Advances in Immobilized Organocatalysts for the Heterogeneous Asymmetric Direct Aldol Reactions

The aim of this article is to collect the results published from the beginning (2000) on asymmetric direct aldol reactions taking place in the presence of immobilized chiral organocatalysts. The seven groups of organocatalysts discussed are: asymmetric direct aldol reactions catalyzed by: (1) covalently bonded immobilized hydroxyproline organocatalysts; (2) covalently bonded immobilized prolinamide organocatalysts; (3) covalently bonded immobilized peptide organocatalysts; (4) other covalently bonded immobilized chiral organocatalysts; (5) chiral organocatalysts bonded by ionic groups; (6) chiral organocatalysts with adsorptive bonding; and (7) other types of immobilized chiral organocatalysts. The main objective of this article based on results obtained by using about 360 immobilized organocatalysts, to bring to the focus of catalyst systems in which the aldol reactions yield beta-hydroxyketones of maximal optical purity, while keeping catalyst concentrations and reaction times as low and as short as possible. Trends recognized in data obtained in this field of investigation may mark out further tasks for the purpose of practical application.     

手性伯胺催化剂催化Michael加成反应的研究进展

在许多不对称有机反应中,手性伯胺催化剂已被证实是一种高效的催化剂,被广泛应用于各种Michael加成反应中。Michel加成是有机合成中构建碳一碳键的重要反应之一,本文综述了近年来手性伯胺催化剂在Michael加成反应中的研究新进展。     

Efficient Recovery and Reuse of an Immobilized Peptidic Organocatalyst

Readily reusable immobilized organocatalysts are important from a practical, economic, and environmental viewpoint. However, their successful development has proven challenging and only limited reaction and recovery cycles have been achieved. We report an extraordinarily robust resin‐bound tripeptidic organocatalyst that can be readily reused for at least 30 reaction and recovery cycles without loss in catalytic activity or stereoselectivity. The immobilized catalyst can be directly reused for conjugate addition reactions between aldehydes and nitroolefins after a simple filtration from the reaction products. The catalytic efficiency and chemoselectivity of the immobilized peptidic catalysts is so high that a broad range of γ‐nitroaldehydes were isolated easily after filtration and removal of all volatiles in quantitative yields, excellent diastereoselectivities and enantioselectivities and, most remarkably, perfect analytical purities. The ease of handling allows for a facile scale‐up of reactions catalyzed by the immobilized peptidic catalyst. In addition, the results provide a guide for the further development of immobilized organocatalysts.     

(硫)脲催化剂催化杂原子Michael加成反应的研究进展

(硫)脲催化剂已被证实是一种高效的有机催化剂,被广泛应用于各种Michael加成反应中。关于C-C键生成的Michael加成反应的综述较多,但关于杂原子的Michael加成反应的文章较少。本论文简述了(硫)脲催化剂在杂原子Michael加成反应中的研究新进展。     

脯氨酸及其衍生物有机小分子催化剂的研究进展

近几年来,脯氨酸及其衍生物等手性有机小分子催化剂,主要为酰胺类、二胺类和肽类催化剂,凭借自己独特的优势,比如不含金属、容易制备、价格低廉、反应条件温和、稳定性好、对环境友好等,在不对称合成中发挥着越来越重要的作用,受到人们越来越多的关注。已经发现,这些新的有机小分子能够催化许许多多的有机反应。     

<Emphasis Type="SmallCaps">l</Emphasis>-Valine Dipeptide Organocatalysts with Two Amide Units for the Direct Asymmetric Aldol Reaction in Brine

Abstract  

A series of valine dipeptide organocatalysts containing a primary amine group and two amide units have been developed and evaluated in the direct asymmetric intermolecular aldol reaction of 4-nitrobenzaldehyde and cyclohexanone. When 2,4-dinitrophenol (DNP) was used as an acidic additive, the catalyzed reactions of various aldehydes and ketones gave the corresponding aldol products with moderate to high enantioselectivities (up to 95%) and diastereoselectivities (up to >99/1, anti/syn) in the presence of 3c in brine.     

