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. 2025 Jul 4;11(8):1275–1288. doi: 10.1021/acscentsci.5c00393

Future Trends in Asymmetric Organo-Metal Combined Catalysis

Dian-Feng Chen †, Jin Song ‡, Liu-Zhu Gong †,§,*
PMCID: PMC12404124  PMID: 40904752

Abstract

Asymmetric organo-metal combined catalysis, which integrates the catalytic functions of chiral organocatalysts and metal complexes, enables the enantioselective formation of challenging chemical bonds and facilitates cascade transformations, often without the need for intermediate purification. Since its inception in 2001, this paradigm has evolved into a versatile strategy for the rapid construction of molecular complexity with a high level of enantioselectivity. In this Outlook, we have highlighted the most recent contributions to this field, showcasing exciting opportunities to overcome current efficiency limits. Looking ahead, we foresee the continued evolution of asymmetric organo-metal catalysis, particularly through the exploration of new catalyst scaffolds, the incorporation of external stimuli, the use of heterogeneous metal catalysts, and the application in macromolecular synthesis.

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1. Introduction

Collaboration between catalyst entities is prevalent in nature, as exemplified by the biosynthesis of structurally complicated big molecules from fundamental small compounds based on reaction sequences enabled by multiple catalysis. Notably, such a cooperative or relay catalysis might even happen in prebiotic metabolism. A similar concept was applied to asymmetric catalysis two decades ago. In 2001, Gong and Mi demonstrated that chiral phase-transfer catalysts (PTCs) could cooperate with an achiral palladium complex to enable asymmetric allylic alkylation reactions (AAAs). Through deprotonation of tert-butyl­(diphenylmethylene)­glycinate 1 by CsOH and subsequent ion exchange with a cinchonidine-derived chiral ammonium salt, a chiral cation-paired nucleophile INT-1 was formed, while the oxidative addition of allyl acetate 2 to the palladium complex gave an electrophilic π-allylpalladium species INT-2 (Scheme ). The merger of these intermediates successfully produced α-alkylated glycinate 3 with a moderate enantiomeric excess (ee) of 59%. At the same time, Takemoto et al. independently reported a similar catalytic system combining a chiral ammonium salt 5 and a palladium-triphenylphosphite complex, which enhanced the enantioselectivity to 94% ee in the same reaction.

1. Chiral Ammonium Salts and Achiral Palladium Cooperative Catalysis.

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Since these inaugural findings, , the combination of chiral PTCs, such as chiral ammonium- and phosphonium salts, with achiral transition metal complexes has evolved as a new platform for AAA reactions. , A broad range of soft nucleophiles including α-imino esters, − oxindoles, , and α-cyanoesters have been employed to couple with electrophilic π-allyl-palladium species that are in situ generated from allyl acetates, , β,γ-unsaturated ketones, and 1,3-dienes, or with π-allyl-iridium species to tune the linear/branch selectivity. Notably, Chen and co-workers demonstrated the use of a cinconine-derived ammonium salt to stabilize π-allyl-palladium-based 1,4-carbodipoles by forming a compact diploid ion-pair species. This distinct double activation strategy has enabled a highly regio-, diastereo-, and enantioselective [4 + 2] annulation reaction with 2-alkylidene indene-1,3-diones.

Chiral PTC-Pd or Ir-cocatalyzed AAA reactions have underlined the crucial role of ion-pairing interactions in the enantio-differentiating step. This mode then evolves from the chiral cation-nucleophile attraction into an unprecedented chiral cation-transition metal complex, significantly expanding the chemical space of chiral PTC-transition metal cooperative catalysis. , The metal-involved chiral cation-pairing can date back to a KMnO4-mediated oxidative cyclization and dihydroxylation reaction, in which a hydrogenated cinchonidine-derived PTC 6 provides a chiral cation that stabilizes the resultant organo-permanganate intermediate, leading to moderate enantioselectivity (Figure a, left). In 2015, Tan and co-workers reported an even more effective bisguanidinium chloride catalyst for KMnO4-mediated dihydroxylation and oxohydroxylation of acrylate derivatives. They further developed a dual tungstate/bisguanidinium chloride system, which assembled into chiral cation-directed tungstate catalyst 7 (Figure a, center). This system has rendered highly enantioselective sulfoxidation of thioethers and epoxidation of alkenyl amides. In a related approach, Maruoka and co-workers demonstrated that a biaryl-derived spiro PTC 8 (Figure a, right) could act as the cation of an alkynyl silver halide anionic species, achieving highly enantioselective alkynylation of isatins. In an electron-inverse sense, Toste et al. combined robust chiral anionic PTC with palladium catalysis, opening new avenues for enantioselective difunctionalization of alkenes (Figure b), including arylborylation, , diarylation, alkynylborylation, and other transformations. −

1.

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PTC activation of transition metal catalysis: (a) chiral cation-pairing transition-metal catalysis; (b) chiral anion-pairing palladium catalysis; (c) chiral ionic ligands.

A notable front on the broader application of chiral ion-pairing interactions derived from chiral PTC-transition-metal cooperative catalysis is the stunning design of ionic ligands. Although ionic ligands seem to be out of the scope of previous “organo-transition metal combined catalysis”, they may be considered as specially designed chiral PTCs, which carry pendant phosphine functionalities to impart supramolecular coordination. A prime example was that Ooi et al. developed an ion-paired ammonium-phosphine ligand bearing a chiral binaphtholate moiety for the palladium-catalyzed AAA reaction of α-nitrocarboxylate with cinnamyl carbonate. They also designed a well-defined chiral ammonium-phosphine hybrid ligand 10 (Figure c, left) for the [3 + 2] annulation reaction of 5-vinyloxazolidinones with activated trisubstituted alkenes. The diploid electrostatic interactions effectively prevent the unfavorable intramolecular coordination of the sulfonamide anion to the palladium center, thus enhancing both reactivity and enantioselectivity. Afterward, the Phipps group created a preeminent ligand consisting of N-substituted dihydroquinine and 5-bipyridylmethyl sulfonate. This ligand has facilitated iridium-catalyzed enantioselective and desymmetrizing meta-C–H borylation of benzhydrylamides and diaryl phosphinamides. Control experiments probing the ligand-cation interactions have revealed that the anionic sulfonate group anchors to the substrates via hydrogen bonding and/or π–π interactions, resulting in a highly organized complex 11 (Figure c, right) that promotes excellent meta-selectivity and enantioselectivity.

In parallel with the development of integrated chiral PTCs and transition-metal catalysis, a variety of distinct chiral organocatalysts, in cooperation with versatile transition-metal complexes, have been explored over the past two decades. , This organo-metal cooperative catalysis employs sophisticated but synchronous activation modes to address challenges associated with reactivity and selectivity, including chemo-, regio-, diasetereo-, and enantioselectivity, particularly in the redistribution of chemical bonds to build up molecular complexity. As illustrated in Figure , three primary activation models broadly dominate the selection of chiral organocatalysts: iminium/enamine activation with chiral amines (Figure a), − hydrogen bonding interactions with chiral Brønsted acids (Figure b), − and nucleophilic activation with chiral Lewis bases, such as nitrogen-heterocyclic carbenes (NHCs), isothioureas (ITUs) , and phosphines (Figure c). The most frequently used organometallic intermediates in these systems include metal π-alkynes, π-allyl- , and benzyl-metallic species, metal-complexed allenylidenes, and acyl metalloids (Figure c). Notably, matching a chiral organocatalyst and a chiral transition-metal complex has enabled extraordinary access to all stereoisomers of products bearing multiple stereogenic centers, − including chiral amine/iridium-chiral phosphoramidite-catalyzed α-allylation of aldehydes, − chiral ITU/iridium- , or palladium-catalyzed α-allylation of esters, chiral amine/rhodium-catalyzed hydroalkylation of alkynes, chiral amine, or chiral PTC/palladium-catalyzed hydroalkylation of 1,3-dienes, chiral squaramide/nickel-catalyzed α-propargylation of oxindoles, and chiral NHC/copper-catalyzed β-propargylation of enals. In a word, a number of preceding reviews on asymmetric organo-metal cooperative catalysis have been published, − and we encourage readers to consult them for a comprehensive understanding of the discovery, evolution, and principles underlying this research field.

2.

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Representative asymmetric organocatalysis that cooperates with metal complexes: a) chiral iminium/enamine catalysis; b) chiral hydrogen-bonding catalysis; c) chiral nucleophilic catalysis.

In this Outlook, we focus on recent advancements in aligning organocatalysts and transition-metal complexes to enhance the synthesis of enantioenriched molecules and explore the future trends in this field. Emphasis has been placed on the rational design of chiral organocatalysts that feature novel scaffolds or new activation modes. We aim to advance the understanding of each catalyst’s role in bond-forming events, thereby unlocking the full potential of this strategy for synthetic chemistry.

This Outlook reviews recent advancements in the alignment of organocatalysts and transition-metal complexes to enhance the synthesis of enantioenriched molecules and explores the future trends in this field.

