Passerini多组分反应研究进展

多组分反应操作简便、原子经济性高,是一类重要的有机反应。经典Passerini反应是以异腈、醛酮、羧酸为原料一步合成α-酰氧基酰胺的多组分反应,其产物作为重要的有机中间体,可以进一步合成许多重要的药物、天然产物和功能材料等复杂有机分子,具有广泛的应用价值。本文从反应底物、串联反应及相关应用的角度阐述近5年来Passerini多组分反应研究的新进展。     

不对称多组分反应

由于多组分反应自身所具有的优势及其在新药发现中的应用,多组分反应特别是不对称多组分反应成为一个非常有吸引力的研究领域。本文从非对映选择性和对映选择性控制两个方面对不对称多组分反应的最新研究进展进行了综述。重点介绍了反应中所使用的催化剂体系及有关反应机理。最后提出了不对称多组分反应研究中存在的一些问题,并对其今后的发展方向进行了展望。     

以多组分点击化学为基础的高分子合成——高分子合成的新机遇

高分子合成是高分子学科的基础,合理选择有机反应制备新型聚合物是高分子合成方法学的重要研究内容.最近,利用多组分反应合成高分子引起了人们的广泛关注,成为高分子合成中充满活力的新领域.在研究多组分反应的过程中,人们发现了多组分反应与点击反应存在交集,并提出了多组分点击化学的概念,即某些高效、原子经济、环境友好的多组分反应也可视为点击反应.本文将系统介绍多组分点击反应的特点、以多组分点击反应为基础的聚合物合成方法、通过多组分点击反应得到的功能聚合物及其应用等,归纳总结这一新兴领域的初步结果,并对其未来发展提出一些拙见.     

多组分参与的氟烷基化反应研究进展

多组分参与的氟烷基化反应是当前有机氟化学研究的一个热点.在过去的几年里,由于新试剂新方法的不断涌现,多组分参与的氟烷基化反应取得了长足的进展,不仅可以经济有效地一步将氟烷基基团与其他官能团同步引入,而且可以将起始原料转化为多种含有生物活性或药物活性的化合物.按照三组分二氟烷基化反应、三组分三氟甲基化反应、三组分全氟烷基化反应、三组分单氟烷基化反应、三组分氟化反应以及四组分氟烷基化反应和总结7个部分,总结了多组分参与的氟烷基化反应在过去近十年时间里的发展进程,同时对该类反应进行了总结和展望.     

丙二腈在多组分反应中的应用*

丙二腈分子中的氰基作为强吸电子基团活化亚甲基,也是良好的离去基团,以及氰基的碳氮三键可进行加成反应,使得丙二腈是一种非常特别的化合物。它具有非常丰富的反应性质,可以发生Knoevenagel缩合、Michael加成、环化和消去等反应,是进行多组分合成反应的优良试剂。由其参加的多组分合成反应已经成为合成众多碳环和杂环化合物的重要方法。本文综述了丙二腈在多组分反应中的研究进展,介绍了近年来丙二腈参加的多组分反应合成环状化合物的成功事例,展望了丙二腈反应的发展方向。     

二芳基脯氨醇衍生物催化的硝基烯参与的多组分不对称串联合成研究进展

硝基烯是一类重要的有机合成子,以硝基烯烃为原料,二芳基脯氨醇衍生物催化的多组分不对称串联反应是构建复杂手性化合物的重要方法,被广泛应用于有机合成和新药开发领域.根据构建的目标化合物类型,较全面地总结了基于二芳基脯氨醇衍生物催化、硝基烯为合成子的多组分不对称串联反应的合成研究,从反应的催化剂体系、反应机理、实验结果、反应优点、存在的问题和局限性等方面进行介绍,并对今后的发展做出展望.     