Construction of Contiguous Tetrasubstituted Carbon Stereocenters by Intramolecular Crossed Benzoin Reactions Catalyzed by N‐Heterocyclic Carbene (NHC) Organocatalyst

Bicyclic compounds with two contiguous tetrasubstituted carbon stereocenters at bridgehead positions were synthesized by N‐heterocyclic carbene (NHC)‐catalyzed intramolecular crossed benzoin reactions of symmetrical compounds. This desymmetrization strategy was applied to asymmetric synthesis with chiral NHC organocatalysts. Transition‐state models were proposed to explain the enantioselectivity. A tricyclic compound with three contiguous tetrasubstituted carbon stereocenters was synthesized by a stepwise strategy. The molecular structure and absolute configuration of the (+)‐enantiomer of this tricyclic compound were determined by X‐ray crystallographic analysis.     

Polyvinylidene chloride supported L‐prolineamide as recoverable catalyst for asymmetric aldol reaction between ketone and aromatic aldehyde

A series of prolineamide modified by polyvinylidene chloride (PVDC) was synthesized and used as green recoverable organocatalysts for the asymmetric Aldol reactions between various ketones and aromatic aldehydes. The effects of solvent and catalyst dosage on the catalytic performances of as‐synthesized organocatalysts were investigated. It was found that as‐synthesized PVDC‐supported L ‐prolineamides possessed good catalytic performance for the asymmetric Aldol reactions between cyclohexanone and a variety of aromatic aldehydes, affording high yields of up to 99%, excellent diastereoselectivities of up to above 8 : 92 d.r. value, and high enantioselectivities of up to above 92.3% e.e. value. In general, the catalytic performance of as‐synthesized organocatalysts closely depended on the catalyst dosage and solvent type as well. Particularly, as‐synthesized organocatalyst 1c, at a dosage of 5 mol % in 10 μL of water, exhibited high catalytic activity and stereoselectivity for the asymmetric Aldol reaction between cyclohexanone and p‐nitrobenzaldehyde at room temperature. In the meantime, it could be easily recovered and recycled, while the activity and enantioselectivity were nearly completely retained even after five cycles of recovery, showing promising application as an efficient green organocatalyst for the aforementioned asymmetric Aldol reactions. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

Asymmetric organocatalysis of structurally well-defined chiral quaternary ammonium fluorides

Unique organocatalysis of both naturally occurring cinchona alkaloid-derived and purely synthetic chiral quaternary ammonium fluorides in synthetically useful stereoselective bond-forming reactions is overviewed. The development of this chemistry was initiated by the in situ generation of generally hygroscopic ammonium fluorides from the corresponding easy-to-handle ammonium salts in the presence of excess metal fluorides and their direct use for subsequent enantioselective reactions. On the other hand, chiral ammonium fluorides have been prepared by using ion-exchange resins and successfully applied as catalyst to various asymmetric bond formation reactions under homogeneous conditions. In addition, utilization of chiral quaternary ammonium bifluorides as organocatalysts in asymmetric synthesis is described, featuring their characteristic reactivity and selectivity.     

Brønsted-acid-catalyzed asymmetric multicomponent reactions for the facile synthesis of highly enantioenriched structurally diverse nitrogenous heterocycles

