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By virtue of a fundamentally new reaction model of azomethine ylide serving as a two-atom synthon, we present the first example of stereodivergent preparation of γ-butyrolactones via synergistic Cu/Ir-catalyzed asymmetric cascade allylation/lactonization, and all four stereoisomers of γ-butyrolactones bearing two vicinal stereocenters are accessible with excellent diastereoselective and enantioselective control. The chiral IrIII -π-allyl intermediate was separated and characterized to understand the origin of the regio- and stereoselectivity of the initial C-C bond formation process. Control experiments shed some light on the catalyst/substrate and catalyst/catalyst interactions in this dual catalytic system to rationalize the related kinetic/dynamic kinetic resolution process with different catalyst combinations. The enantioenriched γ-butyrolactone products were converted into an array of structurally complex chiral molecules and organocatalysts that were otherwise inaccessible.

We describe cooperative bimetallic catalysis that enables regio-/stereodivergent asymmetric α-allylations of aldimine esters. By employing Et

An unprecedented hydroalkylation of racemic allylic alcohols and racemic ketimine esters enabled by Cu/Ru relay catalysis has been developed via merging the ruthenium-catalyzed asymmetric borrowing-hydrogen reaction with a copper-catalyzed asymmetric Michael addition in a one-pot procedure. The current method enables the efficient preparation of highly functionalized δ-hydroxyesters bearing 1,4-nonadjacent stereocenters in good yields with high levels of diastereoselectivity and excellent enantioselectivity under mild reaction conditions. The full complement of the four stereoisomers of hydroalkylation products could be readily accessed by orthogonal permutations of two chiral metal catalysts. The current work highlights the power of relay catalysis for the stereodivergent construction of 1,4-nonadjacent stereocenters that were otherwise inaccessible.

An unprecedented enantioselective allylic alkylation of readily available aldimine esters has been developed, and is catalyzed by a synergistic Cu/Pd catalyst system. This strategy provides facile access to nonproteinogenic α,α-disubstituted α-amino acids in high yield with excellent enantioselectivity. The more challenging double allylic alkylation of glycinate-derived imine esters was also realized. Furthermore, this methodology was applied for the construction of the key intermediate of PLG peptidomimetics.

An efficient copper(I)-catalyzed one-pot domino reaction for the (Z)-selective construction of diazabicyclo[5.3.0]decatriene derivatives under mild conditions has been developed. This protocol was initiated by a Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC), followed by a ring opening rearrangement and then subsequent higher-order [8+2] cycloaddition of azaheptafulvene with ketenimine intermediates at the corresponding C-2 and N-3 sites, affording biologically active heterocycles in good to high yields.

An unprecedented asymmetric allenylic alkylation of readily available imine esters, which was enabled by a synergistic Cu/Pd catalysis, has been developed. This dual catalytic system possesses good substrate compatibility, delivering a diverse array of nonproteinogenic α-allenylic α-mono- or α,α-disubstituted α-amino acids (α-AAs) with high yields and generally excellent enantioselectivities. Furthermore, the scalability and practicability of the current synthetic protocol were proven by performing gram-scale reactions and by the first catalytic asymmetric synthesis of naturally occurring (S)-γ-allenic α-amino acid, respectively.

An unprecedented copper(II)-catalyzed enantioselective 1,3-dipolar [3+4] cycloaddition of azomethine imines with in situ formed azoalkenes has been realized. This strategy provides a facile access to biologically important 1,2,4,5-tetrazepine derivatives in high yield with exclusive regioselectivity and high stereoselectivity. Moreover, enantioenriched azomethine imines could be obtained via an efficient kinetic resolution using the same approach.

The first copper(I)-catalyzed asymmetric 1,3-dipolar [3+4] cycloaddition of nitrones with azoalkenes has been developed, affording a variety of biologically important 1,2,4,5-oxatriazepane derivatives in good yields with exclusive regioselectivities and excellent enantioselectivities.

