Steering Asymmetric Lewis Acid Catalysis Exclusively with Octahedral

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Steering Asymmetric Lewis Acid Catalysis Exclusively with Octahedral Metal-Centered Chirality Lilu Zhang and Eric Meggers* Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Strasse 4, 35043 Marburg, Germany CONSPECTUS: Catalysts for asymmetric synthesis must be chiral. Metal-based asymmetric catalysts are typically constructed by assembling chiral ligands around a central metal. In this Account, a new class of effective chiral Lewis acid catalysts is introduced in which the octahedral metal center constitutes the exclusive source of chirality. Specifically, the here discussed class of catalysts are composed of configurationally stable, chiral-at-metal Λ-configured (left-handed propeller) or Δ-configured (right-handed propeller) iridium(III) or rhodium(III) complexes containing two bidentate cyclometalating 5-tert-butyl-2-phenylbenzoxazole (dubbed IrO and RhO) or 5-tert-butyl-2-phenylbenzothiazole (dubbed IrS and RhS) ligands in addition to two exchange-labile acetonitriles. They are synthetically accessible in an enantiomerically pure fashion through a convenient auxiliary-mediated synthesis. Such catalysts are of interest due to their intrinsic structural simplicity (only achiral ligands) and the prospect of an especially effective asymmetric induction due to the intimate contact between the chiral metal center and the metal-coordinated substrates or reagents. With respect to chiral Lewis acid catalysis, the bis-cyclometalated iridium and rhodium complexes provide excellent catalytic activities and asymmetric inductions for a variety of reactions including Michael additions, Friedel−Crafts reactions, cycloadditions, α-aminations, α-fluorinations, Mannich reactions, and a cross-dehydrogenative coupling. Mechanistically, substrates such as 2-acyl imidazoles are usually activated by two-point binding. Exceptions exist as for example for an efficient iridium-catalyzed enantioselective transfer hydrogenation of arylketones with ammonium formate, which putatively proceeds through an iridium-hydride intermediate. The bis-cyclometalated iridium complexes catalyze visible-light-induced asymmetric reactions by intertwining asymmetric catalysis and photoredox catalysis in a unique fashion. This has been applied to the visible-light-induced α-alkylation of 2-acyl imidazoles (and in some instances 2-acylpyridines) with acceptor-substituted benzyl, phenacyl, trifluoromethyl, perfluoroalkyl, and trichloromethyl groups, in addition to photoinduced oxidative α-aminoalkylations and a photoinduced stereocontrolled radical−radical coupling, each employing a single iridium complex. In all photoinduced reaction schemes, the iridium complex serves as a chiral Lewis acid catalyst and at the same time as precursor of in situ assembled photoactive species. The nature of these photoactive intermediates then determines their photochemical properties and thereby the course of the asymmetric photoredox reactions. The bis-cyclometalated rhodium complexes are also very useful for asymmetric photoredox catalysis. Less efficient photochemical properties are compensated with a more rapid ligand exchange kinetics, which permits higher turnover frequencies of the catalytic cycle. This has been applied to a visible-light-induced enantioselective radical α-amination of 2-acyl imidazoles. In this reaction, an intermediate rhodium enolate is supposed to function as a photoactivatable smart initiator to initiate and reinitiate an efficient radical chain process. If a more efficient photoactivation is required, a rhodium-based Lewis acid can be complemented with a photoredox cocatalyst, and this has been applied to efficient catalytic asymmetric alkyl radical additions to acceptorsubstituted alkenes. We believe that this class of chiral-only-at-metal Lewis acid catalysts will be of significant value in the field of asymmetric synthesis, in particular in combination with visible-light-induced redox chemistry, which has already resulted in novel strategies for asymmetric synthesis of chiral molecules. Hopefully, this work will also pave the way for the development of other asymmetric catalysts featuring exclusively octahedral centrochirality.

1. BACKGROUND ON OCTAHEDRAL CHIRALITY IN ASYMMETRIC CATALYSIS Chirality is a pivotal feature of asymmetric catalysts and predominantly originates from tetrahedral stereogenic centers, axial chirality, planar chirality, or a combination thereof.1 Octahedral centrochirality is mostly observed when induced on a metal center by chiral ligands,2 whereas catalysts that © 2017 American Chemical Society

exclusively derive their absolute configuration from octahedral metal-centered chirality are a rarity. Pioneering work by Fontecave and Gladysz demonstrated that octahedral chiralat-metal complexes with solely achiral ligands are capable of Received: November 22, 2016 Published: January 27, 2017 320

DOI: 10.1021/acs.accounts.6b00586 Acc. Chem. Res. 2017, 50, 320−330

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Accounts of Chemical Research

Figure 1. Previous work on octahedral chiral-at-metal catalysts with exclusively achiral ligands. BArF = tetrakis[(3,5-di-trifluoromethyl)phenyl]borate.

