Recent Advances in Enantioselective Transition Metal Catalysis Mediated by Ligand–Substrate Noncovalent Interactions

Abstract

Enantioselective transition metal catalysis is undoubtedly a cornerstone at the frontier of chemistry, attracting intense interest from both academia and the pharmaceutical industry. Central to this field is the strategic utilization of noncovalent interactions (NCIs), including hydrogen bonding, ion pairing, and π-system engagements, which not only drive asymmetric synthesis but also enable precise stereochemical control in transition metal-catalyzed transformations. Recent breakthroughs have unveiled a new generation of rationally designed ligands that exploit ligand–substrate noncovalent interactions, emerging as indispensable tools for stereocontrolled synthesis and setting new paradigms in ligand engineering. These advancements establish a transformative framework for ligand engineering, bridging fundamental mechanistic insights with practical synthetic utility. In this review, the judicious design concepts and syntheses of novel ligands from the past five years were highlighted and their synthetic applications in asymmetric catalysis were detailed.

1. Introduction

Enantioselective transition metal catalysis is indispensable for addressing the growing demand for chiral molecules in medicine, materials science, and sustainable chemistry [1,2,3]. By enabling precise control over molecular handedness, it bridges the gap between fundamental science and practical applications, while continuously redefining the limits of synthetic efficiency and selectivity. Notwithstanding these advancements, transition metals retain their enduring value in the development of novel catalytic asymmetric methodologies due to their exceptional reactivity profiles and redox versatility. A defining characteristic of these metals lies in the synergistic metal–ligand interactions that enable the precise modulation of both reaction activity and stereochemical outcomes. The coordination of multidentate chiral ligands with transition metal centers remains a foundational approach, serving as the cornerstone for numerous established catalytic systems. In ligand architecture, the predominant tactic involves a strategic placement of steric bulk to direct stereochemical control during the enantio-determining transition state through spatial constraints. Although achieving high enantioselectivity frequently requires considerable empirical optimization, privileged ligand frameworks have demonstrated remarkable versatility across diverse transformations, maintaining their status as indispensable tools in asymmetric catalysis [4]. A modern evolution of this established strategy involves leveraging attractive interactions as a deliberate design principle. This approach posits that positioning substrates in proximity to the chiral ligand environment, rather than relying solely on steric repulsion, could enhance stereochemical control while enabling more streamlined ligand architectures [5,6]. Noncovalent interactions (NCIs), which have long underpinned enzyme catalytic mechanisms, have seen transformative applications in synthetic catalysis over recent decades. By integrating the versatile reactivity of transition metals with ligands that engage in targeted noncovalent interactions with substrates, researchers may unlock a potent paradigm for designing enantioselective transformations. This dual-action strategy of combining covalent metal-substrate activation with spatially precise noncovalent recognition holds exceptional promise for advancing reaction innovation while reducing structural complexity in catalyst design [7,8].

An early seminal work was well-presented by Ito that introduced catalytic asymmetric synthesis via secondary interaction between chiral ligands and substrates [9]. Building on this framework, Gupta and co-workers disclosed the pivotal role of NCIs in supramolecular catalysis [10]. Phipps and co-workers provided a comprehensive review in 2020 on enantioselective transition metal catalysis mediated by noncovalent interactions, highlighting their versatility in stereochemical control [11]. More recently, Reek and co-workers demonstrated how hydrogen bonding within the coordination sphere preorganizes substrates, thereby enhancing both reactivity and enantioselectivity in transition metal-catalyzed transformations [7].

Over the last five years, a series of novel ligands bearing noncovalent interactions have been rationally designed, acting as a powerful strategy in accessing enantiopure products. This review aims to provide an update in this field and inspire novel ligand design for enantioselective catalysis. The general model of NCIs that are engaged enantioselective transition metal catalysis is shown in Figure 1.