2. New Trends in Organic Synthesis

While systematic combinations of well-established chiral organocatalysts and transition-metal–ligand complexes have led to the early success of asymmetric organo-metal cooperative catalysis, substantial efforts devoted to the development of electronically and sterically distinct catalyst scaffolds are proving essential. These innovations not only enhance bond activation efficacy but also present new paradigms for stereocontrol, thereby fueling the continued growth of this field in addressing the synthetic challenges associated with enantioenriched molecules. In this section, we highlight four key catalyst innovations involving chiral scaffolds that have recently emerged: (1) quaternized cinchona alkaloid cations; (2) chiral aldehyde catalysis; (3) multiple catalyst systems; and (4) external stimuli-endowed organo-metal combined catalysis.

2.1. Quaternized Cinchona Alkaloid Cations

Enantioselective C­(sp3)–H amination with high regioselectivity and stereoselectivity still remains a grand challenge. In this context, paddlewheel rhodium­(II) dicarboxylate complexes have emerged as efficient catalysts capable of generating rhodium nitrenoids, which can insert into C­(sp3)–H bonds to facilitate direct aminative functionalization. To render an enantioselective C­(sp3)–H amination, incorporation of chiral carboxylic acids or carboxamides into the rhodium­(II) complexes remains a unique and effective strategy. ,

The Phipps group has demonstrated an elegant strategy using an anionic sulfonate ligand paired with a quaternized cinchona alkaloid cation, which implements excellent enantiocontrol in an iridium-catalyzed, meta-selective arene borylation reaction. This chiral cation-directed approach was recently extended to the synthesis of a family of ion-paired chiral rhodium­(II) complexes (Scheme a). Compared to classical rhodium dimers bearing chiral carboxylate or carboxamidate ligands, the chiral source of cation-paired rhodium­(II) catalysts, i.e., the quaternized cinchona alkaloid cation, is located at a considerably closer distance from the reactive axial site, which likely influences the enantio-determining step to a higher degree. By using perfluorinated sulfamate ester 20 as the nitrogen source and iodosobenzene (PhIO) as the oxidant, the group evaluated the influence of cinchona alkaloid cation’s absolute configuration on the reaction of 4-phenybutan-1-ol, identifying a catalyst bearing the dihydroquinidine motif (16) as particularly effective in creating the optimal chiral environment for this intermolecular benzylic C­(sp3)–H amination. Compared to commercially available achiral Rh2(esp)2, the optimal ion-paired catalyst also resulted in significantly improved yields. This strategy was then applied to a broad scope of 4-arylbutanols 19, yielding chiral 1,4-aminoalcohols 21 in 29–90% yields and with up to 93% ee (Scheme b), which is much higher than the ee value (74%) achieved by rhodium­(II) catalyst with chiral dicarboxylate. Notably, removal of the hydroxyl group from the substrate led to a drastically decreased yield and enantioselectivity (∼3% yield, 28% ee), while variation in alcohol chain length was found against the best catalyst scaffold for 4-phenybutan-1-ol. These findings highlight the importance of a well-defined chiral pocket formed by the quaternized dihydroquinidine unit, which facilitates superior reactivity and enantio-differentiation through a network of noncovalent interactions between the substrate and catalyst. Subsequently, this benzylic C­(sp3)–H amination reaction was expanded to include tertiary amides 22 derived from butyric and valeric acids (Scheme c). More recently, this cinchona alkaloid cation-directed rhodium­(II) catalysis was also applied to an asymmetric nitrene transfer to alkenyl alcohols 24 (Scheme d), providing a unique method for accessing chiral aziridines with varied substitution patterns that have not been covered by traditional rhodium­(II,II) tetracarboxylate dimer catalysts.

2. a) Design of Quarternized Cinchona Alkaloid Cation-Directed Sulfonate Ligand for Rhodium Complexes and Their Application in b) Benzylic C–H Amination Reactions of 4-Arylbutanols and c) Tertiary Amides, and in d) Aziridination of Alkenyl Alcohols.

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2.2. Chiral Aldehyde Catalysis

The reversible condensation of chiral amines with aldehydes or ketones forms the fundamental for asymmetric enamine/iminium catalysis. − In a reversed sense, catalytic amounts of chiral aldehydes or ketones hold potentials of activating the α-C–H bonds of primary amines by forming imine intermediates. − This proposed activation mode mimics the way that pyridoxal-dependent aldolases function in biological systems. Chiral aldehyde catalysis remained unknown in organic synthetic chemistry until 2011, when Beauchemin and co-workers documented its practicality in an enantioselective Cope-type hydroamination of allylic amines with hydroxyamines. Since then, Beauchemin, , Guo, − and Zhao − have made significant contributions to advancing this field, achieving a broad range of enantioselective C–C bond-forming transformations (Scheme a).

3. (a) Representative Chiral Aldehydes. (b) Mechanism of Imine Activation of Primary Amines. (c) First Example of Chiral Aldehyde/Palladium Cooperative Catalysis.

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As illustrated in Scheme b, the acidity of α-hydrogen in amines significantly increases upon imine activation by the chiral aldehyde catalyst, which enhances the subsequent reactivity of deprotonation and nucleophilic substitution and addition reactions. Finally, either hydrolysis or amine exchange of the resultant imine intermediate completes the catalytic cycle. Through this mechanism, direct and highly enantioselective α-functionalization of various primary amines has been achieved, including alkylation, arylation, transamination, Mannich reaction, and others. −

Despite these exciting advancements, the scope of electrophiles has remained narrow, with only highly reactive reagents proving effective. Combining the unique aldehyde chemistry with transition-metal complexes could, in principle, offer a solution to this limitation. In 2019, Guo and co-workers reported a sophisticated combined catalyst system in which the chiral aldehyde 27a and ZnCl2 imparted double activation of α-imino esters 30 by forming a highly nucleophilic complex, while a Pd(0) complex routinely transformed allyl acetates 31 into the electrophilic π-allyl-palladium species INT-8. The coupling of these in situ-generated intermediates afforded optically active α,α-disubstituted α-amino acids 32 in moderate yields and with excellent enantioselectivity (Scheme c). Moreover, analogous pathways for generating π-allyl-palladium species from alternative precursors, such as 1,3-disubstituted allylacetates, aryl iodides/allyl esters or carbonates, bromomethyl ammonium salt/styrenes, 1,3-dienes/allenes, allenylic acetates, and methylenecyclopropanes, were also compatible with the chiral aldehyde/Zn­(II)-mediated catalytic cycles.

Developing of catalyst scaffolds with distinct electronic and steric properties can improve bond activation efficacy, offering new paradigms for stereocontrol and fueling the continued growth of asymmetric organo-metal combined catalysis.

In addition to palladium-catalyzed α-allylation reactions, nickel-catalyzed α-propargylation was also successfully integrated with chiral aldehyde catalysis, producing α-propargylamino esters 36 in up to 95% yields and 98% ee (Scheme a). Notably, starting from either product (S)-36a or (R)- 36a, all four stereoisomers of 37 were synthesized with good enantioselectivity, ultimately enabling the stereodivergent total synthesis of natural pyrrolizidine alkaloid NP25302 (Scheme b).

4. (a) Chiral Aldehyde/Nickel Co-Catalyzed α-Propargylation of Amino Acid Esters. (b) Stereodivergent Synthesis of NP25302.

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2.3. Multiple Catalysis to Streamline Value-Added Chiral Molecule Synthesis

Nature has provided inspiration for improving the overall synthetic efficiency through multiple catalysis. On one hand, multiple-component reactions (MCRs) offer high atom and step economy, enabling expeditious construction of molecules with high structural and functional diversity and intensity. On the other hand, sophisticated multiple catalytic system is capable of forging otherwise inaccessible chemical bonds from readily available feedstocks. These catalysts can operate in either full or relayed cooperation; the significance of such approaches lies in the in situ manipulation of key yet unstable or transient intermediates.

A highly reactive intermediate recently identified for asymmetric MCRs is the transition metal-associated protic ammonium/onium ylides, generated via the catalytic insertion of carbenoids into heteronucleophiles. Trapping these active species with electrophiles through delayed proton transfer provides opportunities for the development of novel MCRs. In 2008, Hu and Gong demonstrated that chiral phosphoric acid could impart a high level of enantio-differentiation in the addition of rhodium-associated onium ylides to imines, laying the foundation for subsequent enantioselective trapping with a range of stable, unsaturated electrophiles. More recently, Xu, Liang, and Hu presented a remarkable ternary cooperative catalytic system consisting of Rh2(OAc)4, an achiral Pd-complex, and chiral phosphoric acid (CPA) 41, which extended the trapping process to substitution-type interception (Scheme ). Specifically, catalytic N2-extrusion of the diazo substrate 38 by Rh2(OAc)4 produced a highly active rhodium carbenoid INT-13, which underwent a O–H insertion reaction with alcohol 39 to give an oxonium ylide INT-14. Synchronously, oxidative addition of allyl carbonate 40 to the Pd(0) complex afforded π-allyl-Pd species INT-11. The combination of two in situ generated active intermediatesenols INT-15 derived from the oxonium ylide-INT-14 and π-allyl-Pd species INT-11resulted in the formation of chiral α,α-disubstituted ketones 42 in high yields and with excellent enantioselectivity. Control experiments and DFT calculations revealed that CPA played a crucial role in enhancing both the reactivity and enantioselectivity via hydrogen bonding.

