Carbon-carbon bonds by hydrolytic enzymes

Enzymes are efficient catalysts in synthetic chemistry, and their catalytic activity with unnatural substrates in organic reaction media is an area attracting much attention. Protein engineering has opened the possibility to change the reaction specificity of enzymes and allow for new reactions to take place in their active sites. We have used this strategy on the well-studied active-site scaffold offered by the serine hydrolase Candida antarctica lipase B (CALB, EC 3.1.1.3) to achieve catalytic activity for aldol reactions. The catalytic reaction was studied in detail by means of quantum chemical calculations in model systems. The predictions from the quantum chemical calculations were then challenged by experiments. Consequently, Ser105 in CALB was targeted by site-directed mutagenesis to create enzyme variants lacking the nucleophilic feature of the active site. The experiments clearly showed an increased reaction rate when the aldol reaction was catalyzed by the mutant enzymes as compared to the wild-type lipase. We expect that the new catalytic activity, harbored in the stable protein scaffold of the lipase, will allow aldol additions of substrates, which cannot be reached by traditional aldolases.     

The Catalytic Asymmetric Aldol Reaction

The construction of C-C bonds with complete control of the stereochemical course of a reaction is of utmost importance for organic synthesis. The aldol reaction-the simple addition of an enolate donor to a carbonyl acceptor-is one of the most powerful reactions available to the synthetic chemist. In general, control of the relative and absolute configuration of the newly formed stereogenic centers has been achieved through the use of chiral starting materials or chiral auxiliaries. In recent years the search for catalytic methods that efficiently and effectively transfer chirality information has become a major effort in synthetic organic chemistry. Two different approaches have been taken toward the catalytic asymmetric aldol reaction: biocatalysis and catalysis with small molecules. Both approaches have specific advantages and limitations, and as a result are complementary to each other. The important efforts toward both approaches are reviewed in this article.     

Application of Polyamines and Amino Acid Derivatives Based on 2-Azabicycloalkane Backbone in Enantioselective Aldol Reaction

Carbon–carbon bond forming reactions, such as aldol reaction and condensation, belong to extremely desired transformations as manifested by >25,000 entries in SciFinder. Their stereoselective variant requires the use of an appropriate catalyst with a strictly defined structure. Hence, chiral 2-azabicycloalkane-based catalysts were designed, synthesized and tested in a stereoselective aldol reaction between cyclic/acyclic ketone and p-nitrobenzaldehyde both in organic and aqueous media. Among catalysts containing a chiral bicyclic backbone, amide based on 2-azabicyclo[3.2.1]octane and pyrrolidine units showed the best catalytic activity and afforded aldol product in excellent chemical yields (up to 95%) and good diastereo- and enantioselectivity (dr 22:78, ee up to 63%).     

Current progress in the asymmetric aldol addition reaction

Control of stereochemistry during aldol addition reactions has attracted considerable interest over the years as the aldol reaction is one of the most fundamental tools for the construction of new carbon-carbon bonds. Several strategies have been implemented whereby eventually any single possible stereoisomeric aldol product can be accessed by choosing the appropriate procedure. With earlier methods, stoichiometric quantities of chiral reagents were required for efficient asymmetric induction, with the auxiliary most often attached covalently to the substrate carbonyl. Lewis acid catalyzed addition reactions of silyl enolates to aldehydes (Mukaiyama reaction) later opened the way for catalytic asymmetric induction. In the last few years, both chiral metal complexes and small chiral organic molecules have been found to catalyse the direct aldol addition of unmodified ketones to aldehydes with relatively high chemical and stereochemical efficiency. These techniques along with the more recent developments in the area are discussed in this tutorial review.     

手性季铵盐类相转移催化剂的新进展

叙述了手性季铵盐类相转移催化剂在不对称催化反应（包括活性亚甲基的烷基 化、Michael加成、双键的环氧化、Darzens缩合、氮杂环丙烷的合成、羟醛缩合以 及Horner-Wadsworth-Emmons反应）中应用的新进展。     

手性胺有机小分子不对称催化的研究进展

扼要综述了有机手性胺催化在过去十年中的发展,列举了具有代表性的活化模式(如仲胺催化的活化模式)、催化剂(如手性叔胺有机催化剂)和反应类型(如分子内Aldol环化反应,分子间Aldol缩合反应,Lewis酸活化羰基化合物机制,手性胺催化等),并提出了该领域新的研究方向.手性胺不对称催化在手性合成中具有广阔的应用前景.     

