A Highly Selective,Polymer‐Supported Organocatalyst for Michael Additions with Enzyme‐Like Behavior

A polymer‐supported α,α‐diarylprolinol silyl ether displays catalytic activity and enantioselectivity comparable to the best homogeneous catalysts in the Michael addition of aldehydes to nitroolefins. Above all, the combination of polymer backbone, triazole linker, and catalytic unit confers to it an unprecedented substrate selectivity in favor of linear, short‐chain aldehydes.     

Bifunctional Transition Metal-Based Molecular Catalysts for Asymmetric C–C and C–N Bond Formation

This paper describes recent advances in the development of the asymmetric catalytic reactions promoted by conceptually new bifunctional molecular catalysts. These reactions include the enantioselective Michael addition of 1,3-dicarbonyl compounds to cyclic enones and nitroalkenes, and the enantioselective direct amination of α-cyanoacetates to diazoesters. The nature of the catalyst in each particular case was delicately tuned by adjusting the combination of the central metal together with the structures of the cooperating ligands, applied solvents, and the reaction conditions to achieve the utmost catalytic performance in terms of reactivity and selectivity. In the presence of the optimized catalyst the addition reactions proceeded smoothly with a 1:1 M ratio of the reagents to give the corresponding chiral adducts with excellent yields and ee’s. Preliminary mechanistic studies based on NMR spectroscopy and DFT analysis showed that the key step of the catalytic cycle is the interaction of the bifunctional catalyst with a pronucleophilic reagent that leads to stereoselective formation of C-, O-, or N-bound amino complexes. The resulting amino catalyst bearing metal-bound nucleophiles readily reacts with an electrophile that acquires the reactive conformation through the cooperative effect of the acidic NH protons. This results in the formation of a C–C or a C–N bond yielding the corresponding products in a highly stereoselective manner.     

α,β-不饱和醛/酮中双键选择性加氢催化剂的研究进展

α,β-不饱和醛/酮中双键选择性加氢制备相应的饱和醛/酮是一类重要的精细化工反应,高选择性催化剂的设计和制备是实现该类反应工业化的关键。从活性金属、助剂和载体材料等方面综述了国内外α,β-不饱和醛/酮中双键选择性加氢催化剂的研究进展,并且从反应物分子在金属活性位上的吸附模型和空间位阻效应等方面理论上阐释了活性金属种类、金属粒径等影响α,β-不饱和醛/酮中双键加氢选择性的本质原因。对近期α,β-不饱和醛/酮选择性加氢制备相应饱和醛/酮反应工艺方面的研究进展进行了评述。     

Aqueous Asymmetric Mukaiyama Aldol Reaction Catalyzed by Chiral Gallium Lewis Acid with Trost‐Type Semi‐Crown Ligands

The combination of Ga(OTf)₃ with chiral semi‐crown ligands ( 1a – e ) generates highly effective chiral gallium Lewis acid catalysts for aqueous asymmetric aldol reactions of aromatic silyl enol ethers with aldehydes. A ligand‐acceleration effect was observed. Water is essential for obtaining high diastereoselectivity and enantioselectivity. The p‐phenyl substituent in aromatic silyl enol ether ( 2 h ) plays an important role and increases the enantioselectivity up to 95% ee. Although aliphatic silyl enol ethers provided low enantioselectivities and silylketene acetal is easily hydrolyzed in aqueous alcohol, the aldol reactions of silylketene thioacetal ( 12 ) with aldehydes in the presence of gallium‐Lewis acid catalysts give the β‐hydroxy thioester with reasonable yields and high diastereo‐ (up to 99 : 1) and enantioselectivities (up to 96% ee).     

