Highly efficient asymmetric Michael addition of aldehyde to nitroolefin using perhydroindolic acid as a chiral organocatalyst

Perhydroindolic acids, the by-products obtained in the industrial production of a trandolapril intermediate, were used as chiral organocatalysts in asymmetric Michael addition reactions of aldehydes to nitroolefins. These proline-like catalysts are unique for their rigid bicyclic structure with two H atoms attached to the bridgehead C atoms lying on the opposite side of the ring. They therefore showed high efficiency in asymmetric Michael additions of aldehydes to nitroolefins. Under the optimal conditions, excellent diastereo- and enantioselectivities (up to 99/1 dr and 98% ee) were obtained with high chemical yields for a series of aldehydes and nitroolefins using only 5 mol% catalyst loading. The methodology features easily available catalysts, high catalytic efficiency and environmentally green procedures.     

Enantioselective Michael addition of aldehydes to nitroolefins catalyzed by pyrrolidine-HOBt

The oxytriazole catalyst “pyrrolidine-HOBt” developed for asymmetric Michael addition of cyclohexanone to nitroolefins is now evaluated for the asymmetric Michael addition of aldehydes to nitroolefins under similar reaction conditions. The results of this study indicate that, the oxytriazole catalyst “pyrrolidine-HOBt” is equally effective in promoting the Michael addition of aldehydes to nitroolefins on employing benzoic acid as an additive. The desired products, γ-nitrocarbonyl compounds were obtained in good yields and high enantioselectivities.     

Highly enantioselective Michael addition of aldehydes to nitroolefins catalyzed by primary amine thiourea organocatalysts

Asymmetric Michael addition reactions of aldehydes to nitroolefins have been successfully initiated by a series of primary amine thiourea bifunctional catalysts, with high enantioselectivities (90-98% ee) and excellent yields (80-96%). The privileged quinine scaffold was found to be essential to the reaction efficiency and enantioselectivity.     

Self-assembly of an organocatalyst for the enantioselective synthesis of Michael adducts and α-aminoxy alcohols in a nonpolar medium

A proline–thiourea host–guest complex is described as a self-assembled organocatalyst for the enantioselective Michael addition of aldehydes to nitroolefins and for the asymmetric α-aminoxylation of both aldehydes and ketones. The Michael adducts were obtained in good yields of up to 80%, high diastereoselectivities of up to 5:95, and high enantiomeric excesses of up to 98%. The optically active aminoxy alcohols were synthesized in 60–85% yields with 94–99% enantiomeric excesses after reduction of the α-oxidation products using NaBH₄.     

Chiral quaternary alkylammonium ionic liquid [Pro-dabco][BF4]: as a recyclable and highly efficient organocatalyst for asymmetric Michael addition reactions

A novel series of chiral quaternary ammonium ionic liquids have been synthesized and shown to be very effective catalysts for the asymmetric Michael addition reactions of ketones and aldehydes to nitroolefins with excellent yields (up to 100%), diastereoselectivities (syn/anti = 99:1), and enantioselectivities (up to 97%). The catalytic system, an ionic liquid organocatalyst in [Bmim][BF₄], could be reused five times without a significant loss in catalytic activity or stereoselectivity.     

结构简单的4-羟基脯氨酰胺高效催化醛和硝基烯不对称迈克尔加成反应

开发了两种结构简单的反式-4-羟基-L-脯氨酰胺有机小分子催化剂,用于高效催化不对称迈克尔加成反应。在醛和硝基烯的不对称迈克尔加成反应中,以（S）-1,1’-联-2-萘酚为协同催化剂,对两种脯氨酰胺衍生物的催化活性进行研究,发现催化剂摩尔分数仅为0.5%～1%时,产物的收率最高可达96%,非对映和对映选择性值最高可达99/1和99%。该方法为开发低成本、高效率的不对称迈克尔加成反应有机催化剂体系提供了简单易行的选择。     

Novel chiral ammonium ionic liquids as efficient organocatalysts for asymmetric Michael addition of aldehydes to nitroolefins

Two chiral ammonium ionic liquids 1a and 1b have been newly synthesized from commercially available (+)-cis-2-benzamidocyclohexanecarboxylic acid. These CILs have been demonstrated to be efficient organocatalysts for asymmetric Michael addition of aldehydes to nitroolefins with excellent yields (up to 99%), high enantioselectivities (up to 90%) and modest to high diastereoselectivities (syn/anti ratio up to 99/1).     