5. Triple Rh­(II)-Chiral Phosphoric Acid-Pd(0) Catalysis for Substitution-type Trapping of Onium Ylides.

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The consecutive construction of chemical bonds in multiple-component reactions (MCRs) can significantly reduce material, labor, and time costs, making them highly appealing for industrial applications. A notable example is the transformation of syngas and its subsequent derivatization. In 2018, Han and Gong reported a quadruple catalysis system consisting of an achiral Rh­(I) complex, amine, Pd(0) complex, and a CPA catalyst 47 (Scheme ). Starting from syngas, the in situ-generated rhodium hydride complex coordinates with styrene derivatives 43 and then undergoes a migratory insertion reaction to form alkyl rhodium species INT-18. Ligand exchange of INT-18 with CO affords INT-19, which undergoes sequential carbonylation, oxidative addition with H2, and reductive elimination to release branched aldehydes 48. HOMO activation of 48 by the quaternary amine 45 gives an enamine intermediate INT-22, which then participates in an enantioselective allylic alkylation reaction with a π-allyl-palladium chiral phosphate INT-23 generated from allylic alcohol 44, Pd(0) complex, and CPA 46 (Scheme ). The pressure of syngas played a crucial role in this MCR, as excess CO could poison the Pd(0) complex, halting the entire catalytic cycle, while a low syngas pressure typically led to low-yielding hydroformylation reactions. Consequently, 1 bar of syngas was employed to optimize the reactivity and leverage the competing effects.

6. α-Quaternary Chiral Aldehydes from Styrenes, Syngas, and Allylic Alcohols via Quadruple Relay Catalysis.

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2.4. External Stimuli-Endowed Organo-Metal Combined Catalysis

In contrast to ionic intermediates, harnessing highly reactive radical species for the synthesis of enantioenriched molecules still remains a significant challenge. A novel redox strategy for organic synthesis through external stimuli, such as light and electricity, has seen an explosive development in recent years. Particularly, photoredox catalysis, utilizing molecules capable of harvesting visible light, has emerged as a mild and versatile approach to tame the generation and transformation of radicals. , The recent integration of photoredox catalysis with transition metal catalysis, termed metallaphotoredox catalysis, , has further expanded the potential for bond formation. The core processes of photoredox catalysis, including single-electron and energy transfer, can be triggered by either transition-metal-based photocatalysts or purely organic dyes, a topic that has been extensively reviewed. In this section, we focus on the emerging field of multiple asymmetric catalysis, which combines photoredox, organocatalysis, and transition-metal catalysis.

Nature has inspired higher-order chemical processes to create complex molecules, including multiple component reactions with high atom and step economy, as well as multiple catalysis capable of forging otherwise inaccessible chemical bonds.

In 2022, Luo and colleagues utilized photoredox-catalyzed single-electron oxidation of a chiral enamine intermediate to enable an asymmetric C–H dehydrogenative allylic alkylation reaction. As shown in Scheme , the oxidative quenching of an Ir-based photocatalyst Ir­(ppy)2(dtbbpy)­PF6 51 in its excited state by cobaloxime 53 generated an Ir­(IV) species and a Co­(II)-metalloradical. The oxidation of the in situ generated chiral enamine INT-25 by the Ir­(IV) complex, followed by deprotonation, yields an α-imino radical INT-26. The cooperative addition of this radical and the Co­(II)-metalloradical to alkene 50 produced alkyl Co­(III) intermediate INT-27, which undergoes photochemical dehydrogenation to afford the allylation product INT-28 and a Co­(III)–H species. Subsequent hydrolysis of the imine motif in INT-28 affords the final product 54, and heterolytic C–H cleavage by a proton regenerates the chiral amine 52 and the Co­(III) catalyst. Control experiments indicated that no product was formed in the dark, and elevated temperature (from −20 °C to room temperature) resulted in improved reactivity but with reduced stereoselectivity. This work has exemplified a triple-catalysis strategy to address challenges in bond formation using planar Co­(II)-metalloradicals.

7. Ternary Visible-Light Photoredox-Cobalt-Chiral Primary Amine Catalysis Enabled an Asymmetric C–H Dehydrogenative Allylic Alkylation Reaction.

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Recently, Yang et al. demonstrated a triple photoredox-Fe-chiral primary amine catalysis, overcoming the challenges associated with chiral Fe­(III)-metalloradical catalysis in accessing quaternary stereocenters through alkyl–alkyl cross-coupling. As shown in Scheme , single-electron oxidation of the in situ generated chiral enamine INT-29 by a highly oxidizing excited-state Ir-based photocatalyst Ir­[dF­(CF3)­ppy]2(dtbbpy) PF6 57, followed by deprotonation, produces an α-imino radical INT-30. The reduced Ir­(II) complex then donates an electron to the redox-active NHPI ester 56, initiating a decarboxylation process that generates a primary alkyl radical INT-31. This radical INT-31 is captured by the Fe­(II) complex 59, forming an alkyl-Fe­(III) species INT-32, which subsequently reacts with the α-imino radical INT-30 via an outer-sphere radical rebound mechanism. Finally, hydrolysis of the chiral imine INT-33 yields the alkylated product 60 in good yield and excellent enantioselectivity while regenerating the chiral primary amine catalyst.

8. Triple Photoredox-Fe-Chiral Primary Amine Catalysis Enabled Enantioselective Construction of Quaternary Stereocenters.

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3. Conclusion and Perspectives

In conclusion, we have provided a brief overview of the early development of asymmetric organo-metal combined catalysis and outlined the general activation modes employed in numerous bond-forming processes. These processes, often enabled by the use of chiral organocatalysts, exhibit a high degree of stereocontrol. While the field has evolved from dual to multiple catalysis, the most exciting and practical progress lies in the discovery of unprecedented catalyst scaffolds. These scaffolds enable otherwise inaccessible transformations and provide unparalleled capacity for combined catalysis in various subfields of synthetic chemistry.

With that in mind, we offer our perspective on the future opportunities to pursue in the field of asymmetric organo-metal combined catalysis:

  • (1)

    New catalyst scaffold: Beyond the rational design of covalently bonded ligands, recent work by Ooi, Toste, and Phipps has highlighted the unique and flexible role of ionic interactions in tuning both the steric and electronic properties of metal centers. Remarkably, Jacobsen and colleagues employed a chiral bis-thiourea hydrogen-bonding donor to bind the anion of a cationic transition-metal complex. This cooperative anion-binding approach not only accelerated the rate of a Ru-catalyzed intramolecular propargylic substitution reaction but also induced high enantioselectivity (up to 99% ee). This example provides a solution to the challenge of poor stereochemical communication in traditional chiral ligand–transition metal catalysis.

  • (2)

    Heterogeneous catalysis: The development of well-defined heterogeneous metal catalysts, especially those utilizing surface modification techniques, and supported chiral organocatalyst, offer exciting opportunities to unlock new chemical processes with unprecedented reactivity, selectivity, and sustainability. For example, Wang et al. has reviewed the influence of ligands on single-atom catalysts (SACs) and their growing application in organic synthesis, although the asymmetric version of single-atom catalysis remains underexplored. Recently, Xiao and Ge achieved a cascade Suzuki coupling and asymmetric kinetic resolution reaction by anchoring a lipase to the Pd-based SAC. This work has the potential to inspire broader applications of heterogeneous catalysis in conjunction with enzymatic or organocatalysis in asymmetric synthesis. Despite notable advances, future development of heterogeneous asymmetric organo-metal combined catalysis may consider the synergistic effect of supporting materials, facile recovery of catalysts, reproductivity, scalability, etc.

  • (3)

    Electrochemical catalysis: Electrochemistry, as a rapidly advancing “green” technology, offers the potential to significantly expand the capabilities of traditional metal or organocatalysis. − It facilitates the straightforward generation of reactive intermediates and/or supports the regeneration of redox metal catalysts. Additionally, the combination of photocatalysis and electrocatalysisknown as photoelectrocatalysis or electrophotocatalysis − has found increasing application in asymmetric synthesis. We believe that integrating electrochemical or photoelectrochemical regulation with asymmetric organo-metal combined catalysis will further enhance its efficiency and open new avenues for synthetic chemistry.

  • (4)

    Macromolecular synthesis: The stereoregularity of polymers plays a profound role in determining their material properties. Achieving stereoselective polymerization that controls potentially hundreds of consecutive stereocenters still remains a grand challenge. Inspired by asymmetric ion-pairing catalysis, Leibfarth et al. combined a chiral phosphoric acid with TiCl4 for the highly stereoselective cationic polymerization of vinyl ethers, yielding isotactic poly­(vinyl ethers). This work serves as a reminder of how catalysis can reshape fundamental polymerization concepts and drive advancements in macromolecular synthesis. Future efforts may be directed to the discovery of novel catalyst combination that can polymerize a broad scope of vinyl monomers, as well as the development of industrial-relevant large-scale synthetic technologies.