2. Ligand–Substrate Noncovalent Interactions

Noncovalent interactions (NCIs) have long been integral to the mechanisms of enantioselective transition metal catalysis and their applications have been proven to be a remarkably powerful strategy for developing new enantioselective reactions over the past decades. This review will start with representative examples related to ligand–substrate NCIs before 2020, along with a brief introduction of their synthetic applications. The following sections are three subdivisions featuring with types of NCIs. In each subdivision, the judicious design and synthesis of novel ligands with NCIs over the past five years will be highlighted and their synthetic applications in asymmetric catalysis will be detailed.

2.1. Representative Examples Involve NCIs Before 2020

Ito and co-workers made an early contribution by using bifunctional ligands in a gold-catalyzed asymmetric aldol reaction in 1986 [12]. Since then, the applications of NCIs in enantioselective transition metal catalysis have dramatically accelerated [7,8,9,10,11,13,14,15]. The representative examples with NCIs in enantioselective transition metal catalysis are outlined in Figure 2.

2.2. Hydrogen Bonding and Ion Pairing Involved Enantioselective Transition Metal Catalysis

Pd-BaryPhos as catalysts for enantioselective cross-coupling reaction. Rationally designed ligands with hydrogen bonding are ubiquitously utilized in enantioselective transition metal catalysis. Tang and co-workers originally developed a novel chiral monophosphorus ligand BaryPhos in 2020, featured with bulky steric hinderance and a tethered hydrogen bonding donor (Figure 3a) [30]. The synthesis of BaryPhos commenced with oxidized chiral BIDIME as the starting material [31]. Sequential functionalization involved NBS-mediated dibromination, followed by a Suzuki coupling with a pinacol boronic ester and subsequent hydrogenation to construct the two cyclopentane rings. The intermediate was then treated with acetone under LDA-mediated conditions to install the gem-dimethyl hydroxyl moiety via ketone tethering. Finally, trichlorosilane reduction afforded the target BaryPhos (Figure 3b). The first application of BaryPhos was demonstrated by a Pd-catalyzed sterically hindered Suzuki–Miyaura coupling, providing a broad range of synthetically challenging chiral tetra-ortho-substituted biaryls in excellent enantioselectivities and yields (Figure 4a) [30]. The proposed H-bonding between BaryPhos and aldehyde substrates turned out to be crucial for high enantioselectivity (92% ee) compared to ligands with similar skeletons, as iPr-BIDIME and NitinPhos afford lower enantioselectivities (45% ee and 36% ee, respectively) (Figure 4b). This protocol is robust and practical, allowing for a concise enantioselective synthesis of therapeutically valuable male contraceptive and antitumor agent gossypol (Figure 4d). Taking advantage of privileged BaryPhos-facilitated asymmetric Suzuki–Miyaura cross-coupling, the same group has established a general, efficient, and enantioselective construction of the ortho sulfur- or nitrogen-substituted axially chiral biaryls in excellent yields and enantioselectivities (Figure 5a) [32]. The protocol shows excellent compatibility with various functional groups and structural features, delivering chiral biaryl structures with ortho-sulfonyl groups or with ortho-nitro groups at a broad range of molecular diversity and complexity (Figure 5b). Moreover, the immobilization of BaryPhos on polyethylene glycol (PEG) support has enabled homogeneous enantioselective cross-coupling in aqueous media and palladium catalyst recycling on multiple occasions. This method has enabled a concise step asymmetric synthesis of isoplagiochin D (Figure 5d) as well as the construction of chiroptical molecules with circularly polarized luminescence properties.

More recently, scientists from AstraZeneca systematically examined the synthesis of the complex macrocyclic active pharmaceutical ingredient AZD5991 with a pivotal and challenging Suzuki–Miyaura cross-coupling reaction between tetra-ortho-substituted heteroaryls. BaryPhos was found to be far more superior to all other ligands with 73% isolated yield and 97% ee (Figure 6a) [33]. In order to exploit the mechanistic insight, the product of oxidative addition of aryl bromide was isolated as a dimeric palladium intermediate, which indicates that the hydroxyl moiety on BaryPhos serves as a hemilabile ligand for metal coordination (Figure 6b). The hydrogen bonding between BaryPhos and pyrazole substrate is probably responsible for the excellent enantioselectivity (Figure 6c).