Aminocatalytic Asymmetric Diels-Alder Reactions via HOMO Activation

In the first successful catalytic asymmetric Diels-Alder reaction in 1979, Koga and colleagues used a chiral aluminum complex as a Lewis acid catalyst, but since then, researchers have developed numerous catalytic systems for these reactions. By 2000, several chiral organic compounds, such as the salts of imidazolidinones or TADDOLs, emerged as robust catalysts in the asymmetric Diels-Alder reactions. According to frontier molecular orbital theory, most of these catalysts employ a LUMO-lowering strategy as a means of activating electron-deficient dienophiles. Only rarely do chiral catalysts take advantage of the alternative strategy of activating the HOMO. In this Account we will discuss the development of asymmetric Diels-Alder reactions based on the HOMO-raising effects of chiral amines. First, we show that enamine intermediates formed in situ between an amine catalyst and enolizable aliphatic aldehydes can act as electron-rich dienophiles in inverse-electron-demand Diels-Alder reactions. We describe the preparation of a variety of oxygen- or nitrogen-containing heterocycles with high optical purity. Then, we demonstrate that the dienamine species from α,β-unsaturated aldehydes can act either as electron-rich dienes in normal-electron-demand Diels-Alder reactions or as dienophiles in inverse-electron-demand Diels-Alder reactions. These reactions generally occur with high chemo-, regio-, and stereoselectivity. Finally, we introduce a new activation mode for Diels-Alder reactions, in which reactive trienamine intermediates derived from 2,4-dienals or even 2,4-dienones play a key role. Notably, we observe remarkable β,ε-regioselectivity and obtain excellent stereocontrol even at the very remote ε-reactive center-up to seven bonds away from the chiral center of the amine catalyst. These results demonstrate that a HOMO-activation strategy via aminocatalysis could become a significant tool in asymmetric Diels-Alder reactions. In addition, these reactions using enamine, dienamine, or trienamine intermediates produce a diverse array of densely functionalized cyclic scaffolds, which may serve as valuable structures in drug discovery and natural product synthesis.     

Recyclable tetraarylphosphonium supported chiral imidazolidin-4-one organocatalyst for Diels–Alder reactions

The tetraarylphosphonium supported chiral imidazolidin-4-ones were synthesized and used to catalyze the Diels–Alder reactions of cyclopentadiene and α,β-unsaturated aldehydes. High enantiomeric excesses and good yields were obtained, and catalyst recycling (up to five cycles) was accompanied by almost intact enantioselectivity and some loss of the chemical efficiency.     

Enantioselective One‐Pot Reaction: Organocatalyzed Synthesis of Fully Functionalized Oxabicyclo[2.2.2]octanes with Seven Contiguous Stereocenters

An enantioselective one‐pot Michael/Michael/Henry/hemiacetalization reaction between α,β‐unsaturated aldehydes, α‐ketoamides, and nitroalkenes under mild conditions catalyzed by a diarylprolinol silyl ether has been developed. The sequential methodology provides a direct approach to a wide range of fully substituted chiral oxabicyclo[2.2.2]octanes with seven contiguous stereocenters in moderate to excellent yields (up to 99%), high to excellent diastereoselectivities (up to >25:1 dr), and high to excellent enantioselectivities (up to 99% ee).

     

Chiral N,N'-dioxides: new ligands and organocatalysts for catalytic asymmetric reactions