Acknowledgments

This project was supported by the National Key R&D Program of China (2023YFA1506700).

The authors declare no competing financial interest.

References

  1. Fahrenbach A. C., Tran Q. P.. Prebiotic metabolism gets a boost. Nat. Chem. 2020;12:982–985. doi: 10.1038/s41557-020-00567-0. [DOI] [PubMed] [Google Scholar]
  2. Chen G.-S., Deng Y.-J., Gong L.-Z., Mi A.-Q., Cui X., Jiang Y.-Z., Choi M. C. K., Chan A. S. C.. Palladium-Catalyzed Allylic Alkylation of Tert-Butyl­(diphenylmethylene)-Glycinate with Simple Allyl Esters under Chiral Phase Transfer Conditions. Tetrahedron-Asymmetry. 2001;12:1567–1571. doi: 10.1016/S0957-4166(01)00276-2. [DOI] [Google Scholar]
  3. Nakoji M., Kanayama T., Okino T., Takemoto Y.. Chiral Phosphine-Free Pd Mediated Asymmetric Allylation of Prochiral Enolate with a Chiral Phase-Transfer Catalyst. Org. Lett. 2001;3:3329–3331. doi: 10.1021/ol016567h. [DOI] [PubMed] [Google Scholar]
  4. Dong Y.-F., Wang S.-R., Han Z.-Y., Wuu X.. Advances in Combined Asymmetric Catalysis of Transition Metal/Phase Transfer Catalysts. Eur. J. Org. Chem. 2025;28:e202401088. doi: 10.1002/ejoc.202401088. [DOI] [Google Scholar]
  5. Wang X., Peng Y., Zhao L., Huo X., Zhang W.. Synergistic catalysis for stereocontrol of prochiral nucleophiles in palladium-catalyzed asymmetric allylic substitution. Sci. China. Chem. 2023;66:2238–2255. doi: 10.1007/s11426-022-1547-0. [DOI] [Google Scholar]
  6. Nakoji M., Kanayama T., Okino T., Takemoto Y.. Pd-Catalyzed Asymmetric Allylic Alkylation of Glycine Imino Ester Using a Chiral Phase-Transfer Catalyst. J. Org. Chem. 2002;67:7418–7423. doi: 10.1021/jo0260645. [DOI] [PubMed] [Google Scholar]
  7. Wuts P. G. M., Ashford S. A.. A new approach to the synthesis of the carbon framework of SC-84536, an inducible nitric oxide synthase inhibitor. Tetrahedron Lett. 2008;49:4033–4035. doi: 10.1016/j.tetlet.2008.04.083. [DOI] [Google Scholar]
  8. Su Y.-L., Li Y.-H., Chen Y.-G., Han Z.-Y.. Ir/PTC Cooperatively Catalyzed Asymmetric Umpolung Allylation of α Imino Ester Enabled Synthesis of α-Quaternary Amino Acid Derivatives Bearing Two Vicinal Stereocenters. Chem. Commun. 2017;53:1985–1988. doi: 10.1039/C6CC09654A. [DOI] [PubMed] [Google Scholar]
  9. Ran G.-Y., Yang X.-X., Yue J.-F., Du W., Chen Y.-C.. Asymmetric Allylic Alkylation with Deconjugated Carbonyl Compounds: Direct Vinylogous Umpolung Strategy. Angew. Chem., Int. Ed. 2019;58:9210–9214. doi: 10.1002/anie.201903478. [DOI] [PubMed] [Google Scholar]
  10. Han J., Liu R., Lin Z., Zi W.. Stereodivergent Construction of Csp3–Csp3 Bonds Bearing Vicinal Stereocenters by Synergistic Palladium and Phase-Transfer Catalysis. Angew. Chem., Int. Ed. 2023;62:e202215714. doi: 10.1002/anie.202215714. [DOI] [PubMed] [Google Scholar]
  11. Guo C., Dong Y., Wang Y., Du X., Ma R., Tan C.-H., Luan X., Ren J.. Enantioselective Synthesis of Chiral Acyclic Nitriles Containing α-All Carbon Quaternary Stereocenters via Synergistic Palladium and Phase-Transfer Catalysis. ACS Catal. 2024;14:18841–18850. doi: 10.1021/acscatal.4c06364. [DOI] [Google Scholar]
  12. Yang Y., Zhu B., Zhu L., Jiang Y., Guo C.-L., Gu J., Ouyang Q., Du W., Chen Y.-C.. Combining palladium and ammonium halide catalysts for Morita–Baylis–Hillman carbonates of methyl vinyl ketone: from 1,4-carbodipoles to ion pairs. Chem. Sci. 2021;12:11399–11405. doi: 10.1039/D1SC03517G. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Ye X., Tan C.-H.. Enantioselective transition metal catalysis directed by chiral cations. Chem. Sci. 2021;12:533–539. doi: 10.1039/D0SC05734G. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gillespie J. E., Fanourakis A., Phipps R. J.. Strategies That Utilize Ion Pairing Interactions to Exert Selectivity Control in the Functionalization of C–H Bonds. J. Am. Chem. Soc. 2022;144:18195–18211. doi: 10.1021/jacs.2c08752. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Brown R. C. D., Keily J. F.. Asymmetric Permanganate-Promoted Oxidative Cyclization of 1,5-Dienes by Using Chiral Phase-Transfer Catalysis. Angew. Chem., Int. Ed. 2001;40:4496–4498. doi: 10.1002/1521-3773(20011203)40:23<4496::AID-ANIE4496>3.0.CO;2-F. [DOI] [PubMed] [Google Scholar]
  16. Bhunnoo R. A., Hu Y., Laine D. I., Brown R.. An Asymmetric Phase-Transfer Dihydroxylation Reaction. Angew. Chem., Int. Ed. 2002;41:3479–3480. doi: 10.1002/1521-3773(20020916)41:18<3479::AID-ANIE3479>3.0.CO;2-O. [DOI] [PubMed] [Google Scholar]
  17. Wang C., Zong L., Tan C.-H.. Enantioselective Oxidation of Alkenes with Potassium Permanganate Catalyzed by Chiral Dicationic Bisguanidinium. J. Am. Chem. Soc. 2015;137:10677–10682. doi: 10.1021/jacs.5b05792. [DOI] [PubMed] [Google Scholar]
  18. Ye X., Moeljadi A. M., Chin K. F., Hirao H., Zong L., Tan C. H.. Enantioselective Sulfoxidation Catalyzed by a Bisguanidinium Diphosphatobisperoxotungstate Ion Pair. Angew. Chem., Int. Ed. 2016;55:7101–7105. doi: 10.1002/anie.201601574. [DOI] [PubMed] [Google Scholar]
  19. Chin K. F., Ye X., Li Y., Lee R., Kabylda A. M., Leow D., Zhang X., Ang C. X. E., Tan C.-H.. Bisguanidinium-Catalyzed Epoxidation of Allylic and Homoallylic Amines under Phase Transfer Conditions. ACS Catal. 2020;10:2684–2691. doi: 10.1021/acscatal.9b04862. [DOI] [Google Scholar]
  20. Paria S., Lee H.-J., Maruoka K.. Enantioselective Alkynylation of Isatin Derivatives Using a Chiral Phase-Transfer/Transition-Metal Hybrid Catalyst System. ACS Catal. 2019;9:2395–2399. doi: 10.1021/acscatal.8b04949. [DOI] [Google Scholar]
  21. Rauniyar V., Lackner A. D., Hamilton G. L., Toste F. D.. Asymmetric Electrophilic Fluorination Using an Anionic Chiral Phase-Transfer Catalyst. Science. 2011;334:1681–1684. doi: 10.1126/science.1213918. [DOI] [PubMed] [Google Scholar]
  22. Nelson H. M., Williams B. D., Miro J., Toste F. D.. Enantioselective 1,1-Arylborylation of Alkenes: Merging Chiral Anion Phase Transfer with Pd Catalysis. J. Am. Chem. Soc. 2015;137:3213–3216. doi: 10.1021/jacs.5b00344. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Tao Z.-L., Adili A., Shen H.-C., Han Z.-Y., Gong L.-Z.. Catalytic Enantioselective Assembly of Homoallylic Alcohols from Dienes, Aryldiazonium Salts, and Aldehydes. Angew. Chem., Int. Ed. 2016;55:4322–4326. doi: 10.1002/anie.201600148. [DOI] [PubMed] [Google Scholar]
  24. Yamamoto E., Hilton M. J., Orlandi M., Saini V., Toste F. D., Sigman M. S.. Development and Analysis of a Pd(0)-Catalyzed Enantioselective 1,1-Diarylation of Acrylates Enabled by Chiral Anion Phase Transfer. J. Am. Chem. Soc. 2016;138:15877–15880. doi: 10.1021/jacs.6b11367. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Shen H.-C., Wang P.-S., Tao Z.-L., Han Z.-Y., Gong L.-Z.. An Enantioselective Multicomponent Carbonyl Allylation of Aldehydes with Dienes and Alkynyl Bromides Enabled by Chiral Palladium Phosphate. Adv. Synth. Catal. 2017;359:2383–2389. doi: 10.1002/adsc.201700621. [DOI] [Google Scholar]