Chiral tricyclic octahydro-1H-4,7-methanoisoindol-1-one-derived transition metal catalysis for enantioselective functionalization. Ligands with a hydrogen bonding site can be used to preorganize substrate, pulling certain reactive sites on the substrate close to the metal’s center. Crabtree, Brudvig, and co-workers conducted a pioneering work in selective oxygenation of a saturated C−H bond on a cyclohexane ring using a dimanganese catalyst (Figure 7a) [34]. Alternatively, Bach and co-workers developed a tricyclic octahydro-1H-4,7-methanoisoindol-1-one-derived chiral Ru porphyrin catalyst [24], and expanded further to Mn and Fe porphyrin catalysts (Figure 7b) [35,36]. The catalytically active metal center and hydrogen bonding site are spatially separated, which accounts for the high enantio- and regioselectivity with a clear conformational preference.

Based on this concept, a silver-catalyzed amination was reported that occurs at the aliphatic C3-substituent of various quinolones and pyridones in good yields and excellent enantioselectivities (Figure 8a) [37]. The key to its success is the use of a hydrogen-bonded silver complex, in which hydrogen bonding can preorganize the substrate and the C−H bond on quinolones and pyridones is exposed to the catalytic reaction center. Later on, an enantioselective sulfimidation of 3-thiosubstituted 2-quinolones and 2-pyridones was achieved, delivering chiral sulfimides in good yields and excellent enantioselectivities by employing the same catalytic system (Figure 8b) [38]. Interestingly, the enantioselectivity does not depend on the size of the two substituents at the sulfur atom but only on the binding properties of the heterocyclic lactams. The sulfimidation proceeds with high site-selectivity and can also be employed for the kinetic resolution of chiral sulfoxides. The proposed mechanism suggests that the intermediacy of a heteroleptic silver complex in which the silver atom is bound to one molecule of the chiral ligand and one molecule of an achiral 1,10-phenanthroline (Figure 8d). Support for the suggested reaction course was obtained by ESI mass spectrometry, DFT calculations, and a Hammett analysis. After a short while, the enantioselective sulfoxidation of diaryl-type sulfides was accomplished using a chiral manganese porphyrin complex equipped with a remote molecular recognition site, providing chiral sulfoxides with exquisite enantioselectivities and good yields (Figure 9a) [35]. Instead of repulsive collision, the attractive hydrogen bonding interactions account for the highly selective oxidation that facilitates the precise orientation of an eligible substrate despite the marginal size difference between the two sulfide substituents.

Recently, an enantioselective amination reaction of various 3-arylmethyl-substituted 2-quinolones and 2-pyridones was achieved in the presence of 1 mol% of a chiral iron porphyrin catalyst under mild conditions, affording chiral secondary amines in good yields and excellent enantioselectivities (Figure 10) [36]. The selectivity of the reaction is governed by a two-point hydrogen bond interaction between the ligand of the iron catalyst and the substrate (Figure 10c). Hydrogen bonding directs the amination to a specific hydrogen atom within the substrate that is displaced by the nitrogen substituent either in a concerted fashion or by a rebound mechanism.

