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Electron-rich benzofulvenes serve as 2π-components in Cu-catalyzed asymmetric 1,3-DC reactions of azomethine ylides, affording chiral spiro-pyrrolidines in high yields with exclusive chemo-/regioselectivity and moderate to excellent stereoselectivity.

Highly selective assembly of 2,3-fused indolizines was achieved via a cascade allylation/Friedel–Crafts type reaction with Cu/Ir catalysis. This protocol furnishes a stereodivergent synthesis of chiral indolizines bearing three stereogenic centers with excellent results.

Phosphonates and derivatives with an α-chiral center are of great importance and they are widely distributed in many natural products, pharmaceuticals, and agrochemicals with various bioactive features. Great effort has been made toward the development of efficient methods for their synthesis. In this short review, recent advances in the asymmetric catalytic synthesis of phosphonates with an α-chiral center are summarized, including asymmetric hydrogenation of α,β-unsaturated phosphonates, asymmetric addition of phosphonates to unsaturated electrophiles, and asymmetric addition of nucleophiles to α,β-unsaturated phosphonates. In addition, continuous development of enantioselective catalytic synthetic methods and the application of phosphonates and derivatives with α-chiral center are future prospects.1 Introduction2 Asymmetric Hydrogenation of α,β-Unsaturated Phosphonates3 Asymmetric Addition of Phosphonates to Unsaturated Electrophiles4 Asymmetric Addition of Nucleophiles to α,β-Unsaturated Phosphonates5 Conclusion

We report an unprecedented Pd-catalyzed asymmetric allylic alkylation of 1-(indol-2-yl)cyclobutanols followed by an α-iminol rearrangement. High yields with excellent chemo-, regio-, diastereo-, an...

The synergistic chiral Lewis acid/achiral Pd catalyst system was successfully applied in the enantioselective benzylation of various imine esters, giving a range of α-benzyl-substituted α-amino acid derivatives in satisfactory yield with excellent enantioselectivity. It is worth noting that this strategy exhibits good tolerance for bicyclic and monocyclic benzylic electrophiles. Furthermore, the utility of this synthetic protocol was demonstrated by the expedient preparation of enantioenriched antihypertensive drug α-methyl-l-dopa.

Iridium-catalyzed cascade allylation/macrolactonization between vinylethylene carbonate (VEC) and isatoic anhydride derivatives was successfully developed, readily generating a wide range of

A stereodivergent synthesis of azepino[3,4,5-cd]-indoles bearing three stereogenic centers was established via synergistic dual-metal catalysis followed by acid-promoted epimerization, and up to all eight stereoisomers could be predictably achieved.

A serendipitous and efficient approach to access various δ-carbolines was developed through base-promoted cascade β-F-elimination/electrocyclization/Diels–Alder/retro-Diels–Alder reaction in good to high yields with excellent regio/chemoselectivity.

Chiral fluoropyrrolidines were synthesized by Cu(i)-catalyzed enantioselective 1,3-dipolar cycloaddition of azomethine ylides with less active fluorinated styrenes, with broad substrate scope and high yield, stereoselectivity and biological activity.

Cu-catalyzed endo-selective asymmetric 1,3-dipolar cycloaddition of azomethine ylides with ethenesulfonyl fluorides (ESFs) was successfully developed, this protocol provided an efficient and facile method to a wide range of chiral pyrrolidine-3-sulfonyl fluorides with good to excellent results (up to 87% yield, >20:1 dr, 94% ee). Some other chiral sulfonyl derivatives, such as sulfonamide and sulfonate, were easily accessible through simple transformations with high yields, which demonstrated that the cycloaddition products could be synthetically useful in the sulfur(VI) fluoride exchange (SuFEx) chemistry.