An unprecedented catalytic asymmetric inverse-electron-demand aza-Diels–Alder reaction of indoles with in situ formed azoalkenes is reported. A diverse set of [2,3]-fused indoline heterocycles were achieved in generally good yields (up to 97 %) with high regioselectivity and diastereoselectivity (>20:1 d.r.), and with excellent enantioselectivity (up to 99 % ee).

Ylides at a crossing: An unprecedented 1,3-dipolar cycloaddition (cross-cycloaddition) between two different ylides was realized by using the chiral Cu(I) /tBu-Phosferrox complex as the catalyst under mild reaction conditions. This catalytic system provides an expeditious approach to the construction of highly functionalized 1,2,4-triazinane derivatives in good yields with excellent diastereoselectivities and enantioselectivities.

An unprecedented Ag(I)-catalyzed ligand-controlled stereodivergent 1,3-dipolar cycloaddition of azomethine ylides with 3-methyl-4-nitro-5-styrylisoxazoles has been developed to afford heterocycles bearing both methylisoxazole and pyrrolidine moieties. The endo- and exo-cycloadducts were obtained in good yields with excellent stereoselectivities, assisted by tBu-Phosferrox and phosphoramidite as chiral ligands, respectively.

A highly efficient Ag(I)-catalyzed atroposelective desymmetrization of N-(2-t-butylphenyl)maleimide via 1,3-dipolar cycloaddition of in situ generated azomethine ylides has been established successfully, affording a facile access to a series of biologically important and enantioenriched octahydropyrrolo[3,4-c]pyrrole derivatives in generally high yields (up to 99%) with excellent levels of diastereo-/enantioselectivities (up to 99% ee, >20:1 dr). Subsequent transformations led to fascinating 2H-pyrrole and polysubstituted pyrrole compounds without loss of stereoselectivity. The absolute configuration of the generated chiral axis has been unambiguously identified as (M) through single-crystal X-ray diffraction analysis. Furthermore, on the basis of the comprehensive experimental results and the absolute configuration of one of the cycloadducts, the origin of the stereoselectivity was proposed to be attributed to the steric congestion imposed by the bulky PPh2 group of the chiral ligand and the tert-butyl g...

An unprecedented asymmetric desymmetrization of meso-epoxides, derived from cyclopentene-1,3-diones, with 2-mercaptobenzothiazoles has been realized. It was efficiently catalyzed by a chiral Dy(III) /N,N'-dioxide complex through a thiolysis/elimination sequence. This remote stereocontrol strategy provides facile access to synthetically versatile cyclopentene derivatives bearing an all-carbon quaternary stereogenic center in high yield and excellent enantioselectivity. Intriguingly, optically active thiophene could be readily generated from the obtained product through an efficient one-pot protocol.

An unprecedented multicomponent cascade asymmetric inverse-electron-demand Diels–Alder/nucleophilic addition/ring-opening reaction involving 2-methoxyfurans as efficient dienophiles was successfully developed with Cu(I)/tBu-Box complex as the catalyst. A diverse array of tetrahydropyridazines containing unexpectedly stable γ-hydroxyl ester moiety was obtained in generally good yield with exclusive regioselectivity and excellent stereoselectivity.

A highly enantioselective desymmetrization of prochiral cyclopentenediones via Ag(I)-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylide has been developed successfully. The methodology performs well over a broad scope of substrates, which provides facile access to a series of highly functionalized bicyclic pyrrolidine/cyclopentane derivatives in good to high yields with excellent stereoselectivities.

A highly efficient Cu(II)-catalyzed enantioselective inverse-electron-demand aza-Diels–Alder reaction of in situ formed azoalkenes with enol ethers is reported. This methodology provides a facile entry to biologically important and enantioenriched tetrahydropyridazine derivatives in generally good yield (up to 95% yield) with good to excellent enantioselectivity (up to 94% ee).

Spiro(γ-butyrolactam-γ-butyrolactone): a route to enantioenriched spiro(γ-butyrolactam-γ-butyrolactone) compounds, a valuable motif for drug discovery, was developed by use of a highly efficient copper(I)/TF-BiphamPhos-catalyzed tandem Michael addition-elimination of homoserine lactone derived cyclic imino esters with Morita-Baylis-Hillman (MBH) bromides, followed by treatment with para-toluenesulfonic acid.