  26. Avila C. M., Patel J. S., Reddi Y., Saito M., Nelson H. M., Shunatona H. P., Sigman M. S., Sunoj R. B., Toste F. D.. Enantioselective Heck–Matsuda Arylations through Chiral Anion Phase-Transfer of Aryl Diazonium Salts. Angew. Chem., Int. Ed. 2017;56:5806–5811. doi: 10.1002/anie.201702107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Reddi Y., Tsai C. C., Avila C. M., Toste F. D., Sunoj R. B.. Harnessing Noncovalent Interactions in Dual-Catalytic Enantioselective Heck–Matsuda Arylation. J. Am. Chem. Soc. 2019;141:998–1009. doi: 10.1021/jacs.8b11062. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Tran V. T., Nimmagadda S. K., Liu M., Engle K. M.. Recent Applications of Chiral Phosphoric Acids in Palladium Catalysis. Org. Biomol. Chem. 2020;18:618–637. doi: 10.1039/C9OB02205H. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Ohmatsu K., Ooi T.. Cationic Organic Catalysts or Ligands in Concert with Metal Catalysts. To. Curr. Chem. 2019;377:31. doi: 10.1007/s41061-019-0256-1. [DOI] [PubMed] [Google Scholar]
  30. Wiester M. J., Ulmann P. A., Mirkin C. A.. Enzyme Mimics Based Upon Supramolecular Coordination Chemistry. Angew. Chem., Int. Ed. 2011;50:114–137. doi: 10.1002/anie.201000380. [DOI] [PubMed] [Google Scholar]
  31. Ohmatsu K., Ito M., Kunieda T., Ooi T.. Ion-paired chiral ligands for asymmetric palladium catalysis. Nat. Chem. 2012;4:473–477. doi: 10.1038/nchem.1311. [DOI] [PubMed] [Google Scholar]
  32. Ohmatsu K., Imagawa N., Ooi T.. Ligand-enabled multiple absolute stereocontrol in metal-catalysed cycloaddition for construction of contiguous all-carbon quaternary stereocentres. Nat. Chem. 2014;6:47–51. doi: 10.1038/nchem.1796. [DOI] [PubMed] [Google Scholar]
  33. Genov G. R., Douthwaite J. L., Lahdenperä A. S. K., Gibson D. C., Phipps R. J.. Enantioselective remote C–H activation directed by a chiral cation. Science. 2020;367:1246–1251. doi: 10.1126/science.aba1120. [DOI] [PubMed] [Google Scholar]
  34. Ermanis K., Gibson D. C., Genov G. R., Phipps R. J.. Interrogating the Crucial Interactions at Play in the Chiral Cation-Directed Enantioselective Borylation of Arenes. ACS Catal. 2023;13:13043–13055. doi: 10.1021/acscatal.3c03384. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Arndtsen, B. A. ; Gong, L.-Z. . Topics in Current Chemistry Collections: Asymmetric Organocatalysis Combined with Metal Catalysis; Springer Nature: Cham, Switzerland, 2020. [Google Scholar]
  36. Gong, L.-Z. Asymmetric Organo-Metal Catalysis: Concepts, Principles, and Applications; Wiley-VCH: Weinheim, Germany, 2021. [Google Scholar]
  37. Mukherjee S., Yang J. W., Hoffmann S., List B.. Asymmetric Enamine Catalysis. Chem. Rev. 2007;107:5471–5569. doi: 10.1021/cr0684016. [DOI] [PubMed] [Google Scholar]
  38. Melchiorre P., Marigo M., Carlone A., Bartoli G.. Asymmetric AminocatalysisGold Rush in Organic Chemistry. Angew. Chem., Int. Ed. 2008;47:6138–6171. doi: 10.1002/anie.200705523. [DOI] [PubMed] [Google Scholar]
  39. Erkkilä A., Majander I., Pihko P. M.. Iminium Catalysis. Chem. Rev. 2007;107:5416–5470. doi: 10.1021/cr068388p. [DOI] [PubMed] [Google Scholar]
  40. List, B. The Ying and Yang of Asymmetric Aminocatalysis. Chem. Commun. 2006, 819–824. 10.1039/b514296m [DOI] [PubMed] [Google Scholar]
  41. Doyle A. G., Jacobsen E. N.. Small-Molecule H-Bond Donors in Asymmetric Catalysis. Chem. Rev. 2007;107:5713–5743. doi: 10.1021/cr068373r. [DOI] [PubMed] [Google Scholar]
  42. Terada M.. Chiral Phosphoric Acids as Versatile Catalysts for Enantioselective Transformations. Synthesis. 2010;2010:1929–1982. doi: 10.1055/s-0029-1218801. [DOI] [Google Scholar]
  43. Akiyama T., Mori K.. Stronger Brønsted Acids: Recent Progress. Chem. Rev. 2015;115:9277–9306. doi: 10.1021/acs.chemrev.5b00041. [DOI] [PubMed] [Google Scholar]
  44. Min C., Seidel D.. Asymmetric Brønsted Acid Catalysis with Chiral Carboxylic Acids. Chem. Soc. Rev. 2017;46:5889–5902. doi: 10.1039/C6CS00239K. [DOI] [PubMed] [Google Scholar]
  45. Flanigan D. M., Romanov-Michailidis F., White N. A., Rovis T.. Organocatalytic Reactions Enabled by N-Heterocyclic Carbenes. Chem. Rev. 2015;115:9307–9387. doi: 10.1021/acs.chemrev.5b00060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Taylor J. E., Bull S. D., Williams J. M. J.. Amidines, isothioureas, and guanidines as nucleophilic catalysts. Chem. Soc. Rev. 2012;41:2109–2121. doi: 10.1039/c2cs15288f. [DOI] [PubMed] [Google Scholar]
  47. Morrill L. C., Smith A. D.. Organocatalytic Lewis base functionalisation of carboxylic acids, esters and anhydrides via C1-ammonium or azolium enolates. Chem. Soc. Rev. 2014;43:6214–6226. doi: 10.1039/C4CS00042K. [DOI] [PubMed] [Google Scholar]
  48. Ni H., Chan W.-L., Lu Y.. Phosphine-Catalyzed Asymmetric Organic Reactions. Chem. Rev. 2018;118:9344–9411. doi: 10.1021/acs.chemrev.8b00261. [DOI] [PubMed] [Google Scholar]
  49. Hashmi, A. S. K. ; Toste, F. D. . Modern Gold Catalyzed Synthesis; John Wiley & Sons: Weinheim, 2012. [Google Scholar]
  50. Trost B. M., Crawley M. L.. Asymmetric Transition-Metal Catalyzed Allylic Alkylations: Applications in Total Synthesis. Chem. Rev. 2003;103:2921–2944. doi: 10.1021/cr020027w. [DOI] [PubMed] [Google Scholar]
  51. Cheng Q., Tu H. F., Zheng C., Qu J. P., Helmchen G., You S. L.. Iridium-Catalyzed Asymmetric Allylic Substitution Reactions. Chem. Rev. 2019;119:1855–1969. doi: 10.1021/acs.chemrev.8b00506. [DOI] [PubMed] [Google Scholar]
  52. Liégault B., Renaud J.-L., Bruneau C.. Activation and Functionalization of Benzylic Deriva-tives by Palladium Catalysts. Chem. Soc. Rev. 2008;37:290–299. doi: 10.1039/B704255H. [DOI] [PubMed] [Google Scholar]
  53. Roh S. W., Choi K., Lee C.. Transition Metal Vinylidene- and Allenylidene-Mediated Catalysis in Organic Synthesis. Chem. Rev. 2019;119:4293–4356. doi: 10.1021/acs.chemrev.8b00568. [DOI] [PubMed] [Google Scholar]
  54. Holownia A., Apte C. N., Yudin A. K.. Acyl metalloids: conformity and deviation from carbonyl reactivity. Chem. Sci. 2021;12:5346–5360. doi: 10.1039/D1SC00077B. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Krautwald S., Carreira E. M.. Stereodivergence in Asymmetric Catalysis. J. Am. Chem. Soc. 2017;139:5627–5639. doi: 10.1021/jacs.6b13340. [DOI] [PubMed] [Google Scholar]
  56. Wei L., Fu C., Wang Z.-F., Tao H.-Y., Wang C.-J.. Synergistic Dual Catalysis in Stereodivergent Synthesis. ACS Catal. 2024;14:3812–3844. doi: 10.1021/acscatal.3c06267. [DOI] [Google Scholar]
  57. Wang H., Zhang Q., Zi W.. Synergistic Catalysis Involving Palladium for Stereodivergent Csp3–Csp3 Coupling Reactions. Acc. Chem. Res. 2024;57:468–488. doi: 10.1021/acs.accounts.3c00639. [DOI] [PubMed] [Google Scholar]
  58. Krautwald S., Sarlah D., Schafroth M. A., Carreira E. M.. Enantio- and Diastereodivergent Dual Catalysis: a-Allylation of Branched Aldehydes. Science. 2013;340:1065–1068. doi: 10.1126/science.1237068. [DOI] [PubMed] [Google Scholar]
