Their outputs for four catalyst samples are reported for different time intervals of 0, 5, 10, 15 min during the reaction. The results of LIBS analysis are compared to Inductively Coupled Plasma Mass Spectrometry (ICP-MS), which shows a good agreement. Experimental data specify that line intensities of palladium (Pd) are decreased significantly with an increment of the reaction time. Moreover, the Field Emission Scanning Electron Microscope with energy dispersive spectroscopy (FESEM-EDS) of catalysts samples show aggregation of palladium particles for some places in the catalyst surface. The changes of Pd content and sintering of Pd particles in the catalyst during the reaction play substantial roles in catalyst deactivation.     

Inside Cover: Structural and Mechanistic Studies on Substrate and Stereoselectivity of the Indole Monooxygenase VpIndA1: New Avenues for Biocatalytic Epoxidations and Sulfoxidations (Angew. Chem. Int. Ed. 17/2023)

Flavoprotein monooxygenases are a versatile group of enzymes for biocatalytic transformations. Among these, group E monooxygenases (GEMs) catalyze enantioselective epoxidation and sulfoxidation reactions. Here, we describe the crystal structure of an indole monooxygenase from the bacterium Variovorax paradoxus EPS, a GEM designated as VpIndA1. Complex structures with substrates reveal productive binding modes that, in conjunction with force-field calculations and rapid mixing kinetics, reveal the structural basis of substrate and stereoselectivity. Structure-based redesign of the substrate cavity yielded variants with new substrate selectivity (for sulfoxidation of benzyl phenyl sulfide) or with greatly enhanced stereoselectivity (from 35.1 % to 99.8 % ee for production of (1S,2R)-indene oxide). This first determination of the substrate binding mode of GEMs combined with structure-function relationships opens the door for structure-based design of these powerful biocatalysts.     

提高金属有机骨架材料在二氧化碳热催化转化中的性能:策略及前景展望

近年来,大气中CO2的浓度不断增加,带来全球变暖等一系列严重后果,成为国际社会共同关注的环境问题.将CO2催化转化为高附加值化学品可有效降低其向大气中的排放,同时可实现其资源化利用,符合低碳社会的发展目标.目前,已有多种催化体系实现了CO2向不同化学品的转化.然而,由于CO2自身的热力学稳定性和动力学惰性,这些转化通常需要在苛刻的反应条件和较高能耗下进行.设计开发高效催化体系、实现温和条件下CO2的转化利用引起了工业界和学术界的广泛兴趣.金属有机骨架材料(MOFs)是一类由有机配体和金属中心通过配位键组装而成的有机-无机杂化材料,在很多方面展现出良好的应用性能.由于其结构的多样性、可设计性、高比表面积和多孔性等独特性质,MOFs在催化领域吸引了很多研究者的关注.其中,MOFs作为非均相催化剂在CO2热催化转化中表现出良好的应用前景,已实现多种CO2向高值化学品的转化路径.但这些催化体系也存在一些缺点,如有些MOFs材料在催化反应中稳定性差以及其微孔性对反应中的传质造成限制等.因此,设计稳定的MOFs和MOF-基材料并对其结构进行优化改性,从而在温和条件下实现高效的CO2转化具有重要意义.本文综述了提高MOFs在CO2热催化转化反应中性能的几种策略:(1)对MOFs结构中的配体进行设计,包括具有活性官能团的配体、活性配合物作为配体和引入混合配体设计多元MOF;(2)调节MOFs结构中的金属中心,设计混合金属中心和包含活性金属团簇的金属中心;(3)构筑多级孔MOFs;(4)设计MOF-基的复合材料,包括MOFs作为载体与金属纳米颗粒、活性配合物和聚合物构建复合材料;(5)利用MOFs作为前驱体制备MOF-基衍生物材料,重点阐述了如何增加MOFs作为非均相催化剂的催化活性位点以及在CO2转化反应中各位点之间的协同作用.此外,介绍了原位表征技术在MOF-基材料用于CO2固定和转化中的应用.最后,分析了MOF-基非均相催化材料在CO2热催化转化领域目前面临的问题和挑战,包括MOFs材料结构优化、催化机理研究和规模化制备等方面,并对未来的发展趋势进行了展望.     

磷酸镁铝分子筛的交换与催化性能研究

用红外与程序升温脱附氨法考察了磷酸镁铝分子筛的酸性,测定了94℃时Ni~(2+)与其进行离子交换的等温线,并在不同温度考察交换上Ni~(2+)后分子筛的催化加氢、裂解活性。     

Catalytic Linkage Engineering of Covalent Organic Frameworks for the Oxygen Reduction Reaction

Metal-free covalent organic frameworks (COFs) have been employed to catalyze the oxygen reduction reaction (ORR). To achieve high activity and selectivity, various building blocks containing heteroatoms and groups linked by imine bonds were used to create catalytic COFs. However, the roles of linkages of COFs in ORR have not been investigated. In this work, the catalytic linkage engineering has been employed to modulate the catalytic behaviors. To create single catalytic sites while avoiding other possible catalytic sites, we synthesized COFs from benzene units linked by various bonds, such as imine, amide, azine, and oxazole bonds. Among these COFs, the oxazole-linkage in COFs enables to catalyze the ORR with the highest activity, which achieved a half-wave potential of 0.75 V and a limited current density of 5.5 mA cm⁻². Moreover, the oxazole-linked COF achieved a conversion frequency (TOF) value of 0.0133 S⁻¹, which were 1.9, 1.3, and 7.4-times that of azine-, amide- and imine-COFs, respectively. The theoretical calculation showed that the carbon atoms in oxazole linkages facilitated the formation of OOH* and promoted protonation of O* to form the OH*, thus advancing the catalytic activity. This work guides us on which linkages in COFs are suitable for ORR.     