Direct Asymmetric Aldol Type Reaction with Ethyl Diazoacetate: Stereoselective Synthesis of α, β-Dihydroxy Esters

Enantioselective aldol condensation under catalytic condition remains a challenging task in modern organic synthesis, and numerous efforts have been directed to this area. In particular, the direct catalytic asymmetric aldol reaction is very attractive considering the requirement of atom efficiency. This has been studied only recently, and several very practical processes have been developed. We have recently initiated a study on the direct asymmetric aldol type reaction with ethyl diazoacetate as nucleophile. Moderate enantioselectivities (65% ～91% ee ) were achieved in the condensation of aldehydes with ethyl diazoacetate catalyzed by the chiral complex of BINOL derivatives-Zr (OBu- t )4. [1]     

Recent advances in solventless organic reactions: towards benign synthesis with remarkable versatility

A paradigm shift away from using solvents in organic synthesis as solventless reactions can lead to improved outcomes, and more benign synthetic procedures, in for example aldol condensation reactions, sequential aldol and Michael addition reactions en route to Kr?hnke type pyridines, reactions leading to 3-carboxycoumarins, benzylidenes, 4-aryl-1,4-dihydropyridines and 2-aryl-1,2,3,4-tetrahydroquinazolines, and oligomerisation reactions for the synthesis of cavitands; kinetic considerations for the reaction of two solids can only be explained if a eutectic melt is formed during the reaction.     

Design of hydroxyapatite-bound transition metal catalysts for environmentally-benign organic syntheses

Novel heterogeneous catalysts, which were designed with atomic precision, easy to prepare, and recyclable, have been developed using a unique inorganic support hydroxyapatite, Ca₁₀(PO₄)₆(OH)₂. The introduction of a Ru cation into the apatite framework can generate a stable monomeric phosphate complex, which exhibits prominent catalytic performances for various oxidation reactions using molecular oxygen as a primary oxidant. Treatment of the RuHAP with an aqueous solution of AgX affords cationic Ru phosphate complexes as Lewis acid catalysts, promoting Diels–Alder and aldol reactions under mild and neutral conditions. Furthermore, two classes of heterogeneous Pd catalysts were synthesized with both stoichiometric and Ca-deficient hydroxyapatites, which show specific functions for aerobic oxidation of alcohols and carbon–carbon bond-forming reactions with extremely high turnover numbers. The catalytic systems described here are simple, efficient, and general for practical organic syntheses; thus meeting the increasing demands for environmentally-benign chemical processes.     

Amino acid catalyzed direct asymmetric aldol reactions: a bioorganic approach to catalytic asymmetric carbon-carbon bond-forming reactions.

Direct asymmetric catalytic aldol reactions have been successfully performed using aldehydes and unmodified ketones together with commercially available chiral cyclic secondary amines as catalysts. Structure-based catalyst screening identified L-proline and 5,5-dimethyl thiazolidinium-4-carboxylate (DMTC) as the most powerful amino acid catalysts for the reaction of both acyclic and cyclic ketones as aldol donors with aromatic and aliphatic aldehydes to afford the corresponding aldol products with high regio-, diastereo-, and enantioselectivities. Reactions employing hydroxyacetone as an aldol donor provide anti-1,2-diols as the major product with ee values up to >99%. The reactions are assumed to proceed via a metal-free Zimmerman-Traxler-type transition state and involve an enamine intermediate. The observed stereochemistry of the products is in accordance with the proposed transition state. Further supporting evidence is provided by the lack of nonlinear effects. The reactions tolerate a small amount of water (<4 vol %), do not require inert reaction conditions and preformed enolate equivalents, and can be conveniently performed at room temperature in various solvents. In addition, reaction conditions that facilitate catalyst recovery as well as immobilization are described. Finally, mechanistically related addition reactions such as ketone additions to imines (Mannich-type reactions) and to nitro-olefins and alpha,beta-unsaturated diesters (Michael-type reactions) have also been developed.     

