Highly stereoselective construction of tetrahydroquinolines via cascade aza-Michael-Michael reaction: Formal [4+2] cycloaddition of β,γ-unsaturated α-ketoesters with 2-aminochalcones

An efficient cascade aza-Michael-Michael sequence for the preparation of tetrahydroquinolines has been established. Three contiguous stereogenic centers are created with high levels of enantioselectivities (79–99% ee) and exclusive diastereoselectivities in the presence of a bifunctional squaramide. This approach is compatible with a broad range of β,γ-unsaturated α-ketoesters and 2-aminochalcones. Our protocol indicated that β-site of β,γ-unsaturated α-ketoester is an available pro-nucleophilic site.     

Synthesis of optically active dihydropyrans from asymmetric [4 + 2] cycloaddition of β,γ-unsaturated α-ketoesters with allenic esters

β-Isocupreidine (β-ICD) catalyzed asymmetric [4 + 2] cycloaddition of β,γ-unsaturated α-ketoesters with allenic esters afforded ester-substituted functionalized dihydropyran derivatives in high yields along with high enantioselectivities under mild conditions.     

Bifunctional cinchona alkaloids-catalyzed asymmetric [4+2] cycloaddition reaction of β,γ-unsaturated α-keto esters with oxazolones

A highly enantioselective [4+2] cycloaddition reaction of β,γ-unsaturated α-keto esters with oxazolones was realized with readily available cinchona alkaloids as the catalysts. Using this reaction, a series of highly functionalized δ-lactones with adjacent α-quaternary-β-tertiary stereocenters were obtained in high yields (up to 97%) and with good-to-excellent enantioselectivities (up to 97% ee).     

Chiral bifunctional squaramide catalyzed asymmetric Michael addition of ethyl α-nitroacetate to β,γ-unsaturated α-ketoesters

We have developed an efficient bifunctional squaramide catalyst for the asymmetric Michael addition of ethyl α-nitroacetate to β,γ-unsaturated α-ketoesters. This organocatalytic asymmetric reaction provides convenient and valuable access to highly functionalized 2-nitro-5-oxo-3-arylhexanedioates in excellent yields with uniformly high levels of enantioselectivity (up to >99% ee) albeit with no diastereoselectivity. The resulting products could be conveniently transformed into 5-nitro-2-oxo-4-arylpentanoic acids without loss of enantiomeric excess via basic hydrolysis and the subsequent decarboxylation. This represents an example of in-direct, but efficient asymmetric conjugate addition of pyruvic acid to nitroolefins.     

Asymmetric cyclopropanation of β,γ-unsaturated α-ketoesters with stabilized sulfur ylides catalyzed by C2-symmetric ureas

A novel organocatalytic asymmetric cyclopropanation of β,γ-unsaturated α-ketoesters with stabilized sulfur ylides using C(2)-symmetric urea as a hydrogen-bond catalyst has been described. This reaction allows an efficient access to 1,2,3-trisubstituted cyclopropane derivatives in moderate to good yields with up to 16:1 dr and 90:10 er under mild reaction conditions. The mechanism study proved that the high stereoinduction originated from the cooperative effect of the hydrogen-bond catalyst.     

Enantioselective rhodium-catalyzed [4+2] cycloaddition of α,β-unsaturated imines and isocyanates

A [4+2] cycloaddition of α,β-unsaturated imines and isocyanates catalyzed by a phosphoramidite-rhodium complex provides pyrimidinones in good yields and high enantioselectivities.     

Highly enantioselective Friedel-Crafts alkylation of indoles and pyrrole with β,γ-unsaturated α-ketoesters catalyzed by heteroarylidene-tethered bis(oxazoline) copper complexes

The simple and cheap chiral catalyst, heteroarylidene-tethered Ph-bis(oxazoline)-Cu(OTf)(2), can efficiently catalyze the asymmetric F-C alkylation of indoles and pyrrole with β,γ-unsaturated α-ketoesters. The 3-indolyl adducts were obtained in up to >99% ee. Moreover, the 2-pyrrolyl adducts were achieved in up to 92% ee for the first time.     

DABCO-catalyzed regioselective cyclization reactions of β,γ-unsaturated α-ketophosphonates or β,γ-unsaturated α-ketoesters with allenic esters

Highly efficient DABCO-catalyzed [4 + 2] cycloaddition of β,γ-unsaturated α-ketophosphonates or β,γ-unsaturated α-ketoesters with allenic esters gives the corresponding highly functionalized tetrahydropyran and dihydropyran derivatives in good to excellent yields and moderate to good regioselectivities under mild conditions.     