填料型固体酸的制备及其催化性能

用阳极氧化法制备了填料式Al₂O₃-Al载体,经浸渍H₂SO₄后再焙烧制得SO₄^2-/Al₂O₃-Al固体酸催化剂.用SEM,BET,XRD和NH3-TPD等手段对其进行了表征,结果显示,载体Al₂O₃膜为无定形结构,SO₄^2-/Al₂O₃-Al为中等酸强度的固体酸.用乙酸-乙醇酯化催化反应评估了该固体酸的催化性能,显示出催化剂具有较高的催化活性,且稳定性较好.     

Artificial intelligence and machine learning for targeted energy storage solutions

With the application of machine learning to large-material data sets, models are being developed that allow us to better predict novel materials with designed properties. Advances in artificial intelligence and its subclasses, as well as compute infrastructure, are making it possible to rapidly compute material properties, to access time/length scales and chemical spaces beyond the current capabilities of density functional theory and to outperform humans in interpretation and characterization of the data. This review highlights the latest developments in the field with special interest to energy storage materials.     

氢化硝基苯合成对氨基酚中活性炭负载铂催化剂的新制备方法研究

采用不同还原剂（甲醛、甲酸、硼氢化钾和氢气）,或于还原Pt(IV)过程中引入少量Pt/AC(AC：活性炭)催化剂“催化”氢气分子,制备了Pt/AC催化剂。其催化氢化硝基苯制对氢基酚的反应结果表明,制备催化剂时所用的还原剂对催化剂的活性影响很大,但对反应选择性影响较小。用甲醛、甲酸和硼氢化钾还原制成的催化剂的活性皆较高;以氢气还原制得的催化剂活性较差;采用“催化”氢气还原法,可大大提高Pt/AC催化剂的活性,与传统甲醛还原法相比,甲酸和“催化”氢气还原制备Pt/AC催化剂的方法较简便、有效。     

Unlocking the Stereoselectivity and Substrate Acceptance of Enzymes: Proline-Induced Loop Engineering Test

Protein stability and evolvability influence each other. Although protein dynamics play essential roles in various catalytically important properties, their high flexibility and diversity makes it difficult to incorporate such properties into rational engineering. Therefore, how to unlock the potential evolvability in a user-friendly rational design process remains a challenge. In this endeavor, we describe a method for engineering an enantioselective alcohol dehydrogenase. It enables synthetically important substrate acceptance for 4-chlorophenyl pyridine-2-yl ketone, and perfect stereocontrol of both (S)- and (R)-configured products. Thermodynamic analysis unveiled the subtle interaction between enzyme stability and evolvability, while computational studies provided insights into the origin of selectivity and substrate recognition. Preparative-scale synthesis of the (S)-product (73 % yield; >99 % ee) was performed on a gram-scale. This proof-of-principle study demonstrates that interfaced proline residues can be rationally engineered to unlock evolvability and thus provide access to new biocatalysts with highly improved catalytic performance.     

ZSM—5芳构化反应活性和稳定性的研究

ＺＳＭ－５以其独特的基于微孔结构特征的形状选择性和强酸中心，而成为具有酸催化择形性能的新型分子筛催化剂．ＺＳＭ－５分子筛表面酸性中心不但是反应的活性中心，同时也是积炭中心，这使得这类催化剂不仅具有很高的催化反应活性，同时也具有较高的结焦活性．催化剂表...     

Computer-Driven Development of Ylide Functionalized Phosphines for Palladium-Catalyzed Hiyama Couplings

Palladium-catalyzed couplings of silicon enolates with aryl electrophiles are of great synthetic utility, but often limited to expensive bromide substrates. A comparative experimental study confirmed that none of the established ligand systems allows to couple inexpensive aryl chlorides with α-trimethylsilyl alkylnitriles. In contrast, ylide functionalized phosphines (YPhos) led to encouraging results. A statistical model was developed that correlates the reaction yields with ligand features. It was employed to predict catalyst structures with superior performance. With this cheminformatics approach, YPhos ligands were tailored specifically to the demands of Hiyama couplings. The newly synthesized ligands displayed record-setting activities, enabling the elusive coupling of aryl chlorides with α-trimethylsilyl alkyl nitriles. The preparative utility of the catalyst system was demonstrated by the synthesis of pharmaceutically meaningful α-aryl alkylnitriles, α-arylcarbonyls and biaryls.