2. CATALYST DESIGN In our basic design, iridium(III)12−19 or rhodium(III)20−27 is cyclometalated by two 5-tert-butyl-2-phenylbenzoxazoles or 5tert-butyl-2-phenylbenzothiazoles in addition to two acetonitriles (Figure 2). The monocationic complexes are typically

asymmetric catalysis, although the achieved enantioselectivities were disappointing (Figure 1).3−5 A first demonstration that chiral information on an octahedral stereogenic center can be transferred in a catalytic fashion to molecular substrates was demonstrated by Fontecave in 2003 with Λ- and Δ-cis-[Ru(2,9dimethyl-1,10-phenanthroline)2(MeCN)2](PF6)2 as a catalyst for the oxidation of organic sulfides to sulfoxides, albeit with a maximum enantiomeric excess of 18% ee.3 Later, in 2007 Fontecave introduced an octahedral ruthenium complex as chiral and inert “metalloligand” for a second, catalytically active metal center.4 However, the asymmetric transfer hydrogenation of arylketones afforded a maximum enantiomeric excess of just 26% ee. One year later, Gladysz reported that the simple Werner complex Δ-[Co(1,2-ethylenediamine)3]3+, employing tetrakis[3,5-trifluoromethyl)phenyl]borate (BArF) counterions in order to render the complex soluble in solvents of low polarity, was capable of catalyzing the Michael addition of dimethyl malonate to 2-cyclopentene-1-one with an enantiomeric excess of 33% ee.5 Vastly improved catalytic performances with octahedral chiral-only-at-metal asymmetric catalysts were reported by us over the past few years with the design of subsitutionally inert bis-cyclometalated iridium(III) complexes for asymmetric transfer hydrogenations with Hantzsch ester, Friedel−Crafts reactions, sulfa-Michael additions, aza-Henry reactions, and an α-amination of aldehydes.6−10 Catalysis in such “metal-templated asymmetric organocatalysts”11 is mediated by the organic ligand sphere whereas the metal center serves as a structural anchorpoint to position the catalytic functional groups using the sophisticated octahedral coordination geometry and at the same time comprises the sole source of chirality. These examples provided a first demonstration of the suitability of octahedral centrochirality to highly effectively steering asymmetric induction in asymmetric catalysis. Our success with asymmetric catalysts based on substitutionally inert chiral-at-metal complexes encouraged us to design reactive, substitutionally labile transition metal complexes with exclusive octahedral centrochirality. Metal coordination is arguably one of the most powerful strategies for activating substrates toward chemical reactions. In addition, we were speculating that a close proximity of metal-centered chirality to the metal-coordinated substrate might provide an especially effective transfer of chirality from the catalyst to the product in the course of the asymmetric induction. Here we provide our first account on a new class of simple chiral Lewis acids that exclusively possess octahedral metal centrochirality and are versatile asymmetric catalysts for a variety of reactions including visible-light-activated photoredox chemistry.

Figure 2. Design of octahedral chiral-only-at-metal iridium and rhodium catalysts Λ- and Δ-IrO (M = Ir, X = O), IrS (M = Ir, X = S), RhO (M = Rh, X = O), and RhS (M = Rh, X = S).

complemented by hexafluorophosphate counterions. Despite all ligands being achiral, octahedral metal-centered chirality leads to Δ- (right-handed propeller) and Λ-enantiomers (left-handed propeller). The two tert-butyl groups provide steric hindrance to ensure an effective asymmetric induction of the propellertype C2-symmetrical scaffold, while the exchange-labile acetonitrile ligands permit the direct coordination of substrates in a mono- or bidentate fashion (one or two point binding). Bis-cyclometalated iridium and rhodium were selected as the basic structural unit for three reasons: First, we expected a high thermal and configurational stability, particularly for the hexacoordinated iridium(III),28 so that the retention of the absolute metal-centered chirality in the course of the catalysis is assured. Second, bis-cyclometalation in this system with the two nitrogens in trans and the phenyl groups in cis occurs with high diastereoselectivity and therefore enables a diastereoselective synthesis of such complexes.29 Third, the bis-cyclometalation with the two nitrogen ligands in trans places the metal−carbon bonds trans to the acetonitrile ligands so that they can profit from a labilizing kinetic trans effect.30