Asymmetric synthesis of chiral β-hydroxy-α-amino acid derivatives by organocatalytic aldol reactions of isocyanoesters with β,γ-unsaturated α-ketoesters

The first organocatalytic asymmetric aldol reaction of isocyanoesters with various β,γ-unsaturated α-ketoesters has been described. Using cinchona alkaloid-derived bifunctional thiourea as the catalyst, chiral β-hydroxy-α-amino acid derivatives can be obtained in excellent yields and enantioselectivities (up to 95% yield and 92% ee) after acidic hydrolysis. This protocol provides a straightforward method to access multiple substituted β-hydroxy-α-amino acid derivatives with high enantiomeric purity.     

Asymmetric cycloaddition of β,γ-unsaturated α-ketoesters with electron-rich alkenes catalyzed by a chiral Er(OTf)3/N,N'-dioxide complex: highly enantioselective synthesis of 3,4-dihydro-2H-pyrans

The asymmetric inverse-electron-demand hetero-Diels-Alder (HDA) reactions of β,γ-unsaturated α-ketoesters with electron-rich alkenes were investigated, with an N,N'-dioxide/erbium(III) complex employed as the catalyst. Quantitative conversion of the β,γ-unsaturated α-ketoesters and excellent enantioselectivities (up to >99% ee) and diastereoselectivities (up to >99:1 d.r.) were observed for a broad range of substrates by using a 0.5-0.05 mol% catalyst loading under mild reaction conditions. The reaction could be scaled up to the gram scale with the same results. In addition, this was the first application of Er(OTf)(3) to the asymmetric inverse-electron-demand HDA reaction and it behaved as an efficient catalyst. Moreover, the synthetic utility of this methodology was demonstrated with the synthesis of key intermediates of some natural products.     

Synthesis of chiral spiro-cyclopentene/cyclopentadiene-oxindoles through an asymmetric [3 + 2] cycloaddition of isatin-derived MBH carbonates and β,γ-unsaturated α-keto esters

A highly stereoselective [3 + 2] cycloaddition for constructing the chiral spiro-cyclopentene/cyclopentadiene-oxindole skeletons is developed. Under the mild reaction conditions, the straightforward cyclization of isatin-derived MBH carbonates and β,γ-unsaturated α-keto esters involving a chiral tertiary amine catalyst provides the corresponding spirooxindole derivatives with an extraordinary level of diastereo- and enantioselectivities. Further synthetic utility of this protocol is demonstrated by the gram-scale experiment and functional transformation of the synthetic compound into other structurally diverse spirooxindole.     

Asymmetric [4+2] cycloaddition of azlactones with dipolar copper–allenylidene intermediates for chiral 3,4-dhydroquinolin-2-one derivatives

In this paper, a pybox-copper catalyzed enantioselective decarboxylative [4+2] cycloaddition reaction of ethynyl benzoxazinanones with azlactones has been developed, which provides optically active 3,4-dihydroquinolin-2-ones in high yields with good enantioselectivities and diastereoselectivities. In this transformation, the chiral dipolar copper–allenylidene intermediates are kinetically generated via decarboxylative ethynyl benzoxazinanones, followed by the attack of the enolate azlactones to form enantiomerically enriched 3,4-dihydroquinolin-2-one structures.     

[2+2+2] cycloaddition reactions of α,β-unsaturated N-arylaldimines,acetylenedicarboxylates and 2-arylidene-1,3-indanediones

The domino [2+2+2] cycloaddition reaction of α,β-unsaturated N-arylaldimines, dialkyl acetylenedicarboxylates and 2-arylidene-1,3-indanediones in dry methylene dichloride at room temperature afforded isomeric 2′-styryl-1,2′,3,4′-tetrahydro-1′H-spiro[indene-2,3′-pyridines] in good yields. Under similar conditions, the reaction of α,β-unsaturated N-arylaldimines with two molecules of dialkyl acetylenedicarboxylates resulted in 1-aryl-6-styryl-1,6-dihydropyridine-2,3,4,5-tetracarboxylates. Additionally, the three-component reaction of α,β-unsaturated N-arylaldimines, dimethylacetylenedicarboxylate and benzoyl cyanide also gave isomeric 1,3-oxazine-4,5-dicarboxylates.     

Highly stereoselective synthesis of β,γ-disubstituted and α,β,γ-trisubstituted butyrolactones

β,γ-Disubstituted butyrolactones were produced effectively and steroeselectively from arsonium ylides generated in situ and substituted olefins. The transformation could be realized in one-pot or in two steps, which depended on the electronic properties of the olefins. With the adjustment of the solvent and in the presence of EtOH, α,β,γ-trisubstituted butyrolactones were also obtained in high yield from arsonium ylides and substituted olefins.     

Highly enantioselective aldol reaction of acetone with β,γ-unsaturated α-keto esters promoted by simple chiral primary-tertiary diamine catalysts

A series of primary-tertiary diamine catalysts were successfully applied to promote the enantioselective aldol reaction of acetone with β,γ-unsaturated α-keto esters in excellent yields (up to 99%) and enantioselectivities (up to 96% ee).