Control of four stereocenters in an organocatalytic domino double Michael reaction: efficient synthesis of multisubstituted cyclopentanes

A highly enantioselective and diastereoselective domino organocatalytic double Michael reaction which provides expedited access to multifunctionalized five-membered rings catalyzed by 9-amino-9-deoxyepiquinine (V) has been developed. Simple operational procedures, high yields (81-92%), excellent enantioselectivity (90-97% ee), diastereoselectivities (95:5->99:1 dr), and immense potential of synthetic versatility of the products render this new methodology highly appealing for asymmetric synthesis.     

Highly enantioselective Michael addition of α,α-disubstituted aldehydes to maleimides catalyzed by new primary amine-squaramide bifunctional organocatalysts

New bifunctional primary amine-squaramides catalyzed asymmetric Michael addition reaction of α,α-disubstituted aldehydes to maleimides has been developed. This organocatalytic asymmetric reaction provides easy access to functionalized succinimides with a broad substrate scope. Both enantiomers of desired succinimide derivatives were obtained in good to excellent yields (up to 98%) with excellent enantioselectivities (up to >99%?ee).     

A chiral thioureido acid as an effective additive for enantioselective organocatalytic Michael additions of nitroolefins

A novel and effective organocatalytic system consisting of pyrrolidinyl-thioimidazole and a chiral thioureido acid efficiently catalyzed the asymmetric Michael addition reactions of ketones to nitroolefins to afford the adducts with high diastereoselectivities (up to 99 : 1) and excellent enantioselectivities (up to 99% ee).     

Catalytic Asymmetric Construction of 3,3′‐Spirooxindoles Fused with Seven‐Membered Rings by Enantioselective Tandem Reactions

The first catalytic asymmetric construction of a spirooxindole scaffold incorporated with a seven‐membered benzodiazepine moiety has been established by a three‐component (isatin, 1,2‐phenylenediamine, cyclohexane‐1,3‐dione) tandem reaction catalyzed by a chiral phosphoric acid. Structurally complex spirobenzodiazepine oxindoles with one quaternary stereogenic center are obtained in high yield with excellent enantioselectivity (up to 99 % yield, enantiomeric ratio>99.5:0.5). This approach takes advantage of organocatalytic asymmetric tandem reactions to efficiently construct the structurally rigid spirobenzodiazepine oxindole architecture with high enantiopurity in a single transformation, which involves a cascade enamine–imine formation/intramolecular Mannich reaction sequence.     

Amino-indanol-catalyzed asymmetric Michael additions of oxindoles to protected 2-amino-1-nitroethenes for the synthesis of 3,3'-disubstituted oxindoles bearing α,β-diamino functionality

An organocatalytic asymmetric Michael addition reaction of 3-substituted oxindoles to protected 2-amino-1-nitroethenes has been developed. The reaction is catalyzed by a simple and readily available amino-indanol derivative and affords the desired products in very high yields (up to 99%) with excellent diastereoselectivities (up to >99:1) and very good enantioselectivities (up to 90%). Significantly, this study provides a general catalytic method for the construction of 3,3'-disubstituted oxindoles bearing α,β-diamino functionality as well as vicinal chiral quaternary/tertiary stereocenters. The potential utility of the protocol also had been demonstrated by gram-scale reaction and the versatile conversion of product. Furthermore, On the basis of the comprehensive experimental results and the absolute configuration of one of the Michael adducts, a work model was also proposed to explain the origin of asymmetric induction.     

Asymmetric aldol reaction organocatalyzed by (S)-proline-containing dipeptides: improved stereoinduction under solvent-free conditions

The organocatalytic activity of the methyl ester of (S)-proline-(S)-phenylalanine, (S,S)-2, in the asymmetric aldol reaction between cyclohexanone and acetone with various aromatic aldehydes under solvent-free conditions in a ball mill has been evaluated. α,α-Dipeptide (S,S)-2 catalyzed the stereoselective formation of the expected aldol products, with higher diastereo- and enantioselectivity relative to similar reactions in solution, up to 91:9 anti:syn diastereomeric ratio and up to 95% enantiomeric excess.     