  59. Krautwald S., Schafroth D., Sarlah D., Carreira E. M.. Stereodivergent α-Allylation of Linear Aldehydes with Dual Iridium and Amine Catalysis. J. Am. Chem. Soc. 2014;136:3020–3023. doi: 10.1021/ja5003247. [DOI] [PubMed] [Google Scholar]
  60. Schafroth M. A., Zuccarello G., Krautwald S., Sarlah D., Carreira E. M.. Stereodivergent total synthesis of Δ9-tetrahydrocannabinols. Angew. Chem., Int. Ed. 2014;53:13898–13901. doi: 10.1002/anie.201408380. [DOI] [PubMed] [Google Scholar]
  61. Sandmeier T., Krautwald S., Zipfel H. F., Carreira E. M.. Stereodivergent Dual Catalytic α-Allylation of Protected α-Amino- and α-Hydroxyacetaldehydes. Angew. Chem., Int. Ed. 2015;54:14363–14367. doi: 10.1002/anie.201506933. [DOI] [PubMed] [Google Scholar]
  62. Næsborg L., Halskov K. S., Tur F., Mønsted S. M. N., Jørgensen K. A.. Asymmetric γ-Allylation of α,β-Unsaturated Aldehydes by Combined Organocatalysis and Transition-Metal Catalysis. Angew. Chem., Int. Ed. 2015;54:10193–10197. doi: 10.1002/anie.201504749. [DOI] [PubMed] [Google Scholar]
  63. Jiang X., Beiger J. J., Hartwig J. F.. Stereodivergent Allylic Substitutions with Aryl Acetic Acid Esters by Synergistic Iridium and Lewis Base Catalysis. J. Am. Chem. Soc. 2017;139:87–90. doi: 10.1021/jacs.6b11692. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Pearson C. M., Fyfe J. W. B., Snaddon T. N.. A Regio- and Stereodivergent Synthesis of Homoallylic Amines by a One-Pot Cooperative-Catalysis-Based Allylic Alkylation/Hofmann Rearrangement Strategy. Angew. Chem., Int. Ed. 2019;58:10521–10527. doi: 10.1002/anie.201905426. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Zhang Q., Zhu M., Zi W.. Synergizing palladium with Lewis base catalysis for stereodivergent coupling of 1,3-dienes with pentafluorophenyl acetates. Chem. 2022;8:2784–2796. doi: 10.1016/j.chempr.2022.07.014. [DOI] [Google Scholar]
  66. Cruz F. A., Dong V. M.. Stereodivergent Coupling of Aldehydes and Alkynes via Synergistic Catalysis Using Rh and Jacobsen’s Amine. J. Am. Chem. Soc. 2017;139:1029–1032. doi: 10.1021/jacs.6b10680. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Wang H., Zhang R., Zhang Q., Zi W.. Synergistic Pd/Amine-Catalyzed Stereodivergent Hydroalkylation of 1,3-Dienes with Aldehydes: Reaction Development, Mechanism, and Stereochemical Origins. J. Am. Chem. Soc. 2021;143:10948–10962. doi: 10.1021/jacs.1c02220. [DOI] [PubMed] [Google Scholar]
  68. Han J., Liu R., Lin Z., Zi W.. Stereodivergent Construction of Csp3–Csp3 Bonds Bearing Vicinal Stereocenters by Synergistic Palladium and Phase-Transfer Catalysis. Angew. Chem., Int. Ed. 2023;62:e202215714. doi: 10.1002/anie.202215714. [DOI] [PubMed] [Google Scholar]
  69. Hu Q., He Z., Peng L., Guo C.. Combining nickel and squaramide catalysis for the stereodivergent α-propargylation of oxindoles. Nat. Synth. 2022;1:322–331. doi: 10.1038/s44160-022-00050-3. [DOI] [Google Scholar]
  70. Wen Y.-H., Zhang Z.-J., Li S., Song J., Gong L.-Z.. Stereodivergent propargylic alkylation of enals via cooperative NHC and copper catalysis. Nat. Commun. 2022;13:1344. doi: 10.1038/s41467-022-29059-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Shao Z.-H., Zhang H.-B.. Combining Transition Metal Catalysis and Organocatalysis: A Broad New Concept for Catalysis. Chem. Soc. Rev. 2009;38:2745–2755. doi: 10.1039/b901258n. [DOI] [PubMed] [Google Scholar]
  72. Zhong C., Shi X.. When Organocatalysis Meets Transition-Metal Catalysis. Eur. J. Org. Chem. 2010;2010:2999–3025. doi: 10.1002/ejoc.201000004. [DOI] [Google Scholar]
  73. Allen A. E., MacMillan D. W. C.. Synergistic Catalysis: A Powerful Synthetic Strategy for New Reaction Development. Chem. Sci. 2012;3:633–658. doi: 10.1039/c2sc00907b. [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Du Z. T., Shao Z.-H.. Combining Transition Metal Catalysis and Organocatalysis–an Update. Chem. Soc. Rev. 2013;42:1337–1378. doi: 10.1039/C2CS35258C. [DOI] [PubMed] [Google Scholar]
  75. Inamdar S. M., Shinde V. S., Patil N. T.. Enantioselective Cooperative Catalysis. Org. Biomol. Chem. 2015;13:8116–8162. doi: 10.1039/C5OB00986C. [DOI] [PubMed] [Google Scholar]
  76. Zhang M.-M., Luo Y.-Y., Lu L.-Q., Xiao W.-J.. Advances on Asymmetric Allylic Substitutions under Synergetic Catalysis System with Transition Metals and Organocatalysts. Acta Chim. Sinica. 2018;76:838–849. doi: 10.6023/A18060237. [DOI] [Google Scholar]
  77. Chen D.-F., Gong L.-Z.. Organo/Transition Metal Combined Catalysis Rejuvenates Both in Asymmetric Synthesis. J. Am. Chem. Soc. 2022;144:2415–2437. doi: 10.1021/jacs.1c11408. [DOI] [PubMed] [Google Scholar]
  78. Song J., Gong L.-Z.. Lewis Base/3d Transition-Metal Cooperatively Catalyzed Asymmetric Reactions. Synlett. 2024;35:1621–1628. doi: 10.1055/a-2192-9185. [DOI] [Google Scholar]
  79. Roizen J. L., Harvey M. E., Du Bois J.. Metal-Catalyzed Nitrogen-Atom Transfer Methods for the Oxidation of Aliphatic C–H Bonds. Acc. Chem. Res. 2012;45:911–922. doi: 10.1021/ar200318q. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. a.Hansen J., Davies H. M. L.. High symmetry dirhodium­(II) paddlewheel complexes as chiral catalysts. Coord. Chem. Rev. 2008;252:545–555. doi: 10.1016/j.ccr.2007.08.019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  81. Davies H. M. L., Liao K.. Dirhodium tetracarboxylates as catalysts for selective intermolecular C–H functionalization. Nat. Rev. Chem. 2019;3:347–360. doi: 10.1038/s41570-019-0099-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  82. Fanourakis A., Williams B. D., Paterson K. J., Phipps R. J.. Enantioselective Intermolecular C–H Amination Directed by a Chiral Cation. J. Am. Chem. Soc. 2021;143:10070–10076. doi: 10.1021/jacs.1c05206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  83. Höke T., Herdtweck E., Bach T.. Hydrogen-bond mediated regio- and enantioselectivity in a C–H amination reaction catalysed by a supramolecular Rh­(II) complex. Chem. Commun. 2013;49:8009–8011. doi: 10.1039/c3cc44197k. [DOI] [PubMed] [Google Scholar]
  84. Paterson K. J., Dahiya A., Williams B. D., Phipps R. J.. Tertiary Amides as Directing Groups for Enantioselective C–H Amination using Ion-Paired Rhodium Complexes. Angew. Chem., Int. Ed. 2024;63:e202317489. doi: 10.1002/anie.202317489. [DOI] [PubMed] [Google Scholar]
  85. Fanourakis A., Hodson N. J., Lit A. R., Phipps R. J.. Substrate-Directed Enantioselective Aziridination of Alkenyl Alcohols Controlled by a Chiral Cation. J. Am. Chem. Soc. 2023;145:7516–7527. doi: 10.1021/jacs.3c00693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. Boquet V., Nasrallah A., Dana A. L., Brunard E., Di Chenna P. H., Duran F. J., Retailleau P., Darses B., Sircoglou M., Dauban P.. Rhodium­(II)-Catalyzed Enantioselective Intermolecular Aziridination of Alkenes. J. Am. Chem. Soc. 2022;144:17156–17164. doi: 10.1021/jacs.2c07337. [DOI] [PubMed] [Google Scholar]
