Chiral phosphoproline-catalyzed asymmetric Michael addition of ketones to nitroolefins: an experimental and theoretical study

A novel pyrrolidine-based chiral phosphoproline is an effective bifunctional organocatalyst for the asymmetric Michael addition of ketones to nitroolefins giving high levels of diastereo- and enantio-selectivities (up to > 99 : 1 dr and 96% ee). anti-SR Transition state has the lowest barrier which controls the stereoselectivity, in agreement with experimental results.     

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.     

Organocatalytic direct asymmetric vinylogous Michael reaction of an α,β-unsaturated γ-butyrolactam with enones

An organocatalytic asymmetric direct vinylogous Michael addition of α,β-unsaturated γ-butyrolactam to enones has been achieved with a simple bifunctional thiourea-tertiary amine catalyst, affording the γ-substituted butyrolactam products with high diastereo- and enantioselectivity (up to >40:1 dr and 94-99% ee).     

C2-symmetric proline-derived tetraamine as highly effective catalyst for direct asymmetric Michael addition of ketones to chalcones

A C(2)-symmetric tetraamine catalyst was developed for the asymmetric Michael addition of ketones to chalcones. The corresponding adducts 1,5-dicarbonyl compounds were obtained in good chemical yields with high levels of diastereo- and enantioselectivities (up to >99 : 1 dr and 93% ee) under mild conditions. By studying the ESI-MS of the intermediates, a proposed mechanism was disclosed.     

Organocatalytic asymmetric cascade Michael/hemiketalization/retro-aldol reaction of 3-acetyl-oxindole with β,γ-unsaturated ketoesters catalyzed by bifunctional amino-squaramides

An unprecedented organocatalytic asymmetric Michael/Hemiketalization/retro-aldol cascade sequence catalyzed by bifunctional amino-squaramides is described. The corresponding adducts were generally obtained in high yields (up to 97%) with moderate diastereo- (up to 79:21 dr) and good enantioselectivities (up to 90% ee).     

Highly enantioselective synthesis of β-hydroxysulfonamides by asymmetric transfer hydrogenation

A series of optically active β-hydroxy sulfonamides were synthesized for the first time by asymmetric transfer hydrogenation of the corresponding β-ketosulfonamides using the Ru-TsDPEN-HCOOH-Et₃N catalytic system, in excellent yields (up to 95%) with excellent diastereo- (up to > 99:1 dr) and enantioselectivities (up to >99% ee).     

Highly efficient asymmetric Michael addition of aldehydes to nitroalkenes with 4,5-methano-l-proline as organocatalysts

The 4,5-methano-l-prolines were used as chiral organocatalysts in asymmetric Michael addition of aldehydes to nitroolefins. These proline-like catalysts are unique for their rigid bicyclic structure with a cyclopropane and two H atoms attached to the bridgehead C atoms lying on the same side of the ring. They therefore showed high efficiency in asymmetric Michael addition of aldehydes to nitroolefins. Under the optimal conditions, excellent diastereo- and enantioselectivities (up to 97/3 dr and 98% ee) were obtained in high 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 friendly procedures.     

Chiral amine thiourea-promoted enantioselective Michael addition reactions of 3-substituted benzofuran-2(3H)-ones to maleimides

A highly diastereo- and enantioselective Michael addition reaction with respect to prochiral 3-substituted benzofuran-2(3H)-ones and maleimides by a chiral bifunctional thiourea-tertiary amine catalyst was investigated. The corresponding adducts, containing a quaternary center at the C3-position of the benzofuran-2(3H)-one as well as a vicinal tertiary center, were generally obtained in high yields (up to 99%) with very good diastereo- (up to >20:1 dr) and enantioselectivities (up to 97% ee).     

Highly diastereo- and enantioselective direct aldol reaction under solvent-free conditions

An efficient, solvent-free protocol for the asymmetric aldol reaction between aldehydes and ketones using prolinamides 1–4 as organocatalysts is reported. Catalysts 2–4, in the presence of TFA (the ratio of catalyst and TFA = 1/1.5), proved to be excellent catalysts, giving the aldol products between aromatic aldehydes and ketones with nearly perfect diastereo- and enantioselectivities (up to >99:1 dr and >99% ee). This catalytic system can also be applied in the cross-aldol reaction of isatin with ketones and the Michael reaction between cyclohexane and nitroalkenes. A mechanism is proposed to account for the formation of the major enantiomer in this reaction.     

Stereodivergent Desymmetrization of Simple Dicarboxylates via Branch-Selective Pd/Cu Catalyzed Allylic Substitution

Asymmetric desymmetrization has been demonstrated to be a powerful strategy for building stereocenters in asymmetric synthesis. Herein, a Pd/Cu catalyzed asymmetric desymmetrization reaction with a simple geminal dicarboxylate is reported. A wide scope of imino esters bearing an aryl or heteroaromatic group were compatible with this bimetallic catalytic system. The reactions proceeded smoothly, giving the desired products in good yields with high to excellent regio-, diastereo-, and enantioselectivity (up to 20 : 1 branched:linear, >20 : 1 dr, >99 % ee). Notably, the reaction favored branched selectivity, which is unusual for the Pd-catalyzed allylic alkylation reaction. In addition, the standard product could be easily transformed to other valuable molecules such as chiral allylic alcohols, carbamates, and organic boron compounds. Furthermore, DFT calculations were conducted to explain the origin of the branched selectivity.     

