Recent Development of Bis-Cyclometalated Chiral-at-Iridium and Rhodium Complexes for Asymmetric Catalysis

Abstract

The field of asymmetric catalysis has been developing to access synthetically efficacious chiral molecules from the last century. Although there are many sustainable ways to produce nonracemic molecules, simplified and unique methodologies are always appreciated. In the recent developments of asymmetric catalysis, chiral-at-metal Lewis acid catalysis has been recognized as an attractive strategy. The catalysts coordinatively activate a substrate while serving the sole source of chirality by virtue of its helical environment. These configurationally stable complexes were utilized in a large number of asymmetric transformations, ranging from asymmetric Lewis acid catalysis to photoredox and electrocatalysis. Here we provide a comprehensive review of the current advancements in asymmetric catalysis utilizing iridium and rhodium-based chiral-at-metal complexes as catalysts. First, the asymmetric transformations via LUMO and HOMO activation assisted by a chiral Lewis acid catalyst are reviewed. In the second part, visible-light-induced asymmetric catalysis is summarized. The asymmetric transformation via the electricity-driven method is discussed in the final section.

1. Introduction

The synthesis of a chiral molecule is one of the most challenging yet vital processes in organic synthesis.^1,2 Decades of investigation have shown the transition metal complexes to be one of the most indispensable tools in asymmetric synthesis and catalysis for making nonracemic molecules.³ Lewis acidity and the availability of interacting orbitals and synergic bonding and back-bonding cooperations are central to their chemistry, where the steric and electronic properties and hence their reactivities are tuned by the presence of organic ligands (Figure 1).⁴⁻⁷ The reaction happens in the metal center, and the chiral ligands create the asymmetric environment surrounding the metal ion. Among different possible ways to generate chirality in the metal center, a less studied one involves the chirality in the absence of any chiral ligands, where the metal center itself is chiral. The nonexistence of the dissymmetric ligands around the metal can align the reacting substrate at the metal center to create discriminative faces of the substrates that the reagents can attack. These characteristics finally lead to the enantioenriched products. This type of complex can be called a chiral-at-metal complex, first anticipated and observed by Werner about a century ago.⁸ Both tetrahedral and octahedral complexes can become chiral-at-metal depending on their ligand environment.^9,10 In an octahedral topology, nonchiral bidentate and tridentate ligands around the metal center can generate twists in the complex. This forms a propeller type structure that assigns the chirality of the chiral-at-metal complex, Λ for the left- and Δ for the right-handed twist.¹¹ The advantages of chiral-at-metal to their achiral counterparts include the tremendous scope of achiral ligands, enabling the installation of multiple functional groups around the metal center.¹² A plethora of chiral-at-metal complexes can thus be generated. However, several challenges are associated with the synthesis of these complexes: (i) It is troublesome to get high enantiomeric excess (ee) for the complexes. (ii) Often, maintaining their configuration stability is highly difficult. (iii) In addition, there are chances of forming many stereoisomers. For example, an octahedral coordination complex having six individual monodentate ligands can adopt up to 30 individual stereoisomers (15 diastereomers as pairs of enantiomers).¹³ It is strenuous to selectively synthesize and isolate a single stereoisomeric complex for catalytic applications. Multidentate ligands can boost selectivity and have recently been applied to isolate configurationally stable single enantiomers of the metal complex.¹⁴ These complexes have recently been involved in a myriad of asymmetric transformations. Some thoughtful reviews focusing on the synthesis and reactivity of chiral-at-metal complexes have been published.¹⁵⁻²⁰ This Review endeavors to comprehensively summarize the recent applications of bis-cyclometalated chiral-at-iridium and rhodium metal complexes in asymmetric catalysis (Figure 2). It provides historical background, describes different modes of substrate activations under thermal, photochemical, and electrochemical conditions, and discusses current challenges and opportunities that lie ahead.

Figure 1.

Asymmetric catalysis with well-explored methodology and new methodology.

Figure 2.

Tetrahedral and octahedral chiral-at-metal complexes.

2. Historical Background

In 1893, Werner proposed his coordination theory, where he revealed octahedral metal complexes with metal center optical activity.⁸ Later in 1911, the octahedral chiral-at-metal complexes of cobalt [Co(en)₂X(NH₃)]²⁺ (X = Cl or Br, en = ethylene diamine) and their resolution with the mirror image of Λ and Δ isomers were reported.⁹ In the next 100 years, however, the use of these complexes, particularly in asymmetric catalysis, was largely overlooked, and only sporadic accounts appear in the literature (Figure 3).²¹ In 1994, the Ohkubo group attempted the enantioselective and photocatalytic oxidation of rac-1,1′-bi-2-naphthols 1, where a chiral-at-ruthenium complex Δ-[Ru(menbpy)₃]²⁺ (menbpy = 4,4′-dimenthoxycarbonyl-2,2′-bipyridine) 3 was used as a photocatalyst and [Co(acac)₃] (acac = pentane-2,4-dione) was used as the terminal oxidant (Scheme 1a).²² However, the enantioselectivity of the corresponding products was improved only up to 15% ee. In 2001, the Soai group reported highly enantioselective asymmetric autocatalysis induced by chiral-at-cobalt complex 6 (Scheme 1b).²³

Figure 3.

Evolution of chiral-at-metal complexes.

Scheme 1. Early Examples of the Enantioselective Reaction by Chiral-at-Metal Complexes.

The enantioselective addition of isopropyl zinc with pyrimidine-5-carbaldehyde 4 yielded pyrimidyl alkanol 5 with 94% ee. Although the reported cobalt complexes are not true chiral-at-metal catalysts, it was initial progress from an asymmetric perspective.

In 2003, the Fontecave group reported the oxidation of sulfide 7 to sulfoxide 8 via chiral-at-ruthenium(II) catalyst 9 (Scheme 1c).²⁴ However, only 18% ee of the sulfoxide product was achieved. In 2007, the same group demonstrated an octahedral chiral-at-ruthenium complex as a chiral ligand for another ruthenium complex 12 (Scheme 1d).²⁵ The asymmetric transfer hydrogenation of aryl ketone 10 was performed, and up to 26% ee of the corresponding alcohol product 11 was obtained. A year later, the Gladysz group reported enantioselective Michael addition of dimethyl malonate 14 to cyclopentenone 13 with simple Werner’s complex 16 having BArF₂₄^– (tetrakis[(3,5-trifluoromethyl)phenyl] borate) as the counteranion, which leads to the corresponding product 15 in 33% ee (Scheme 1e).²⁶

Despite the potential of chiral-at-metal complexes in asymmetric synthesis and catalysis, the applications of these catalysts in highly enantioselective transformations remained challenging. In 2013, the Meggers group made an essential contribution in this area in terms of high enantio-induction. The octahedral chiral-at-iridium complexes 21 and 22 having bis-cyclometalated 2-aryl benzoxazoles and amidopyrazole ligands were prepared in high enantiopurity (Scheme 2a).²⁷ The complex 21 catalyzed the enantioselective transfer hydrogenation of nitroalkene 23, using Hantzsch ester as the reducing agent (Scheme 2b).²⁸ The desired nitro alkane products 24 were obtained in excellent yields (89–96%) and outstanding enantioselectivities (93–99% ee). The high enantioselectivity was rationalized by the formation of a highly ordered enantio-determining transition state. It is hypothesized that the amidopyrazole ligand fragment from two-point hydrogen bonding with the nitroalkene substrate not only lowers the lowest unoccupied molecular orbital of the nitroalkene but also creates facial differentiation. Additionally, the hydroxyl group present in the ligand backbone forms a hydrogen bond with the −NH group of the Hantzsch ester that directs a precise hydride transfer. Notably, the catalysis worked with as low as 0.004 mol % loading without affecting the yield and enantioselectivities.

Scheme 2. Initial Reports on Chiral-at-Metal Through Hydrogen Bonding.

Later, the same group demonstrated the enantioselective Friedel–Crafts alkylation of indoles using chiral-at-iridium complex 22 having the same amidopyrazole hydrogen bonding site (Scheme 2c).²⁹ The reaction affords the alkylated carbon quaternary center products 26 with high yields (72–97% yield) and high enantioselectivities (92–98% ee). These two unique examples provide a novel route for designing the chiral-at-metal catalyst and its diverse applications in catalytic asymmetric transformation.

In 2017, the Yoon group developed a highly efficient stereochemically controlled [2 + 2] cycloaddition reaction of quinolones using a chiral-at-iridium photocatalyst 29 involving a series of hydrogen bonding and π–π interaction (Scheme 3).³⁰ The quinolone substrates organize themselves with the chiral environment of the Ir(III) photosensitizers, which leads to effective energy transfer and also effective stereoinduction.

Scheme 3. Enantioselective [2 + 2] Cycloaddition Controlled by a Chiral-at-Metal Catalyst.

However, the developed chiral-at-metal complexes are coordinately saturated. Catalysis via outer-sphere shape recognition is nontrivial and results in poor selectivities, except in a few cases. In this regard, in 2014–2015, the Meggers group synthesized chiral-at-iridium(III) and rhodium(III) complexes with two exchangeable-labile acetonitrile ligands using tailored chiral bidentate auxiliary ligand-mediated asymmetric synthesis (Scheme 4).³¹ Such chiral auxiliaries assist in implementing the absolute metal-centered configuration and are removed afterward in a traceless fashion. Amazingly, the octahedral complexes exhibit high configurational stability even in the presence of labile acetonitrile ligands that can potentially reduce the racemization barrier. It is worth noting that the tailored choice of the chiral auxiliary varies with the metal and the nature of the cyclometalating ligand. The complexes can coordinatively activate a substrate while serving as the sole source of chirality by virtue of their helical environment. These configurationally stable chiral-at-metal complexes were utilized in a large number of asymmetric transformations, ranging from asymmetric Lewis acid catalysis to photoredox and electrocatalysis. In the following sections, we have summarized the progress.