3. AUXILIARY-MEDIATED SYNTHESIS A few years ago, our laboratory developed a strategy of auxiliary-mediated synthesis of octahedral metal complexes using tailored chiral bidentate ligands.31−33 Such chiral auxiliaries assist in implementing the absolute metal-centered configuration at the metal and are removed afterward in a 321


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Figure 3. Exemplary auxiliary-mediated synthesis of the enantiomerically pure chiral-at-metal iridium complexes Λ-IrS and Δ-IrS and a selection of chiral auxiliaries used for the resolution of metal-centered stereoisomers of bis-cyclometalated iridium and rhodium complexes.

Figure 4. Bis-cyclometalated chiral-only-at-metal iridium and rhodium complexes as chiral Lewis acid catalysts for a variety of reactions.

cyclometalated iridium(III) and rhodium(III) complexes as shown for the synthesis of Λ- and Δ-IrS in Figure 3a, for example.15 Accordingly, the reaction of IrCl3·3H2O with 5-tertbutyl-2-phenylbenzothiazole (1) leads to a well established

traceless fashion under retention of the absolute configuration at the metal. This concept was initially developed for the synthesis of enantiopure ruthenium(II) polypyridine complexes33 and later applied to resolve racemic mixtures of bis322


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Accounts of Chemical Research diastereoselective bis-cyclometalation29 and provides the chloro-bridged iridium(III) dimer [Ir(μ-Cl)(1-H+)2]2 (rac-2) as a racemic mixture. The following reaction with (S)-4isopropyl-2-(2′-hydroxyphenyl)-2-thiazoline {(S)-3} as our chiral auxiliary in the presence of triethylamine and silver triflate provides the two diastereomeric complexes Λ-(S)-4 and Δ-(S)-4, which can be separated by silica gel chromatography. Finally, the individual diastereomers are converted to the corresponding enantiopure and configurationally stable catalysts Λ- and Δ-IrS through a stereospecific substitution of the auxiliary ligands with acetonitriles upon heating at 50 °C in acetonitrile in the presence of the weak acid NH4PF6. Alternatively, the reaction can be executed at room temperature using TFA (followed by anion exchange) or HPF6. It is worth noting that the chiral auxiliary can be reisolated in high yield and without any loss of enantiomeric excess.15 The tailored choice of the chiral auxiliary varies with the metal and the nature of the cyclometalating ligand. A selection of employed auxiliaries for this and related reaction schemes is shown in Figure 3b. Aside from salicylthiazolines and salicyloxazolines,6,12,15,34,35 a fluorinated salicyloxazoline developed by Monari, Bandini, and Ceroni36 is currently our auxiliary of choice for the lighter rhodium congeners,24 while the readily available amino acids proline,10,20,37−39 α-methylproline,38 serine,40 and β-phenylalanine41 are also suitable for this reaction scheme and might be the auxiliaries of choice for potential future economical large scale syntheses.

A few important trends emerged from our studies. First, the benzothiazole complexes (IrS and RhS) compared to the related benzoxazole complexes (IrO and RhO) are often superior asymmetric catalysts by providing higher stereoselectivities. We attribute this to the increased C−S over C− O bond length, which positions the two tert-butyl groups closer to the substrate coordination site producing a higher steric congestion (Figure 5). Second, for many standard Lewis acid

Figure 5. Superimposed crystal structure of Λ-RhS (gray) and inverted Δ-RhO (green). Fitted are the central metal together with the metal-bound atoms as taken from ref 24. Atoms are displayed as 50% thermal ellipsoids.

