Ir-Catalyzed Asymmetric Hydrogenation of Unprotected Indoles: Scope Investigations and Mechanistic Studies

Open AccessCCS ChemistryRESEARCH ARTICLE30 May 2023Ir-Catalyzed Asymmetric Hydrogenation of Unprotected Indoles: Scope Investigations and Mechanistic Studies Gongyi Liu†, Lini Zheng†, Kui Tian, Haifeng Wang, Lung Wa Chung, Xumu Zhang and Xiu-Qin Dong Gongyi Liu† Engineering Research Center of Organosilicon Compounds and Materials, Ministry of Education, College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072 Pharmaceutical Research Institute, Wuhan Institute of Technology, Wuhan, Hubei 430205 , Lini Zheng† Department of Chemistry, Shenzhen Grubbs Institute and Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology, Shenzhen, Guangdong 518000 , Kui Tian Engineering Research Center of Organosilicon Compounds and Materials, Ministry of Education, College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072 , Haifeng Wang Pharmaceutical Research Institute, Wuhan Institute of Technology, Wuhan, Hubei 430205 , Lung Wa Chung Department of Chemistry, Shenzhen Grubbs Institute and Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology, Shenzhen, Guangdong 518000 , Xumu Zhang *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] Department of Chemistry, Shenzhen Grubbs Institute and Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology, Shenzhen, Guangdong 518000 and Xiu-Qin Dong *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] Engineering Research Center of Organosilicon Compounds and Materials, Ministry of Education, College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072 Suzhou Institute of Wuhan University, Suzhou, Jiangsu 215123 https://doi.org/10.31635/ccschem.022.202101643 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Transition metal-catalyzed asymmetric hydrogenation (AH) of unprotected indoles has mainly been applied to alkyl substituted unprotected indoles. However, the challenging aryl substituted unprotected indoles with poor reactivity and enantioselectivity (≤42% ee) could not be hydrogenated well. In this work, a highly efficient Ir/bisphosphine-thiourea ligand ZhaoPhos catalytic system for the AH of challenging aryl substituted unprotected indoles has been successfully developed for the first time with high reactivity and excellent stereoselective control. Moreover, a series of 2-alkyl-substituted and 2,3-disubstituted unprotected indoles were also well tolerated in this catalytic system. A wide variety of chiral indoline derivatives were obtained in good to high yields with excellent stereoselectivities (75–99% yields, >20∶1 dr, and 86–99% ee). The anion-binding activation strategy played an important role in accessing both high reactivity and excellent stereoselectivity, which was formed between the catalyst and unprotected indoles in situ-generating iminium ion with the assistance of Brønsted acid. A possible catalytic mechanism was proposed for this Ir-catalyzed AH according to density functional theory calculations and control experiment results. Readily available substrates, a broad range of substrate tolerance, an efficient chiral catalytic system, and a gram-scale protocol further demonstrated the potential practicality of this methodology. Download figure Download PowerPoint Introduction Chiral indolines are important structural motifs in natural alkaloids and biologically active molecules.1–11 In past decades, considerable attention has been devoted to the synthesis of these valuable enantioenriched indoline derivatives, in which a variety of asymmetric catalytic methods have been developed.12–46 Transition metal-catalyzed asymmetric hydrogenation (AH) has been considered as a powerful and efficient method to construct chiral organic molecules.31–61 And transition metal-catalyzed AH of prochiral indole derivatives represents one of the most straightforward, efficient, and atom-economic approaches to the synthesis of chiral indolines.31–46 In 2000, Kuwano and co-workers36 developed the first AH of N-protected indoles, prompted by Rh/PhTRAP catalytic system. After this pioneering research work, various catalytic systems have proved to be efficient for the AH of N-protected indoles (Scheme 1a).37–40 It is worth mentioning that in 2010 an innovative breakthrough was achieved by Zhou, Zhang and co-workers.41 They successfully realized Pd-catalyzed AH of unprotected