Scheme 4. Auxiliary Mediated Synthesis of Λ- and Δ-IrS, and Λ- and Δ-RhS Complexes.

3. Chiral Lewis Acid Catalysis

Lewis acid catalysis plays an essential role in organic synthesis.³² A Lewis acid functions as an electron pair acceptor to enhance a substrate’s reactivity either by lowering the lowest unoccupied molecular orbital (LUMO lowering catalysis) or by raising the highest occupied molecular orbital (HOMO raising catalysis). In the past few years, chiral-at-metal complexes have been successfully used in asymmetric Lewis acid catalysis. The following sections summarize the progress into two parts, depending upon the reacting substrates.

3.1. LUMO Activation

The two labile acetonitrile ligands of the chiral-at-metal octahedral complex could be displaced by the α,β-unsaturated electrophile, facilitating the LUMO activation for its attachment with the nucleophile. Several reactions belong to this class, showing the importance of this strategy for the vital target.

3.1.1. Friedel–Crafts Alkylation

The Friedel–Crafts reaction is a powerful synthetic tool for constructing carbon–carbon bonds involving an aromatic moiety.³³ The development of efficient Friedel–Crafts alkylations of arenes and heteroarenes using only catalytic amounts of a Lewis acid has gained much attention over the past decade.³⁴ In this regard, the Meggers group demonstrated the feasibility of utilizing the bis-cyclometalated chiral-at-iridium(III) complex (Λ-IrO) 34 as a Lewis acid catalyst for the Friedel–Crafts alkylation of indoles with α,β-unsaturated 2-acyl imidazole 35 (Scheme 5b).³⁵ The chiral-at-iridium complex Λ-IrO 34 was prepared via subsequent reaction of iridium trichloride hydrate with 2-phenyl benzoxazole and the chiral auxiliary ligand (S)-4-isopropyl-2-(2′-hydroxyphenyl)-2-thiazoline followed by the substitution of the chiral auxiliary ligand by two acetonitrile groups in the presence of NH₄PF₆ (Scheme 5a). By displacing the labile acetonitrile ligands, the α,β-unsaturated electrophile coordinates with the octahedral complex, facilitating the LUMO activation for its attachment with the nucleophile. With the employment of 0.25–2 mol % Λ-IrO 34 in THF at room temperature, α,β-unsaturated electrophile 36 undergoes the Friedel–Crafts alkylation reaction with indole derivatives 36 to form 3-alkylated products 37 in 75–99% yields and up to 98% ee.

Scheme 5. Friedel–Crafts Addition of Indole to α,β-Unsaturated 2-Acyl Imidazole.

The proposed model for the asymmetric induction is shown in Scheme 5b, where the bulky tert-butyl group effectively blocks one of the faces of the alkene and the alkylation takes place from the opposite face. Notably, in this enantioselective Friedel–Crafts alkylation method, the chiral Lewis acid catalyst plays a dual role by activating the substrates as well as creating the chiral environment in the reaction medium.

Similarly, the chiral-at-iridium catalysts 34 were employed for the Friedel–Crafts alkylation reactions with other aromatic compounds (Scheme 6).³⁶ It was conceptualized that the cyclometalated 2-phenyl benzothiazole ligand (Λ-IrS complex, 41) might create a higher asymmetric induction because of a longer C–S bond when compared with the 2-phenyl benzoxazole ligand (Λ-IrO complex, 34). The Λ-IrS complex 41 catalyzed Friedel–Crafts alkylation of indole delivered the product 40a in 99% ee, compared to 96% ee for Λ-IrO. A similar trend was also observed for 3-methoxy-N,N-dimethylaniline substrate. However, the Friedel-Craft alkylations of 2-methoxyfuran 40c and pyrrole 40d proceeded in similar enantiomeric excess in both cases. A similar observation was made for the addition of C–H acidic malononitrile and 1,3-dicarbonyls to the α,β-unsaturated 2-acyl imidazole as a Michael acceptor (Scheme 6). This procedure is equally capable of constructing molecules with all-carbon quaternary stereocenters 40g, 40h. In general, the Λ-IrS complex 41 gave better enantioselectivity (ee) than the Λ-IrO complex 34. In fact, the benzothiazole complex’s superiority over the benzoxazole complex was also demonstrated for the chiral-at-rhodium catalyst.³⁷

Scheme 6. Octahedral Chiral-at-Iridium Complex Catalyzed Friedel–Crafts Alkylation and Michael Addition Reaction.

3.1.2. Cycloaddition Reactions

Cycloaddition reaction is a versatile and straightforward reaction where two or more bonds are formed in a single operation accessing carbocyclic or heterocyclic organic compounds.^38,39 Commonly, olefins serve as one reaction partner in a cycloaddition reaction and bond formation occurs at both carbon atoms of the multiple bonds. For the most valuable processes in chemical synthesis, it is highly challenging to develop new efficient chiral catalysts for enantioselective cycloaddition reactions. Various highly enantioselective metal catalysts have been developed for versatile cycloaddition reactions in the past few years. In this regard, chiral-at-iridium(III) complexes 34 and 41 were found to be capable of catalyzing various cycloaddition reactions (Scheme 7).⁴⁰ Using 2.0 mol % Λ-IrS, the reaction of nitrone 42 with α,β-unsaturated 2-acyl imidazole 35a delivered the 1,3-dipolar cycloaddition product 43 with 86% yield and excellent 98% ee, with only one diastereoisomer (Scheme 7a). Lower enantioselectivity was observed with 34 (92% ee) as a catalyst. However, for the inverse electron demand Diels–Alder reaction of 35a,b with dihydrofuran 46, 34 shows superior performance (Scheme 7b,c). On the other hand, both 34 and 41 performed equally in catalyzing the Diels–Alder reaction of 35a with isoprene 48 (Scheme 7d).

Scheme 7. Octahedral Chiral-at-Iridium Complex Catalyzed Cycloaddition Reaction.

The Kang group realized that the chiral-at-rhodium complex 52 (Δ-RhO) acts as an excellent Lewis acid catalyst for the enantioselective cyclopropanation reaction (Scheme 8).⁴¹ Multisubstituted cyclopropanes 51 were obtained from α,β-unsaturated 2-acyl imidazole 35 and α-bromomalonate 50 in high yields and enantioselectivities. It was proposed that, at first, the acyl imidazole substrate 35 was activated by the Lewis acid catalyst 52. The Re-face is blocked by the tert-butyl group present in the achiral ligand enabling the nucleophilic attack by the α-bromomalonate anion from the Si-face to afford the rhodium enolate complex 54. The intramolecular cyclization from 54 yields the intermediate 55, releasing the product and regenerating the catalyst. The practical utility of this methodology was also demonstrated by the gram scale reaction with low catalyst loading (0.1 mol %), obtaining the desired product with 99% yield, 95% enantioselectivity, and >20:1 diastereoselectivity.

Scheme 8. Enantioselective Cyclopropanation Reaction by a Chiral-at-Rhodium Catalyst.

In the past decade, the merger of a gold catalyst with Lewis acid catalysts has made remarkable progress for the enantioselective transformations.^42,43 In this regard, with a combination of achiral gold(I) catalysts, the chiral-at-rhodium(III) Lewis acid catalyst 59 was found to be highly active for the asymmetric relay catalysis of β,γ-unsaturated keto ester 56 with alkynyl alcohols and amides 57 (Scheme 9).⁴⁴ The spiroketal and spiroaminal products 58 were isolated in excellent yields (up to 99% yields) and excellent selectivities (up to 98% ee, and 20:1 dr). The pinene-modified pyridine ligand-based catalyst 59 gave superior yields and selectivities among different chiral-at-metal complexes. It is attributed to the higher steric bulk around the rhodium center. Mechanistically, the gold catalyzed 5-exo-dig intramolecular cyclization of 62 yields an electron-rich exocyclic enol ether intermediate 64. In parallel, 56 coordinates with the chiral Lewis acid to yield the intermediate 61. The inverse-electron-demand hetero-Diels–Alder reaction took place from the Re-face of the chiral Rh(III) complex 61 to deliver the desired product 58 after ligand exchange with the substrate.

Scheme 9. Relay Gold(I)-Chiral-at-Rhodium Catalyzed Asymmetric Synthesis of Spiroketals and Spiroaminals.

1,3-Dipolar cycloaddition between a 1,3-dipole and a dipolarophile is an enticing strategy for forming a five-membered architecture. Several 1,3-dipoles, such as azomethine ylides,^45,46 nitrones,^47,48 nitrile imines,⁴⁹ and nitrile oxides,⁵⁰ have been employed for the cycloaddition reactions. In this context, recently, chiral-at-rhodium(III) complex 67 was implemented for the asymmetric [3 + 2] cycloaddition reaction of N,N′-cyclic azomethine imines 65 with α,β-unsaturated 2-acyl imidazoles 35c (Scheme 10).⁵¹ The Lewis acid catalyst 67 in 2 mol % loading catalyzed the reaction affording the N,N′-bicyclic pyrazolidine derivatives 66, having three contiguous stereocenters in high yields (up to 99%) and excellent stereoselectivities (>99% ee, >20:1 dr). In the proposed stereochemical model 68, the 1,3-dipole approaches the Lewis acid activated electrophile from the Re-face, avoiding the steric crowding in the Si-face.

Scheme 10. Asymmetric [3 + 2] Cycloaddition by a Chiral-at-Rhodium Complex.