Pd-SPhos or RuPhos-derived chiral ligands as catalysts for enantioselective synthesis. Monophosphorus ligand SPhos has been extensively used in metal-catalyzed cross-coupling reactions since it was first discovered by the Buchwald group [40]. Based on its broad utilities, a sulfonated SPhos, named sSPhos, was judiciously designed by the Phipps group considering chirality induction since SPhos had only been used in a racemic form. The sulfonate fragment was installed to exert noncovalent interactions, including hydrogen bond acceptor, ion pairing, and electrostatic interaction, which is believed to proceed enhance stereocontrol in transition metal catalytic transformations. The Phipps group provides a concise synthesis of chiral sSPhos with SPhos as the starting material, which is sulfonated with sulfuric acid, then twice recrystallization with protonated quinidine from acetonitrile, leading to high diastereoselectivity (74:1), and finally treated to AmberLite resin to give (R)-sSPhos in 26% total yield with 98% ee (Figure 11). This facile procedure, which uses commercially available and cheap starting materials, allows rapid access to highly enantioenriched sSPhos without specialist facilities. The fantastic chiral ligand sSPhos was originally applied in an atroposelective Suzuki–Miyaura cross-coupling that allows the rapid and modular synthesis of highly enantioenriched 2,2′-biphenols in good yields and excellent enantioselectivities (Figure 12) [41]. The hydrogen bonding interaction between one phenolic hydroxyl and the ligand sulfonate group is key and it is plausible that the second phenolic hydroxyl forms an additional hydrogen bond in an arrangement that results in the highest ee (Figure 12c). In addition, a desymmetrizing Suzuki–Miyaura cross-coupling was also achieved in 51% yield and 94% ee by employing chiral sSPhos as a ligand (Figure 12b). An ion pairing interaction between sulfonate and substrate is proposed to be responsible for the exquisite enantioselectivity (Figure 12d).

The dearomatization of phenols is typically more challenging than naphthols, indoles, and pyrroles because of their lower electron density. Buchwald and co-workers pioneered a palladium-catalyzed intramolecular arylation of phenols, enabling the synthesis of spirocyclohexadienones with all-carbon quaternary stereocenters [42]. Chiral sSPhos was found to be effective in various enantioselective arylative phenol dearomatization, delivering spirocyclic, spiroheterocyclic, and fused polycyclic scaffolds in good yields and excellent enantioselectivities (Figure 13a) [43]. The chiral sulfonated ligand sSPhos engaged in electrostatic interactions with a phenolate substrate via its associated alkali metal cation, which was attributed to the key success (Figure 13b). The broad generality displayed by sSPhos facilitates the expansion of the dearomatization reaction and highlights the potential of this unusual design principle.

Considering the importance of noncovalent interactions, two variants of RuPhos with phosphonate substitution (L16) and terminal carboxylate substitution (L17 and L18) bearing hydrogen bonding and ion-paired interactions were developed by Zhu and co-workers (Figure 14a) [44,45]. The synthesis of enantioenriched L16 commenced with methyl-substituted chiral RuPhos. This precursor underwent bromination in the presence of trifluoroacetic acid, which was followed sequentially by phosphonylation and hydrolysis to afford the target ligand (Figure 14b). Similarly, the bromination of methyl-substituted chiral RuPhos followed by carboxylation using CO₂ to install 3′-carboxyl group, condensation with amino acids, and hydrolysis gave the chiral ligands L17 and L18 (Figure 14c). Establishing quaternary stereocenters bearing sterically similar geminal substituents poses a major obstacle in catalytic desymmetrization. Zhu and co-workers developed an enantioselective desymmetrizing Suzuki–Miyaura reaction that establishes chirality at a remote quaternary carbon, providing xanthenes in good yields and high enantioselectivities (Figure 15a) [44]. The spatial distancing of a substrate’s reactive group and nonreactive catalyst-binding group from its pro-stereogenic element presents substantial hurdles in asymmetric catalysis. The judicious design and utilization of the phosphonated ligand L16 is responsible for the high enantioselectivity, which demonstrates that precise long-range stereocontrol is achievable by engaging ionic substrate–ligand interactions at a distal position (Figure 15d). After a short while, the desymmetrizing Suzuki–Miyaura reaction, Sonogashira reaction, and Buchwald–Hartwig amination between diverse diarylmethane scaffolds and aryl, alkynyl, and amino coupling partners provide rapid access to enantioenriched acyclic quaternary and tertiary stereocenters with carboxylate ligands (L17 and L18) in good yields and excellent enantioselectivities (Figure 15b,c) [45]. Experimental and computational investigations reveal the electrostatic steering of substrates by the C-terminus of chiral ligands through ionic interactions. Cooperative ion–dipole interactions between the catalyst’s amide group and potassium cation aid in the preorganization that transmits asymmetry to the product, which further demonstrates its practicality for precise long-range stereocontrol through engineering the spatial arrangements of the ionic catalysts’ substrate-recognizing groups and metal centers.

