A new method was developed to rapidly generate a series of spiro-pyrrolidine-pyrazolones by using a squaramide-catalyzed cascade aza-Michael/Michael addition of either tosylaminomethyl enones or enoates to unsaturated pyrazolones. This tandem reaction sequence proceeded well by using 5 mol-% of a chiral bifunctional tertiary amine squaramide catalyst to afford the desired products in good to excellent yields (up to 98 %) with excellent diastereoselectivities [up to >20:1 diastereomeric ratio (dr)] and high to excellent enantioselectivities (up to 98 % ee).

An efficient, asymmetric sulfa-Michael/aldol cascade reaction catalyzed by a chiral squaramide catalyst has been developed. This organocatalytic cascade reaction provides easy access to highly functionalized spirothiochromanones with three contiguous stereocenters, including one quaternary center, in excellent yields of up to 99 % with excellent diastereoselectivity up to >99:1 d.r. and enantioselectivity up to 98 % ee. In addition, the key to the present method is introducing indenones that are readily accessible as hydrogen-bond acceptors with very low catalyst loading of 0.5 mol %.

The spiro[pyrrolidine-3,3′-oxindole] scaffold is common to a range of bioactive compounds; however, the asymmetric synthesis of this scaffold is complicated due to the presence of multiple chiral centers. An organocatalytic asymmetric cascade aza-Michael/Michael addition between tosylaminomethyl enones or enoates and 3-ylideneoxindoles catalyzed by a chiral squaramide that afforded complex and flexible spiro[pyrrolidine-3,3’-oxindole]s has been developed. Single-step construction of molecules with three contiguous stereocenters including one quaternary center in excellent yields with highly diastereo- and enantioselectivity are rare and should be useful in medicinal chemistry and diversity oriented synthesis of this intriguing class of compounds.

A new diastereoselective and enantioselective cyclopropanation reaction has been developed by employing a Michael/alkylation cascade reaction between (E)-3-arylenechroman-4-one or (E)-2-arylideneindan-1-one derivatives and a bromonitroalkane with a chiral squaramide catalyst. This reaction constitutes a facile asymmetric synthesis for nitro-spirocyclopropanes that have three adjacent stereogenic centers, including one quaternary center, in moderate to good yields (up to 90 %) with excellent enantio- [up to >99 % ee (enantiomeric excess)] and diastereoselectivities [up to >99:1 dr (diastereomeric ratio)].

Enantioselective synthesis of biologically active dihydropyrano[2,3-c]pyrazoles has been achieved through a squaramide-catalysed Michael addition/Thorpe-Ziegler type cyclization cascade reaction between arylidenepyrazolones and malononitrile. A series of optically active dihydropyano[2,3-c]pyrazoles were obtained in excellent yields (up to 99%) and moderate to good enantioselectivities (up to 79% ee) under mild reaction conditions.

An organocatalytic enantioselective Strecker reaction was developed for the synthesis of α-amino nitriles that contain a thiazole moiety by using a cinchona-based squaramide catalyst. The corresponding products were obtained in good to excellent yields (up to 99 %) with excellent enantioselectivities (up to 98 % ee) by starting from aromatic-substituted imines. In addition, two trifunctional squaramides with amino acid residues were synthesized, and good enantioselectivities (up to 89 % ee) were achieved when they were employed in the model reaction.

A bifunctional squaramide-catalyzed sulfa-Michael/aldol cascade reaction between benzylidenechroman-4-ones and 1,4-dithiane-2,5-diol with a low catalyst loading has been developed. This reaction constitutes a facile asymmetric synthesis of chiral spirocyclic tetrahydrothiophene chromanone derivatives with three contiguous stereocenters in high to excellent yields (up to 99 %) and with high enantioselectivities (up to 92 % ee). Additionally, a remarkable temperature effect on reaction efficiency was observed and gram-scale syntheses were found to proceed smoothly with the same efficiency as smaller scale reactions.

An efficient enantioselective cascade sulfa-Michael/Michael addition reaction of trans-3-(2-mercaptophenyl)-2-propenoic acid ethyl ester with nitroalkenes catalyzed by a chiral squaramide catalyst was disclosed. This cascade reaction afforded thiochroman derivatives with three contiguous stereocenters in high yields (up to 94%), excellent diastereoselectivities (up to >25:1 dr) and enantioselectivities (up to 99% ee).

The efficient asymmetric Michael addition/intramolecular cyclization of malononitrile with dienones catalyzed by a chiral bifunctional tertiary amine–squaramide catalyst for the synthesis of chiral 2-amino-4H-chromene-3-carbonitrile derivatives was developed. The corresponding products were obtained in good to excellent yields (up to 99 %) with excellent enantioselectivities (up to 98 % ee) for most of the bisarylidenecyclopentanones.