indoles through the substrate activation strategy by introducing Brønsted acid to generate iminium ions, which was conducive to breaking the aromaticity of the indole ring and improving the reactivity. However, only limited successful protocols for the AH of the unprotected indoles mainly containing the alkyl substituted group have been developed through palladium,41,42 iridium,43 rhodium,44 and ruthenium45,46 catalytic systems in recent years (Scheme 1b). Despite some significant progress, transition metal-catalyzed AH of the unprotected indoles has been mainly applicable to alkyl-substituted unprotected indoles. However, aryl substituted unprotected indoles could not be hydrogenated smoothly, exhibiting poor reactivity and enantioselectivity (≤42% ee), possibly due to the much higher aromatic resonance stability that greatly limit on the substrates. The development of the AH of unprotected indoles remains a challenging task due to several tough unsolved issues: (1) The highly efficient chiral transition-metal catalytic systems for enantioselective hydrogenation of 2-aryl-substituted unprotected indoles that have never been achieved with ≥90% ee. Although several research groups have tried to resolve this great challenge, until now there is no efficient transition metal catalytic system that can provide >50% ee for the AH of the unprotected 2-aryl-substituted indoles. (2) The catalytic system for the AH of 2,3-disubstituted unprotected indoles containing at least one aryl group has never been reported. (3) To date, there is no catalytic system simultaneously realizing high reactivity and excellent stereoselectivity for the AH of both 2-alkyl substituted and 2-aryl substituted unprotected indoles. Therefore, the development of a more efficient and compatible catalytic system for the AH of unprotected indoles, especially for aryl substituted unprotected indoles, is in high demand and remains a great challenge. The introduction of an appropriate activation strategy between the catalyst and substrate is a powerful solution for the AH of challenging aryl substituted unprotected indoles.62–68 Based on this principle, we envision that anion-binding activation can be formed between the chiral bifunctional bisphosphine-thiourea ligands developed by our group44,69–78 and aryl-substituted unprotected indoles substrates in situ-generating iminium ions in the presence of Brønsted acid. This could be beneficial to effectively resolve these challenging issues by the assistance of suitable transition metal. Herein, we successfully realized Ir-catalyzed AH of challenging aryl substituted unprotected indoles. Moreover, a wide range of 2-alkyl-substituted and 2,3-disubstituted unprotected indoles were also hydrogenated well in the presence of a bisphosphine-thiourea ligand. A series of chiral indoline derivatives were afforded in good to high yields with excellent stereoselectivities (75–99% yields, >20∶1 dr, and 86–99% ee). Scheme 1 | Some examples of biologically active compounds containing chiral indoline motifs and asymmetric catalytic hydrogenation of indoles. Download figure Download PowerPoint Experimental Methods General procedure for the AH of indoles: A stock solution was made by mixing [Ir(COD)Cl]2 with (S,R)-ZhaoPhos in a 0.5∶1.1 molar ratio in CHCl3 at room temperature for 40 min in an argon-filled glovebox. An aliquot of the catalyst solution (0.3 mL, 0.003 mmol) was transferred by syringe into the vials charged with methanesulfonic acid (0.15 mmol) and substrates 1 (0.1 mmol for each) in anhydrous CHCl3 (1.0 mL). The vials were subsequently transferred into an autoclave, and hydrogen gas was charged. The reaction was then stirred under H2 (50 atm) at 70 °C for 48 h. Upon completion, the hydrogen gas was released slowly and carefully. The resulting mixture was concentrated under vacuum and dissolved in saturated aqueous NaHCO3 (5 mL). After stirring for 10 min, the mixture was extracted with dichloromethane (DCM; 5 mL × 3) and dried over Na2SO4. After being purified by silica gel chromatography using petroleum ether/EtOAc as eluent, the ee values of all compounds were determined by high performance liquid chromatography (HPLC) or gas chromatography analysis in the chiral stationary phase. Results and Discussion Optimization reaction conditions Our initial studies focused on the AH of model substrate unprotected 2-phenyl-1H-indole ( 1a)79,80 to give the desired chiral product 2a, with the expectations of achieving a highly enantioselective transformation. In view of our group's previous work 44 in which we developed the application of chiral bifunctional bisphosphine-thiourea ligand ZhaoPhos to the Rh-catalyzed AH of 2-phenyl-1H-indole ( 1a), and chiral 2-phenylindoline 2a was obtained with just 8% yield. Initially, we speculated the poor reactivity may be caused by the reaction condition with room temperature, which was too mild to break the aromaticity of the unprotected 2-phenylindole using hydrochloric acid as the activator. Therefore, we decided to use another strong acid, TsOH·H2O, instead of volatile hydrochloric acid and increased the reaction temperature from 25 to 70 °C, but the reaction result remained poor (Table 1, entry 1). We then continued our research of the AH of 2-phenyl-1H-indole ( 1a) with [Ir(COD)Cl]2 and ZhaoPhos, TsOH·H2O was introduced as the Brønsted acid. After the screening of solvents, to our delight, the desired hydrogenation product (R)-2-phenylindoline 2a was obtained in moderate to high conversions with excellent enantioselectivities in toluene, DCM, dichloroethane (DCE), and CHCl3 (75–87% conversions, 91–94% ee, Table 1, entries 2–5). Among these solvents, CHCl3 provided the best result with 87% conversion in 94% ee (Table 1, entry 5). Trace conversion was observed in ethyl acetate and alcoholic solvents EtOH and MeOH (Table 1, entries 6–8). The anhydrous TsOH was then applied into this hydrogenation, and it provided a similar result with TsOH·H2O, which indicated that this crystal water almost did not have influence on the reactivity and enantioselectivity (86% conversion, 94% ee, Table 1, entry 9 vs entry 5). Considering the great importance of Brønsted acid, which may relate to the formation of anion-binding activation between the substrate and the ligand, a wide range of Brønsted acids with different strengths were employed for an attempt to further improve reactivity and enantioselectivity. Some sulfonic acids, such as D-CSA (camphor sulfonic acid), L-CSA, EtSO3H, and MeSO3H, could provide 71–88% conversions and 94% ee (Table 1, entries 10–13). The absolute configuration of chiral CSA was found to have little effect on the reaction results. Possibly, this acid additive did not work efficiently in the process of the stereodifferentiation to some extent. Although CF3CO2H and MeCO2H provided excellent enantioselectivities, poor conversions were given with 18–37% conversions (94–95% ee, Table 1, entries 14 and 15). In order to achieve full conversion, the amounts of MeSO3H and catalyst were further increased, and this hydrogenation was finished within 48 h (Table 1, entry 16). We found that the excellent reaction results could be maintained when the amount of MeSO3H was decreased to 0.2 equiv (83% conversion, 94% ee, Table 1, entry 17). In addition, there was no reaction in the absence of the cocatalyst MeSO3H (Table 1, entry 18), which showed that MeSO3H was involved in this AH with great importance. Table 1 | Optimization Reaction Conditions for Ir-Catalyzed AH of 2-Phenyl-1H-Indole (1a)a Entry Acid Solvent Conv. (%)b ee (%)c 1d TsOH·H2O DCM <5 NA 2 TsOH·H2O PhMe 75 91 3 TsOH·H2O CH2Cl2 86 93 4 TsOH·H2O DCE 87 92 5 TsOH·H2O CHCl3 87 94 6 TsOH·H2O Ethyl acetate Trace NA 7 TsOH·H2O EtOH Trace 33 8 TsOH·H2O MeOH Trace NA 9 TsOH CHCl3 86 94 10 D-CSA CHCl3 79 94 11 L-CSA CHCl3 71 94 12 EtSO3H CHCl3 86 94 13 MeSO3H CHCl3 88 94 14 CF3CO2H CHCl3 37 94 15 MeCO2H CHCl3 18 95 16e MeSO3H CHCl3 >99 94 17f MeSO3H CHCl3 83 94 18 – CHCl3 NR NA aUnless otherwise mentioned, all reactions were carried out with an [Ir(COD)Cl]2/ligand (S,R)-ZhaoPhos/substrate 1a (0.1 mmol) ratio of 0.5∶1.1∶100, 1.0 equiv acid in 1.0 mL solvent under 50 atm H2 at 70 °C for 24 h. NR = No reaction. NA = Not available. bDetermined by 1H NMR analysis. cDetermined by HPLC on a chiral phase. dInstead of [Ir(COD)Cl]2 with [Rh(COD)Cl]2. e3.0 mol % catalyst loading, 1.5 equiv MeSO3H, 48 h. f0.2 equiv MeSO3H, 48 h. Substrate scope study With the optimized reaction conditions in hand, we turned our attention to the exploration of the substrate scope generality of this Ir-catalyzed AH of a variety of unprotected 2-aryl-substituted 1H-indoles. As shown in Table 2, a wide range of 2-aryl-substituted 1H-indoles performed well as good reaction partners in this