Direct asymmetric aldol reactions inspired by two types of natural aldolases: water-compatible organocatalysts and Zn(II) complexes

In this article the utility of water-compatible amino-acid-based catalysts was explored in the development of diastereo- and enantioselective direct aldol reactions of a broad range of substrates. Chiral C(2)-symmetrical proline- and valine-based amides and their Zn(II) complexes were designed for use as efficient and flexible chiral catalysts for enantioselective aldol reactions in water, on water, and in the presence of water. The presence of 5 mol % of the prolinamide-based catalyst affords asymmetric intermolecular aldol reactions between unmodified ketones and various aldehydes to give anti products with excellent enantioselectivities. We also demonstrate aldol reactions of more demanding substrates with high affinity to water (i.e., acetone and formaldehyde). Newly designed serine-based organocatalyst promoted aldol reaction of hydroxyacetone leading to syn-diols. For presented catalytic systems organic solvent-free conditions are also acceptable, making the elaborated methodology interesting from a green chemistry perspectives.     

A recyclable bifunctional acid-base organocatalyst with ionic liquid character. The role of site separation and spatial configuration on different condensation reactions

A series of bifunctional organic catalysts containing acid and basic sites with ionic liquid characteristics have been prepared and their catalytic activity and reaction coordinate for aldol and Knoevenagel condensations have been compared. While the only factor controlling catalyst activity for the Knoevenagel condensation was the distance between the acid and base sites, the spatial orientation of the organocatalyst is also key to achieve high activity and selectivity in the Claisen-Schmidt condensation. Mechanistic studies based on theoretical DFT calculations show that the acid-base bifunctional organocatalyst follows a mechanism inspired in natural aldolases for the synthesis of trans-chalcones, being able to produce a large variety of these compounds of industrial interest. The combination of the acid-base pairs within the proper geometry and the ionic liquid nature makes this catalyst active, selective and recyclable.     

Recent Developments on Catalytic Applications of Nano-Crystalline Magnesium Oxide

Nanocrystalline metal oxides, MgO, CuO, ZnO, TiO₂ as catalysts or catalyst supports have been received much attention in the recent years, especially nanocrystalline magnesium oxide (NAP-MgO) has been used as a recyclable catalyst for Wittig, Wadsworth–Emmons, aza-Michael, Baylis–Hillman, Strecker, Aldol, Claisen-Schmidt condensation and other useful organic reactions. In general, it is reported that nanocrystalline magnesium oxide shows better activity in many organic reactions. These high reactivities are due to high surface areas combined with unusually reactive morphologies. The nanomaterials were also explored as supports to make supported metal catalysts for the organic reactions. The higher activity of these catalysts was studied partly to understand the mechanism of the reaction, the putative reaction pathways were preliminarily presented with the help of spectroscopic support, XPS, silicon, and phosphorus NMR spectroscopy. The catalysts are recovered and reused for several cycles. These catalytic systems are expected to contribute to the development of benign chemical processes.     

Current applications of organocatalysts in asymmetric aldol reactions: An update

The aldol reaction is one of the most important carbon–carbon bond formations in synthetic organic chemistry. An enantioselective aldol reaction should provide an enantioenriched product. The organocatalytic asymmetric aldol reaction via an in situ generated enamine intermediate is one of the most powerful synthetic tools to achieve enantiomerically pure products. This approach is often used to obtain chiral β-hydroxycarbonyl compounds with excellent enantioselectivity. In this report, we update our previous review regarding the applications of organocatalysts in asymmetric aldol reactions leading to chiral β-hydroxycarbonyl compounds as versatile synthetic motifs frequently found in pharmaceutically desired intermediates and biologically active naturally occurring compounds.     

环戊二烯基钌配合物催化的高选择性苯乙炔二聚反应

Transition metal vinylidene complexes (M=C=CHR) have attracted a great deal of attention in recent years as a new type of organometallic intermediates that may have unusual reactivity[1]. Their reactivity has been explored and their application to organic synthesis is developed[2]. Recent reports on the ruthenium-vinylidene complexes[3]suggest that the reaction of ruthenium-vinylidene complexes with a base generates the coordinatively unsaturated ruthenium acetylide species, which are involved in a number of catalytic and stoichiometric reactions of alkynes. For example,the coordinatively unsaturated ruthenium acetylide species C5Me5Ru(PPh3)-C≡CPh,formed from the reaction of the vinylidene complex C5Me5Ru(PPh3) (Cl)=C=CHPh with a base was reactive toward a variety of small molecules and active in catalytic dimerization of terminal alkynes[4]. The dimerization of terminal alkyne is an effective method of forming enynes, but its synthetic application in organic synthesis has been limited dueto low selectivity for dimeric products[5]. In this communication, we report that three ruthenium complexes were used as catalysts for the highly selective dimerization of phenylacetylene.     