Organocatalytic asymmetric conjugate addition of 3-monosubstituted oxindoles to (E)-1,4-diaryl-2-buten-1,4-diones: a strategy for the indirect enantioselective furanylation and pyrrolylation of 3-alkyloxindoles

An asymmetric conjugate addition of 3-monosubstituted oxindoles to a range of (E)-1,4-diaryl-2-buten-1,4-diones, catalyzed by commercially available cinchonine, is described. This organocatalytic asymmetric reaction affords a broad range of 3,3'-disubstituted oxindoles that contain a 1,4-dicarbonyl moiety and vicinal quaternary and tertiary stereogenic centers in high-to-excellent yields (up to 98%), with excellent diastereomeric and moderate-to-high enantiomeric ratios (up to 99:1 and 95:5, respectively). Subsequently, cyclization of the 1,4-dicarbonyl moiety in the resultant Michael adducts under different Paal-Knorr conditions results in two new kinds of 3,3'-disubstituted oxindoles--3-furanyl- and 3-pyrrolyl-3-alkyl-oxindoles--in high yields and good enantioselectivities. Notably, the studies presented here sufficiently confirm that this two-step strategy of sequential conjugate addition/Paal-Knorr cyclization is not only an attractive method for the indirect enantioselective heteroarylation of 3-alkyloxindoles, but also opens up new avenues toward asymmetric synthesis of structurally diverse 3,3'-disubstituted oxindole derivatives.     

Organocatalytic asymmetric cyclopropanation of α,β-unsaturated aldehydes with arsonium ylides

A novel organocatalytic asymmetric cyclopropanation of α,β-unsaturated aldehydes with arsonium ylides using diphenylprolinol silylether as a catalyst is described. A variety of chiral cyclopropyl aldehydes are obtained in moderate to good yields with up to 99:1 dr (diastereomeric ratio) and 99% ee under simple and mild reaction conditions.     

Enantioselective synthesis of imidazolines with quaternary stereocenters by organocatalytic reaction of N-(heteroarenesulfonyl)imines with isocyanoacetates

An organocatalytic enantioselective Mannich-type reaction of isocyanoacetate with N-sulfonylimines catalyzed by chiral thioureas derived from quinine yielded 2-imidazolines with high diastereo- and enantioselectivities (up to >99:1 dr. and 96% ee). This reaction provided a convenient route to access various imidazolines and related α,β-diamino acids having a quaternary carbon center in high enantiomeric purities.     

Enantioselective nitroaldol reaction of alpha-ketoesters catalyzed by cinchona alkaloids

The development of highly enantioselective and general catalytic nitroaldol (Henry) reactions with ketones is a challenging yet desirable task in organic synthesis. In this communication, we report an asymmetric nitroaldol reaction with alpha-ketoesters catalyzed by a new C6'-OH cinchona alkaloid catalyst. This is the first highly efficient organocatalytic asymmetric Henry reaction with ketones. This reaction is operationally simple and affords high enantioselectivity as well as good to excellent yield for a broad range of alpha-ketoesters.     

Enantioselective organocatalytic Mannich reactions of ferrocenecarbaldehyde

The first examples of highly enantioselective organocatalytic Mannich reactions of ferrocenecarbaldehyde are disclosed. The reaction is catalyzed by simple amino acids and gives access to β-arylamino-β-ferrocenylketones in high yields and with up to 99% ee.     

Organocatalytic asymmetric domino aza-Michael-Mannich reaction: synthesis of tetrahydroimidazopyrimidine derivatives

Highly substituted tetrahydroimidazopyrimidine derivatives with three chiral centers have been synthesized for the first time using an organocatalytic asymmetric domino aza-Michael-Mannich reaction of α,β-unsaturated aldehydes and N-arylidene-1H-imidazol-2-amines. This efficient approach furnishes the products in good yields (42-87%) with excellent stereoselectivities (>20:1 dr, up to >99% ee).     

Asymmetric synthesis of palitantin by an enzymatic and organocatalytic approach

The natural enantiomer of the fungal metabolite (+)-palitantin has been synthesized by adopting a chemoenzymatic and organocatalytic approach. Lipase catalyzed kinetic resolution, Sharpless asymmetric dihydroxylation and organocatalytic asymmetric hydroxymethylation are the key steps involved in the total synthesis of the target molecule.     

Organocatalytic Asymmetric Conjugate Addition of 3‐Monosubstituted Oxindoles to (E)‐1,4‐Diaryl‐2‐buten‐1,4‐diones: A Strategy for the Indirect Enantioselective Furanylation and Pyrrolylation of 3‐Alkyloxindoles

An asymmetric conjugate addition of 3‐monosubstituted oxindoles to a range of (E)‐1,4‐diaryl‐2‐buten‐1,4‐diones, catalyzed by commercially available cinchonine, is described. This organocatalytic asymmetric reaction affords a broad range of 3,3′‐disubstituted oxindoles that contain a 1,4‐dicarbonyl moiety and vicinal quaternary and tertiary stereogenic centers in high‐to‐excellent yields (up to 98 %), with excellent diastereomeric and moderate‐to‐high enantiomeric ratios (up to 99:1 and 95:5, respectively). Subsequently, cyclization of the 1,4‐dicarbonyl moiety in the resultant Michael adducts under different Paal–Knorr conditions results in two new kinds of 3,3′‐disubstituted oxindoles—3‐furanyl‐ and 3‐pyrrolyl‐3‐alkyl‐oxindoles—in high yields and good enantioselectivities. Notably, the studies presented here sufficiently confirm that this two‐step strategy of sequential conjugate addition/Paal–Knorr cyclization is not only an attractive method for the indirect enantioselective heteroarylation of 3‐alkyloxindoles, but also opens up new avenues toward asymmetric synthesis of structurally diverse 3,3′‐disubstituted oxindole derivatives.     