异腈参与的多组分反应研究进展

多组分反应由于反应本身的经济性和生态价值,越来越受到人们的重视。异腈的亲电和亲核反应均发生在碳原子上,因此在多组分反应中具有重要作用。本文就近年来有异腈参与的多组分反应进行了综述,主要阐述了Ugi反应和Passerini反应及其他含异腈参与的多组分反应的机理、研究开展及应用情况。     

多组分Passerini反应的研究进展

Passerini反应是一类重要的多组分反应,通过该反应可以合成许多重要的天然产物、复杂分子及药物分子,具有很好的使用价值和应用前景。本文从非对映选择性、立体选择性及应用等方面综述了Passerini反应近年来的研究进展。     

多组分反应:丰富生物质基平台分子高值化转化路线的新策略

以廉价易得的可再生生物质基平台化合物为原料,通过多组分"一锅"反应合成结构复杂的产物已成为生物质高值化转化的重要手段之一.生物质基平台分子的多样性和多官能性为多组分反应的构建提供了传统方法难以提供的物质基础.介绍了以构建多组分反应的方式实现生物质基平台化合物高值化转化的典型案例,重点总结了近年来多元醇、二元酸、乙酰丙酸、糠醛衍生物等生物质基平台化合物参与的多组分反应,并对该方向的未来发展进行了展望.     

多组分聚合体系的探索

多组分反应是利用三种或者三种以上反应物一锅法得到终产物的反应。在此过程中,无需对中间产物进行分离提纯,而且几乎所有反应物的原子都出现在生成物当中。因此多组分反应经常被用来合成具有复杂结构的化合物。我们在多组分反应中引入可聚合元素,将功能化单体合成和可控聚合结合在一起,一步合成具有特殊官能结构的聚合物。这个体系中的反应均互不干扰,有着良好的匹配效果。因此,得到的产物具有可控的分子量和很窄的分子量分布。与传统方法相比,这种多组分聚合体系节省了反应时间、降低了合成成本、合成途径更加绿色经济。我们现已发展了多种多组分聚合体系,按照复杂程度不同分为二元、三元和四元体系。通过不同的有机小分子反应与可控聚合的结合,我们成功制备了一些通过其他聚合方法难以或是无法合成的新型聚合物,体现了这一聚合方法的特点和优势。随着对多组分聚合体系认识的不断深入,相信我们能够更简便地合成更多结构新颖的聚合物。     

Multicomponent Reactions,Union of MCRs and Beyond

Multicomponent reactions (MCRs), which are located between one‐ and two‐component and polymerization reactions, provide a number of valuable conceptual and synthetic advantages over stepwise sequential approaches towards complex and valuable molecules. To address current limitations in the number of MCRs and the resulting scaffolds, the concept of union of MCRs was introduced two decades ago by Dömling and Ugi and is rapidly advancing, as is apparent by several recently published works. MCR technology is now widely recognized for its impact on drug discovery projects and is strongly endorsed by industry in addition to academia. Clearly, novel scaffolds accessible in few steps including MCRs will further enhance the field of applications. Additionally, broad expansion of MCR applications in fields such as imaging, materials science, medical devices, agriculture, or futuristic applications in stem cell therapy and theragnostics or solar energy and superconductivity are predicted.     

Electrocatalytic Fast and Efficient Multicomponent Approach to Medicinally Relevant (2‐Amino‐4H‐chromen‐4‐yl) phosphonate Scaffold

‘One‐pot’ electrocatalytic transformation of salicylaldehydes, malononitrile, and triethyl phosphite in an undivided cell results in the formation of diethyl (2‐amino‐3‐cyano‐4H‐chromen‐4‐yl)phosphonates in 88–93% substance yields and 880–930% current efficiency via complex multicomponent process. This novel electrocatalytic chain process opens an effective, fast, and convenient way to cyano‐functionalized (2‐amino‐4H‐chromen‐4‐yl)phosphonate systems which are promising compounds for biomedical applications. This efficient electrocatalytic approach to the (2‐amino‐4H‐chromen‐4‐yl)phosphonate scaffold represents novel synthetic concept for multicomponent reactions (MCR) strategy and allows to combine the synthetic virtues of conventional MCR with ecological benefits and convenience of facile electrocatalytic procedure.     

Short and diverse route toward complex natural product-like macrocycles

[reaction: see text] A general strategy toward macrocyclic compounds using multicomponent reaction (MCR) chemistry, e.g., Passerini and Ugi variants, and ring-closing metathesis (RCM) is introduced. The corresponding bifunctional isocyanides carboxylic acids bearing a terminal olefin are easy to prepare from the corresponding commercially available starting materials. Advantageously, this strategy allows fast access to a diverse conformational space of natural product-like macrocycles and could thus be of interest in the discovery of novel bioactive agents.     