Modified dinuclear Rh complexes for enantioselective C−H functionalization. The chelating dicarboxylate dinuclear rhodium complexes Rh₂(esp)₂ showed unmatched performance compared to other dirhodium complexes in both intra- and intermolecular C−H amination reactions [46]. Harnessing the transcendent superiority, a family of anionic variants of the best-in-class dinuclear rhodium complexes appended with sulfonate moiety, named Rh₂(sulfonesp)₂, have been wisely designed (Figure 16a). The dihydroquinidine-derived chiral cation appears to engage in axial ligation with the rhodium complex, providing improved yields of product versus Rh₂(esp)₂ and highlighting the dual role that the cation is playing. The key sulfonated dicarboxylic acid fragment was synthesized through three steps from tribromomethylbenzene, finally making complexation with Rh₂(TFA)₂; this affords the desired Rh₂(sulfonesp)₂ catalyst with two pendent anion handles (Figure 16b). After the assembly of the rhodium dimers, the bisligated complexes were isolated as the bistetrabutyl ammonium salts and it proved to be straightforward to introduce chiral cations via intermediate protonation using Amberlite IRC120 H. This accessed a series of ‘sulfonesp’ scaffolds with varied geminal dialkyl substitution (Figure 17a). By using the ion-paired Rh catalyst I, Phipps and co-workers performed a rhodium-catalyzed enantioselective intermolecular C−H amination of 4-arylbutanols, obtaining good yields and excellent enantioselectivities (Figure 17b) [47]. The optimal ion-paired catalyst also results in significantly improved yields compared with Rh₂(esp)₂. Furthermore, phenylbutane, as a substrate, was evaluated using the benzylic amination reaction, which lead to a poor yield and enantioselectivity (3% yield, 28% ee) (Figure 17f), indicating the importance of the proposed hydrogen bonding between the substrate hydroxyl and the catalyst sulfonate (Figure 17g). Unlike the former substrate with a hydroxyl group direction, the same group found that butyric and valeric acid-derived tertiary amides can undergo highly enantioselective benzylic amination using an achiral anionic Rh complex that is ion-paired with a Cinchona alkaloid-derived chiral cation (Rh catalyst II in Figure 17a) (Figure 17c) [48]. A broad scope of compounds can be aminated, encompassing numerous arene substitutions, amides, and two different chain lengths. The tertiary amide group of the substrate was believed to engage in hydrogen bonding interactions directly with the chiral cation, enabling a high level of organization at the transition state for C−H amination. Control experiments led to the discovery that methyl ethers also function as proficient directing groups under the optimized conditions, potentially also acting as hydrogen bond acceptors. Surprisingly, the short-chain substrates had not been able to achieve high enantioselectivity with the previously reported Rh catalyst I. After systematically exploring the variants of ion-paired Rh catalysts, Phipps and co-workers described a highly enantioselective nitrene transfer to hydrocinnamyl alcohols (benzylic C−H amination) and allylic alcohols (aziridination) using an optimized ion-paired rhodium catalyst (Rh catalyst III, Figure 17a) (Figure 17d,e) [49]. The modulation of the linker length between the anionic sulfonate group and the central arene spacer provided enhanced compatibility with short-chain substrates, which enabled the design of a versatile biaryl-based scaffold applicable to diverse catalytic systems (Figure 17g). Furthermore, a systematic structural knockout study on the cinchona alkaloid-derived chiral cation has been investigated to elucidate the crucial features for high enantioinduction. A de novo synthesis of the modified scaffolds showed that the quinoline nitrogen of the alkaloid and the substrate hydroxyl group are also crucial for high ee.