Pyrrole into one: The catalytic asymmetric 1,3-dipolar cycloaddition of cyclic aldimino esters has been accomplished for the first time, enabling facile access to spiro(butyrolactonepyrrolidines) containing one spiro quaternary center and three tertiary stereogenic centers (see scheme). The catalytic system performs well with a broad range of substrates, furnishing synthetically useful adducts in high yields, with excellent diastereo- and enantioselectivities under mild conditions.

A new protocol for the efficient construction of chiral trifluoromethylated building blocks was developed via organocatalyzed sulfa-Michael addition of thiols to the cost-efficient trans-trifluorocrotonamide. Introducing the pyrazole moiety is crucial to providing H-bond acceptor sites for better activation and hence affording comparable asymmetric induction with that obtained when employing the expensive cis-4,4,4-trifluorocrotonate as the Michael acceptor.

One of the key features of this ester-controlled endo-selective 1,3-dipolar cycloaddition is that high yields and excellent selectivities are observed for a range of imino esters, especially imino esters derived from α-substituted amino acids.

The first catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides with various sterically hindered α,α,β-trisubstituted 2-alkylidene-cycloketones has been developed successfully with silver acetate/TF-BiphamPhos complex for the construction of spiro heterocyclic compounds containing pyrrolidine motifs and a spiro quaternary stereogenic carbon center. The highly efficient catalytic system exhibited high reactivity, excellent diastereoselectivity, good enantioselectivity and broad substrate scope under mild conditions. Subsequent transformations led to the expedient preparation of synthetically useful spiro[pyrrolidine-tetrahydropyranone] and spiro[pyrrolidine-isochroman-1-one] without loss of the diastereo- and enantiomeric excesses.

The direct asymmetric Mannich reaction of glycine Schiff bases with N-tosylimines has been developed with the tetrakis(acetonitrile)copper(I) tetrafluoroborate [Cu(CH 3 CN) 4 BF 4 ]/TF-Bipham-Phos complex. This catalytic system performs well over a broad range of substrates, furnishing anti-adducts of various α,β-diamino acid esters in good yields with up to 94:6 diastereoselectivity and 97% enantioselectivity.

The first catalytic endo-selective 1,3-dipolar cycloaddition of azomethine ylides and vinyl phenyl sulfone has been developed successfully. The highly efficient silver acetate (AgOAc)/TF-BiphamPhos catalytic system exhibited high reactivity, excellent diastereoselectivity (>98:2), good enantioselectivity (67-92% ee) and broad substrate scope under mild conditions.

An unprecedented cascade vinylogous Mukaiyama 1,6-MA/MA of 2-silyloxyfurans and azoalkenes was realized with a Cu(II)/tBu-Box complex. An array of fused butyrolactones containing multiple stereocenters was generally obtained in good yield (up to 90% yield) with exclusive diastereoselectivity (>20:1 dr) and excellent enantioselectivity (up to 99% ee). Carbon isotope effects measured by 13C NMR revealed a stepwise mechanism for this annulation process.

An efficient method for the construction of β-branched α-amino acids containing adjacent quaternary and tertiary stereogenic centers with excellent diastereo- and enantioselectivities is developed.

Cycloheptatrienyl aryl, hetaryl, and alkyl methanones are successfully converted according to the title reaction with aryl, hetaryl, alkyl, and alkenyl imino esters.

The first Ag(I)-catalyzed [6 + 3] cycloaddition/isomerization of fulvenes and isocyanoacetates for the facile access to fused dihydropyridines with high functionality is reported.

Organocatalysis has proven to be one of the most rapidly developing and competitive research areas in asymmetric catalysis since 2000, and has become a third branch besides biocatalysis and transition metal catalysis. In this feature article, recent progress from our research group on asymmetric organocatalysis, focusing on fine-tunable amine–thiourea catalysis, is described. Design of novel bifunctional amine–thiourea organocatalysts based upon the synergistic activation strategy via multiple hydrogen bonds and their applications in asymmetric C–C, C–N, and C–S bond-forming reactions under mild conditions are discussed in detail. The most attractive feature of the newly designed fine-tunable amine–thiourea catalysts is the incorporation of multiple hydrogen bonding donors and stereogenic centers.