Homochiral catalysts that can effect asymmetric transformations are invaluable in the production of optically active molecules. Researchers are actively pursuing the design of new ligands and organocatalysts by exploiting concepts derived from the application of bifunctional and C(2)-symmetric catalysts. Many homochiral catalysts containing amines, ethers, alcohols, and phosphines as electron-pair donors have been successfully developed. Amine N-oxides are highly polar substances. Despite their pronounced capacity as electron-pair donors, N-oxides have been underutilized in asymmetric reactions; they have only made a visible impact on the field in the preceding decade. Systematic studies have instead largely focused on pyridine- or quinoline-based scaffolds in organosilicon and coordination chemistry. The application of chiral tertiary amine N-oxides has not been widely pursued because of the difficulty of controlling the chirality at the tetrahedral nitrogen of the N-oxide moiety. In this Account, we outline the design of a new family of C(2)-symmetric N,N'-dioxides from readily available chiral amino acids. We then discuss the application of these chiral amine N-oxides as useful metal ligands and organocatalysts for asymmetric reactions. The high nucleophilicity of the oxygen in N-oxides is ideal for organocatalytic reactions that rely on nucleophilic activation of organosilicon reagents. These catalysts have been successfully applied in the asymmetric addition of trimethylsilylcyanide to aldehydes, ketones, aldimines, and ketimines, with good yields and excellent enantioselectivities. Asymmetric organocatalytic chlorination of β-ketoesters with N-chlorosuccinimide has also been achieved through hydrogen bond activation. The molecular framework of these N,N'-dioxides, with their multiple O-donors, also serves as a new tetradentate ligand that can coordinate a range of metal ions, including Cu(I), Cu(II), Ni(II), Mg(II), Fe(II), Co(II), In(III), Sc(III), La(III), Y(III), Nd(III), and others. These versatile metal complexes are efficient catalysts for a variety of asymmetric reactions. Asymmetric cycloadditions have been achieved with these chiral Lewis acid catalysts. We have also found success with asymmetric nucleophilic additions to C═O or C═N bonds; substrates include 3-substituted 2-oxindoles, alkenes, enamides, enecarbamates, diazoacetate esters, nitroalkanes, glycine Schiff bases, and phosphate. Notably, the first catalytic asymmetric Roskamp reaction was realized, which was successful because of the high efficiency of the catalyst. Asymmetric conjugate additions between α,β-unsaturated compounds and nucleophiles such as nitroalkane, malonate, thioglycolate, and indoles have been accomplished. The first asymmetric haloamination of chalcones was discovered, and the reaction proceeded with high regio- and enantioselectivity. In some cases, we were able to reduce the catalyst loading to just 0.01-0.05 mol % while maintaining excellent outcomes. Some particularly interesting phenomena were observed over the course of the research. These include a remarkable amplification of the asymmetry in a sulfa-Michael reaction, as well as the reversal of enantioselectivity after alteration of the central metal or the subunits of the ligand in two other reactions. These unusual results have facilitated a deeper understanding of the catalytic mechanism.     

Enantioselective Organocatalytic Conjugate Addition of Aldehydes to α,β‐Unsaturated Thiol Esters

The first example of an organocatalytic asymmetric Michael addition of aldehydes to α,β‐unsaturated thiol esters promoted by chiral diphenylprolinol silyl ether is presented. The reaction occurs with good yields, diastereoselectivity and excellent enantioselectivity.     

含对硝基苯磺酰基的α,β-不饱和砜的合成

α,β-不饱和砜是以对硝基苯磺酰基乙酸酯为原料与芳香醛在六氢吡啶醋酸盐催化下发生缩合反应制得的。研究了催化剂对反应的影响,发现3-二甲氨基苯丙胺(DPA)是最有效催化剂之一。在NaC l/DMSO/H2O体系中,缩合产物(E)-2-(对硝基苯磺酰基)-3-苯丙烯酸乙酯(Ⅲb)在185℃反应,得到脱羧物〔E-1-苯基-2-(4-硝基苯磺酰基)乙烯(Ⅳb)〕。用1HNMR确证了缩合产物构型为E型。     

