An elegant synergistic catalytic system comprising a ruthenium complex with a chiral Brønsted acid was developed for a four-component Mannich/cascade aza-Michael reaction. The ruthenium-associated ammonium ylides successfully trapped with in situ generated imines indicates a stepwise process of proton transfer in the ruthenium-catalyzed carbenoid NH insertion reaction. The different decomposition abilities of various ruthenium complexes towards diazo compounds were well explained by the calculated thermodynamic data. The transformation features a mild, rapid, and efficient method for the synthesis of enantiomerically pure 1,3,4-tetrasubstituted tetrahydroquinolines bearing a quaternary stereogenic carbon center from simple starting precursors in moderate yields with high diastereo- and enantioselectivity.

Asymmetric functionalization of aromatic CH bonds of N,N-disubstituted anilines with diazo compounds and imines is reported for the efficient construction of α,α-diaryl benzylic quaternary stereocenters in good yields with high diastereoselectivities and excellent enantioselectivities. This Rh^II/chiral phosphoric acid cocatalyzed transformation is proposed to proceed through a metal-carbene-induced zwitterionic intermediate which undergoes electrophilic trapping. To the best of our knowledge, this is the first asymmetric example of metal carbene-induced intermolecular functionalization of aryl CH bonds.

The chiral Rh^I–diene-catalyzed asymmetric three-component reaction of aryldiazoacetates, aromatic amines, and β-nitroacrylates was achieved to obtain γ-nitro-α-amino-succinates in good yields and with high diastereo- and enantioselectivity. This reaction is proposed to proceed through the enantioselective trapping of Rh^I-associated ammonium ylides by nitroacrylates. This new transformation represents the first example of Rh^I-carbene-induced ylide transformation.

Based on the assumption that intramolecularly formed protic oxonium ylides could be trapped by electrophiles, transition-metal-catalyzed reactions of diazoesters bearing a primary hydroxy group with electron-deficient aldehydes and isatins were examined. Good to high chemo- and diastereoselectivities were achieved with reactions catalyzed by Cu(hfacac)₂. The reactions were assumed to occur via tandem intramolecular protic oxonium ylide formation and subsequent aldol-type addition. They not only provided an efficient entry to 3-substituted 1,4-dioxan-2-one heterocycles with at least one quaternary carbon center but also provided experimental evidence for a stepwise pathway for the transition-metal-catalyzed intramolecular OH insertion of diazo compounds.

In recent years, chiral Brønsted acid catalysts have been widely used in numerous enantioselective carbon–carbon and carbon–heteroatom bond-forming reactions. Cascade/domino reactions and multicomponent reactions provide highly efficient, operationally simple, and atom-economical approaches to the synthesis of polyfunctional complex molecules that are useful for modern organic chemistry and drug discovery. The control of stereoselectivity in these reactions remains a great challenge. Chiral Brønsted acid catalysts were rationally introduced as bifunctional catalysts to achieve synergetic catalysis for well-controlled stereoselectivity. The synergy between chiral Brønsted acid catalysts and other compatible catalysts provides additional avenues for the discovery of novel organic transformations and improves reaction selectivity as well. In this Focus Review, recent advances in the uses of chiral Brønsted acids as cooperative catalysts in asymmetric cascade/multicomponent reactions are summarized.

A new strategy for the synthesis of N-alkoxycarbonyl aryl α-imino esters in the presence of dirhodium tetraacetate [Rh₂(OAc)₄] is reported to produce the desired compounds in high yield (up to 96%) under mild reaction conditions. The application of the synthetic method is demonstrated in enantioselective reduction and Friedel–Crafts reaction of indoles to afford the corresponding chiral arylglycines and indole derivatives, respectively, in high yield and excellent ee.

The highly regioselective, three-component reaction of diazoacetates with anilines and β,γ-unsaturated α-keto esters is presented. Ammonium ylides obtained in situ from diazoacetates and anilines can be trapped by β,γ-unsaturated α-keto esters through two distinctly different pathways: 1,2-addition or tandem 1,4-addition/cyclization followed by one-pot dehydration. The course of the reaction is highly dependent on the electronic nature of the diazoacetates. When α-unsubstituted or α-alkyl-substituted diazoacetates are used as the substrates, the three-component reaction proceeds efficiently, in a regiospecific 1,2-addition manner, to afford densely functionalized β-hydroxy α-amino acid derivatives in high yields (71–94 %) and good diastereoselectivities. When α-aryl-substituted diazoacetates are used as the substrates, the three-component reaction occurs smoothly to yield polysubstituted 2,3-dihydropyrrole derivatives through tandem 1,4-addition/cyclization followed by one-pot dehydration. The high regioselectivity observed in the three-component reaction can be rationalized on the basis of the hard and soft acids and bases (HSAB) principle.