An efficient stereoselective Michael addition reaction of homoserine lactone derived cyclic imino esters to nitroolefins promoted by a bis(cinchona alkaloid) (DHQD)2AQN was achieved. This catalytic system features a wide substrate scope, furnishing the corresponding products with excellent diastereoselectivity (>95:5 dr) and good enantioselectivity (up to 87% ee) under mild conditions, and the Michael adducts could be easily transformed into highly functionalized spirocyclic γ-butyrolactone-pyrrolidines through a sequential nitro-Mannich reaction.

This novel transformation allows the facile synthesis of biologically important azepine derivatives with excellent regioselectivity.

Conjugated cyclic trienes without nonbenzenoid aromatic characteristics are applied as fine-tunable dipolarophiles in the Cu(I)-catalyzed asymmetric azomethine ylide-involved cycloaddition, providing a variety of bridged heterocycles in good yields with exclusive regioselectivity and excellent stereoselectivity.

The enantioselective conjugate addition of dialkylzinc or diphenylzinc to enones was catalyzed by a copper(I)-axially chiral binaphthylthiophosphoramide or binaphthylselenophosphoramide ligand system at room temperature (20 degrees C) or 0 degrees C, affording the Michael adducts in high yields with excellent ee for cyclic and acyclic enones. The enantioselectivity and reaction rate achieved here are one of the best results yet for the Cu-catalyzed conjugate addition to enones. It was revealed that this series of chiral phosphoramides was a novel type of S,N-bidentate ligands on the basis of (31)P NMR and (13)C NMR spectroscopic investigations. The mechanism of this asymmetric conjugate addition system has been investigated as well. We found that the acidic proton of phosphoramide in these chiral ligands play a significant role in the formation of the active species. A bimetallic catalytic process has been proposed on the basis of previous literature. The linear effect of product ee and ligand ee further revealed that the active species is a monomeric Cu(I) complex bearing a single ligand [Cu(I):ligand 1:1].

Chiral diphenylthiophosphoramide L2 prepared from diphenylthiophosphinic chloride and ?-(+)-N-ethyl-1,1'-binaphthyl-2,2'-diamine 2 was used as a catalytic chiral ligand in the siver(I)-catalyzed enantioselective allylation reaction of arylaldehydes with allyltribuyltin to furnish high ee (up to 98%) of the homoallylic alcohols.

Catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides with dimethyl itaconate and 2-methyleneglutarate was realized with the Cu(I)/TF–BiphamPhos complex as the catalyst for the efficient construction of pyrrolidine derivatives bearing one unique all carbon-quaternary and two tertiary stereogenic centers. The current catalytic system exhibited excellent diastereoselectivity (> 20:1), good enantioselectivity (88–>99% ee) and broad substrate scope under mild conditions.

An unprecedented catalytic asymmetric inverse-electron-demand aza-Diels–Alder reaction of indoles with in situ formed azoalkenes is reported. A diverse set of [2,3]-fused indoline heterocycles were achieved in generally good yields (up to 97 %) with high regioselectivity and diastereoselectivity (>20:1 d.r.), and with excellent enantioselectivity (up to 99 % ee).

The described reaction allows complete stereo- and regiocontrol and is applicable to imino esters obtained from aromatic, as well as aliphatic aldehydes to afford the products in high yields and with excellent enantioselectivities.

Enantioenriched heterocyclic piperidines are important structural motifs present in numerous natural products and biologically active molecules. This article outlines our recent efforts to develop a straightforward access to highly functionalized piperidine derivatives with multiple stereogenic centers, in good yields and excellent stereoselectivities, via copper(I)/TF-BiphamPhos-catalyzed asymmetric 1,3-dipolar [6+3] cycloadditions of azomethine ylides with fulvenes.