Ir-catalyzed asymmetric cascade allylation/lactonization of indole 2-carboxylates with vinyl cyclic carbonate was successfully developed, which provided efficient access to chiral tricyclic oxazinoindolones with excellent results (up to 85% yield, 99% ee). This protocol could be well extended to pyrroles and other nitrogen-containing aromatic heterocycles. A reasonable reaction pathway was provided on the basis of preliminary mechanistic investigation. Importantly, the key intermediate toward marine alkaloid (+)-agelastatin A could be readily accessible through this methodology.

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.

An enantiomerically enriched 3-hydroxymethyl pentenal unit is one of the key structural cores in plenty of natural products and drug candidates with significant biological activities. However, very few synthetic methodologies for the facile construction of the related skeletons have been reported to date. Herein, an elegant iridium-catalyzed asymmetric cascade allylation/retro-Claisen reaction of readily available β-diketones with VEC was successfully developed, and a wide range of functionalized chiral 3-hydroxymethyl pentenal derivatives could be prepared in good yields with excellent enantioselectivities. Various 1,3-diketones and functionalized ketones containing different electron-withdrawing groups on the β-position were well tolerated as outstanding partners with high reactivity and excellent regio-/chemo-/enantioselectivity. The synthetic utility of product chiral 3-hydroxymethyl pentenal derivatives was well shown through gram-scale transformation, hydrogenation, cyclopropanation, hydroboration, and olefin metathesis. Moreover, this elegant protocol demonstrated synthetic applications in the concise synthesis of synthetically useful chiral building block (

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

Since the discovery of left-handed G-quadruplex (L-G4) structure formed by natural DNA, there has been a growing interest in its potential functions. This study utilised it to catalyse enantioselective Diels-Alder reactions, considering its different optical rotation compared to an ordinary G4. It was determined that when L-G4 was used with a combination of copper(II) ions, there was a good enantioselectivity (−52% ee) without further addition of ligands. When further consideration was given by adding G4 ligands, G4 was further stabilised, even obtaining a better enantioselectivity (up to −80% ee). Moreover, when using ligands that have regulatory effects on G4, the ee value can be adjusted. In this work, a minimal left-handed G4 was reported. A follow-up study was also conducted, which recovers that the minimal left-handed G4 remains its catalytic effect and enantioselectivity, but is not so effective as the former case. This indicates that a complete G4 structure is relatively conducive to chiral catalysis.

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.

A one-pot Cu-mediated H-D exchange with inexpensive heavy water as the deuterium source, followed by Cu- and Ir-catalyzed stereodivergent allylic alkylation, has been developed, providing efficient access to enantioenriched α-deuterium-labeled α-amino acids from readily available glycine imine esters in a high yield with excellent stereoselectivity. High deuterium enrichment, exquisite regioselectivity, precise stereoselectivity control, and operationally convenient procedures make this protocol appealing for the preparation of highly synthetically useful α-deuterated α-amino acids.

Copper-catalyzed asymmetric propargylic substitution with salicylaldehyde-derived imine esters and propargylic carbonates has been successfully realized, generating a wide range of chiral amino acid derivatives containing propargylic groups with excellent results (up to 95% yield and 94% ee). The

Ir-catalyzed asymmetric tandem allylation/iso-Pictet-Spengler cyclization of arylidenaminomalonates with indolyl allylic methyl carbonates was successfully developed, which provided a direct and practical approach to access synthetically useful and biologically active tetrahydro-γ-carboline derivatives bearing multiple functional groups and stereogenic centers in good to high yields and excellent stereoselective control (44%-96% yields, >20:1 dr, 94% → 99% ee). A wide range of substrate generality, easily available substrates, and simple chiral catalytic system displayed great potential practicality of this efficient protocol.