Spirocyclic oxindoles moieties represent core structural elements in many natural products, alkaloids, and biologically active compounds.^52,53 The importance of these building blocks prompted synthetic chemists to explore novel methods for producing particularly enantiopure spirocyclic oxindoles. One such approach includes a [3 + 2]-annulation reaction of an activated olefin with a 2-oxindole derived spirovinylcylopropane (SVCP) where a Pd(0)-catalyst assists in creating a three-carbon dipole by releasing the strain energy of the cyclopropane ring from the vinyl cyclopropane (VCPs) moieties.⁵⁴ Recently, Du and co-workers reported the synthesis of multisubstituted spirocyclopentane oxindoles 70 empowered by Pd/chiral-at-rhodium(III) cooperative catalysis (Scheme 11).⁵⁵ The reaction proceeds with extreme synergism where the Pd(0) catalyst enables the generation of a three-carbon dipole and the chiral Lewis acid lowers the LUMO of the olefin partner. The desired product was obtained with up to 99% yield and outstanding selectivities, 99% ee, and 20:1 dr.

Scheme 11. Synthesis of Multisubstituted Spirocyclopentane Oxindoles Enabled by a Pd/Rh(III) Complex.

Very recently, Du and Su collaboratively reported the asymmetric decarboxylative cycloaddition of racemic vinyl ethylene carbonates (VECs) and α,β-unsaturated 2-acyl imidazoles for the catalytic synthesis of multisubstituted chiral tetrahydrofuran derivative via Pd(0)/chiral-at-rhodium(III) synergistic catalysis (Scheme 12).⁵⁶ It is noted that the nucleophilic 1,3-dipolar π-allylpalladium intermediate 76 formed after the decarboxylation from the VEC 73 can undergo [3 + 2] cycloaddition with α,β-unsaturated 2-acyl imidazole 35 to provide the desired product 74 with up to 98% yield, 99% ee, and >20:1 dr. The mechanism of the reaction is described in Scheme 12. The α,β-unsaturated 2-acyl imidazole substrate was activated by the chiral-at-rhodium(III) complex via bidentate N,O-coordination. Simultaneously, VEC forms zwitterionic 1,3-dipolar π-allylpalladium intermediate 76 via the Pd(0)-mediated decarboxylation process. Then, the intermediate 76 attacks the intermediate 75 from the Si-face and the intermediate 78 is formed after coordination dissociation and electron neutralization. Finally, the ligand exchange delivers the target molecule and closes the cycle.

Scheme 12. Asymmetric Synthesis of Multisubstituted Tetrahydrofuran via Pd/Rh Catalysis.

3.1.3. Enantioselective Michael Addition to α,β-Unsaturated Carbonyls

The Michael addition reaction is one of the powerful and valuable tools for forming C–X (X = C, O, N, S) bonds in organic synthesis.⁵⁷⁻⁶⁰ Recently, the Meggers and the Kang groups independently demonstrated synergistic dual catalysis by a chiral-at-metal Lewis acid and organocatalyst for the Michael addition of α,α-disubstituted aldehydes to α,β-unsaturated 2-acyl imidazoles (Scheme 13).^61,62 The chiral-at-rhodium complex Δ_Rh-S_C-Rh1 (81) was prepared as a single stereoisomer via the reaction of rhodium trichloride hydrate with 2-phenyl benzoxazole and subsequently with l-β-phenylalanine (Scheme 13a).⁶¹ It was found that Δ_Rh-S_C-Rh1 (81) acts as an excellent precatalyst for the Michael addition of 83 with 82, and the products 84 were isolated in high yields and up to 99% ee and 5.8:1 dr (Scheme 13b). It was shown that the protonation of the precatalyst released the amine l-β-Phe and formed the rhodium complex 85 after coordination with 82 in a bidentate fashion. The amine condenses with the aldehyde 83 to form the enamine intermediate 88, which was intercepted by 85. The hydrolysis of the resultant intermediate 86 yields the intermediate 87 that upon substrate exchange delivers the product 84 and closes the cycle. Kang utilized the combination of Δ-RhO (52) and diethylamine as a catalyst for the same reaction and observed a similar level of isolated yields and enantioselectivities (Scheme 13c).

Scheme 13. Example of Dual Catalysis of Chiral Lewis Acid Catalysis and Amine Catalysis.

Additionally, to increase the Lewis acidity of the chiral-at-metal catalysts, the Kang group incorporated a strongly electron-withdrawing 3,5-ditrifluoromethyl phenyl group in the ligand backbone of the chiral-at-rhodium complex Λ-RhO(Ar’) 93 (Scheme 14).⁶³ The newly designed complex 93 was found to be efficient for the asymmetric conjugate addition of p-vinylanilines 91 to 35, affording the products 92 with good yields (67–95% yield) and excellent enantioselectivities (86–95% ee). Mechanistically, substrate 35 is activated by the Rh(III)-complex 93 through bidentate N,O-coordination to form intermediate 94. The bulky tert-butyl group blocked the Si-face. The nucleophile 91 attacked the Re-face of 94 to form iminium cation 95. Rearomatization and protonation of the rhodium enolate 95 yielded the product-bound intermediate 96. Product 92 is released after the ligand exchange with the substrate. The aliphatic groups at the β-position of α,β-unsaturated 2-acyl imidazoles (Me, Et, ⁱPr, CO₂Et) were also equally compatible under the reaction conditions, affording the corresponding vinylated adducts 92 in 67–84% yields with 93–95% ee.

Scheme 14. Chiral-at-Rhodium Complex Catalyzed Asymmetric Conjugate Addition of p-Vinyl Anilines to α,β-Unsaturated 2-Acyl Imidazoles.

The asymmetric decarboxylative addition reaction is a valuable method for constructing C-X (X = C, O, N, S) bonds.⁶⁴ In the past decade, much progress has been made to develop catalytic asymmetric decarboxylative reactions with various organocatalysts⁶⁵ and the transition metal catalyst.⁶⁶ Recently, the enantioselective decarboxylative Michael addition of β-keto acids 99 to α,β-unsaturated 2-acyl imidazole 35d and α,β-unsaturated 2-acylpyridines 98 was explored using a chiral-at-rhodium(III) Lewis acid catalyst (Scheme 15).⁶⁷ The complex Λ-RhO(Ar) 101 having a 3,5-dimethyl phenyl group in the ligand backbone was found to be most effective for this transformation, delivering the products 100 in 94–98% yields with 88–96% ee. The α,β-unsaturated substrate has similarly been activated through bidentate N,O-coordination to form the intermediate 102. The nucleophilic attack then takes place from the Re-face to yield the rhodium enolate 103. Subsequent protonation, decarboxylation, and ligand exchange delivers the product 100 and closes the cycle. The practical utility of this protocol is demonstrated by a gram-scale reaction of α,β-unsaturated 2-acyl imidazoles with β-keto acid, affording the desired product in 98% yield with 96% ee. It was observed that when lowering the catalyst loading to 0.05 mol % the reactivity and selectivity remained unchanged.

Scheme 15. Chiral-at-Rhodium Complex Catalyzed Decarboxylative Michael Addition of β-Keto Acids.

Similarly, it was found that the chiral-at-rhodium Lewis acid 101 is highly efficient in catalyzing the enantioselective Michael addition of pyrazolones 105 to α,β-unsaturated 2-acyl imidazoles 35e (Scheme 16).⁶⁸ The products 106 were isolated in good yields (85–96% yield) and excellent enantioselectivities (up to >99% ee).

Scheme 16. Asymmetric Michael Addition of Pyrazolones by a Chiral-at-Rhodium Complex.

The collaborative work of the Du and Kang groups revealed an asymmetric reduction–Michael addition cascade for the coupling of α,β-unsaturated 2-acyl imidazoles 35 with malononitrile 107 catalyzed by chiral-at-metal rhodium catalyst 93 in the presence of a Hantzsch ester as the hydride source (Scheme 17).⁶⁹ The chiral-at-rhodium complex 93, having a 3,5-ditrifluoromethyl phenyl group in the ligand backbone, was found to be superior in reactivity and selectivity. The desired product 108 was obtained in up to 82% yield and up to 96% ee in CCl₄ solvent. The substrate 35 was similarly activated through the bidentate coordination with the chiral Rh(III) complex. On the other hand, the hydride transfer to 107 from the Hantzsch ester generated nucleophilic anionic intermediate 110, which attacked the Re-face of 111.

Scheme 17. Chiral-at-Rhodium Complex Catalyzed Cascade Reduction–Michael Addition Reaction.

Recently, our group proposed a new approach for the enantioselective C(sp³)–H bond functionalizations of 2-alkyl azaarenes via cooperative dual Lewis acid catalysis (Scheme 18).⁷⁰ The strategy utilizes the activation of unactivated azaarene partners 112 by an achiral Lewis acid catalyst. Cooperatively, a chiral-at-iridium Lewis acid catalyst enables LUMO lowering of α,β-unsaturated 2-acyl imidazoles 35 to induce chirality. The complex Λ-IrO(Ph) having a phenyl group in the ligand backbone was found to be the most effective chiral-at-metal Lewis acid catalyst, while among the achiral Lewis acid catalysts scandium triflate shows the best efficiency for this transformation, delivering products 113 in excellent yields (up to 99%) and good enantiomeric ratios (up to 1.9:98.1 er), tolerating a wide range of functionalities in both the coupling partner. It was proposed that a stronger scandium Lewis acid preferentially activates the more basic quinoline moiety 112, enabling the generation of nucleophilic metal enamine species 115. It was supported by speedy deuterium incorporation in the presence of scandium triflate. On the other hand, a chiral-at-iridium complex undergoes bidentate N,O-coordination with α,β-unsaturated acyl imidazole substrate 116, facilitating the LUMO activation. The nucleophilic attack could then take place from the Re-face to yield the iridium enolate 117. Subsequent protonation and ligand exchange could deliver product 113 and effectively close the catalytic cycle. The practical utility of this methodology was also demonstrated by the gram scale reaction obtaining the desired product in a high yield of 71% and a good enantiomeric ratio of 3.9:96.1 er.