AH, resulting in the desired chiral products (R)-2-arylindolines in good to high reactivities with excellent enantioselectivities (84–>99% conversions, 75–99% yields, and 86–96% ee). The electronic effect and position of the substituted group on the phenyl ring was firstly investigated. We found that the 2-aryl-substituted 1H-indoles containing electron-donating ( 1b– 1f, 1k, and 1p) or electron-withdrawing ( 1g– 1j) groups on the phenyl ring could be hydrogenated efficiently to provide the corresponding products with excellent results. It is noteworthy that the substrate 1k bearing potential coordination methylthio group, which may cause catalyst deactivation, also worked well in this transformation with 84% conversion, 75% yield, and 90% ee. The ortho-substituted substrate 1p with steric hindrance also proceeded smoothly to furnish the desired product 2p with excellent results. Moreover, different substituted groups on the indole ring were then investigated, which had little influence on the reaction results, leading to the expected products 2l-2o and 2q in 93–>99% conversions, 90–98% yields, and 90–96% ee. Remarkably, the heteroaromatic substrate 2-(thiophen-2-yl)-1H-indole ( 1r) was well tolerated in this catalytic system to give the desired product ( 2r) in full conversion and high yield with excellent enantioselectivity (>99% conversion, 95% yield, and 95% ee). Table 2 | Substrate Scope Study for Ir-Catalyzed AH of 2-Aryl-Substituted 1H-Indolesa aUnless otherwise mentioned, all reactions were carried out with an [Ir(COD)Cl]2/ligand (S,R)-ZhaoPhos/substrate 1 (0.1 mmol) ratio of 1.5∶3.3∶100, 1.5 equiv MeSO3H in 1.0 mL CHCl3 under 50 atm H2 at 70 °C for 48 h. Conversion was determined by 1H NMR analysis. Ee value was determined by HPLC on a chiral phase. b72 h. c96 h. Encouraged by the above excellent results, we then extended this catalytic system to the AH of unprotected 2,3-disubstituted 1H-indoles containing at least one aryl group (Table 3), which are much more challenging substrates for the hydrogenation of unprotected indoles. Notably, transition-metal-catalyzed AH of this class of substrates has not yet been reported. To our delight, when the methyl group was attached on the 2-position, we found that the 2,3-disubstituted indoles bearing an electron-neutral ( 1s), electron-donating ( 1t– 1v) or electron-withdrawing ( 1w– 1z) group of the phenyl ring on the 3-position worked well, providing the hydrogenation products ( 2s– 2z) with 95–>99% conversions, 88–98% yields, >20∶1 dr, and 95–99% ee. Moreover, the 2-ethyl-3-phenyl-1H-indole bearing ethyl group on the 2-position ( 1aa) could be well employed into this AH, and the desired product ( 2aa) was easily available in full conversion and high yield with excellent stereoselective control (>99% conversion, 98% yield, >20∶1 dr, and 98% ee). Owing to the unfavorable bulky steric hindrance, the challenging 2-phenyl-3-methyl-1H-indole ( 1ab) and 2,3-diphenyl-1H-indole ( 1ac) could not be hydrogenated well, and no reaction was observed under the standard conditions. Table 3 | Substrate Scope Study for Ir-Catalyzed AH of 3-Aryl-Substituted 1H-Indolesa aUnless otherwise mentioned, all reactions were carried out with an [Ir(COD)Cl]2/ligand (S,R)-ZhaoPhos/substrate 1 (0.1 mmol) ratio of 1.5∶3.3∶100, 1.5 equiv MeSO3H in 1.0 mL CHCl3 under 50 atm H2 at 70 °C for 48 h. Conversion was determined by 1H NMR analysis. Ee value was determined by HPLC on a chiral phase. b3.0 mol % catalyst loading, 70 °C, 72 h. NR = No reaction. Following the success in the AH of various aryl substituted 1H-indoles, we next continued to examine 2-alkyl-substituted and 2,3-dialkyl indoles to further investigate generality of the substrate scope. These reaction results were presented in Table 4. The 2-alkyl-substituted substrate containing methyl group 1ad was hydrogenated smoothly to afford product (S)-2-methylindoline 2ad with full conversion, 98% yield, and 97% ee. Subsequently, the substituted groups with different electronic properties on the benzo ring of 2-methyl-1H-indole, such as methyl ( 1ae), methoxy ( 1af), fluorine ( 1ag), and chlorine ( 1ah), were then investigated to deliver the desired products 2ae– 2ah with excellent results (>99% conversion, 95–98% yields, and 96–98% ee). In addition, other 2-alkyl substituted indoles substrates 1ai and 1aj containing ethyl group and benzyl group were also