Methods that enable rapid construction of multiple C-C bonds using a single catalyst, with high diastereo- and enantiocontrol are particularly valuable in organic synthesis. Here, we report an Ir-catalyzed double allylic alkylation reaction in which bisnucleophilic cyanoacetate reacted successionally with the electrophilic π-allyl-Ir species, producing various pseudo-C2-symmetrical cyanoacetate derivatives in high yield with excellent stereocontrol. The more challenging sequential allylic alkylation/allylic alkylation with two distinct allylic carbonates that can deliver the corresponding products bearing three contiguous tertiary-quaternary-tertiary stereocenters were also developed by using a modified catalytic system, which is revealed to be associated with quasi-dynamic kinetic resolution of the initially-formed diastereomeric monoallylation intermediates. Notably, the stereodivergence for this sequential process depending on a single iridium catalyst was successfully realized, and up to six stereoisomers could be predictably prepared by combining the appropriate enantiomer of chiral ligand for iridium catalyst and adjusting the adding sequence of two distinct allylic precursors.

Aza-Cope rearrangement, as one of the fundamental reactions for C-C and C-N bond formation, has been extensively utilized for the rapid construction of synthetically challenging organic molecules. Despite significant achievements having been made in the past 80 years, catalytic enantioselective versions still remain a challenge, mainly due to the inherent nature of the reversibility of aza-Cope rearrangement. Recently, owing to the intensive development of asymmetric catalysis strategies, various chiral organocatalysts and transition-metal catalysts have been successfully applied to control the stereoselectivity of aza-Cope rearrangement, and remarkable advances have been achieved. This review highlights recent progress relating to catalytic asymmetric aza-Cope rearrangement and covers important features of these studies, including catalytic system design, mechanistic insights, stereochemistry analysis, and synthetic applications.

An unprecedented base-promoted and catalyst-free inverse-electron-demand aza-Diels–Alder (IEDDA) reaction between easily available in situ generated azoalkenes and 3-vinylindoles has been developed. This efficient protocol afforded structurally important tetrahydropyridazines containing indole scaffolds with excellent results (72%–89% yields, >20 : 1 dr). Moreover, the catalytic asymmetric version of this reaction was preliminarily realized through a Cu/(S,S)-iPr-box system to prepare the desired chiral product with 81% yield and >20 : 1 dr and 93% ee. The cyclization products could also be well functionalized to access other useful organic molecules through simple transformations.

Ugi’s amine has become one type of privileged chiral skeleton for chiral ligand design bearing central/planar chirality, and such ligands have exhibited tremendous success in various asymmetric cat...