Scheme 18. Enantioselective C(sp³)–H Bond Functionalization of 2-Alkyl Azaarenes Enabled by Cooperative Lewis Acid Catalysis.

The asymmetric vinylogous Michael addition of carbon and heteroatom nucleophiles to Michael acceptors is a powerful tool for constructing highly functionalized synthetic building blocks. Notably, the nitroisoxazole derivatives as carbon nucleophiles have attracted considerable attention due to the prevalence of isoxazole-containing units in several drugs and bioactive compounds.^71,72 Recently, the chiral-at-rhodium complex 67 has successfully been employed for the catalytic asymmetric vinylogous Michael addition of 5-methyl 4-nitrosoxazoles 119 to α,β-unsaturated 2-acyl imidazoles 35 (Scheme 19).⁷³ A substoichiometric amount of diisopropylethylamine was used as a base to facilitate the deprotonation of the nucleophile. The C5-substituted chiral oxazoles derivatives 120 were isolated in high yields (80–96% yield) and excellent enantioselectivities (90–96% ee). The stereochemical outcome of the product can be explained by the substrate’s activation via coordination with the Lewis acid catalyst and subsequent Re-face attack of the nucleophile.

Scheme 19. Chiral-at-Rhodium Complex Catalyzed Enantioselective Synthesis of C5-Substituted Chiral Oxazole Derivatives.

However, when the chiral-at-rhodium complex 127 catalyzed vinylogy was applied for α,α-dicyanoolefin substrates to construct molecular skeletons possessing potential bioactivities, poor yields or stereoselectivities were obtained. To boost the catalysis, a chiral-at-rhodium complex 127 with a bulky electron-rich, naphthyl-containing ligand was developed.⁷⁴ The complex efficiently catalyzed the enantioselective vinylogous Michael addition of α,α-dicyanoolefin 125 with α,β-unsaturated 2-acyl imidazoles 35 without the aid of a base (Scheme 20). The products 126 were obtained in high yields (up to 89%) and high enantioselectivities (up to 95%). A Re-face approach of the nucleophile 129 to the catalyst activated complex 128 explained the observed stereochemistry.

Scheme 20. Chiral-at-Rhodium Complex Catalyzed Enantioselective Michael Addition of α,α-Dicyanoolefins.

The Lewis acid catalyzed asymmetric aza-Michael reaction is a valuable synthetic tool for constructing nonracemic nitrogen-containing heterocycles.^75,76 In this context, the chiral-at-rhodium complex (Δ-RhO) 52 was found to be effective for catalyzing the enantioselective hydroamination of α,β-unsaturated 2-acyl imidazoles 35 with N-protected hydroxylamine 130 (Scheme 21).⁷⁷ Diverse N-protected β-amino acid derivatives 131 were isolated in up to 84% yields and up to 97% enantioselectivities. Among chiral-at-iridium and rhodium catalysts having a similar ligand framework, Δ-RhO displayed the best reactivity and selectivity. The bulkier N-substituent (ⁱPr, Ph vs Me) showed higher reactivity and selectivity. Based on the observed stereochemistry of the product, the author proposed a transition state model 132. The Re-face attack of the nitrogen center explains the observed stereochemistry.

Scheme 21. Enantioselective Hydroamination by a Chiral-at-Rhodium Catalyst.

A multifunctional catalytic system is one of the effective catalytic systems for double activation in metal-based or organocatalytic asymmetric reactions. In this case, two reacting substrates bind with the active sites already installed in the catalysts. This will make the two reacting substrates come close to each other in a disciplined manner, which increases the reaction rate and stereoselectivities. In this regard, Meggers and co-workers have reported inert octahedral 3-aminopyrazolato iridium(III) complexes 139 and 140 for the highly efficient asymmetric sulfa-Michael and aza-Henry reaction (Scheme 22). In the sulfa-Michael addition reaction, α,β-unsaturated N-acyl pyrazole reacts with the aryl thiol to provide the desired product 135 with high yield and excellent enantioselectivities. The bifunctional approach can justify the iridium complex’s role through the iridium catalyst’s hydrogen bonding after the proton transfer from the thiol where the catalyst acts as a Brønsted base (Complex 141, Scheme 22). Proton transfer from the thiol to the iridium complex makes an ion pair where the thiolate and cationic iridium complex are accumulated through a double hydrogen bond.

Scheme 22. Asymmetric Sulfa-metric Reaction and Aza-Henry Reaction by a Chiral-at-Iridium Catalyst.

On the other hand, α,β-unsaturated N-acyl pyrazole forms a hydrogen bond with the hydroxymethyl substituent of the benzoxazole moiety. Thus, two reactants arrange themselves via hydrogen bonding and electrostatic attraction, which enables the Michael addition reaction. The aza-Henry reaction was then studied. Fortunately, nitromethane substituent 136 and N-Boc Schiff base 137 gave the desired product 138 with 98% yield and 98% ee. The previously reported Ir(III) catalysts could not provide the aza-Henry reaction’s prime condition. However, the presence of an additional 3,5-^tBuC₆H₃ group increases the steric demand of the catalyst, which leads to the highest enantiomeric excess.

In this rapidly developing field, the Meggers group also developed a chiral-at-metal complex from earth-abundant iron rather than a noble transition metal (Scheme 23).⁷⁸ This catalyst with two chelating N-(2-pyridyl)-substituted N-heterocyclic carbene (PyNHC) ligands coordinates Fe(II) in a C₂-symmetric fashion. Two labile acetonitrile ligands coordinatively saturate the Fe(II) center.

Scheme 23. Asymmetric Hetero-Diels–Alder Reaction by a Chiral-at-Iron Catalyst.

The helicity obtained due to the steric of the achiral PyNHC ligands provided the chiral induction around the Fe(II) complex. The chiral-at-iron complex is capable of catalyzing the inverse electron demand hetero-Diels–Alder reaction between β,γ-unsaturated α-carbonyl ester 56 and enol ethers 142 to deliver 3,4-dihydro-2H-pyrans 143 in high yield with excellent diastereoselectivities (up to 99:1) and magnificent enantioselectivities (up to 98%). Even though this is outside the scope of this Review, we discuss this significant development for the convenience of the reader.

3.1.4. Other Reactions

In developing new methods toward the asymmetric preparation of multisubstituted benzofuran derivatives, the Kang and the Du group collaboratively explored the chiral-at-rhodium complex 93 as a Lewis acid catalyst for the enantioselective C2-alkylation of 3-aminobenzofurans 144 with 35 (Scheme 24).⁷⁹ The C2-substituted benzofuran derivatives 145 were obtained in good to excellent yields (76–99%) and excellent enantioselectivities (up to 98% ee). Even the reaction can be performed at the gram scale utilizing 0.5 mol % catalyst loading.

Scheme 24. Chiral-at-Rhodium Complex Catalyzed Synthesis of C2-Substituted Benzofuran Derivatives.

Optically active axially chiral molecules play a crucial role in organic chemistry as a chiral catalyst, building blocks of natural products, bioactive molecules, and functional materials.⁸⁰N-Arylpyrroles molecules are important biaryl molecules due to their specific electronic and structural properties. However, the catalytic asymmetric synthesis of N-arylpyrroles remains a vigorous challenge for synthetic chemists. Tan and co-workers developed combined Lewis acid and chiral phosphoric acid catalyzed asymmetric synthesis of N-arylpyrroles by the Paal–Knorr method.⁸¹ The same group reported the kinetic resolution of 2,5-disubstituted N-arylpyrroles to access highly enantioenriched products.⁸² However, the requirement of bulky ketoamides at the 3,4-positions at the pyrrole moiety poised limitations. In this context, Meggers et al. synthesized highly enantioselective axially chiral N-arylpyrroles via a direct electrophilic aromatic substitution reaction using a rhodium-based chiral Lewis acid catalyst in up to >99.5% ee (Scheme 25).⁸³ A functional group at the α-position of the pyrrole ring controls the rotation along the C–N bond and configurational stability.

Scheme 25. Synthesis of Axially Chiral N-Arylpyrroles by Chiral-at-Rhodium Catalysts.

3.2. HOMO Activation

The chiral-at-metal complexes have also been utilized as Lewis acid catalysts for the HOMO activation strategy. The following section summarizes such reactions.

3.2.1. Transfer Hydrogenation of Carbonyls

Asymmetric transfer hydrogenation is a powerful approach to reduce organic compounds without using flammable hydrogen gas.⁸⁴ Notably, this field has made significant advances, and several new catalysts have been developed. In this regard, the Meggers group explored bis-cyclometalated chiral-at-iridium(III) complex Λ-IrS 41 for the enantioselective transfer hydrogenation of ketones using ammonium formate as the hydrogen source (Scheme 26).⁸⁵ The combination of Λ-IrS (0.002–1.0 mol %) and pyrazole (10 mol %), as a coligand, in THF/H₂O (1:1) solvent delivered the reduced alcohol products 154 in high yields and excellent ee (up to 99% ee). Among the various coligands examined, 5-(4-methoxyphenyl)-3-methyl-1H-pyrazole markedly improved the yields and selectivities. The reaction was efficient even at low catalyst loading up to 0.002 mol % without significantly affecting the conversion and the selectivity. It was proposed that the labile acetonitrile group in Λ-IrS undergoes fast ligand exchange with the pyrazole. Then the active iridium hydride species is generated upon reaction with ammonium formate. In the transition state 155, the aromatic ring of the ketone forms π–π stacking with the benzothiazole ligand of Λ-IrS (41). The N–H group of the ancillary pyrazole ligand plays a vital role by forming a hydrogen bond with the ketone oxygen.