Chiral squaramides catalyzed diastereo- and enantioselective Michael addition of α-substituted isocyanoacetates to N-aryl maleimides

An efficient diastereo- and enantioselective Michael addition of α-substituted isocyanoacetates to N-aryl maleimides catalyzed by quinine or cyclohexane-1,2-diamine derived squaramide catalysts has been disclosed, affording the corresponding adducts in good yields (up to 99%), high diastereoselectivities (up to >20:1 dr) and good to excellent enantioselectivities (up to 94% ee) under mild conditions.     

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.     

Enantioselective tandem Michael reaction to nitroalkene catalyzed by bifunctional thiourea: total synthesis of (−)-epibatidine

Successive treatment of γ,δ-unsaturated β-ketoesters and nitroalkenes with a bifunctional thiourea and TMG promoted the tandem Michael addition, giving rise to highly functionalized cyclohexanones in good yields. The three contiguous stereogenic centers of the obtained products were constructed with high diastereo- and enantioselectivity (up to >99% de and 92% ee). The reaction was successfully applied to the asymmetric synthesis of (−)-epibatidine, which was synthesized from the cyclohexanone derivative in seven steps in 30% overall yield.     

Thiophosphoramide catalyzed asymmetric Michael addition of cyclopentanone to chalcones

Thiophosphoramide 1b was found to be an effective bifunctional organocatalyst in the asymmetric Michael reaction of cyclopentanone to various chalcones, affording the corresponding adducts in satisfactory yields with moderate to excellent diastereo- (up to 90/10 dr) and enantioselectivities (up to 92% ee).     

Catalytic asymmetric 1,4-addition reactions using alpha,beta-unsaturated N-acylpyrroles as highly reactive monodentate alpha,beta-unsaturated ester surrogates

Synthesis and application of alpha,beta-unsaturated N-acylpyrroles as highly reactive, monodentate ester surrogates in the catalytic asymmetric epoxidation and Michael reactions are described. alpha,beta-Unsaturated N-acylpyrroles with various functional groups were synthesized by the Wittig reaction using ylide 2. A Sm(O-i-Pr)(3)/H(8)-BINOL complex was the most effective catalyst for the epoxidation to afford pyrrolyl epoxides in up to 100% yield and >99% ee. Catalyst loading was successfully reduced to as little as 0.02 mol % (substrate/catalyst = 5000). The high turnover frequency and high volumetric productivity of the present reaction are also noteworthy. In addition, a sequential Wittig olefination-catalytic asymmetric epoxidation reaction was developed, providing efficient one-pot access to optically active epoxides from various aldehydes in high yield and ee (96-->99%). In a direct catalytic asymmetric Michael reaction of hydroxyketone promoted by the Et(2)Zn/linked-BINOL complex, Michael adducts were obtained in good yield (74-97%), dr (69/31-95/5), and ee (73-95%). This represents the first direct catalytic asymmetric Michael reaction of unmodified ketone to an alpha,beta-unsaturated carboxylic acid derivative. The properties of alpha,beta-unsaturated N-acylpyrrole are also discussed. Finally, the utility of the N-acylpyrrole unit for further transformations is demonstrated.     

Thiourea-catalyzed asymmetric formal [3+2] cycloaddition of azomethine ylides with nitroolefins

A chiral thiourea catalyst possessing an amine function catalyzes an asymmetric [3+2] cycloaddition of azomethine ylides to nitroolefins to provide highly functionalized pyrrolidines with high diastereo- and enantioselectivities (up to 98:1:1 dr, 92% ee). The reaction proceeds in a stepwise manner consisting of Michael addition and subsequent intramolecular aza-Henry reaction. Both reactions are promoted by the thiourea catalyst, and the reaction rate of the latter step is efficiently enhanced by the addition of 2,2,2-trifluoroethanol.     

Asymmetric Michael Addition of Ketones to Alkylidene Malonates and Allylidene Malonates via Enamine-Metal Lewis Acid Bifunctional Catalysis

Novel enamine-metal Lewis acid bifunctional catalysts were successfully applied to the asymmetric Michael addition of ketones to alkylidene malonates, offering excellent stereoselectivity (up to >99% ee and >99:1 dr). The asymmetric Michael addition of ketones to allylidene malonates was also achieved.     

Direct catalytic asymmetric Mannich-type reaction of beta-keto phosphonate using a dinuclear Ni2-Schiff base complex

Direct catalytic asymmetric Mannich-type reactions of beta-keto phosphonates are described. A homodinuclear Ni 2-Schiff base complex promoted the reaction at 0 degrees C, giving beta-amino phosphonates in up to 90% yield, 20:1 dr, and 99% ee. Control experiments suggested that two Ni metals are important for achieving high yield and stereoselectivity.     

Pyrrolidine-thioxotetrahydropyrimidinone as an efficient organocatalyst for the enantioselective Michael addition of cyclic ketones to nitrodienes

Among the various Michael additions, the enantioselective reaction between cyclic ketones and nitrodienes has received little attention in comparison to the corresponding reaction with nitroolefins. A bifunctional organocatalyst consisting of the pyrrolidine moiety and a thioxotetrahydropyrimidinone ring successfully catalyzed this asymmetric transformation. The products of the reaction between various ketones and nitrodienes were obtained in high yields (up to 96%) with excellent diastereo- (up to >98:2 dr) and enantioselectivities (up to 99:1% er).     

Highly enantioselective Michael addition of cyclic ketones to chalcones catalyzed by pyrrolidine-based imides

An efficient procedure for asymmetric Michael addition reaction of cyclic ketones with low activated chalcones catalyzed by pyrrolidine-based phthalimide and 1,8-Naphthalimide catalysts was developed. The corresponding products were obtained in high yields with high diastereoselectivities (up to 99:1 dr) and high enantioselectivities (up to 96% ee) under mild conditions.