Binaphthyl-based chiral ligands for enantioselective gold catalysis. Gold catalysis has emerged as a robust and versatile tool that enables the efficient formation of new C−C bonds to construct molecular complexity toward nucleophilic attacks [50]. The introduction of noncovalent interactions on ligands has demonstrated a fascinating cooperative gold catalysis [51]. Recently, a set of 1,1′-binaphthy-based chiral bifunctional ligands containing amide (L19 and L20), phosphite (L21), and phosphine oxide (L23 and L24) moieties acting as a hydrogen bonding acceptor was designed and developed, and received particular attention from Zhang’s group (Figure 18) [52,53,54,55,56,57,58]. Due to the linear coordination feature of gold catalysis, a remote interaction between ligand and substrate is often required to achieve gold-catalyzed enantioselective transformations [51,59,60].

By using this strategy, a gold-catalyzed enantioselective dearomatization of naphthol and phenol derivatives is achieved via metal chiral ligand cooperation, delivering a spirocarbocyclic skeleton bearing a chiral all-carbon quaternary center and synthetically versatile enones in excellent yields and enantioselectivities (Figure 19a) [52]. This asymmetric gold catalysis is enabled by chiral binaphthyl phosphine ligands featuring a remote amide or phosphonate substituent. The proposed mechanism involves hydrogen bonding between the substrate and ligand remote basic group. DFT calculations lend support to the cooperative catalysis and substantiate the reaction stereochemical outcomes. After a while, a gold-catalyzed efficient and highly enantioselective dearomatization of phenols is achieved with an amide-substituted ligand (L20), furnishing spirocyclohexadienone-pyrrol-2-ones, spirocyclohexadienone-butenolides, and spirocyclohexadenone-cyclopentenones in remarkably high yields and enantioselectivities (Figure 19b) [55]. Interestingly, a gold-catalyzed highly enantioselective desymmetrization of 1-ethynylcyclobutanols is achieved by employing a phosphine oxide-substituted ligand (L23), permitting access to chiral α-methylenecyclopentanones featuring a diverse array of chiral quaternary and tertiary centers in excellent yields and enantioselectivities (Figure 19c) [56]. The noncovalent interaction between the phosphine oxide motif and the hydroxyl substrates is calculated to be responsible for the stereochemical outcomes. More recently, a highly enantioselective trapping of an in situ-generated alkenyl/acyl gold carbene by an alcoholic nucleophile is enabled by an amide-functionalized chiral binaphthylphosphine ligand via cooperative gold catalysis, accessing γ-alkoxy-α,β-unsaturated imides with excellent enantiomeric excesses (Figure 19d) [58]. The intermediacy of a carbene species is supported by its alternative access via dediazotization. The reaction tolerates a broad range of alcohols and can accommodate dienynamide substrates, in addition to arylenynamides.

In 2024, Che and co-workers reported gold-catalyzed highly enantioselective [4+2] cycloadditions of 1,6-enynes or 1,6-diynes assisted by remote hydrogen bonding interaction, providing enantioenriched 5-6-6fused tricyclic compounds under mild reaction conditions with excellent enantioselectivities (Figure 20) [64]. DFT calculations and control experiments were performed to rationalize the origin of precise stereocontrol. This implies that hydrogen bonding interaction between the ester group of substrates and the secondary amine of the chiral P,N ligands plays a pivotal role in the control of enantioselectivity.