Optically pure nitrogenous compounds, and especially nitrogen-containing heterocycles, have drawn intense research attention because of their frequent isolation as natural products. These compounds have wide-ranging biological and pharmaceutical activities, offering potential as new drug candidates. Among the various synthetic approaches to nitrogenous heterocycles, the use of asymmetric multicomponent reactions (MCRs) catalyzed by chiral phosphoric acids has recently emerged as a particularly robust tool. This method combines the prominent merits of MCRs with organocatalysis, thus affording enantio-enriched nitrogenous heterocyclic compounds with excellent enantioselectivity, atom economy, bond-forming efficiency, structural diversity, and complexity. In this Account, we discuss a variety of asymmetric MCRs catalyzed by chiral phosphoric acids that lead to the production of structurally diverse nitrogenous heterocycles. In MCRs, three or more reagents are combined simultaneously to produce a single product containing structural contributions from all the components. These one-pot processes are especially useful in the construction of heterocyclic cores: they can provide a high degree of both complexity and diversity for a targeted set of scaffolds while minimizing the number of synthetic operations. Unfortunately, enantioselective MCRs have thus far been relatively underdeveloped. Particularly lacking are reactions that proceed through imine intermediates, which are formed from the condensation of carbonyls and amines. The concomitant generation of water in the condensation reaction can deactivate some Lewis acid catalysts, resulting in premature termination of the reaction. Thus, chiral catalysts typically must be compatible with water for MCRs to generate nitrogenous compounds. Recently, organocatalytic MCRs have proven valuable in this respect. Br?nsted acids, an important class of organocatalysts, are highly compatible with water and thereby offer great potential as chiral catalysts for multicomponent protocols that unavoidably release water molecules during the course of the reaction. We present a detailed investigation of several MCRs catalyzed by chiral phosphoric acids, including Biginelli and Biginelli-like reactions; 1,3-dipolar cycloadditions; aza Diels-Alder reactions; and some other cyclization reactions. These approaches have enabled the facile preparation of 3,4-dihydropyrimidinones, pyrrolidines, piperidines, and dihydropyridines with high optical purity. The synthetic applications of these new protocols are also discussed, together with theoretical studies of the reaction transition states that address the regio- and stereochemistry. In addition, we briefly illustrate the application of a recently developed strategy that involves relay catalysis by a binary system consisting of a chiral phosphoric acid and a metal complex. This technique has provided access to new reactions that generate structurally diverse and complex heterocycles. Enantioselective organocatalytic MCRs remain a challenge, but we illustrate success on several fronts with chiral phosphoric acids as the primary catalysts. Further progress will undoubtedly provide even better access to the chiral nitrogen-containing heterocycles that are not only prevalent as natural products but also serve as key chiral building blocks in organic synthesis.     

Update and challenges in organo-mediated polymerization reactions

Organocatalysis has become a very powerful tool for precision macromolecular chemistry, as judged by the number of articles published in this field in the past decade. A variety of small organic molecules, including Brønsted/Lewis bases and acids, based on amines, phosphines or carbenes, but also on bi-component systems, have been employed as a means to catalyze the polymerization of miscellaneous monomers. Not only can organocatalysts be employed to promote the ring-opening polymerization of various heterocyclics (e.g. lactones, lactide, cyclic carbonates, epoxides, lactams, cyclocarbosiloxanes), but some of them also allow activating vinylic monomers such as (meth)acrylics, or triggering the step-growth polymerization of monomers such as diisocyanates and diols for polyurethane synthesis. The reduced toxicity of organocatalysts in comparison to their metallic counterparts is also driving their development in some sensitive applications, such as biomedical or microelectronics. Overall, organocatalysts display specific monomer activation modes, thereby providing a unique opportunity to control the polymerization of various functional monomers, under mild conditions. This review article focuses on advances of the past 4 years (>150 publications) in polymerization reactions utilizing small organic molecules either as direct initiators or as true catalysts, with a special emphasis on monomer activation modes, as well as polymerization mechanism aspects.     

Novel synthesis of carbohydrate-derived organocatalysts and their application in asymmetric aldol reactions

Carbohydrate as a kind of important chiral scaffold is widely recognized for its obvious advantages cheap and readily available. A new type of prolinamide organocatalysts, derived from carbohydrate, was synthesized in high yield, and the novel organocatalysts were applied to the direct asymmetric aldol reactions of cyclohexanone and various aromatic aldehydes. The corresponding aldol products were obtained in high yields (up to 99%) with excellent diastereoselectivities (up to > 98:2 dr) and enantioselectivities (up to 97% ee) under mild reaction conditions.     