Trost氮杂半冠醚手性配体在不对称催化反应中的应用

双功能手性金属络合物催化的不对称反应是目前有机化学研究的热点之一。本文综述了氮杂半冠醚手性配体与金属有机试剂络合的双金属催化剂,在催化不对称aldol反应、不对称Henry反应、不对称Michael反应、不对称Mannich反应、不对称Friedel-Crafts烷基化反应、不对称炔基化反应、不对称硅氰化反应、共聚反应、去对称化反应以及不对称Nozaki-Hiyama烯丙基化反应体系中的应用进展,重点介绍了不同催化体系对催化剂和反应底物之间立体效应和电子效应的影响,总结了控制反应立体选择性的规律以及有关催化反应的机理。     

Highly diastereo- and enantioselective direct aldol reactions of aldehydes and ketones catalyzed by siloxyproline in the presence of water

Proline-based organocatalysts have been developed for a highly enantioselective, direct aldol reaction of aldehydes and ketones in the presence of water. While several surfactant-proline combined catalysts have proved effective, proline derivatives with a hydrophobic moiety such as trans-siloxy-L-proline and cis-siloxy-D-proline, both of which are easily prepared from the same commercially available 4-hydroxy-L-proline, have been found to be the most effective organocatalysts examined in this study, affording the aldol product with excellent diastereo- and enantioselectivities, these two catalysts generating opposite enantiomers. Water affects the selectivity, and poor results are obtained under neat reaction conditions or in dry organic solvents. More than three equivalents of water are required for the best diastereo- and enantioselectivities, while three equivalents is the recommended amount from a synthetic point of view. The reaction proceeds in the organic phase, and also proceeds in the presence of a large amount of water. The large-scale preparation of aldols with the minimal use of an organic solvent, including in the purification step, is described.     

Cs/ZSM-35 分子筛催化甲缩醛和乙酸甲酯发生一步法羟醛缩合反应

丙烯酸及其酯是重要的化工原料, 广泛应用于涂料、粘结剂、纤维等领域, 目前工业上常采用丙烯两段氧化法进行制备. 然而该方法以石油基原料丙烯为源头, 采用 V/Mo/Bi 等金属催化剂, 不符合可持续发展理念, 且存在环境污染及氧气下产物易过度氧化等问题. 因此, 如何高效、安全、大规模工业化制备丙烯酸及其酯是研究者追求的目标. 以乙酸甲酯(MAc) 和甲醛为原料, 通过羟醛缩合一步制备丙烯酸及其酯是一条完全不同于丙烯氧化法的合成路径, 原料均可由煤基甲醇得到, 符合我国"富煤、贫油、少气"的基本能源结构, 且该方法碳原子利用率为 100%, 副产物仅为水, 属于绿色环保合成路径.羟醛缩合是典型的碳链增长反应, 可在酸性催化剂、碱性催化剂、以及酸碱双功能催化剂存在下发生. 碱性催化剂一般为负载型碱金属氧化物, 例如以 SiO2为载体的负载型 Na, K, Cs 氧化物催化剂等, 但都存在活性组分流失的问题, 进而导致催化剂的失活, 难以实现工业化. 酸碱双功能催化剂是目前研究的热点, 由于具有酸催化剂的高选择性和碱催化剂的高活性, 其反应性能要远优于单一酸性催化剂和单一碱性催化剂, 广大研究者对此进行了深入广泛的研究, 目前基本处于实验室阶段. 相对而言, 目前酸性催化剂上通过羟醛缩合反应制备丙烯酸及其酯的研究工作较少, 特别是以固体酸为催化剂进行乙酸甲酯和甲醛气固相反应研究非常少见.我们以甲缩醛为甲醛源, 创新性地采用固体硅铝分子筛为酸性催化剂, 催化甲缩醛 (DMM) 和 MAc 发生羟醛缩合反应来制备丙烯酸. 硅铝分子筛具有较高的活性, 可高效地催化羟醛缩合反应, 且由于分子筛催化剂具有很好的再生性能, 即使催化剂寿命较短, 也可采用流化床或移动床等反应器进行工业化, 因此存在良好的工业化前景. 为了进一步深入研究酸性位和碱性位各自对 DMM 和 MAc 羟醛缩合反应的影响, 本文以 HZSM-35 分子筛为载体, 采用浸渍法制备不同碱金属铯氧化物含量的催化剂, 利用氮气吸附/脱附方法和化学程序升温 (NH3-TPD) 方法对其孔结构和酸性质进行表征, 并进一步考察催化剂的性能. 结果表明, 微孔体积随着碱金属 Cs 负载量的增加而逐渐减小, 当 Cs 负载量增加至 10 wt% 时, 样品微孔体积从初始 0.105 cm3/g 降至 0.063 cm3/g. NH3-TPD 结果显示, 当 Cs 负载量为 1 wt%, 酸性催化剂载体上的强酸和弱酸活性位被大量碱性氧化物占据; 当负载量超过 5 wt% 时, 所有的酸性位均被覆盖. 随后考察负载不同碱金属含量分子筛的羟醛缩合反应性能, 发现碱金属氧化物的引入不利于羟醛缩合反应的进行, 这主要是由于作为甲醛源的 DMM 只有在酸中心上才能进行分解产生甲醛, 促使羟醛缩合反应顺利进行. 当采用 DMM 为甲醛源时, 体系中必须有酸性位存在. 同时得知, 分子筛 HZSM-35 中强酸和弱酸均是羟醛缩合反应的有效酸性位, 但强酸同时催化原料发生类甲醇制烯烃过程, 致使大量烃类副产物生成, 产生较重的积炭物种. 羟醛缩合反应在含有大量弱酸催化剂上 (如γ-Al2O3) 也可顺利进行, 且具有较高的活性和稳定性.     