Scheme 26. Chiral-at-Iridium Complex Catalyzed Enantioselective Transfer Hydrogenation of Ketones.

3.2.2. Mannich Reaction

The Mannich reaction is one of the most fundamental and widely used reactions for constructing C–C and C–N bonds in organic synthesis, withstanding large varieties of functional groups. In this case, a chiral-at-metal Lewis acid catalyst was also found to be effective for the enantioselective Mannich reaction of 2-acyl imidazole 156 with 1,3,5-triaryl-1,3,5-triazines 157 (Scheme 27).⁸⁶ Using chiral-at-rhodium complex 101 as the catalyst (0.1–0.2 mol %), a variety of β-amino carbonyls 158 were obtained in high yields (up to 99%) and excellent enantioselectivities (up to >99%). The reaction can be performed at the gram scale using a 0.1 mol % catalyst loading, and the product was obtained in 95% yield without loss in enantioselectivity (95% ee). It was proposed that the substrate 156 coordinates at the Lewis acidic rhodium center replacing the acetonitrile ligand. Subsequent deprotonation generates the rhodium enolate 159, which attacks the imine 160 from the Re-face to yield enantioenriched β-amino carbonyls 158.

Scheme 27. Chiral-at-Rhodium Complex Catalyzed Enantioselective Mannich Reactions.

The multicomponent Mannich reaction with aldehydes and amine derivatives provides facile access to β-amino carbonyl structures with two or more stereocenters.^87,88 Chiral-at-metal complexes have also been explored for the three-component Mannich reaction of N-acyl pyrazole 161, aldehyde 162, and primary or secondary amine 163 (Scheme 28).⁸⁹ The chiral-at-metal rhodium complex 67 operated at 0.5–1 mol % loading delivered the desired products in good yields of 60–90% and excellent enantioselectivities of 91–98% ee. The proposed reaction mechanism involved the in situ formations of an iminium intermediate 166 followed by its Re-face attack at the in situ generated rhodium enolate 165 to deliver products 164.

Scheme 28. Chiral-at-Rhodium Complex Catalyzed Asymmetric Three-Component Mannich Reaction.

The catalytic enantioselective oxidative Mannich reaction using molecular oxygen as a terminal oxidant was developed recently (Scheme 29).⁹⁰ The chiral-at-rhodium catalyst 67 combined with a catalytic amount of TFA enabled the C(sp³)–C(sp³) cross dehydrogenative coupling of 2-acyl imidazole 167 and imino ester 168. Product 169 having two successive stereocenters was obtained in good yields (69–85%) and excellent enantioselectivities (96–98% ee). However, under the same reaction conditions, the analogous chiral-at-iridium catalyst fails to give the desired products. It is proposed that an in situ generated rhodium-enolate 170 reacts with the oxidatively generated carbon electrophiles 171 from the Re-face to yield the products in high selectivities.

Scheme 29. Chiral-at-Rhodium Complex Catalyzed Asymmetric Dehydrogenative Cross-Coupling.

3.2.3. Addition to Nitro Alkenes

The highly Lewis acidic chiral-at-rhodium complex 93 with a 3,5-ditrifluoromethyl phenyl group in the ligand backbone was also found to be effective for the enantioselective conjugate addition of 2-acyl imidazoles 171 to nitroalkenes 173 (Scheme 30).⁹¹ The γ-nitro ketone derivatives 174 were synthesized in good yields (up to 99%) and excellent enantioselectivities (up to >99% ee). The stereoselectivity can similarly be assigned by the Re-face attack of the in situ rhodium enolate 175 to the nitroalkene electrophile 176.

Scheme 30. Chiral-at-Rhodium Complex Catalyzed Asymmetric Conjugate Addition to Nitroalkenes.

3.2.4. α-Amination of Carbonyls

In 2015, the Meggers group disclosed chiral-at-rhodium complex 67 catalyzed α-amination of 2-acyl imidazoles 171a using dibenzyl azodicarboxylate 178 as the electrophilic nitrogen source (Scheme 31).⁹² The rhodium complex 67 displayed a better catalytic activity than the analogous iridium complex. The products 179 were isolated in high 64–95% yields and excellent enantioselectivities (90–97% ee). The Re-face attack of the in situ generated rhodium enolate 180 analogously explains the observed stereoselectivity.

Scheme 31. Chiral-at-Rhodium Complex Catalyzed Enantioselective α-Amination Reaction.

3.2.5. α-Fluorination of carbonyls

The Xu group utilized a similar approach for the asymmetric α-fluorination of 2-acyl imidazoles 171 using selectfluor as the fluorinating agent (Scheme 32).⁹³ The chiral-at-iridium complex Δ-IrS 181 catalyzed the reaction in 4 mol % loading, delivering the α-fluorinated ketones 182 in good yields (60–97%) and excellent enantioselectivities (77–99% ee). The formation of N,O-coordinated Z-iridium enolate 183 and the attack from the Si-face were proposed to explain observed stereoselectivity.

Scheme 32. Chiral-at-Iridium Complex Catalyzed Enantioselective α-Fluorination Reaction.

4. Visible-Light-Induced Asymmetric Catalysis

In the past decade, visible-light-induced organic transformations have become a versatile synthetic tool for forging organic molecules in an environmentally benign way.^94,95 The enantioselective variant of such a reaction is in the developing phase. The progress is challenged by the requirement to combine the asymmetric catalysts with the photocatalytic process, which invariably involves short-lived reactive species, including excited state photocatalysts, radicals and radical anions, or cations.⁹⁶ Generally, the visible-light-induced asymmetric transformation employs a dual catalytic system where an achiral photocatalyst is accountable for the photochemistry and a chiral catalyst is responsible for the stereodifferentiation.⁹⁷ Moreover, there are single catalytic systems that can interface the visible-light photocatalysis and asymmetric catalysis. In such a case, a single catalyst would provide a new mechanistic pathway that can give control over the entire reaction pathway, especially at the most crucial stereocontrol step. The following section summarizes the chiral-at-metal complex catalyzed asymmetric photocatalysis.

4.1. Asymmetric Synthesis of α- and β-Functionalized Carbonyls

4.1.1. Alkyl Halide/Borate as an Alkyl Radical Precursor

Photocatalysis offers convenient access to radical intermediates from unconventional precursors R–X (R = alkyl group, X = I, Br) by breaking a relatively weak bond. In the initial stages of the investigation for asymmetric catalysis with chiral-at-metal complexes, Meggers and co-workers realized that an electrophilic alkyl radical could be generated from a benzyl bromide precursor 186 in the presence of a light source by the assistance of excited chiral-at-iridium catalyst 41 (Scheme 33a).⁹⁸ In this process, the sole chiral-at-iridium complex 41 simultaneously serves as the chiral Lewis acid and the photoredox catalyst. The electrophilic alkyl radical then combines with the enolate complex 188, formed by the bidentate coordination of 2-acyl imidazole 171 with 41. The reaction tolerates the electronically biased aryl bromide substituents, and the α-alkylated products 187 were obtained in up to 100% yield and up to 99% enantioselectivity in the presence of a weak base Na₂HPO₄.

Scheme 33. Enantioselective α-Alkylation Reactions.

A general mechanism is depicted in Scheme 33. The catalytic cycle started with the bidentate coordination of the substrate by replacing two labile acetonitrile groups of Λ-IrS complex. The α-deprotonation of the resultant intermediate 188 forms the iridium enolate complex 189. The cyclovoltammetry and photoluminescence study proved that the complex 189 acts as a photosensitizer in the reaction medium. Visible light irradiation excites the enolate complex 189, enabling single-electron transfer (SET) to the electron-deficient halide substrate 186. Mesolysis of the resultant radical anion yields an electron-deficient radical intercepted by the iridium enolate complex and generates the iridium ketyl radical complex 190. The product was then ejected via SET and ligand exchange.

The strategy was further extended for the enantioselective trichloromethylation of 2-acyl imidazoles and 2-acylpyridines,⁹⁹ and α-perfluoroalkylation of 2-acyl imidazoles (Scheme 33b).¹⁰⁰

The Xu group found that an iridium complex Ir(ppy)₂(dtbbpy)PF₆ is necessary as a photosensitizer for the chiral-at-rhodium complex 152 catalyzed α-functionalization of acyl imidazole 171b (Scheme 34).¹⁰¹ Under these conditions, a variety of chiral gem-difluoroalkyl group containing γ-keto amides 196 and a series of fluorine-containing α,β-unsaturated-γ-keto esters 197 were afforded in excellent yields and excellent stereoselectivities. Experimentally, it was observed that the in situ formed Rh-enolate 198 is capable of reductively quenching the visible-light excited photocatalyst [{Ir(ppy)₂(dtbbpy)}⁺]*. The reduced photocatalyst [PC]^(n-1)+ involved a single electron transfer with 195, generating the difluoroacetyl radical, which subsequently combines with the electron-rich double bond of 199. The generated intermediate 200 then quenched the excited photocatalyst [PC*]ⁿ⁺ and produced 201 and the reduced photoredox sensitizer [PC]⁽ⁿ⁻¹⁾⁺. The ligand exchange via path A yields the difluoroalkylated product 196. On the other hand, the α,β-unsaturated γ-keto ester 197 was formed via E1cB elimination and ligand exchange (path B). Further, the quantum yield of the difuoroalkylation reaction was determined as 2.00, suggesting the involvement of a radical chain process. Moreover, the chemoselectivity of this process was found to be dependent on the fluorine reagents besides the Lewis acid catalysts.

Scheme 34. Visible-Light-Mediated Enantioselective α-Amination and α-Alkylation Reaction Enabled by a Chiral-at-Rhodium(III) Catalyst.