Chiral anion-binding directed enantioselective transformations. Despite counterions often playing a significant effect in gold-catalyzed transformations, achieving enantioselective metal catalysis by chiral anion is conceptually new. In 2022, a successful implementation of this paradigm was demonstrated in 5-exo-dig and 6-endo-dig cyclizations of 1,6-enynes, combining an achiral phosphinourea Au(I) chloride complex with a BINOL-derived phosphoramidate Ag(I) salt and thus allowing the first general use of chiral anions in Au(I)-catalyzed reactions of challenging alkyne substrates (Figure 21) [65]. The hydrogen bond donor placed on the ligand of a cationic complex allowed the precise positioning of the chiral counteranion responsible for asymmetric induction. Two years later, a similar approach was applied in a gold(I)-catalyzed enantioselective addition of indole to diphenylallene via anion-binding catalysis (Figure 22) [66]. Experimental and computational studies support an anion-binding mechanism for gold(I) precatalyst activation. Noncovalent interactions were identified as the source of enantio-differentiation, providing insights into the cooperativity between achiral phosphine ligands and chiral ureas.

In 2023, Jacobsen and co-workers reported a anion-binding approach for inducing enantioselectivity in a transition metal-catalyzed reaction that relies on neutral hydrogen bond donors, binding anions of cationic diruthenium complexes to achieve enantiocontrol and rate enhancement through ion pairing together with other noncovalent interactions. A cooperative anion-binding effect of a chiral bis-thiourea hydrogen bond donor was demonstrated to lead to excellent enantioselectivities in intramolecular ruthenium-catalyzed propargylic substitution reactions (Figure 23a) [67]. A significant anion effect was observed, which implies that the anion involves noncovalent interactions (Figure 23d). Experimental and computational mechanistic studies show the attractive interactions between electron-deficient arene components of the hydrogen bond donor and the metal complex that underlie enantioinduction and the acceleration effect.

Miscellaneous ligands for enantioselective transition metal catalysis. Chiral ligands bearing noncovalent interaction groups, such as chiral carbonyl acids, chiral salicyloxazolines, and chiral phosphoric acids, were also applied in enantioselective C−H activation reactions [15]. Shi and co-workers described an Ir(III)-catalyzed asymmetric C−H activation enabled by noncovalent interactions between chiral carbonyl acid ligand and sulfoximine substrates, generating a broad range of sulfur-stereogenic sulfoximines in high yields with excellent enantioselectivities (Figure 24a) [68]. Detailed DFT calculations suggested that the N−H···O hydrogen bonding interaction between sulfoximine and the chiral carboxylic acid ligand was crucial for high enantiocontrol (Figure 24c). Additionally, a silver-catalyzed asymmetric aldol reaction of isocyanoacetic acid derivatives with aldehydes was developed by employing a chiral prolinol–phosphine as a hydrogen-bond-donating P,N,O ligand (L27), affording oxazolines in high yields and enantioselectivities (Figure 25a). DFT calculations indicated that the reaction proceeds in a stepwise manner, involving a carbonyl addition and subsequent enantioselectivity-determining oxazoline ring formation, which also suggests that additional nonclassical C−H···O hydrogen bonds participate synergistically in the stereocontrol (Figure 25b). Recently, a Cu-catalyzed asymmetric borylation of α,β-unsaturated ketones was reported by employing a novel chiral bipyridine ligand bearing a flexible side chain with a molecular recognition site, leading to the corresponding borylated products in good yields with high enantioselectivities (Figure 26a). Further studies indicate that the hydrogen bonding donor appended on the chiral bipyridine ligand might benefit the chemo- and site selectivity in addition to stereoselectivity.

2.3. π Interactions Involved Enantioselective Transition Metal Catalysis

π-system-engaged interactions have been broadly utilized in ligand design and transition metal-catalyzed transformations [72,73,74,75,76]. In 2021, Tu and co-workers developed a Cu-catalyzed aerobic oxidative cross-coupling of 2-naphthylamine and 2-naphthol by employing a chiral spirocyclic pyrrolidine ligand (L29) under mild conditions, yielding 3,3′-disubstituted 2-amino-2′-hydroxy-1,1′-binaphthyls in high yields and enantioselectivities (Figure 27a) [77]. The DFT calculations suggest that the F–H interactions between the CF₃ of the ligand and H-8 of 2-naphthol and the stacking between the two coupling partners could play vital roles in the enantiocontrol of this cross-coupling reaction.