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).     

Asymmetric Friedel-crafts reaction of indoles with imines by an organic catalyst

In this communication, we report an asymmetric Friedel-Crafts reaction of indoles with imines catalyzed by a bifunctional cinchona alkaloid catalyst. This is the first efficient organocatalytic asymmetric Friedel-Crafts reaction of indoles with imines. This reaction is operationally simple and, unprecedentedly, affords high enantioselectivity for a wide range of indoles and both aryl and alkyl imines. This establishes a direct, convergent, and versatile approach to optically active 3-indolyl methanamines, a structural motif embedded in numerous indole alkaloids and synthetic indole derivatives.     

Organocatalytic Asymmetric Annulation of ortho‐Alkynylanilines: Synthesis of Axially Chiral Naphthyl‐C2‐indoles

A chiral Brønsted base catalyzed asymmetric annulation of ortho‐alkynylanilines has been developed to access axially chiral naphthyl‐C2‐indoles via vinylidene ortho‐quinone methide (VQM) intermediates. This strategy provides a unique organocatalytic atroposelective route to axially chiral aryl‐C2‐indole skeletons with excellent enantioselectivity and functional‐group tolerance. This transformation was applicable to decagram‐scale preparation (50.0 g) with perfect enantioselectivity through simple recrystallization. Moreover, the utility of this reaction was demonstrated by a variety of transformations towards chiral naphthyl‐C2‐indoles for a series of carbon–heteroatom bond formations. Furthermore, the prepared axially chiral naphthyl‐C2‐indoles were applied as a chiral skeleton for organocatalytic aza‐Baylis–Hillman reaction and asymmetric formal [4+2] tandem cyclization to give the corresponding adducts in high yields with improved enantioselectivity and diastereoselectivity.     

Three‐Component Triple Organocascade Synthesis of Hexahydropyridazine Derivatives via a Sequential Michael/Amination/Cyclization Reaction

The organocatalytic asymmetric synthesis of hexahydropyridazines were performed through a unique Michael/amination/cyclization reaction. The organocascade reaction proceeded smoothly between 2‐arylidene‐1,3‐indandiones and aldehydes followed by the addition of azodicarboxylates catalyzed by the privileged organocatalyst α,‐α‐L‐diphenylprolinol trimethylsilyl ether (10 mol%) in the presence of a base additive Et₃N (20 mo%) at 0 °C. A series of substituted hexahydropyridazines were obtained in good to high chemical yields (55–78 %) and reasonable to high levels of stereoselectivities (51–93 % ee and 4 : 1 d.r.).     

Asymmetric domino Michael–Henry reaction of 1,2-diones with nitroolefins catalyzed by a chiral bisoxazolidine–Ni(acac)2 complex

The asymmetric domino Michael–Henry reaction of 1,2-cyclohexadione with nitroolefins catalyzed by chiral ligand bisoxazolidine 1 and Ni(acac)₂ has been developed. This process provided highly functionalized chiral bicycle[3,2,1] octane derivatives with the generation of four new stereogenic centers in high yields (76–99%), and with excellent enantioselectivities (up to 99%) and good diastereoselectivities (up to 9:1) under mild reaction conditions. The procedure presented is simple and makes this method suitable for practical use.     

Asymmetric Brønsted Base Catalyzed and Directed [3+2] Cycloaddition of 2‐Acyl Cycloheptatrienes with Azomethine Ylides

Conjugated cyclic trienes have the potential for different types of cycloaddition reactions. In the present work, we will, in a novel asymmetric cycloaddition reaction, demonstrate that the organocatalytic reaction of 2‐acyl cycloheptatrienes with azomethine ylides proceeds as a [3+2] cycloaddition, which is in contrast to the Lewis acid‐catalyzed reaction, in which a [3+6] cycloaddition takes place. In the presence of a chiral organosuperbase, 2‐acyl cycloheptatrienes react in a highly enantioselective manner in the [3+2] cycloaddition with azomethine ylides, providing the 1,3‐dipolar cycloaddition product in high yields and up to 99 % ee. It is also shown that the diene formed by the reaction can undergo stereoselective dihydroxylation, bromination, and cycloaddition reactions. Finally, based on experimental observations, some mechanistic considerations are discussed.