In 2016, the Meggers group utilized organotrifluoroborates 205 as the alkyl radical precursor for enantioselective alkyl radical addition into Michael acceptors (Scheme 35).¹⁰² A chiral-at-rhodium Lewis acid catalyst 207 catalyzed the reaction in the presence of [Ir{dF(CF₃)ppy}₂(bpy)]PF₆ or [Acr-Mes]ClO₄ as a photoredox catalyst under visible-light irradiation. The enantioenriched β-alkylated carbonyl derivatives 206 were generated in up to 97% yields and 99% ee. This reaction tolerates a wide range of substrates having diverse functionalities. By a competition experiment, the authors determined that the rhodium coordination increases the radical addition rate to the α,β-unsaturated electrophiles by a factor of at least 3 × 10⁴. The observed high enantioselective radical addition at a low loading of the chiral Lewis acid can thus be explained. The postulated reaction mechanism involves a carbon-centered radical generation from 205 by a photoinduced single electron transfer mechanism. The coupling of the produced radical with N,O-rhodium coordinated α,β-unsaturated electrophile 204’ gives the intermediate 208. A SET reduction produced the rhodium enolate 209. Protonation and ligand exchange released product 206 and closed the cycle.

Scheme 35. Enantioselective Radical Addition to α,β-Unsaturated Carbonyls.

4.1.2. Alkyl Amine as α-Amino Radical Precursors

In the past decade, α-amino radicals have been used as reactive open-shell intermediates, capable of engaging in a plethora of synthetic transformations providing amine-containing chemical motifs with a wide range of applications.^103,104 Classically, α-amino radicals can be derived from different pathways.^105,106 One such route involves leaving groups such as TMS (trimethylsilyl) in alkyl amine, which oxidatively generates the α-amino radical intermediates after photocatalytic C–Si bond cleavage. Meggers et al. exploited the enantioselective α-functionalization of acyl-imidazole 171c using silyl amine 211 as an α-amino radical precursor using a chiral-at-iridium photosensitizer 34 and air as the terminal oxidant under visible-light irradiation (Scheme 36).¹⁰⁷ The enantioselective amino alkylation products were isolated in 61–93% yield and excellent 90–98% ee. The reductive quenching of the excited photocatalyst by 217 afforded the corresponding iminium ion 219 via photoinduced electron transfer, loss of Me₃Si⁺, and oxidation. The iminium ion 219 was then trapped by the chiral enolate complex 215 and led to the formation of α-functionalized ketone 216. Amazingly, the single iridium complex simultaneously serves three distinct functions: the exclusive source of chirality, the catalytically active Lewis acid, and a photoredox catalyst.

Scheme 36. Visible-Light-Mediated Enantioselective Oxidative α-Amino Alkylation with a Single Chiral-at-Iridium(III) Catalyst.

The Kang group utilized tetrahydroisoquinoline as the α-amino radical precursor for the chiral-at-rhodium complex Λ-RhO(Ar’) 93 catalyzed enantioselective functionalization of α,β-unsaturated electrophile 35c (Scheme 37).¹⁰⁸ The substrate-bound rhodium complex 222 served as a photoredox mediator (PS), which delivers the α-amino radical 226 after excitation, SET, and deprotonation processes. Subsequently, the radical 226 reacts with 222 to generate α-radical intermediate 223. The SET process followed by protonation and ligand exchange liberated the product 221 and closed the cycle. The single chiral-at-rhodium complex served as the Lewis acid and the photoredox catalyst. The desired products 221 were isolated in 74–86% yields with 92–96% ee.

Scheme 37. Chiral-at-Rhodium Complex Catalyzed Enantioselective Conjugate Addition of α-Amino Radicals to Michael Acceptors.

The enantioselective synthesis of α-amino carbonyls has also been achieved by the photoinduced stereocontrolled radical–radical coupling between electron-deficient trifluoroacetyl imidazole 227 and amine derivatives 228 involving the same chiral-at-iridium complex 34 as a photocatalyst (Scheme 38).¹⁰⁹ It is proposed that, under visible-light irradiation, two substrates, one electron donor 228 and one electron acceptor 227, are involved in electron exchange, creating two odd-electron species. The bidentate coordination of 227 with the iridium complex makes it a strong photo-oxidant. A single electron transfer from the amine donor 228 results in the ketyl radical complex 234. A radical–radical coupling and the ligand exchange delivered the desired products 230 in up to 97% yields and up to 99% ee. However, the less electron deficient 2-acetyl imidazole fails to give the desired products.

Scheme 38. Visible-Light-Mediated Enantioselective Radical–Radical Cross-Coupling Reaction Enabled by a Chiral-at-Iridium(III) Catalyst.

N-(Acyloxy)phthalimides are another class of precursors of α-aminoalkyl radical intermediates via photoinduced reductive decarboxylation.¹¹⁰ The chiral-at-rhodium complex 207 was utilized for the visible-light-mediated β-aminoalkylations of α,β-unsaturated N-acylpyrazole 239 using glycine derived N-acyloxy phthalimides 237 as the precursor (Scheme 39).¹¹¹ The Hantzsch ester was used as a sacrificial reductant. Notably, complex 207 serves as both the photoredox catalyst and the chiral Lewis acid catalyst.

Scheme 39. Decarboxylative Conjugate Addition to Alkene through Enantioselective Photoredox Catalysis.

A wide range of β-substituted chiral γ-amino butyric acids 240 were synthesized in up to 89% yields and 99% ee. Using β-fluoro-α,β-unsaturated N-acylpyrazole substrate, a library of β-fluoro-β-aryl-γ-aminobutyric acid derivatives has also been synthesized under these conditions in up to 80% yields and 96% ee. The importance of this protocol is highlighted by synthesizing Boc-(S)-nebracetam 243 and β-substituted chiral γ-aminobutyric acids such as (R)-balcofen and (R)-rolipram derivatives. Mechanistically, the ground state N,O-coordinated rhodium complex 244 undergoes a photoinduced SET reduction of 237 to yield the α-aminoalkyl radical 247, eliminating CO₂ and phthalimide. Adopting the unique property of 244, the enantioselective addition of 247 takes place where the metal-centered chirality controls the selectivity.

4.1.3. Nitrogen-Centered Radicals (NCRs)

Nitrogen-centered radicals (NCRs) are a versatile class of highly reactive species. A wide variety of methods can generate NCRs via a SET reduction pathway or the energy transfer pathway under mild conditions.^112,113 Depending on the hybridization and substitution patterns, NCRs can serve as electrophiles or nucleophiles.¹¹⁴ In this context, the Meggers group highlighted the use of (ODN)-N-functionalized carbamates 248 (ODN = 2,4-dinitrophenylsulfonyloxy) to access the corresponding NCRs and their enantioselective coupling with 2-acyl imidazole 171c (Scheme 40).¹¹⁵ A chiral-at-rhodium complex at 2 mol % loadings catalyzed the reaction in the presence of 2,6-lutidine. The products 251 were isolated in up to 99% yields and 98% ee in a short reaction time under visible-light irradiation. It was proposed that, upon photoactivation, the in situ generated rhodium enolate complex 253 underwent efficient SET to 248. Subsequent fragmentation generates a sulfonate anion 256 and the electrophilic aminyl radical 250, which then is successively intercepted by the enolate 253. It is worth mentioning that a chiral-at-iridium complex with an identical ligand environment fails to catalyze the reaction. The authors attributed the preferences for rhodium over iridium to the much faster ligand exchange kinetics of the rhodium complexes, which is crucial to control the highly reactive and short-lived nitrogen-centered radical intermediates.

Scheme 40. Visible-Light-Mediated Enantioselective α-Amination Reaction Enabled by a Chiral-at-Rhodium(III) Catalyst.

Organic azides have long been known as versatile and valuable precursors for the NCRs via the extrusion of molecular N₂. The resulting reactive intermediates can be conveniently employed to synthesize various cyclic and acyclic nitrogen-containing compounds. In this regard, the asymmetric α-aminations of 2-acyl imidazoles 171 using organic azides 257 have recently been obtained via a combination of chiral-at-rhodium(III) Lewis acid 207 and a secondary photosensitizer such as Ru(bpy)₃PF₆ (Scheme 41).¹¹⁶ The latter has been used to counterbalance the restricted photochemical properties of the in situ generated rhodium enolate 262. The products 260 were isolated in good yields up to 90% and 99% ee, tolerating different substituents in the aryl azide 257 coupling partners. It was proposed that, upon visible-light irradiation, the nitrogen-centered radicals are generated via SET from strongly reducing [Ru(bpy)₃]⁺ to the organic azide substrate, followed by N₂ extrusion and protonation. The subsequent stereoselective addition of these electron-deficient radicals to the electron-rich double bond of the rhodium enolate 262 constitutes the chirality generating step and provides the Rh-coordinated ketyl radical 263. The oxidation of ketyl radical leads to a Rh-coordinated product, which engages in a new catalytic cycle after product elimination.

Scheme 41. Visible-Light-Mediated Enantioselective α-Amination and α-Alkylation Reaction Enabled by a Chiral-at-Rhodium(III) Catalyst.

The proton-coupled electron transfer (PCET) is another innovative strategy to convert N–H into NCRs.^117,118 Recently, in the presence of a mild phosphate base, the PCET strategy was devised for the photoinduced enantioselective β-amination of α,β-unsaturated 2-acyl imidazoles 35e with the aid of 267 as the photoredox catalyst (PC) and chiral-at-rhodium complex 52 as a Lewis acid catalyst (Scheme 42).¹¹⁹ The desired products 268 were obtained in excellent yields (up to 98%) and enantioselectivities (up to 99% ee), tolerating a wide range of electron-rich and electron-deficient functionalities in both coupling partners. The intermediate N-centered radical formation was verified by an intramolecular radical trapping to an alkene 270 followed by the reaction of the formed carbon-centered radical with the unsaturated 2-acyl imidazole 35e. In addition, the formation of the enolate radical 273 is experimentally evidenced by the appearance of cyclobutane 271 in the absence of the Rh catalyst. The construction of 271 is viable by photoredox-mediated [2 + 2] cycloaddition through the single electron reduction of 35f.