Amine‐Catalyzed Asymmetric Epoxidation of α,β‐Unsaturated Aldehydes

The direct organocatalytic enantioselective epoxidation of α,β‐unsaturated aldehydes with different peroxides is presented. Proline, chiral pyrrolidine derivatives, and amino acid‐derived imidazolidinones catalyze the asymmetric epoxidation of α,β‐unsaturated aldehydes. In particular, protected commercially available α,α‐diphenyl‐ and α,α‐di(β‐naphthyl)‐2‐prolinols catalyze the asymmetric epoxidation reactions of α,β‐unsaturated aldehydes with high diastereo‐ and enantioselectivities to furnish the corresponding 2‐epoxy aldehydes in high yield with up to 97:3 dr and 98 % ee. The use of non‐toxic catalysts, water and hydrogen peroxide, urea hydroperoxide or sodium percarbonate as the oxygen sources could make this reaction environmentally benign. In addition, one‐pot direct organocatalytic asymmetric tandem epoxidation‐Wittig reactions are described. The reactions were highly diastereo‐ and enantioselective and provide a rapid access to 2,4‐diepoxy aldehydes. Moreover, a highly stereoselective one‐pot organocatalytic asymmetric cascade epoxidation‐Mannich reaction, which proceeds via the combination of iminium and enamine activation, is presented. The mechanism and stereochemistry of the amino acid‐ and chiral pyrrolidine‐catalyzed direct asymmetric epoxidation of α,β‐unsaturated aldehydes are also discussed.     

Organocatalytic and Stereoselective [3 + 2] Cycloadditions of Azomethine Imines with α,β‐Unsaturated Aldehydes

Bipyrazolidin‐3‐one derivatives are biologically significant compounds and their importance has increased in the past decades. In this paper, the first stereoselective [3 + 2] dipolar cycloadditions of azomethine imines with α,β‐unsaturated aldehydes catalyzed by readily available α,α‐diarylprolinol salts are reported, providing a facile route to the synthesis of various chiral bipyrazolidin‐3‐one derivatives under mild conditions. The organocatalyst 1 g with strongly electron‐withdrawing groups exhibited the best stereoselectivity (exo:endo up to 98:2, for exo product up to 97 % ee), in the combination with trifluoroacetic acid.     

手性铜试剂在羰基化合物加成反应中的应用

介绍了有机铜试剂具有价格低廉、毒性小、配位能力好等的优点,总结了有机铜试剂在不饱和羰基化合物的不对称共轭加成反应中的应用,特别是催化不饱和酯、硫酯、砜、醛和酮等α,β-不饱和羰基化合物的不对称共轭加成反应,提出了手性铜试剂催化不对称共轭加成反应在底物选择上仍然具有一定的局限性,该反应的底物主要集中于酮类化合物,而砜类和...     

Highly Efficient Asymmetric Three‐Component Vinylogous Mannich Reaction Catalyzed by a Chiral Scandium(III)‐ N,N′‐Dioxide Complex

The asymmetric three‐component vinylogous Mannich reaction of an acyclic silyl dienol ester, an aldehyde and 2‐aminophenol was accomplished using a chiral N,N′‐dioxide‐scandium(III) complex as the catalyst. A variety of aldehydes were found to be suitable substrates for the reaction and the desired δ‐amino‐α,β‐unsaturated esters were obtained in 90–99% yields with good to excellent enantioselectivities (up to >99% ee) and complete regioselectivities. Moreover, the simple experimental procedures were air‐tolerant and convenient. The present catalytic process provides the potential for large‐scale syntheses of the chiral δ‐amino‐α,β‐unsaturated esters.     

合成肽在不对称催化反应中的应用

综述了合成肽作为催化剂在不对称催化反应中的应用,总结了各种合成肽催化剂的结构及其在催化不同类型反应如氰醇化反应、Strecker反应、Aldol反应、Michael加成反应、Morita-Baylis-Hillman反应和Stetter反应等中的催化活性及影响因素.     

Stereoselective Diels?Alder Reactions Promoted under Continuous-Flow Conditions by Silica-Supported Chiral Organocatalysts

Silica nanoparticles of different morphological properties were functionalized with enantiomerically pure imidazolidinones, through different immobilization techniques; stainless-steel columns were then loaded with silica bearing chiral organocatalysts to realize chiral “homemade” reactors. The influence of the material properties and immobilization procedures on the chemical and stereochemical activities of the chiral HPLC columns was studied by performing organocatalyzed Diels Alder reactions between cyclopentadiene and α,β-unsaturated aldehydes under continuous-flow conditions. In some cases, excellent enantioselectivities were obtained, thus showing that a catalytic reactor may work efficiently to continuously produce enantiomerically enriched cycloadducts for more than 200 h. Regeneration of the organocatalytic column was also partially accomplished, although associated with a slightly lower enantioselectivity, thus prolonging the “life” of the reactor to more than 300 h.     