  87. Li B.-J., EI-Nachef C., Beauchemin A. M.. Organocatalysis Using Aldehydes: The Development and Improvement of Catalytic Hydroaminations, Hydrations and Hydrolyses. Chem. Commun. 2017;53:13192–13204. doi: 10.1039/C7CC07352F. [DOI] [PubMed] [Google Scholar]
  88. Wang Q., Gu Q., You S.-L.. Enantioselective Carbonyl Catalysis Enabled by Chiral Aldehydes. Angew. Chem., Int. Ed. 2019;58:6818–6825. doi: 10.1002/anie.201808700. [DOI] [PubMed] [Google Scholar]
  89. Wen W., Guo Q.-X.. Recent Advances in Chiral Aldehyde Catalysis for Asymmetric Functionalization of Amines. Synthesis. 2023;55:719–732. doi: 10.1055/a-1973-4292. [DOI] [Google Scholar]
  90. Xiao X., Zhao B.. Vitamin B 6-Based Biomimetic Asymmetric Catalysis. Acc. Chem. Res. 2023;56:1097–1117. doi: 10.1021/acs.accounts.3c00053. [DOI] [PubMed] [Google Scholar]
  91. Wen W., Guo Q.-X.. Chiral Aldehyde Catalysis-Enabled Asymmetric α-Functionalization of Activated Primary Amines. Acc. Chem. Res. 2024;57:776–794. doi: 10.1021/acs.accounts.3c00804. [DOI] [PubMed] [Google Scholar]
  92. Duckers N., Baer K., Simon S., Gröger H., Hummel W.. Threonine Aldolases-Screening, Properties and Applications in the Synthesis of Non-Proteinogenic β-Hydroxy-α-Amino Acids. Appl. Microbiol. Biotechnol. 2010;88:409–424. doi: 10.1007/s00253-010-2751-8. [DOI] [PubMed] [Google Scholar]
  93. MacDonald M. J., Schipper D. J., Ng P. J., Moran J., Beauchemin A. M.. A Catalytic Tethering Strategy: Simple Aldehydes Catalyze Intermolecular Alkene Hydroaminations. J. Am. Chem. Soc. 2011;133:20100–20103. doi: 10.1021/ja208867g. [DOI] [PubMed] [Google Scholar]
  94. Guimond N., MacDonald M. J., Lemieux V., Beauchemin A. M.. Catalysis through Temporary Intramolecularity: Mechanistic Investigations on Aldehyde-Catalyzed Cope-type Hydroamination Lead to the Discovery of a More Efficient Tethering Catalyst. J. Am. Chem. Soc. 2012;134:16571–16577. doi: 10.1021/ja303320x. [DOI] [PubMed] [Google Scholar]
  95. MacDonald M. J., Hesp C. R., Schipper D. J., Pesant M., Beauchemin A. M.. Highly Enantioselective Intermolecular Hydro amination of Allylic Amines with Chiral Aldehydes as Tethering Catalysts. Chem.Eur. J. 2013;19:2597–2601. doi: 10.1002/chem.201203462. [DOI] [PubMed] [Google Scholar]
  96. Xu B., Shi L.-L., Zhang Y.-Z., Wu Z.-J., Fu L.-N., Luo C.-Q., Zhang L.-X., Peng Y.-G., Guo Q.-X.. Catalytic Asymmetric Direct α Alkylation of Amino Esters by Aldehydes via Imine Activation. Chem. Sci. 2014;5:1988–1991. doi: 10.1039/c3sc53314j. [DOI] [Google Scholar]
  97. Wen W., Chen L., Luo M.-J., Zhang Y., Chen Y.-C., Ouyang Q., Guo Q.-X.. Chiral Aldehyde Catalysis for the Catalytic Asymmetric Activation of Glycine Esters. J. Am. Chem. Soc. 2018;140:9774–9780. doi: 10.1021/jacs.8b06676. [DOI] [PubMed] [Google Scholar]
  98. Chen L., Luo M.-J., Zhu F., Wen W., Guo Q.-X.. Combining Chiral Aldehyde Catalysis and Transition-Metal Catalysis for Enantioselective α-Allylic Alkylation of Amino Acid Esters. J. Am. Chem. Soc. 2019;141:5159–5163. doi: 10.1021/jacs.9b01910. [DOI] [PubMed] [Google Scholar]
  99. Wen W., Luo M.-J., Yuan Y., Liu J.-H., Wu Z.-L., Cai T., Wu Z.-W., Ouyang Q., Guo Q.-X.. Diastereodivergent Chiral Aldehyde Catalysis for Asymmetric 1,6-Conjugated Addition and Mannich Reactions. Nat. Commun. 2020;11:5372. doi: 10.1038/s41467-020-19245-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  100. Shi L., Tao C., Yang Q., Liu Y. E., Chen J., Chen J., Tian J., Liu F., Li B., Du Y., Zhao B.. Chiral Pyridoxal-Catalyzed Asymmetric Biomimetic Transamination of α-Keto Acids. Org. Lett. 2015;17:5784–5787. doi: 10.1021/acs.orglett.5b02895. [DOI] [PubMed] [Google Scholar]
  101. Chen J., Gong X., Li J., Li Y., Ma J., Hou C., Zhao G., Yuan W., Zhao B.. Carbonyl Catalysis Enables a Biomimetic Asymmetric Mannich Reaction. Science. 2018;360:1438–1442. doi: 10.1126/science.aat4210. [DOI] [PubMed] [Google Scholar]
  102. Hou C., Peng B., Ye S., Yin Z., Cao J., Xiao X., Zhao B.. Catalytic Asymmetric α C­(sp3)–H Addition of Benzylamines to Aldehydes. Nat. Catal. 2022;5:1061–1068. doi: 10.1038/s41929-022-00875-3. [DOI] [Google Scholar]
  103. Zhou Q., Yin Z.-W., Wu Z.-L., Cai T., Wen W., Huang Y.-M., Guo Q.-X.. Asymmetric α-Allylation of N-Unprotected Amino Acid Esters with 1,3-Disubstituted Allyl Acetates Enabled by Chiral Aldehyde/Palladium Catalysis. Org. Lett. 2023;25:5790–5794. doi: 10.1021/acs.orglett.3c02027. [DOI] [PubMed] [Google Scholar]
  104. Liu J.-H., Wen W., Wu Z.-L., Cai T., Huang Y.-M., Guo Q.-X.. Asymmetric three-component Tsuji–Trost allylation reaction enabled by chiral aldehyde/palladium combined catalysis. Chem. Sci. 2024;15:10232–10236. doi: 10.1039/D4SC02594F. [DOI] [PMC free article] [PubMed] [Google Scholar]
  105. Han H., Yi W., Ding S., Ren X., Zhao B.. Enantioselective Three-Component α-Allylic Alkylation of α-Amino Esters by Synergistic Photoinduced Pd/Carbonyl Catalysis. Angew. Chem., Int. Ed. 2025;64:e202418910. doi: 10.1002/anie.202418910. [DOI] [PubMed] [Google Scholar]
  106. Liu J.-H., Zhou Q., Lin Y., Wu Z.-L., Cai T., Wen W., Huang Y.-M., Guo Q.-X.. Modular Chiral-Aldehyde/Palladium Catalysis Enables Atom-Economical α-Allylation of N-Unprotected Amino Acid Esters with 1,3-Dienes and Allenes. ACS Catal. 2023;13:6013–6022. doi: 10.1021/acscatal.3c00790. [DOI] [Google Scholar]
  107. Zhang H., Wen W., Lu Z.-X., Wu Z.-L., Cai T., Guo Q.-X.. Core Structure-Oriented Asymmetric α-Allenylic Alkylation of Amino Acid Esters Enabled by Chiral-Aldehyde/Palladium Catalysis. Org. Lett. 2024;26:153–159. doi: 10.1021/acs.orglett.3c03762. [DOI] [PubMed] [Google Scholar]
  108. Zhu F., He H., Wen W., Guan H.-L., Wu Z.-L., Cai T., Ni S.-F., Guo Q.-X.. Chiral Aldehyde/Palladium Catalysis Enables Asymmetric Branched Selective Ring-Opening Functionalization of Methylenecyclopropanes with Amino Acid Esters. J. Am. Che. Soc. 2025;147:2315–2322. doi: 10.1021/jacs.4c16934. [DOI] [PubMed] [Google Scholar]
  109. Zhu F., Li C.-X., Wu Z.-L., Cai T., Wen W., Guo Q.-X.. Chiral Aldehyde-Nickel Dual Catalysis Enables Asymmetric α-Propargylation of Amino Acids and Stereodivergent Synthesis of NP25302. Nat. Commun. 2022;13:7290. doi: 10.1038/s41467-022-35062-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  110. Romiti F., del Pozo J., Paioti P. H. S., Gonsales S. A., Li X., Hartrampf F. W. W., Hoveyda A. H.. Different Strategies for Designing Dual-Catalytic Enantioselective Processes: From Fully Cooperative to Non-cooperative Systems. J. Am. Chem. Soc. 2019;141:17952–1796. doi: 10.1021/jacs.9b05464. [DOI] [PubMed] [Google Scholar]
  111. Guo X., Hu W.. Novel multicomponent reactions via trapping of protic onium ylides with electrophiles. Acc. Chem. Res. 2013;46:2427–2440. doi: 10.1021/ar300340k. [DOI] [PubMed] [Google Scholar]