Catalytic phosphorus(V)-mediated nucleophilic substitution reactions: development of a catalytic Appel reaction

Catalytic phosphorus(V)-mediated chlorination and bromination reactions of alcohols have been developed. The new reactions constitute a catalytic version of the classical Appel halogenation reaction. In these new reactions oxalyl chloride is used as a consumable stoichiometric reagent to generate the halophosphonium salts responsible for halogenation from catalytic phosphine oxides. Thus, phosphine oxides have been transformed from stoichiometric waste products into catalysts and a new concept for catalytic phosphorus-based activation and nucleophilic substitution of alcohols has been validated. The present study has focused on a full exploration of the scope and limitations of phosphine oxide catalyzed chlorination reactions as well as the development of the analogous bromination reactions. Further mechanistic studies, including density functional theory calculations on proposed intermediates of the catalytic cycle, are consistent with a catalytic cycle involving halo- and alkoxyphosphonium salts as intermediates.     

Iron‐ and Bismuth‐Catalyzed Asymmetric Mukaiyama Aldol Reactions in Aqueous Media

We have developed asymmetric Mukaiyama aldol reactions of silicon enolates with aldehydes catalyzed by chiral Fe^II and Bi^III complexes. Although previous reactions often required relatively harsh conditions, such as strictly anhydrous conditions, very low temperatures (?78 °C), etc., the reactions reported herein proceeded in the presence of water at 0 °C. To find appropriate chiral water‐compatible Lewis acids for the Mukaiyama aldol reaction, many Lewis acids were screened in combination with chiral bipyridine L1 , which had previously been found to be a suitable chiral ligand in aqueous media. Three types of chiral catalysts that consisted of a Fe^II or Bi^III metal salt, a chiral ligand ( L1 ), and an additive have been discovered and a wide variety of substrates (silicon enolates and aldehydes) reacted to afford the desired aldol products in high yields with high diastereo‐ and enantioselectivities through an appropriate selection of one of the three catalytic systems. Mechanistic studies elucidated the coordination environments around the Fe^II and Bi^III centers and the effect of additives on the chiral catalysis. Notably, both Brønsted acids and bases worked as efficient additives in the Fe^II‐catalyzed reactions. The assumed catalytic cycle and transition states indicated important roles of water in these efficient asymmetric Mukaiyama aldol reactions in aqueous media with the broadly applicable and versatile catalytic systems.