4. CHIRAL LEWIS ACID CATALYSIS Over the last three years, we and others demonstrated that the bis-cyclometalated iridium(III) and rhodium(III) complexes Λand Δ-IrO, -IrS, -RhO, and -RhS are versatile catalysts for a variety of transformations. With respect to the class of conjugate additions, we realized enantioselective Friedel−Crafts reactions,12 Michael additions,15 and cycloadditions.15 With respect to enolate chemistry, we reported an α-amination,20 a Mannich reaction,22 and a cross-dehydrogenative coupling22 (Figure 4). The Xu group recently reported a Δ-IrS-catalyzed very enantioselective α-fluorination of 2-acyl imidazoles with selectfluor.42 Furthermore, our group41 and independently Kang and co-workers43 recently demonstrated that chiral-atmetal rhodium-based Lewis acid catalysis can be synergistically combined with enamine organocatalysis to achieve the enantioand diastereoselective Michael addition of aldehydes to α,βunsaturated 2-acyl imidazoles, including the formation of vicinal quaternary/tertiary stereocenters. The typical substrate, most prominent in the form of 2-acyl imidazoles, binds to the iridium or rhodium center in a bidentate fashion as verified by multiple X-ray crystal structures13−15,20,23,25,27 (Figure 4a−c), and this permits very high asymmetric inductions, most likely due to the highly rigid, propeller type C2-symmetrical catalyst geometry. The requirement for two point binding currently constitutes the most severe limitation for the substrate scope. However, we recently demonstrated that Λ- and Δ-IrS is an excellent catalyst for asymmetric transfer hydrogenations with ammonium formate, which does not require any substrate coordination but instead putatively proceeds through an intermediate iridium hydride complex.19 Interestingly, rate and enantioselectivity are significantly improved in the presence of a pyrazole coligand, which apparently allows additional metal−ligand cooperativity through the formation of a hydrogen bond between the coordinated pyrazole and the ketone (Figure 4d).

activation schemes, for example, conjugate additions or enolate chemistry, the rhodium catalysts provide better results, and we have traced this back to significantly faster ligand exchange kinetics,20,23 which also permits lower reaction temperature, whereas in the iridium system ligand exchange is too decelerated below room temperature. On the other hand, the higher configurational stability of the iridium catalysts permits execution of reactions at elevated temperatures of up to approximately 70−80 °C. Third, due to the robustness of the catalysts, for many reactions no stringent exclusion of air and moisture is necessary.

5. VISIBLE-LIGHT-INDUCED ASYMMETRIC CATALYSIS 5.1. Asymmetric Photoredox Catalysis with Chiral Iridium Complexes

Bis-cyclometalated iridium complexes are well-known for their photophysical and photochemical complexes44 and, recently, are extensively used as visible-light-activated photoredox catalysts.45−49 In pioneering work, MacMillan employed first [Ru(bpy)3]Cl2 and subsequently the bis-cyclometalated iridium complex [Ir(ppy)2(dtb-bpy)](PF6), with ppy = 2-phenylpyridine and dtb-bpy = 4,4′-di-tert-butyl-2,2′-bipyridine, as photoredox catalysts in combination with a chiral imidazolidinone organocatalyst to facilitate a visible-light-induced enantioselective α-alkylation of aldehydes.50,51 This and work by other groups regarding merging asymmetric catalysis with photoinduced electron transfer,45−51 encouraged us to seek asymmetric photoredox catalysis schemes in which photo323


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Figure 6. Proposed mechanism for combining photoredox and asymmetric catalysis with a chiral iridium complex. Iridium enolate complex II constitutes the in situ formed photoredox mediator and serves as the key intermediate in the asymmetric cycle (EWG = electron withdrawing group). a Reaction performed with catalyst Λ-IrS. bReaction performed with catalyst Λ-IrS(tBu).

trifluoromethylations and α-perfluoroalkylations of 2-acyl imidazoles.16,18 Enantioselectivities of these reactions are in several examples ≥99% ee, which indicates that the absolute metal-centered configuration must be retained throughout the catalysis. Elaborate mechanistic investigations support the mechanism shown in Figure 6 in which photoredox catalysis intertwines with asymmetric catalysis in a unique fashion.13,16,18 Correspondingly, the asymmetric catalysis cycle starts with a replacement of the two labile acetonitrile ligands by the 2acyl imidazole or 2-acylpyridine substrate, which coordinates to the catalyst in a bidentate fashion (intermediate I). This is followed by α-deprotonation to afford an iridium enolate

activation, substrate activation, and asymmetric induction is all mediated by a single chiral iridium complex. In our first realization of this concept, we found that Λ- and Δ-IrS in the presence of visible light, for example, by irradiation with a household compact fluorescent lamp, catalyzes the reaction between 2-acyl imidazoles and acceptor-substituted benzyl bromides or phenacyl bromides to provide the αalkylation products in excellent to quantitative yields and with high enantioselectivity of up to 99% ee in the presence of a weak base (Figure 6 and Figure 7a).13 In subsequent work, we expanded this combined chiral Lewis acid/photoredox catalysis with a single catalyst to enantioselective α-trichloromethylations of 2-acyl imidazoles and 2-acylpyridines, as well as α324