一种新型双亲性有机小分子催化剂在水相体系中催化环己酮与硝基烯烃直接不对称Michael加成反应

设计合成了一系列基于脯氨酸巯基咪唑衍生物的新型双亲性有机小分子催化剂,在水相中加入酸作为助催化剂,可以高效高选择性的催化环己酮与硝基烯烃的不对称Michael加成反应,非对映选择性和对映选择性分别高达99：1和96%.     

Chiral (thio)phosphorodiamides as excellent hydrogen bond donor catalysts in the asymmetric Michael addition of 2-hydroxy-1,4-naphthoquione to nitroolefins

A novel type of bidentate hydrogen bond donor catalysts based on (thio)phosphorodiamides catalophore has been developed for the asymmetric Michael addition of 2-hydroxy-1,4-naphthoquione to nitroolefins, affording the corresponding adducts in high yields with excellent level of enantioselectivities (97- >99% ee).     

Chiral pyrrolidine quaternary derivatives as organocatalysts for asymmetric Michael additions

A series of chiral pyrrolidine quaternary derivatives were designed and synthesized. It was found that these derivatives are highly efficient organocatalysts for the asymmetric Michael addition reactions of aldehydes and ketones to nitroolefins with high yields (up to 96%), high enantioselectivities (up to 99% ee), and high diastereoselectivities (up to 97:3 dr). Furthermore, catalyst 7a could be recycled without remarkable loss of catalytic activity and stereoselectivity.     

A new class of chiral pyrrolidine-pyridine conjugate base catalysts for use in asymmetric Michael addition reactions

Direct catalytic asymmetric Michael addition reactions of ketones to nitroolefins using newly developed chiral pyrrolidine-pyridine conjugate bases as catalysts are described. The desired 1,4-adducts are obtained in excellent yields with high enantio- and diastereoselectivities.     

3,3'-bimorpholine derivatives as a new class of organocatalysts for asymmetric Michael addition

New N-alkyl-3,3'-bimorpholine derivatives (iPBM) were revealed to be efficient organocatalysts for the asymmetric direct Michael addition of aldehydes to nitroolefins and a vinyl sulfone. In these transformations using iPBM, 1,4-adducts were afforded in high yields, with good to high levels of diastereo- and enantioselectivity. The stereochemical outcome of the reaction could be explained by an acyclic synclinal model. [reaction: see text]     

Polystyrene-supported diarylprolinol ethers as highly efficient organocatalysts for Michael-type reactions

α,α-Diphenylprolinol methyl- and trimethylsilyl ethers anchored onto a polystyrene resin have been prepared by a copper-catalyzed azide-alkyne cycloadditions (CuAAC). The catalytic activity and enantioselectivity displayed by the O-trimethylsilyl derivative are comparable to those exhibited by the best known homogeneous catalysts for the addition of aldehydes to nitroolefins and of malonates or nitromethane to α,β-unsaturated aldehydes. The combination of the catalytic unit, the triazole linker, and the polymeric matrix provides unprecedented substrate selectivity, in favor of linear, short-chain aldehydes, when the organocatalyzed reaction proceeds by an enamine mechanism. High versatility is noted in reactions that proceed via an iminium ion intermediate. The catalytic behavior of polystyrene-supported α,α-diphenylprolinol methyl ether was also evaluated in asymmetric Michael addition reactions. As a general trend, the CuAAC immobilization of diarylprolinol ethers onto insoluble polystyrene resins offers important operational advantages, such as high catalytic activity, easy recovery from the reaction mixture by simple filtration, and the possibility of extended reuse.     