Enantioselective Organocatalytic Reactions of 4‐Hydroxycoumarin and 4‐Hydroxypyrone with α,β‐Unsaturated Aldehydes – An Efficient Michael Addition‐Acetalization Cascade to Chromenones,Quinolinones and Pyranones

An efficient, organocatalytic enantioselective addition‐cyclization reaction of cyclic 1,3‐dicarbonyl compounds with different α,β‐unsaturated aldehydes has been developed. The diarylprolinol ether‐catalyzed reaction cascade provides a variety of chromenones, quinolinones and pyranones in good yields and with excellent enantioselectivities.     

Asymmetric Ring-Opening Reactions of Donor-Acceptor Cyclopropanes and Cyclobutanes

Donor-acceptor (DA) cyclopropanes are particularly useful synthetic building blocks, which have been widely applied in the total synthesis of natural products and important chiral molecules in organic synthesis. The asymmetric ring-opening reactions of racemic DA cyclopropanes and cyclobutanes, for example, aryl-substituted 1,1-cyclopropane diesters and aryl-substituted 1,1-cyclobutane diesters, with nucleophiles provides versatile access to optically active γ- and δ-functionalized carbon skeletons, as well as the kinetic resolution of racemic DA cyclopropanes, which are useful chiral skeletons in organic synthesis. Recently, we have developed a series of highly enantioselective ring-opening and annulation reactions of DA cyclopropanes and cyclobutanes with various nucleophiles, such as amines, alcohols, nitrones, azomethine imines, enol silyl ethers, and indoles, by employing nickel and copper catalysts with TOX and SaBOX as ligands. The reactions worked smoothly with excellent diastereoselectivities and enantioselectivities (up to >99/1 dr and up to 99 % ee) over broad substrate scopes.     

Preparation of recoverable Ru catalysts for liquid-phase oxidation and hydrogenation reactions

We here report the synthesis, characterization and catalytic performance of new supported Ru(III) and Ru(0) catalysts. In contrast to most supported catalysts, these new developed catalysts for oxidation and hydrogenation reactions were prepared using nearly the same synthetic strategy, and are easily recovered by magnetic separation from liquid phase reactions. The catalysts were found to be active in both forms, Ru(III) and Ru(0), for selective oxidation of alcohols and hydrogenation of olefins, respectively. The catalysts operate under mild conditions to activate molecular oxygen or molecular hydrogen to perform clean conversion of selected substrates. Aryl and alkyl alcohols were converted to aldehydes under mild conditions, with negligible metal leaching. If the metal is properly reduced, Ru(0) nanoparticles immobilized on the magnetic support surface are obtained, and the catalyst becomes active for hydrogenation reactions.     

Bifunctional asymmetric catalysis: cooperative Lewis acid/base systems

In the field of catalytic, asymmetric synthesis, there is a growing emphasis on multifunctional systems, in which multiple parts of a catalyst or multiple catalysts work together to promote a specific reaction. These efforts, in part, are result-driven, and they are also part of a movement toward emulating the efficiency and selectivity of nature's catalysts, enzymes. In this Account, we illustrate the importance of bifunctional catalytic methods, focusing on the cooperative action of Lewis acidic and Lewis basic catalysts by the simultaneous activation of both electrophilic and nucleophilic reaction partners. For our part, we have contributed three separate bifunctional methods that combine achiral Lewis acids with chiral cinchona alkaloid nucleophiles, for example, benzoylquinine (BQ), to catalyze highly enantioselective cycloaddition reactions between ketene enolates and various electrophiles. Each method requires a distinct Lewis acid to coordinate and activate the electrophile, which in turn increases the reaction rates and yields, without any detectable influence on the outstanding enantioselectivities inherent to these reactions. To place our results in perspective, many important contributions to this emerging field are highlighted and our own reports are chronicled.