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Figure 7. Cooperative asymmetric and photoredox catalysis with chiral iridium(III) complexes.

complex (intermediate II). In the subsequent chirality generating step, a reductively generated electrophilic radical adds to the electron rich enolate double bond under formation of an iridium-coordinated ketyl radical (intermediate III). The following single electron oxidation of this ketyl intermediate provides the iridium-coordinated product (intermediate IV). Steric congestion renders the product a less favorable bidentate ligand compared to the starting material and thus drives product release with the initiation of a new catalytic cycle. Along the same lines, stereoelectronic arguments can be made accountable for the absence of any epimerization of intermediate IV through deprotonation/protonation. Importantly, based on cyclovoltammetry and luminescence experiments, we deduce that it is the iridium enolate complex intermediate II that connects the asymmetric catalysis cycle with the photoredox cycle by not only being responsible for the asymmetric induction in the catalytic cycle but also serving as the in situ formed photoactive species, which upon absorption of visible light, transfers an electron to the electron deficient organohalide, followed by a halide release under generation of the electron deficient radical intermediate. Overall, this reaction can be classified as an electron-transfer-catalyzed nucleophilic substitution (SRN1)52 in which a photoredox catalyst is involved in every cycle or alternatively the ketyl intermediate instead transfers a single electron to the electron deficient organohalide substrate, thereby leading to a chain process.53 The mechanistic cycle bears similarity to elegant diastereoselective redoxmediated haloalkyl radical additions to metal enolates developed by the Zakarian laboratory.54−56

We recently also reported a photoinduced enantioselective oxidative α-alkylation (Figure 7b)14 and a photoinduced stereocontrolled radical−radical coupling (Figure 7c)17 using single chiral iridium catalysts. Importantly, in all reported reaction schemes, the photoactive species are assembled in situ upon substrate coordination (optionally followed by deprotonation), and the photochemical properties of these intermediates determine the course of the photoreaction as concluded from mechanistic studies including luminescence quenching experiments and cyclovoltammetry. The neutral intermediate iridium enolate (see Figure 7a and intermediate II in Figure 6) is a strong photoactivated reductant as discussed above. In contrast, the cationic iridium complex obtained upon bidentate coordination of a 2-acyl imidazole constitutes a photoactive weak oxidant (Figure 7b), whereas the coordination of more electron deficient 2-trifluoroacetyl imidiazoles provides a significantly stronger light-activated oxidant (Figure 7c). The nature of these photoactive intermediates are key to triggering distinct chemistry, ranging from photoreductively activated but overall redox neutral enantioselective alkylations and photooxidative enantioselective α-aminoalkylations under air to asymmetric radical−radical couplings initiated by photoinduced electron transfer. To conclude this section, it is surprising that the structurally quite simple chiral-at-metal iridium complexes IrO and IrS are capable of catalyzing such complex visible-light-activated transformations in which asymmetric catalysis intimately cooperates with photoinduced redox chemistry. It is also worth pointing out that in these reactions, the metal center serves several functions at the same time: it constitutes the 325


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Figure 8. Catalytic, bis-cyclometalated rhodium catalyst superior over iridium congeners for enantioselective radical amination activated by visible light.

redox conditions using Ir[dF(CF3)ppy]2(bpy)PF6 or [AcrMes]ClO4 as additional photoredox catalysts (Figure 9).25 Intriguingly, with catalyst loadings of just 4 mol %, yields up to 97% and excellent enantioselectivities up to 99% ee were achieved.

exclusive center of chirality and the Lewis acid center and additionally functions as the key component of the photoactive species generated in situ. 5.2. Asymmetric Photoredox Catalysis with Chiral Rhodium Complexes