Asymmetric synthesis of fluorine-containing compounds using organocatalysts

Asymmetric synthesis of fluorine-containing compounds using organocatalysts has been extensively investigated and several important strategies have been developed in the last decade. This review focuses on the recent advances in the introduction of the fluorine atom into organic molecules by: i) electrophilic fluorination reactions; ii) the use of easily available fluorine-containing building blocks, both of interest in our research laboratory.     

双功能有机硫脲催化剂在不对称合成中的应用

综述了双功能有机硫脲催化剂的发现,及其在Michael加成反应、Mannich反应及其它不对称合成反应中的应用,并展望了其应用前景。     

Chiral Ionic Liquid/ESI-MS Methodology as an Efficient Tool for the Study of Transformations of Supported Organocatalysts

An efficient approach to the study of deactivation pathways of chiral organocatalysts in asymmetric Michael reactions by modifying original catalysts with ionic-liquid fragments followed by the electrospray ionization mass spectrometry analysis of recovered catalyst samples has been proposed.     

Derivatives of Natural Organocatalytic Cofactors and Artificial Organocatalytic Cofactors as Catalysts in Enzymes

Catalytically active non-metal cofactors in enzymes carry out a variety of different reactions. The efforts to develop derivatives of naturally occurring cofactors such as flavins or pyridoxal phosphate and the advances to design new, non-natural cofactors are reviewed here. We report the status quo for enzymes harboring organocatalysts as derivatives of natural cofactors or as artificial ones and their application in the asymmetric synthesis of various compounds.     

Asymmetric Organocatalytic Diels–Alder Reactions on Solid Support

Asymmetric organocatalysis on solid support combines the environmental advantages of metal‐free catalysts and the ease of operation of solid‐supported reagents. Enantioselective organocatalytic Diels Alder reactions have been demonstrated by two different solid‐supported chiral organocatalysts. The catalysts are easy to recover and they can be reused. The reactivity of the catalyst can be tuned by changing the solid support.     

A Periodic DFT Study of the Isomerization of Thiophenic Derivatives Catalyzed by Acidic Mordenite

A periodic density functional theory study of the isomerization reactions of alkylated benzothiophene derivatives (i.e., dimethylated and monomethylated dibenzothiophenes and monomethylated benzotiophenes) catalyzed by acidic mordenite zeolite is reported. Monomolecular isomerization reactions have been considered and analyzed. The different reaction pathways are discussed in detail. The use of periodic structure calculations takes into consideration the electrostatic contributions and steric constraints that occur within the zeolite micropore. The isomerization reactions have been regarded as being helpful in hydrodesulfurization reactions of alkylated benzothiophene derivatives catalyzed by solid acid–metallic sulfide bifunctional catalysts.     

Enantioselective Organocatalysis of Strecker and Mannich Reactions Based on Carbohydrates

Efficient organocatalysts for enantioselective Strecker and Mannich reactions were constructed from glucosamine as a readily accessible chiral scaffold. A variety of aromatic aldimines were subjected to hydrocyanation with good to excellent yield (72–98 %) and, in part, high enantioselectivity (69–95 % ee). Influence of the catalyst architecture on the enantioselectivity obviously arises from restrictions imposed on the conformational flexibility of the monosaccharidic backbone. In the asymmetric Mannich reaction moderate yields (up to 76 %) and enantioselectivities (up to 58 % ee) have been achieved with the described catalyst.     

Proline‐Functionalized Magnetic Core‐Shell Nanoparticles as Efficient and Recyclable Organocatalysts for Aldol Reactions

Novel magnetically tagged organocatalysts have been developed based on core‐shell nanoparticles consisting of magnetite cores and polyacrylate shells containing 4‐hydroxyproline moieties. These catalysts allow the performance of direct asymmetric aldol reactions of aromatic aldehydes with ketones in the presence of benzoic acid providing high yields and ees. Straightforward magnetic separation and recycling of a catalyst for up to 9 runs is possible without a significant loss of efficiency.