Tripeptides of the Type H‐D‐Pro‐Pro‐Xaa‐NH2 as Catalysts for Asymmetric 1,4‐Addition Reactions: Structural Requirements for High Catalytic Efficiency

Analysis of the structural and functional requirements within the asymmetric peptidic catalyst H‐D ‐Pro‐Pro‐Asp‐NH₂ led to the development of the closely related peptide H‐D ‐Pro‐Pro‐Glu‐NH₂ as an even more efficient catalyst for asymmetric conjugate addition reactions of aldehydes to nitroolefins. In the presence of as little as 1 mol % of H‐D ‐Pro‐Pro‐Glu‐NH₂, a broad range of aldehydes and nitroolefins react readily with each other. The resulting γ‐nitroaldehydes were obtained in excellent yields and stereoselectivities at room temperature. Within the structure of the peptidic catalysts, the D ‐Pro‐Pro motif is the major contributor to the high stereoselectivities. The C‐terminal amide and the spacer to the carboxylic acid in the side‐chain of the C‐terminal amino acid are responsible for the fine‐tuning of the stereoselectivity. The peptidic catalysts not only allow for highly effective asymmetric catalysis under mild conditions, but also function in the absence of additives.     

Self-assembled proline-amino thioureas as efficient organocatalysts for the asymmetric Michael addition of aldehydes to nitroolefins

A small co-catalyst library of amino thioureas has been established from chiral 1,3-diamines. These bifunctional thioureas can form assemblies with proline to cooperatively catalyze the asymmetric Michael addition of aldehydes to nitroolefins. Both the reaction rate (up to 98% yield for 18 h) and the enantioselectivity (up to 94% ee) were significantly improved upon in less polar solvents.     

First organocatalyzed asymmetric Michael addition of aldehydes to vinyl sulfones

[reaction: see text] The first asymmetric direct Michael addition of aldehydes to vinyl sulfones catalyzed by N-iPr-2,2'-bipyrrolidine is described. 1,4-Adducts are obtained in good yields and enantioselectivities. The determination of absolute configuration allowed us to postulate a Si,Si transition state model, as shown previously for nitroolefins.     

Enantioselective Michael addition of α,α-disubstituted aldehydes to nitroolefins catalyzed by a pyrrolidine-pyrazole

An efficient protocol for the asymmetric catalytic Michael additions of α,α-disubstituted aldehydes to nitroolefins with a pyrrolidine-pyrazole is described. The desired products γ-nitrocarbonyl compounds possessing an all-carbon quaternary center, were obtained in good yields and with high levels of enantioselectivities under solvent-free reaction conditions, employing benzoic acid as an additive.     

A recyclable organocatalyst for asymmetric Michael addition of acetone to nitroolefins

Based on different chiral diamine skeletons, a series of bifunctional primary amine-thiophosphoramides were synthesized and screened as the catalysts for the asymmetric Michael addition of acetone to both aromatic and aliphatic nitroolefins. Under the catalysis of a thiophosphoramide derived from 1,2-diphenylethane-1,2-diamine, the corresponding adducts were obtained in high yields (up to >99%) with excellent enantioselectivities (97-99% ee) under mild reaction conditions. Moreover, the catalyst could be recovered via simple phase separation and reused at least five times without any loss of both catalytic activity and stereocontrol.     

Highly efficient asymmetric organocatalytic Michael addition of α,α-disubstituted aldehydes to nitroolefins under solvent-free conditions

A chiral pyrrolide-based diamine in combination with benzoic acid has been found to be an effective organocatalyst for Michael addition of α,α-disubstituted aldehydes with nitroolefins. The reaction provided the desired Michael products possessing all-carbon quaternary center with high yields (76–98%) and high levels of enantioselectivities (up to 97% ee) under solvent-free reaction conditions. The procedure presented is simple and makes this method suitable for practical use.     

Asymmetric direct vinylogous carbon-carbon bond formation catalyzed by bifunctional organocatalysts

The bifunctional chiral thiourea-tertiary amine organocatalysts have been applied to a direct asymmetric vinylogous Michael addition of α,α-dicyanoolefins to nitroolefins with 2-10 mol % catalyst loadings. The electronic properties of the thiourea-based catalysts have significant influences on this reaction. Moderate to excellent enantioselectivities (57-95% ee) have been achieved with low to good isolated yields through fine tuning the structures of the bifunctional organocatalysts. Much better ees were obtained for some α,α-dicyanoolefinic substrates compared with that catalyzed by modified cinchona alkaloids.