An organocatalyzed diastereo- and enantioselective cascade aza-Michael/Michael addition of 2-tosylaminoenones to unsaturated pyrazolones has been developed to afford novel chiral spiropyrazolone tetrahydroquinolines containing three contiguous stereocenters. This cascade reaction proceeded well with 2 mol % chiral bifunctional tertiary amine squaramide catalyst to give the desired products in excellent yields (up to 99 %) with excellent diastereoselectivity (up to >25:1 diastereomeric ratio) and high enantioselectivity (up to 91 % enantiomeric excess).

An efficient enantioselective aza-Henry reaction of nitroalkanes to imines bearing a benzothiazole moiety catalyzed by a Cinchona-based squaramide has been developed. In the reaction of imines, the corresponding products were obtained in good to excellent yields (up to 99%) with excellent enantioselectivities (up to >99% ee) for most of the aromatic substituted imines. The imines with electron-withdrawing groups gave better yields than those bearing electron-donating groups in the aza-Henry reaction. Moreover, a one-pot three-component enantioselective aza-Henry reaction using 2-aminobenzothiazoles, aldehydes, and nitromethane was also developed. Moderate to good yields and high enantioselectivities were obtained in the one-pot cases (up to 98% ee).

The catalytic asymmetric Friedel–Crafts reaction of indoles with nitrodienes and 2-propargyloxy-β-nitrostyrenes was systematically investigated with diphenylamine-linked bis(oxazoline)–Zn(OTf)₂ complexes. Moderate to good enantioselectivities were obtained with both kinds of substrates (up to 89 % ee for nitrodienes and up to 93 % ee for β-nitrostyrene derivatives). Further transformation of the corresponding Friedel–Crafts alkylation product of indole with 2-propargyloxy-β-nitrostyrene was carried out to give the chiral isoxazolobenzoxepane derivative, which is of medicinal chemistry interest, with retained enantiomeric purity.

Binaphthyl sulfonimides have been developed to catalyze the asymmetric Michael addition of ketone to alkylidene malonates, affording the corresponding Michael products in good to high yields (up to 98%) with good to excellent diastereoselectivity (up to 99:1 dr) and enantioselectivity (up to 92% ee) under mild conditions using environmentally benign water as the solvent.

A chiral squaramide-organocatalyzed, highly enantioselective Michael addition of 2-hydroxy-1,4-naphthoquinones to nitroalkenes has been developed. This reaction afforded the chiral naphthoquinones in excellent yields (up to 99%) and excellent enantioselectivity (up to 98% ee) under very low catalyst loading (0.25 mol%). This organocatalytic asymmetric Michael addition provides an efficient alternative route toward the synthesis of chiral functionalized naphthoquinones.

A 16-member library of C₂-symmetric modular chiral BINOL-oxazoline Schiff base copper(II) complex catalysts generated in situ was easily generated in a one-pot, three-component manner. This approach avoided the need for isolation and characterization of ligands and greatly improved the catalyst screening efficiency. This modular catalyst library was evaluated in the asymmetric Henry reaction, for which good yields (up to 98 %) and good to excellent enantioselectivities (up to 98 % ee) were obtained under mild conditions.

Diphenyl sulfide linked bis(imidazoline) ligands with electron-withdrawing N-Ts substitution and electron-donating N-alkyl or N-H substitutions were synthesized through different routes. The electronic effects of the ligands were tuned rationally, and dramatic variation in their catalytic behavior was observed. N-Alkyl and N-H ligands demonstrated much higher catalytic activity and improved enantioselectivity than N-Ts ligands in Pd-catalyzed asymmetric allylic alkylation reactions.

The new diphenylamine-linked bis(imidazoline) ligands were prepared through Kelly-You’s imidazoline formation procedure mediated by Hendrickson’s reagent in good yields. The novel ligands were tested in the asymmetric Friedel–Crafts alkylation of indole derivatives with nitroalkenes. In most cases, good yields (up to 97%) and excellent enantioselectivities (up to 98%) can be achieved. The optimized bis(imidazoline) ligand with trans-diphenyl substitution on the imidazoline ring gave better enantioselectivity than the corresponding bis(oxazoline) ligand.

Novel types of L-proline-based binaphthyl sulfonimides and sulfonamides were found to be efficient organocatalysts for the asymmetric Michael addition of ketones to nitroalkenes to provide optically active γ-nitroketone derivatives of synthetic and biological importance. After the fine optimization of solvents, temperature, and additive, good to excellent enantioselectivities and diastereoselectivities (71–96 % ee, up to >99:1 dr) can be achieved.

A diphenylamine-linked bis(oxazoline) ligand with trans-diphenyl substitution on the oxazoline rings has been immobilized onto one- to three-generation Fréchet-type dendrimers and a C₃-symmetric core structure. The catalytic activities and enantioselectivities of these new ligands were tested in the asymmetric Friedel–Crafts alkylation reactions of indole derivatives with nitroalkenes. The two types of immobilized ligands exhibited similar enantioselectivities and substrate compatibilities to the free ligand trans-DPBO we reported previously. No dendrimer effect was observed in the kinetic investigation of the Fréchet-type dendrimer-immobilized ligands. The in situ recycling of the catalysts was also tested to illustrate the effect of reducing catalyst loading and the efficiency of our system.