Optically active nitrogen-containing compounds have attracted substantial attention due to their ubiquity in the cores of natural products and bioactive molecules. Among the various synthetic approaches to nitrogenous frameworks, catalytic asymmetric 1,3-dipolar cycloadditions are one of the most attractive methods because of their powerful ability to rapidly construct various chiral N-heterocycles. In particular, N-metallated azomethine ylides, common and readily available 1,3-dipoles, have been extensively applied in dipolar cycloaddition reactions. Despite the fact that asymmetric transformations of azomethine ylides have been investigated for decades, most of the efforts have been directed toward the preparation of pyrrolidines using glycinate-derived α-unsubstituted aldimine esters as the precursors of the azomethine ylides. While α-substituted azomethine ylides derived from amino esters other than glycinate have seldom been harnessed, the construction of non-five-membered chiral N-heterocycles via 1,3-dipolar cycloadditions remains underexplored. In addition, the asymmetric α-functionalization of aldimine esters to prepare acyclic nitrogenous compounds such as α-amino acids, in which an in situ-generated N-metallated azomethine ylide serves as the nucleophile, has not been sufficiently described.In this Account, we mainly discuss the achievements we have made in the past decade toward broadening the applications of N-metallated azomethine ylides for the preparation of nitrogen-containing compounds. We began our investigation with the design and synthesis of a new type of chiral ligand, TF-BiphamPhos, which not only coordinates with Lewis acids to activate dipolar species but also serves as an H-bond donor to increase the reactivity of dipolarophiles with significantly enhanced stereochemical control. Using the Cu(I) or Ag(I)/TF-BiphamPhos complex as the catalyst, we achieved highly stereoselective (3+2) cycloadditions of glycinate and non-glycinate-derived azomethine ylides with diverse dipolarophiles, producing a variety of enantioenriched pyrrolidines with multiple stereocenters in a single step. To further expand the synthetic utility of N-metallated azomethine ylides, we successfully developed higher order cycloadditions with fulvenes, tropone, 2-acyl cycloheptatrienes, and pyrazolidinium ylides serving as the reaction partner, and this reaction provides straightforward access to enantioenriched fused piperidines, bridged azabicyclic frameworks, and triazines via (3+6)- and (3+3)-type cycloadditions. Using N-metallated azomethine ylides as the nucleophile, we realized Cu(I)-catalyzed asymmetric 1,4-Michael additions with α,β-unsaturated bisphosphates/Morita-Baylis-Hillman products, furnishing an array of structurally diverse unnatural α-amino acids. Based on the strategy of synergistic activation, we achieved highly efficient dual Cu/Pd and Cu/Ir catalysis for the α-functionalization of aldimine esters via the asymmetric allylic/allenylic alkylation of N-metallated azomethine ylides. Notably, Cu/Ir catalysis allowed the stereodivergent synthesis of α,α-disubstituted α-amino acids via a branched allylic alkylation reaction, in which the two distinct chiral metal catalysts independently have full stereochemical control over the corresponding nucleophile and electrophile. Furthermore, an expedient and stereodivergent preparation of biologically important tetrahydro-γ-carbolines was realized through a Cu/Ir-catalyzed cascade allylation/iso-Pictet-Spengler cyclization. In addition, when the steric congestion in the allylation intermediates was increased, the combined Cu/Ir catalysts provided an asymmetric cascade allylation/2-aza-Cope rearrangement, producing various optically active homoallylic amines with impressive results.

Pd-phosphinooxazoline (Pd-PHOX)-catalyzed asymmetric hydroalkylation of 1,3-dienes with azlactones was successfully developed for the first time, affording various enantioenriched α-quaternary α-amino acid derivatives bearing contiguous quaternary and tertiary stereogenic centers in good yields with exclusive regioselectivity and excellent stereoselective control (up to 92% yield, >20:1 dr, and >99% ee). The scale-up catalytic asymmetric hydroalkylation was performed well without loss of reactivity and stereoselectivities, which exhibited great potential application. The synthetic utility of the current methodology was demonstrated through product transformations to access other biologically important compounds such as chiral β-amino alcohol and α-quaternary cyclic α-amino acid derivatives.

In this study, we developed an efficient Ir-catalyzed cascade umpolung allylation/2-aza-Cope rearrangement of tertiary α-trifluoromethyl α-amino acid derivatives for the preparation of a variety of quaternary α-trifluoromethyl α-amino acids in high yields with excellent enantioselectivities. The umpolung reactivity empowered by the activation of the key isatin-ketoimine moiety obviates the intractable enantioselectivity control in Pd-catalyzed asymmetric linear α-allylation. In combination with quasi parallel kinetic resolution or kinetic resolution, the generality of this method is further demonstrated by the first preparation of enantioenriched quaternary trifluoromethyl β-, γ-, δ- and e-amino acid derivatives.

Here, we developed an expedient access route to highly functionalized pyrroles from readily available α-amino acid ester hydrochlorides and alkynals via a cascade condensation/intramolecular cyclization followed by a unique C-N ester migration process. A variety of 1,2,3-trisubstituted pyrroles, which were difficult to acquire with the common methodologies, were successfully prepared in good yields under mild conditions.

With the increasing interest in photodynamic therapy (PDT), the assessment of the level of reactive oxygen species produced during PDT has also become increasingly important. However, most of the fluorescent probes for reactive oxygen species (ROS) evaluation were separated from photosensitizers in the PDT process, resulting in