The enantioselective hydroarylation of unactivated terminal akenes constitutes a prominent challenge in organic chemistry. Shi and co-workers reported the co-catalyzed asymmetric hydroarylation of unactivated aliphatic terminal alkenes assisted by tailored amino acid ligand (L30), providing a broad range of 2-alkylated indoles in high yields and excellent enantioselectivities (Figure 28a) [78]. Critical to the chiral induction was the engaging of a π-π interaction between the ligand and substrate (Figure 28c). DFT calculations revealed the reaction mechanism and elucidated the origins of chiral induction in the stereodetermining alkene insertion step.

In the meanwhile, a palladium-catalyzed conjugate arylation of α,β-unsaturated δ-lactam was achieved by using a designed pyridine-dihydroisoquinoline ligand (L31), delivering β-quaternary δ-lactams in excellent yields and enantioselectivities (Figure 29a) [79]. The ligand plays a key role in the formation of attractive noncovalent π interactions with substrates in an enantioselectivity-determining step (Figure 29c), which was further elucidated by DFT calculations.

The direct incorporation of specific π interactions into the design of catalysts as a key stereocontrol element remains a challenge. To address this challenge, Xu, Yu, and co-workers described an efficient chiral molecular recognition via engineered ligand and substrate design that enables the dihydroxylation-based kinetic resolution involving a lone pair-π interaction and a π-π stacking interaction operating collectively, accessing a wide range of alcohols and alkenes in excellent yields and enantioselectivities (Figure 30a) [80]. DFT calculations shed light on the crucial role played by the lone pair-π interaction between the carbonyl oxygen of the cinchona alkaloid ligand and the electron-deficient phthalazine π moiety of the substrate in the stereoselectivity-determining transition states (Figure 30c). By using the same strategy, asymmetric dihydroxylation-based desymmetrization was reported, further expanding to a broad aryl-substituted substrates (Figure 31a). The lone pair-π interaction between the carbonyl in mono-cinchona alkaloids and the electron-deficient phthalazine in the symmetric alkene substrates accounts for the highly efficient asymmetric dihydroxylation-based desymmetrization (Figure 31c), which was difficult to execute following the traditional Sharpless asymmetric dihydroxylation method.

More recently, a chiral Ir-SpiroPAP (iridium complexes of bidentate chiral spiro aminophosphine ligands bearing an added pyridine group) catalyst facilitating the hydrogenation of a wide variety of 4-substituted 3-ethoxycarbonylquinolines was developed, yielding chiral 1,4-dihydroquinolines in high yields (up to 95%) with exceptional enantioselectivity and efficiency (up to 99% ee and 1840 TONs) (Figure 32a) [82]. The judicious substrate design cooperating with ligand design is responsible for the high enantioselectivity, where a N−H−π interaction was observed based on DFT calculations (Figure 32c). Its synthetic utility was illustrated with a highly efficient synthesis of an anti-cancer agent (Figure 32e).

3. Conclusions and Perspectives

Noncovalent interactions in ligands play a vital role in enantioselective transition metal catalysis and generally engage in mechanistic insight. For instance, the monophosphorus ligand BaryPhos turned out to be efficient for palladium-catalyzed hydrogen-bonding related asymmetric cross-coupling reactions. As an update to this rapidly evolving field, we summarize recent advances in the design of chiral ligands leveraging NCIs, including hydrogen bonding, ion pairing, and π-system interactions, to enable stereocontrolled transition metal-catalyzed asymmetric transformations. This review highlights representative NCI-driven ligand architectures that have emerged over the past five years, emphasizing their mechanistic roles in achieving precise enantioselectivity.

Most substrates intrinsically possess some functional handle with which they might engage in NCIs with a suitable ligand. These interactions can help to draw the substrate to the catalyst, leading to an increasing reaction rate, but also importantly providing an extra level of organization as the enantio-determining transition state is approached. We envision that this review will inspire the design of the next generation of ligands in enantioselective catalysis.