Scheme 42. Enantioselective Catalytic β-Amination through Proton-Coupled Electron Transfer.

4.1.4. Via 1,5 Hydrogen Atom Transfer

Hydrogen atom transfer (HAT) often enables selective generation of R^• via the direct activation of R–H bonds. In recent years, photocatalysis has contributed to developing this field boosted by the visible-light absorbing transition metal complexes¹²⁰ and organic dyes.⁹⁵ It is well-known that the alkoxy radical is susceptible for the hydrogen atom abstraction from the δ-carbon atom via a 1,5-HAT process. Recently, a combination of a chiral-at-rhodium Lewis acid catalyst and fac-[Ir(ppy)₃] as a photoredox catalyst has been applied for the enantioselective C(sp³)–H functionalization of N-alkoxy phthalimides 278 via a 1,5-HAT process (Scheme 43).¹²¹ α,β-Unsaturated N-acyl pyrazoles 279 acts as the radical acceptor and a Hantzsch ester is used as the terminal reductant. Following the absorption of visible light, the excited state fac-[Ir(ppy)₃]* is reductively quenched by the Hantzsch ester. The generated reduced state of the photocatalyst then transfers a single electron to N-alkoxyphthalimide substrate 280. It triggers a homolytic N–O bond cleavage, yielding an alkoxy radical 281, which then undergoes intramolecular 1,5-HAT. The formed C-centered radical 282 then adds to the rhodium-activated enone substrates in an asymmetric fashion that delivers the desired product 280 in 49–85% yields and 82–97% ee.

Scheme 43. Enantioselective Translocated Radical Addition to Alkene via Visible-light Photoredox Catalysis with a Chiral-at-Rhodium(III) Complex.

The Meggers group reported the chiral-at-rhodium complex catalyzed asymmetric photorearrangement of 3-(2-formylphenyl)-1-pyrazol-1-yl-propenone substrate 283 (Scheme 44).¹²² Mechanistic experiments and DFT computations suggest that, upon visible-light absorption, the rhodium bound α,β-unsaturated N-acyl pyrazole complex 283 undergoes a π–π* photoexcited state and generates the diradical rhodium complex 287. The aldehyde moiety present nearby suffers a HAT process. The resultant intermediate 289 then undergoes an intramolecular hetero-Diels–Alder reaction, and the product 285 is liberated after ligand exchange. The synthetic utility of this methodology was further demonstrated by gram scale reactions that afforded the product with an improved yield of 90% and 99% ee. The chiral-at-rhodium complex can be recovered in 86% yield. Further, the deuterium-labeling experiment varifies the HAT process where the deuterium in aldehydic position ended up forming a deuterated cyclopropane ring in 78%.

Scheme 44. Photoinduced Asymmetric Intramolecular HAT Reaction.

4.1.5. Visible-Light Mediated β-Functionalization of Carbonyls

Allyl sulfones are versatile radical acceptors for allylation reactions. However, the fragmented sulfonyl radicals are often discarded as waste. The Meggers group demonstrated reductive β-allylation of α,β-unsaturated 2-acyl-pyrazole 292 with allyl sulfones 293 as the allylating agent, and simultaneously, the generated waste sulfonyl radicals were used via a radical addition for the synthesis of nonracemic β-sulfonyl carbonyls (Scheme 45).¹²³ A chiral-at-rhodium complex catalyzed the reaction, efficiently controlling the stereochemistry in the visible-light-generated prochiral radical addition for the allylation reaction and the asymmetric sulfonyl addition reaction. A stoichiometric amount of Hantzsch ester 294 served as a sacrificial reductant. The author suggested that the visible-light-activated Hantzsch ester [E^(HE•+/HE*) = −2.23 V vs Fc/Fc⁺] can efficiently reduce the Rh-coordinated substrate RhO-297 (−1.62 V vs Fc/Fc⁺) to form rhodium enolate radical 298. The free substrates (−2.59 V vs Fc/Fc⁺ for 292) could not efficiently quench the luminescence of HE. The generated Rh-coordinated radical intermediate 298 can be trapped by allyl sulfone and produce the chiral β-substituted product 295 in high yields and up to 97% ee. Successive fragmentation of 299 would result in a sulfonyl radical that can efficiently trap RhO-297 to yield 296 in high yields and up to 89% ee.

Scheme 45. Enantioselective C–C Bond Formation via Stereocontrolled Coupling.

In recent years, it has been found that 4-alkyl substituted Hantzsch ester (HE) derivatives are excellent precursors for alkyl radicals under photocatalytic conditions.^124,125 In the presence of a photoredox catalyst, it undergoes single-electron oxidation, which homolytically cleaves the C–C bond of the 4-position of the HE to generate free alkyl radicals. The Meggers group developed a systematic and feasible catalytic asymmetric Giese reaction using a rhodium-based chiral Lewis acid catalyst and 4-alkyl substituted Hantzsch ester as a reasonable radical precursor (Scheme 46).¹²⁶ The rhodium complex 152 performed a dual role in this reaction as a visible-light-absorbing unit after substrate binding and as the sole source of chirality.

Scheme 46. Asymmetric β-Alkylation of α,β-Unsaturated Acyl Imidazole.

This procedure provides β-functionalized 2-acyl imidazole derivatives 304 in quantitative yields and excellent enantioselectivities (up to 98%). The substrate-bound rhodium complex 306 absorbs in the visible region. The photoexcited rhodium complex acts as a strong oxidant (E^red* = +0.88 V Fc/Fc⁺) and transfers a single electron to the HE derivative (E_p^Ox = +1.03 V Ag/AgCl) and forms HE^•+, which undergoes C–C bond fragmentation to generate the free alkyl radical. Now, the radical can react in two ways. The radical can be captured by the reduced rhodium bound substrates (enolate radical anion 308) to form intermediate 309 that, after protonation and ligand exchange, gives the desired product 304. Alternatively, the radicals generated from the HE derivative can engage in radical addition reactions with 306 to form intermediate 311. Subsequent SET reduction, protonation, followed by ligand exchange liberated the desired product 304.

The enantioselective synthesis of β-dicarbonyls 314 has been achieved by merging the neutral eosin-Y as a HAT catalyst and Λ-RhS complex 207 as a chiral Lewis acid catalyst (Scheme 47).¹²⁷ The protocol tolerates a variety of primary aliphatic aldehydes 313 at a lower temperature, delivering the enantioenriched products 314 in moderate yields (23–60%) and moderate to excellent ee (61–94% ee). The aryl aldehydes displayed a lower reactivity, and the reactions had to be conducted at 30 °C to achieve synthetically useful conversions. Under these conditions, electron-neutral, electron-rich, and electron-deficient aryl aldehydes reacted to afford the desired products in moderate yields (32–46%) and good to excellent enantioselectivities (76–99% ee). The direct oxidation of 313 to an acyl radical by the neutral eosin-Y is not possible (E^S*^/S– = +0.83 V vs SCE in CH₃CN/H₂O). The author described acyl radical generation via polarity matching a HAT process with the photoexcited eosin-Y. The N,O-coordinated Rh-complex 315 then intercepts the acyl radical to deliver the intermediate 316. A reverse HAT reaction with eosin–Y-H completes the HAT catalytic cycle and generates the Rh-coordinated product 317, which upon ligand exchange liberates the product 314.

Scheme 47. Asymmetric synthesis of 1,4-Dicarbonyls via the Merging of HAT Catalysis with Chiral Lewis Acid Catalysis.

While different methods are available for introducing functionalities at the β-position of the carbonyls with soft nucleophiles, β-functionalization via direct activation of the β-C(sp3)–H bond is challenging. Recently, chiral-at-rhodium complex 321 catalyzed asymmetric β-C(sp³)–H functionalization of α,β-unsaturated carbonyls 318 with 1,2-dicarbonyls 319 has been accomplished (Scheme 48).¹²⁸ Under visible-light irradiation, the ketyl radical 325 is generated from photoexcitation of the rhodium enolate complex 323 via SET. The resultant radicals 324 and 325 subsequently combine to deliver the intermediate 326. The protonation and ligand exchange then liberate the products 320. Notably, a related iridium complex (Δ-IrS, 41) failed to promote this transformation. Further, the control experiments with the radical trapping agent indicate the intermediacy of β-carbon radical enolate intermediate 324.

Scheme 48. Enantioselective β-C–H Functionalization of Acceptor Substituted Ketones with 1,2-Dicarbonyl Compounds.

4.2. Photocycloaddition Reaction

The photoinduced cycloaddition reaction is one of the frequently used chemical reactions to construct ring systems.¹²⁹ In this context, Meggers et al. explored the chiral-at-rhodium complex 152 catalyzed visible-light-mediated [2 + 2]-cycloaddition reaction for the catalytic asymmetric dearomatization of benzofuran 331 and benzothiophene 332 derivatives (Scheme 49a).¹³⁰ The reaction presumably proceeds through the association of N-acyl pyrazolyl substrate 328 with the rhodium complex 152. After absorbing blue light, the latter gets excited to its singlet excited state 334. The highly reactive diradical 335 is then generated after intersystem crossing (ISC). An olefin then stereoselectively combines with 335 to create 1,4-diradical 336. Subsequent recombination results in the products 331 and 332 in high yields with excellent ee (up to 99%) and dr (up to 20:1).

Scheme 49. Chiral-at-Rhodium Complex Catalyzed Asymmetric [2 + 2] and [2 + 3] Cycloaddition Reactions under Visible-Light Irradiation.