We recently unexpectedly observed that in contrast to the visible-light-induced enantioselective alkylation via carboncentered intermediate radicals (Figure 7a), an analogous enantioselective amination via intermediate nitrogen-centered radicals is not catalyzed in a satisfactory fashion by our iridium catalysts but instead works smoothly and with high enantioselectivity with the related rhodium complexes (Figure 8).23 We used MacMillan’s 2,4-dinitrophenylsulfonyloxy (ODN)-N-functionalized carbamates, which fragment into a sulfonate anion and an aminyl radical upon single electron reduction. 57 The reaction proceeds in analogy to the mechanism shown in Figure 6 with the electrophilic nitrogencentered radical reacting with an intermediate chiral rhodium enolate in a stereocontrolled fashion. The superiority of RhO15 and RhS24 over their iridium congeners in this reaction scheme can be attributed to much faster ligand exchange rates in the rhodium system, which is required to match the high reactivity and short lifetime of the intermediate nitrogen-centered radicals. Amidyl radicals are highly reactive electrophilic πtype radicals and prone to reduction.58 A correlated short lifetime of these nitrogen-centered radicals therefore requires a fast turnover frequency of the catalysis cycle, which is apparently fulfilled for the rhodium but not the iridium catalysis cycle. Indeed, measured initial rates for the exchange of acetonitrile ligands against a bidentate coordinated 2-acyl imidazole substrate reveal a much faster rate constant for the rhodium complex by at least 3 orders of magnitude.23 At the same time, the inferior photoredox properties of the biscyclometalated rhodium complexes,59 resulting from a short excited state lifetime, do not play an important role here due to an efficient chain propagation as demonstrated by a measured high quantum yield of 14.60,61 Thus, this example demonstrates the importance of fine-tuned kinetics for radical formation, propagation, and regeneration of key catalytic intermediates in photoredox catalysis. In a subsequent application, we used a dual catalysis strategy,48,62 namely, complementing the rhodium-based chiral Lewis acid with an additional photoredox catalyst in order to compensate for the limited photochemical properties of the rhodium system while at the same time exploiting the excellent turnover frequencies during rhodium catalysis. By doing so, we were able to address the challenging catalytic enantioselective addition of alkyl radicals to acceptor-substituted alkenes (Giese reaction).25,26 Specifically, we reported a RhS-catalyzed enantioselective addition of alkyl radicals, oxidatively generated from organotrifluoroborates,63−65 to α,β-unsaturated 2-acyl imidazoles and α,β-unsaturated N-acyl pyrazoles under photo-

Figure 9. Catalytic, enantioselective radical addition to alkenes via visible-light activation and asymmetric catalysis with a chiral rhodium(III) complex.

The proposed mechanism is shown in Figure 9. The established photoinduced single electron oxidation of organotrifluoroborates generates carbon-centered radicals,63−65 which then add to the N,O-rhodium-coordinated α,β-unsaturated 2acyl imidazole or N-acyl pyrazole substrate (intermediate I). The hereby formed secondary radical intermediate II is then reduced by SET to a rhodium enolate (intermediate III). Upon 326


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alkoxyphthalimides upon photolysis with a compact fluorescent lamp in the presence of Λ-RhS (8 mol %), the photoredox catalyst fac-[Ir(ppy)3] (1 mol %), and Hantzsch ester as a reducing agent to afford a C−C bond formation product with high enantioselectivity (up to 97% ee) and, where applicable, some diastereoselectivity (3.0:1 dr). The reaction is based on a method recently developed by Chen and co-workers to release alkoxy radicals from N-alkoxyphthalimides under reductive photoredox conditions.69 The oxygen-centered radical then undergoes a 1,5-hydrogen shift to generate a carbon-centered radical,70 followed by a rhodium-catalyzed stereocontrolled Giese reaction. Thus, by combining visible-light-activated photoredox catalysis, radical translocation, and chiral-at-metal rhodium Lewis acid catalysis we were able to functionalize C(sp3)−H bonds in a catalytic asymmetric fashion. To conclude this section, we found that the bis-cyclometalated rhodium catalysts can strongly accelerate the conjugate addition of alkyl radicals to alkenes, which provides the foundation to achieve very efficient catalytic asymmetric Giese reactions.