  112. Hu W., Xu X., Zhou J., Liu W., Huang H., Hu J., Yang L., Gong L.-Z.. Cooperative Catalysis with Chiral Brønsted Acid-Rh2(OAc)4: Highly Enantioselective Three-Component Reactions of Diazo Compounds with Alcohols and Imines. J. Am. Chem. Soc. 2008;130:7782–7783. doi: 10.1021/ja801755z. [DOI] [PubMed] [Google Scholar]
  113. Kang Z., Chang W., Tian X., Fu X., Zhao W., Xu X., Liang Y., Hu W.. Ternary Catalysis Enabled Three Component Asymmetric Allylic Alkylation as a Concise Track to Chiral alpha, alpha-Disubstituted Ketones. J. Am. Chem. Soc. 2021;143:20818–20827. doi: 10.1021/jacs.1c09148. [DOI] [PubMed] [Google Scholar]
  114. Meng J., Fan L.-F., Han Z.-Y., Gong L.-Z.. a-Quaternary Chiral Aldehydes from Styrenes, Allylic Alcohols, and Syngas via Multi-catalyst Relay Catalysis. Chem. 2018;4:1047–1058. doi: 10.1016/j.chempr.2018.03.010. [DOI] [Google Scholar]
  115. Jiang G., List B.. Direct Asymmetric α-Allylation of Aldehydes with Simple Allylic Alcohols Enabled by the Concerted Action of Three Different Catalysts. Angew. Chem., Int. Ed. 2011;50:9471–9474. doi: 10.1002/anie.201103263. [DOI] [PubMed] [Google Scholar]
  116. Liu J., Lu L., Wood D., Lin S.. New Redox Strategies in Organic Synthesis by Means of Electrochemistry and Photochemistry. ACS Cent. Sci. 2020;6:1317–1340. doi: 10.1021/acscentsci.0c00549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  117. Xuan J., Xiao W.-J.. Visible-Light Photoredox Catalysis. Angew. Chem., Int. Ed. 2012;51:6828–6838. doi: 10.1002/anie.201200223. [DOI] [PubMed] [Google Scholar]
  118. Prier C. K., Rankic D. A., MacMillan D. W. C.. Visible Light Photoredox Catalysis with Transition Metal Complexes: Applications in Organic Synthesis. Chem. Rev. 2013;113:5322–5363. doi: 10.1021/cr300503r. [DOI] [PMC free article] [PubMed] [Google Scholar]
  119. Twilton J., Le C., Zhang P., Shaw M. H., Evans R. W., MacMillan D. W. C.. The Merger of Transition Metal and Photocatalysis. Nat. Rev. Chem. 2017;1:0052. doi: 10.1038/s41570-017-0052. [DOI] [Google Scholar]
  120. Chan A. Y., Perry I. B., Bissonnette N. B., Buksh B. F., Edwards G. A., Frye L. I., Garry O. L., Lavagnino M. N., Li B. X., Liang Y., Mao E., Millet A., Oakley J. V., Reed N. L., Sakai H. A., Seath C. P., MacMillan D. W. C.. Metallaphotoredox: the Merger of Photoredox and Transition Metal Catalysis. Chem. Rev. 2022;122:1485–1542. doi: 10.1021/acs.chemrev.1c00383. [DOI] [PMC free article] [PubMed] [Google Scholar]
  121. Zhu L., Wang D., Jia Z., Lin Q., Huang M., Luo S.. Catalytic asymmetric oxidative enamine transformations. ACS Catal. 2018;8:5466–5484. doi: 10.1021/acscatal.8b01263. [DOI] [Google Scholar]
  122. Jia Z., Zhang L., Luo S.. Asymmetric C-H Dehydrogenative Allylic Alkylation by Ternary Photoredox-Cobalt-Chiral Primary Amine Catalysis under Visible Light. J. Am. Chem. Soc. 2022;144:10705–10710. doi: 10.1021/jacs.2c03299. [DOI] [PubMed] [Google Scholar]
  123. Li L.-J., Zhang J.-C., Li W.-P., Zhang D., Duanmu K., Yu H., Ping Q., Yang Z.-P.. Enantioselective Construction of Quaternary Stereocenters via Cooperative Photoredox/Fe/Chiral Primary Amine Triple Catalysis. J. Am. Chem. Soc. 2024;146:9404–9412. doi: 10.1021/jacs.4c01842. [DOI] [PubMed] [Google Scholar]
  124. Ovian J. M., Vojáčková P., Jacobsen E. N.. Enantioselective transition-metal catalysis via an anion-binding approach. Nature. 2023;616:84–89. doi: 10.1038/s41586-023-05804-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  125. Liu L., Corma A.. Metal Catalysts for Heterogeneous Catalysis: From Single Atoms to Nanoclusters and Nanoparticles. Chem. Rev. 2018;118:4981–5079. doi: 10.1021/acs.chemrev.7b00776. [DOI] [PMC free article] [PubMed] [Google Scholar]
  126. Benaglia M., Puglisi A., Cozzi F.. Polymer-Supported Organic Catalysts. Chem. Rev. 2003;103:3401–3430. doi: 10.1021/cr010440o. [DOI] [PubMed] [Google Scholar]
  127. Ye B.-C., Li W.-H., Zhang X., Chen J., Gao Y., Wang D., Pan H.. Advancing Heterogeneous Organic Synthesis With Coordination Chemistry-Empowered Single-Atom Catalysts. Adv. Mater. 2024;36:2402747. doi: 10.1002/adma.202402747. [DOI] [PubMed] [Google Scholar]
  128. Qiao B., Wang A., Yang X., Allard L. F., Jiang Z., Cui Y., Liu J., Li J., Zhang T.. Single-atom catalysis of CO oxidation using Pt1/FeOx . Nat. Chem. 2011;3:634–641. doi: 10.1038/nchem.1095. [DOI] [PubMed] [Google Scholar]
  129. Li X., Cao Y., Xiong J., Li J., Xiao H., Li X., Gou Q., Ge J.. Enzyme-metal-single-atom hybrid catalysts for one-pot chemoenzymatic reactions. Chin. J. Catal. 2023;44:139–145. doi: 10.1016/S1872-2067(22)64179-2. [DOI] [Google Scholar]
  130. Möhle S., Zirbes M., Rodrigo E., Gieshoff T., Wiebe A., Waldvogel S. R.. Modern Electrochemical Aspects for the Synthesis of Value-Added Organic Products. Angew. Chem., Int. Ed. 2018;57:6018–6041. doi: 10.1002/anie.201712732. [DOI] [PMC free article] [PubMed] [Google Scholar]
  131. Horn E. J., Rosen B. R., Baran P. S.. Synthetic Organic Electrochemistry: an Enabling andInnately Sustainable Method. ACS Cent. Sci. 2016;2:302–308. doi: 10.1021/acscentsci.6b00091. [DOI] [PMC free article] [PubMed] [Google Scholar]
  132. Yan M., Kawamata Y., Baran P. S.. Synthetic Organic Electrochemical Methods Since 2000: On the Verge of a Renaissance. Chem. Rev. 2017;117:13230–13319. doi: 10.1021/acs.chemrev.7b00397. [DOI] [PMC free article] [PubMed] [Google Scholar]
  133. Huang H., Steiniger K. A., Lambert T. H.. Electrophotocatalysis: Combining Light and Electricity to Catalyze Reactions. J. Am. Chem. Soc. 2022;144:12567–12583. doi: 10.1021/jacs.2c01914. [DOI] [PubMed] [Google Scholar]
  134. Wu S., Kaur J., Karl T. A., Tian X., Barham J. P.. Synthetic Molecular Photoelectrochemistry: New Frontiers in Synthetic Applications, Mechanistic Insights and Scalability. Angew. Chem., Int. Ed. 2022;61:e202107811. doi: 10.1002/anie.202107811. [DOI] [PMC free article] [PubMed] [Google Scholar]
  135. Xiong P., Xu H.-C.. Molecular Photoelectrocatalysis for Radical Reactions. Acc. Chem. Res. 2025;58:299–311. doi: 10.1021/acs.accounts.4c00739. [DOI] [PubMed] [Google Scholar]
  136. Huang C., Xiong P., Lai X.-L., Xu H.-C.. Photoelectrochemical asymmetric catalysis. Nat. Catal. 2024;7:1250–1254. doi: 10.1038/s41929-024-01260-y. [DOI] [Google Scholar]
  137. Teator A. J., Varner T. P., Knutson P. C., Sorensen C. C., Leibfarth F. A.. 100th Anniversary of Macromolecular Science Viewpoint: The Past, Present, and Future of Stereocontrolled Vinyl Polymerization. ACS Macro Lett. 2020;9:1638–1654. doi: 10.1021/acsmacrolett.0c00664. [DOI] [PubMed] [Google Scholar]
  138. Teator A. J., Leibfarth F. A.. Catalyst-Controlled Stereoselective Cationic Polymerization of Vinyl Ethers. Science. 2019;363:1439–1443. doi: 10.1126/science.aaw1703. [DOI] [PubMed] [Google Scholar]
  139. Foster J. C., O’Reilly R. K.. How to better control polymer chemistry. Science. 2019;363:1394. doi: 10.1126/science.aaw9863. [DOI] [PubMed] [Google Scholar]

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