Similarly, under visible-light irradiation, the chiral-at-rhodium complex 152 catalyzed the asymmetric [2 + 2]²⁰ and [2 + 3]¹³¹ photocycloaddition reactions of α,β-unsaturated 2-acyl imidazoles 338 with alkene 339 and vinyl azide 340, respectively (Scheme 49b). The enantioenriched cyclobutanes 341 and 1-pyrrolines 342 were synthesized in high yields with broad substrate scope and excellent enantiomeric and diastereomeric ratios.

The chiral-at-rhodium complex 207 catalyzed enantioselective [3 + 2] photocycloaddition of acyl cyclopropane 343 with alkene 344 and alkyne 345 was accomplished under visible-light irradiation with an aliphatic amine as a sacrificial reductant (Scheme 50).¹³² Previously inaccessible chiral cyclopentanes 346 and cyclopentenes 347 were isolated in up to 99% yields with excellent enantioselectivities of up to >99% ee. The authors indicated that the substrate coordination to the Lewis acid catalyst lowers the reduction potential, creating a strongly oxidizing excited state that a mild reducing agent can reduce. The resulting reduced complex 350 then opens the cyclopropane ring to yield 351 that consecutively reacts with alkene 344 and alkyne 345, leading to the formation of chiral cyclopentane 346 and cyclopentene 347 derivatives, respectively.

Scheme 50. Visible-Light-Induced [3 + 2] Cycloaddition Reactions.

4.3. Multicomponent Coupling Reaction

The multicomponent reaction is an attractive strategy for constructing two or more new chemical bonds that generate molecular complexity from simple substrates.¹³³ Meggers et al. reported an exciting application of a chiral-at-rhodium Lewis acid catalyst 133 and 4,4′-difluorobenzil 341 photoredox mediator for the asymmetric three-component fluoroalkylation reaction generating a diverse library of fluoroalkyl-containing chiral compounds (Scheme 51).¹³⁴

Scheme 51. Visible-Light-Mediated Three-Component Asymmetric Fluoroalkylation Reaction.

Under visible-light irradiation, the photoredox mediator enabled the SET oxidation of perfluoroalkylsulfinate 353 substrates. The generated perfluoroalkyl radicals R_F^• are trapped by the electron-rich vinyl ether 354 to deliver α-oxy carbon-centered radicals 359. The latter was subsequently intercepted by the rhodium-coordinated α,β-unsaturated N-acyl pyrazoles 360 in a stereocontrolled fashion. The nonracemic fluoroalkyl containing products 356 were isolated in high yields (up to 98% yields) and excellent selectivities (up to 98% ee and up to 6:1 dr).

4.4. Other Reactions

Recently, Meggers and co-workers described the catalytic α-deracemization of ketones 363 having a stereocenter at the α-position of the pyridylketones via deprotonation/enantioselective protonation induced by the chiral-at-metal Λ-RhInd to obtain the nonracemic pyridylketone 364 up to 97% ee (Scheme 52).¹³⁵ Here, the chiral-at-metal Rh(III) complex not only creates the chiral environment during deracemization but also instigates the redox process. Notably, a tertiary amine serves as the electron donor, HAT reagent, and proton source. The proposed mechanism of photo-deracemization of the pyridylketone is described. A mixture of two diastereomeric configurations [(R)-365 and (S)-365] is formed when the racemic pyridylketone substrate undergoes bidentate N,O-coordination with the chiral-at-rhodium complex. The Rh(III) complex 365 is excited under visible-light irradiation to generate 366. The latter undergoes SET with the tertiary amine to form rhodium ketyl radical complex 367, which experiences HAT from the radical cation of the tertiary amine to give rise to rhodium enolate complex 368. Diastereoselective proton transfer from the protonated amine to the rhodium enolate complex forms rhodium coordinated ketone 365 as a single diastereomer. Detachment of the nonracemic ketone leads to a new catalytic cycle.

Scheme 52. α-Deracemization of Ketone Enabled by a Chiral-at-Rhodium Catalyst.

Cyclic imines are present in a wide range of natural products and synthetically useful organic molecules.¹³⁶ Among those, pyrroline moieties are even more important because of their diverse biological activities.¹³⁷ Over the last decades, significant progress has been made in photoredox catalysis for the synthesis of racemic pyrroline.^138,139 In 2020, the Alemán group synthesized optically active substituted cyclic imines by a photoredox/chiral-at-rhodium(III) dual catalytic strategy (Scheme 53).¹⁴⁰ This procedure requires acyl imidazole 369 and ketimines 370 to provide the substituted cyclic imines 371 via a HAT, radical coupling, and cyclization process. The desired products were obtained in high yields and excellent enantioselectivities, tolerating a broad range of functional groups. Scheme 53 illustrates the proposed mechanism. The Λ-RhS complex was coordinated with the acyl imidazole substrate to form intermediate 372. At the same time, the excited photocatalyst *Ir(III) oxidizes DABCO to form a radical cation, which abstracts the hydrogen atom from intermediate 372 to generate radical intermediate 373. In another cycle, the reduced photocatalyst Ir(II) reduces the ketimines to A/B and regenerates the photocatalyst. After that, α-amino radical A reacts with the alkyl radical in an enantiocontrolled fashion to provide intermediate 374. The intramolecular cyclization process delivers intermediate 375, which releases water to yield the enantioenriched cyclic imines.

Scheme 53. Enantioselective Synthesis of Pyrroline Derivatives via a Radical Polar Cascade Reaction.

5. Electricity Driven Asymmetric Catalysis

Electricity-driven organic synthesis avoiding the stoichiometric amount of chemical oxidant or reductant has become a rapidly growing field in the last decades.^141−146 However, due to the presence of highly reactive radicals and ionic intermediates on the catalyst surface, it is very challenging to merge asymmetric catalysis with organic electrosynthesis, and limited success is achieved.^147,148 In this regard, the Meggers group has utilized a chiral-at-rhodium complex 378 as a Lewis acid catalyst for the electricity-driven oxidative cross-coupling of 2-acyl imidazoles 376 with silyl enol ethers 377 (Scheme 54).¹⁴⁹ The resulting nonracemic 1,4-dicarbonyl compounds 379 were isolated in up to 91% yields and up to 99% ee with excellent functional group tolerance. It was proposed that the in situ generated rhodium-enolate complex 381 (oxidation potential +0.52 V vs Ag/AgCl) undergoes anodic oxidation to generate α-radical Rh-complex 382. After combining with the silyl enol ether 377 and another anodic oxidation, the desired product 379 was formed without forming a homocoupling partner. Free acyl imidazole and silyl enol ether could not oxidize during the catalytic cycle as both have an oxidation potential of greater than +2.0 and +1.72 V vs Ag/AgCl, respectively.

Scheme 54. Electricity-Driven Asymmetric Reaction Using Chiral Lewis Acid Catalyst.

6. Conclusion and Outlook

Recent developments in chiral-at-metal catalysis in nucleophilic, electrophilic, photochemical, and electrochemical reactions have revolutionized the field of asymmetric catalysis. The strategy stands out with evident advantages desired in modern synthetic chemistry without using chiral ligands or chiral auxiliaries. The complexes are easy to synthesize in an enantiopure manner and are structurally manipulable. Additionally, the complexes are thermally and configurationally stable, even in the presence of assessable labile ligands. Moreover, the photochemical and redox characteristics of the in situ produced substrate-activated complex enabled their use in photoredox and electrocatalysis.

Despite recent advances in this field, there is still potential for improvement in the novel applications in asymmetric catalysis with broader substrates. For example, the developed reactions have intensively explored utilizing substrates with two coordination sites, such as an acyl imidazole or acyl pyrazole, that bind with the chiral-at-metal catalyst in a bidentate manner. On the other hand, various substrates with or without two coordination sites have yet to be studied. Moreover, the catalyst design could be improved with modulated stereoelectronics with easy synthesis and resolution. Additionally, the catalyst design solely concentrated on the octahedral space. The chemistry buried in other geometrical environments is largely unexplored. Further mechanistic exploration and synthetic applications are yet to be investigated to achieve novel asymmetric transformations, particularly the development of sustainable processes.

Biographies

Purusattam Dey was born in West Bengal, India. He did B.Sc. chemistry at Midnapore College (Autonomous) and M.Sc. chemistry at Indian Institute of Technology, Madras. Since 2019 he has been doing his Ph.D. under the supervision of Dr. Biplab Maji at IISER Kolkata. His current research focuses on photoredox catalysis and asymmetric synthesis.

Pramod Rai was born in 1993 in West Bengal (India). After completing his B.Sc. at North Bengal University and M.Sc. at Sikkim University, he joined the research group of Dr. Biplab Maji as a Ph.D. student at IISER Kolkata. His research interest is the development of a new methodology in asymmetric photoredox catalysis.

Biplab Maji was born in 1987 in West Bengal (India). He obtained his M.Sc. from IIT Kanpur in 2009 (thesis supervisor: Prof. Dr. Manas K. Ghorai) and Ph.D. from Ludwig-Maximilians-Universität Munich in 2012 (thesis supervisor: Prof. Dr. Herbert Mayr). He did postdoctoral studies with Prof. Dr. Hisashi Yamamoto at Chubu University, Japan, and Prof. Dr. Frank Glorious at Westfälische Wilhelms-Universität Münster, Germany (as an Alexander von Humboldt fellow). In 2016, he joined the Department of Chemical Sciences, IISER Kolkata as an assistant professor, and in 2021 he was promoted to associate professor in the same department. His research focuses on organic synthesis, catalysis, and mechanistic studies.

Author Contributions

^‡ P.D. and P.R. contributed equally to this work.

The authors declare no competing financial interest.