protonation, the rhodium-coordinated product is generated and subsequently exchanged with new substrate to initiate a new catalytic cycle. Pioneering work on enantioselective conjugate radical additions catalyzed by chiral Lewis acids goes back to Sibi and Porter.66,67 In a particularly impressive example, a magnesium bisoxazoline complex at a catalyst loading as low as 5 mol % was used for catalyzing an enantioselective conjugate isopropyl radical addition to an oxazolidinone cinnamate with 90% ee.68 However, the reaction was reported to require equimolar amounts of a toxic stannane and was executed at −78 °C. The challenges to achieve high enantioselectivity at low catalyst loading for this reaction can be pinpointed to difficulties with suppressing the uncatalyzed background reaction. It is therefore intriguing that in our rhodium-catalyzed reaction, enantioselectivities of up to 99% ee are achieved with catalyst loading as low as 4 mol % at room temperature. This can be rationalized by a very strong acceleration of the radical addition in the presence of the rhodium Lewis acid. Indeed, we determined that rhodium coordination to a representative α,β-unsaturated 2-acyl imidazole accelerates the rate of benzyl radical addition by a factor of at least 3 × 104. The exceptional suitability of the chiral Lewis acid RhS to catalyze the enantioselective Giese reaction was further exploited by us to realize a catalytic asymmetric C(sp3)−H functionalization under photoredox conditions as shown in Figure 10.26 α,β-Unsaturated N-acyl pyrazoles react with N-

6. CONCLUSIONS Despite the demonstration of metal-centered chirality in octahedral metal complexes by Alfred Werner more than a century ago,71,72 the development of asymmetric catalysts that draw their chirality exclusively from octahedral centrochirality is only a recent development.11,73,74 The here summarized asymmetric reactions catalyzed by bis-cyclometalated iridium and rhodium complexes provide the most convincing demonstration of the power of this approach. The catalysts are structurally quite simple as they only contain achiral ligands, are synthetically acessible in an enantiomerically pure and convenient fashion through auxiliary-mediated synthesis, are configurationally stable at room temperature and elevated temperatures, and provide excellent asymmetric inductions for a large variety of transformations. The bis-cyclometalated iridium catalysts are capable of catalyzing visible-light-activated asymmetric reactions in which asymmetric catalysis cooperates with photoredox catalysis.75−77 The “photoredox catalyst” is typically assembled in situ upon coordination to the substrate, and the photochemical properties of these intermediates determine the course of the reaction. If higher turnover frequencies of the catalytic cycle are required for a particular transformation, the rhodium complexes are the catalysts of choice. The less efficient photochemical properties do not play a crucial role when the reaction involves an efficient radical chain process. Otherwise, the rhodium-based Lewis acid can be complemented with a photoredox cocatalyst and this has been applied to the catalytic asymmetric Giese reaction. Future work on this novel class of catalysts needs to explore the dependence of catalytic and photochemical properties upon variation of the ligand sphere, the exchange-labile ligands, and the nature of the counterion. It is also interesting to furnish the exchange-labile ligands or the counterions with additional functions for performing tailored dual catalysis. Finally, the expansion of these iridium- and rhodium-based catalysts to other metals should be taken into consideration.

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Figure 10. Catalytic asymmetric C(sp3)−H functionalization under photoredox conditions via radical translocation followed by stereocontrolled alkene addition: phth = N-phthalimide, dmp = N-(3,5dimethylpyrazole).

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Eric Meggers: 0000-0002-8851-7623 Notes

The authors declare no competing financial interest. Biographies Lilu Zhang received a Bachelor degree in Polymer Science from Nanjing University of Technology, P. R. China, and a Ph. D. degree in Inorganic Chemistry from Hong Kong Baptist University, Hong Kong. After postdoctoral research at the University of Texas at Austin and the University of Pennsylvania, she started as an Assistant Professor in the Department of Chemistry and Biological Chemistry at Nanyang Technological University, Singapore. Since 2007, Lilu Zhang has been in the Department of Chemistry of the University of Marburg, Germany, and currently holds the position of a staff scientist (Akademische Rätin). Eric Meggers received a Diploma in Chemistry from the University of Bonn (Germany) and a Ph.D. degree in Organic Chemistry from the University of Basel (Switzerland). After postdoctoral research at the Scripps Research Institute (La Jolla, CA, USA), he started his independent career as Assistant Professor at the University of Pennsylvania (USA). Since 2007, Eric Meggers is Full Professor in the Department of Chemistry at the University of Marburg (Germany). He was holding a secondary appointment as Professor at the College of Chemistry and Chemical Engineering of Xiamen University (P. R. China) from 2012 to 2016. His research program focuses on exploiting metal-centered stereochemistry for applications in medicine, chemical biology, and asymmetric catalysis.

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ACKNOWLEDGMENTS The authors thank present and past laboratory members for their invaluable contributions to this project. We gratefully acknowledge funding for this project from the German Research Foundation (ME1805/13-1).

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REFERENCES

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Steering Asymmetric Lewis Acid Catalysis Exclusively with Octahedral

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