Discovery of a Potent Allosteric Kinase Modulator by Combining Computational and Synthetic Methods

The rational design of allosteric kinase modulators is challenging but rewarding. The protein kinase PDK1, which lies at the center of the growth‐factor signaling pathway, possesses an allosteric regulatory site previously validated both in vitro and in cells. ANCHOR.QUERY software was used to discover a potent allosteric PDK1 kinase modulator. Using a recently published PDK1 compound as a template, several new scaffolds that bind to the allosteric target site were generated and one example was validated. The inhibitor can be synthesized in one step by multicomponent reaction (MCR) chemistry when using the ANCHOR.QUERY approach. Our results are significant because the outlined approach allows rapid and efficient scaffold hopping from known molecules into new easily accessible and biologically active ones. Based on increasing interest in allosteric‐site drug discovery, we foresee many potential applications for this approach.     

Organocatalysis in synthesis: L-proline as an enantioselective catalyst in the synthesis of pyrans and thiopyrans

The multicomponent reaction (MCR) of aromatic aldehydes 1 and malononitrile (2) with active methylenes 5a-h in the presence of L-proline produced pyrans and thiopyrans 6a-h stereospecifically and in good yields. Moreover a novel MCR of ethyl propiolate (8) with 1 and 2 in the presence of L-proline to afford (R)-polysubstituted pyran is also reported. X-ray structures, e.e. and optical activity of the synthesized compounds indicated that L-proline as a catalyst is responsible for the observed enantioselectivity in the studied reactions.     

Microchip-based synthesis and analysis: control of multicomponent reaction products and intermediates

A miniaturised-SYNthesis and Total Analysis System (mu SYNTAS) was used for the solution-phase synthesis and on-line analysis (TOF-MS) of Ugi multicomponent reaction (MCR) products. This approach provides an unusually high degree of control of the MCR and delivers detailed, novel information on reaction intermediates in real-time. Specifically, the Ugi 4 component condensation (4CC) involving the reaction of an amine, acid, aldehyde and isocyanide species was performed at room temperature in a controllable fashion. Furthermore, observation of the nitrilium intermediate, cyclohexyl(2-piperidin-1-ylethylidyne)ammonium chloride, is presented for the first time.     

One-pot multicomponent synthesis of novel tricyclic pyrrolo[2, 1-c][1, 4]benzoxazines

A simple and efficient synthetic protocol has been developed using a one-pot multicomponent reaction （MCR） involving 2-aminophenols, dialkyl acetylenedicarboxylates, and ethyl bromopyruvate in poly（ethyleneglycol）. This protocol was utilized to prepare novel pyrrolo[2,1-c][1,4]benzoxazines in excellent yields.     

Multi‐component reaction‐functionalized chitosan complexed with copper nanoparticles: An efficient catalyst toward A3 coupling and click reactions in water

A novel bio‐nanocomposite nanocatalyst with highly dispersed particles is synthesized through covalent functionalization of chitosan biopolymer by the multicomponent reaction (MCR) strategy. Surface functionalization of chitosan through MCR is led to the grafting of carboxamide type ligands with a high affinity toward complexation with copper nanoparticles. The catalytic activity of the synthesized catalyst was explored in various transformations such as A³ coupling and click reactions in water. Reusability and non‐hazardous nature of the catalyst, mild reaction conditions, operational simplicity, high yielding, and using water as a solvent are the main advantages of this catalytic protocol.     

Synthesis of Chromeno[3,4-b]piperazines by an Enol-Ugi/Reduction/Cyclization Sequence

Keto piperazines and aminocoumarins are privileged building blocks for the construction of geometrically constrained peptides and therefore valuable structures in drug discovery. Combining these two heterocycles provides unique rigid polycyclic peptidomimetics with drug-like properties including many points of diversity that could be modulated to interact with different biological receptors. This work describes an efficient multicomponent approach to condensed chromenopiperazines based on the novel enol-Ugi reaction. Importantly, this strategy involves the first reported post-condensation transformation of an enol-Ugi adduct.     

Synthesis of Polyheterocyclic Dimers Containing Restricted and Constrained Peptidomimetics via IMCR-Based Domino/Double CuAAC Click Strategy

A novel strategy via the triple process (multicomponent reactions (MCR)-domino)/tandem was developed for the synthesis of restricted and constrained bis-1,2,3-triazole-linked pyrrolo[3,4-b]pyridine peptidomimetics dimers in overall yields of 20–55%. This strategy allows the construction of six heterocycles in two stages of the reaction.