Squaramide-catalyzed asymmetric Mannich reactions between 3-fluorooxindoles and pyrazolinone ketimines.

An enantioselective Mannich reaction between 3-fluorooxindoles and pyrazolinone ketimines has been developed for the construction of amino-pyrazolone-oxindoles containing stereogenic C-F units. Based on this new protocol that allows for the generation of two adjacent tetrasubstituted stereocenters, a variety of structurally diverse fluorinated amino-pyrazolone-oxindoles were obtained in good to excellent yields with excellent diastereoselectivities and enantioselectivities (up to 98% yield, >20 : 1 dr and >99% ee). What's more, good yield and high stereoselectivities were obtained in the gram-scale reaction.

Bifunctional Squaramide-Catalyzed Asymmetric [3 + 2] Cyclization of 2-(1-Methyl-2-oxoindolin-3-yl)malononitriles with Unsaturated Pyrazolones To Construct Spirooxindole-Fused Spiropyrazolones.

The present paper reports a highly stereoselective synthesis of spirooxindole-fused spiropyrazolones through the asymmetric [3 + 2] cyclization reaction of 2-(1-methyl-2-oxoindolin-3-yl)malononitriles with unsaturated pyrazolones under mild conditions. With only a 1 mol % bifunctional squaramide catalyst, a series of chiral dispirocyclic pyrazolone derivatives were attained in high yields (85-97%) with excellent stereoselectivities (up to >99% ee and in all cases >20:1 dr). Moreover, gram-scale synthesis and further transformation of the products were also demonstrated.

Organocatalytic Asymmetric Synthesis of 3,3'-Pyrrolidinyl-bispirooxindoles via Michael/ N-Hemiketalization Cascade Reaction between 3-Aminooxindoles and Isatin-Derived β,γ-Unsaturated α-Keto Esters.

A novel strategy for the construction of 3,3'-pyrrolidinyl-bispirooxindoles through a Michael/ N-hemiketalization cascade reaction of 3-aminooxindoles and isatin-derived β,γ-unsaturated α-keto esters was developed. Under mild conditions, a series of 3,3'-pyrrolidinyl-bispirooxindoles were obtained in moderate to good yields with high diastereo- and enantioselectivities by using a cinchona-derived bifunctional squaramide organocatalyst. This work represents the first example using the 3-aminooxindoles for the construction of 3,3'-pyrrolidinyl-bispirooxindoles.

Chiral squaramide-catalysed enantioselective Michael/cyclization cascade reaction of 3-hydroxyoxindoles with α,β-unsaturated N-acylated succinimides.

A bifunctional squaramide-catalysed asymmetric Michael/cyclization cascade reaction of 3-hydroxyoxindoles with α,β-unsaturated N-acylated succinimides is disclosed. With quinine-derived squaramide as the catalyst, a broad range of the desired spirooxindole lactone derivatives bearing two contiguous stereocenters were obtained in good yields (up to 89%) with high diastereoselectivities (up to >95 : 5 dr) and excellent enantioselectivities (up to 99% ee).

Squaramide-Catalyzed Asymmetric Reactions.

Bifunctional squaramides have emerged as powerful hydrogen-bonding catalysts for promoting a wide array of useful asymmetric reactions, which provides convenient methods for the construction of complex molecular structures and chiral biologically active compounds. This review highlights the recent advances of our research group in the chiral squaramide-catalyzed asymmetric reactions, including Michael addition, Mannich reaction, aza-Henry reaction, Strecker reaction as well as cascade or sequential reactions.

Enantioselective Squaramide-Catalyzed Trifluoromethylthiolation-Sulfur-Michael/Aldol Cascade Reaction: One-Pot Synthesis of CFS-Containing Spiro Cyclopentanone-Thiochromanes.

A novel bifunctional squaramide-catalyzed one-pot electrophilic trifluoromethylthiolation-sulfur-Michael/aldol cascade reaction for the construction of CFS-containing spiro-cyclopentanone-thiochromanes was developed. This convenient, one-pot cascade reaction serves as a powerful tool for the enantioselective construction of potential bioactive spiro-cyclopentanone-thiochromanes, which have one quaternary stereocenter containing a CFS group and three contiguous stereocenters including one spiro all-carbon quaternary center, in moderate to good yields with excellent stereoselectivities (up to 15:1 dr, >99% ee). The synthetic transformations of the resulting products were also be achieved.

Organocatalytic asymmetric Michael addition of α-alkylidene succinimides to nitrostyrenes.

A bifunctional squaramide-catalyzed asymmetric Michael addition reaction of α-alkylidene succinimides with nitrostyrenes and a nitrodiene has been developed. This organocatalytic asymmetric reaction provides easy access to functionalized succinimides with two contiguous stereocenters with a broad substrate scope. The desired succinimide derivatives were obtained in good to excellent yields (up to 98%) with high to excellent diastereoselectivities (up to >99 : 1 dr) and excellent enantioselectivities (up to 99% ee).

Organocatalytic cascade Michael/Michael reaction for the asymmetric synthesis of spirooxindoles containing five contiguous stereocenters.

A bifunctional squaramide-catalyzed Michael/Michael cascade reaction for the construction of five-membered spirooxindoles was developed. This reaction afforded the corresponding products with five contiguous stereocenters including a quaternary center in good to excellent yields (up to 93%) with excellent stereoselectivities (up to >99 : 1 dr, 98% ee). Meanwhile, the practicality of this methodology was illustrated by a gram-scale synthesis, one-pot four-component reaction and synthetic transformation of the resulting adduct.

Squaramide-catalysed asymmetric cascade aza-Michael/Michael addition reaction for the synthesis of chiral trisubstituted pyrrolidines.

A bifunctional squaramide catalysed aza-Michael/Michael cascade reaction between nitroalkenes and tosylaminomethyl enones or enoates has been developed. This organocatalytic cascade reaction provides easy access to highly functionalized chiral pyrrolidines with a broad substrate scope, giving the desired products in good yields (up to 99%) with good diastereoselectivities (up to 91 : 9 dr) and excellent enantioselectivities (up to >99% ee) under mild conditions. This protocol provides a straightforward entry to highly functionalized chiral trisubstituted pyrrolidine derivatives from simple starting materials.

Chiral squaramide-catalysed one-pot enantioselective sulfa-Michael addition/thioesterification of thiols with α,β-unsaturated N-acylated succinimides.

A novel highly enantioselective one-pot dithiolation through sulfa-Michael addition/thioesterification of thiols with α,β-unsaturated N-acylated succinimides catalysed by squaramide has been developed. This organocatalysed reaction proceeded well in high to excellent yields (up to >99%) to afford useful bioactive β-sulfated thioester derivatives with high enantioselectivities (up to 96% ee).