hydrogenated well to provide the corresponding products 2ai and 2aj with high yields and excellent enantioselectivities (full conversion, 99% yield, and 96% ee; full conversion, 95% yield, and 97% ee, respectively). Subsequently, the 2-substituted indoles substrates containing functional groups, such as 1H-indole-2-carboxylic acid ( 1ak), methyl 1H-indole-2-carboxylate ( 1al), and 2-(trifluoromethyl)-1H-indole ( 1am), were also investigated in this asymmetric transformation. Unfortunately, they did not work in this catalytic system, and no reaction was observed. Moreover, a wide variety of 2,3-disubstituted indoles were further extended, which are compatible in this process to generate the expected products with excellent results. When the methyl group was attached on the 2-position, the 2,3-disubstituted indoles bearing alkyl groups such as methyl ( 1an), cyclohexylmethyl ( 1ao), and benzyl ( 1ap) group on the 3-position or fused cyclohexyl ( 1aq) group could also be performed efficiently to give the corresponding products ( 2an– 2aq) with full conversion, 95–96% yields, >20∶1 dr, and 97–98% ee. The 3-aryl or alkyl substituted indole substrates were then examined, and 3-(4-fluorophenyl)-1H-indole ( 1ar) and 3-methyl-1H-indole ( 1as) could be hydrogenated easily with high reactivity, but poor to moderate enantioselectivities were provided (95% conversion, 92% yield, 46% ee; >99% conversion, 90% yield, and 24% ee, respectively). Table 4 | Substrate Scope Study for Ir-Catalyzed AH of 2-Alkyl and 2,3-Dialkyl 3H-Indolesa aUnless otherwise mentioned, all reactions were carried out with an [Ir(COD)Cl]2/ligand (S,R)-ZhaoPhos/substrate 1 (0.1 mmol) ratio of 0.5∶1.1∶100, 1.5 equiv MeSO3H in 1.0 mL CHCl3 under 50 atm H2 at 50 °C for 24 h. Conversion and dr value were determined by 1H NMR analysis. Ee value was determined by HPLC on a chiral phase. b48 h. Mechanism study To understand the origin of the highly enantioselective Ir-catalyzed hydrogenation of indole 1a, we carried out density functional theory (DFT) calculations mainly using the solvation model based on density (SMD) M06//B3LYP-D3 method.a,81–87 On the basis of previous as well as current studies,88–94 the possible catalytic cycle of the current AH is proposed in Scheme 2a (More details are given in the Supporting Information). The Ir(I) catalyst A first underwent oxidative addition with H2 to form a Ir(III)-dihydride intermediate C. Addition of MeSO3H and 1a to C generated intermediate C1, and then the proton transfers from the MeSO3H moiety in intermediate C1 to the indole C3 site and proceeded to form intermediate C2 ( Supporting Information Figure S6 for the detailed protonation process). A minor position change of the protonated substrate part results in lower energy and the key intermediate D before the enantiodetermining hydride-transfer step, in which the MeSO3– anion forms H-bonds with the thiourea motif (the anion-binding activation strategy). As shown in Figure 1, the lowest-energy hydride-transfer transition state for the (R)-product ( TS-R1) was computed to be lower in free energy than that for the (S)-product ( TS-S1) by about 2.6 kcal/mol, which is qualitatively in agreement with the experimental observation. The phenyl group of the substrate preferentially pointed toward the C6H3(CF3)2 rings in TS-R1 and TS-S1, that should avoid steric repulsion between the larger indole and the C6H3(CF3)2 rings (Figure 1 and Scheme 2). In addition, (relative) distortion/interaction analysis95–100 further showed that a larger interaction energy between the metal-ligand and substrate in TS-R1 than TS-S1 (ΔΔEint = 6.7 kcal/mol) played the key role in determining the observed enantioselectivity (Figure 1). In this connection, compared to TS-S1, TS-R1 gained more stabilization from a new C–H bond formation (1.59 vs 1.61 Å in TS-S1) as well as from a larger electrostatic attraction between the Cl ligand and cationic indole NH part (NH–Cl: 2.42 vs 5.58 Å in TS-S1, respectively). Although another and less stable conformer TS-S2 (ΔΔGsoln = 4.0 kcal/mol) can form an electrostatic attraction between the Cl ligand and indole NH part, switching the position between the phenyl and indole rings of the substrate in TS-S2 was found to have a lower dispersion (D3) energy correction84 (1.4 kcal/mol) than TS-S1 based on our dispersion decomposition analysis ( Supporting Information Figures S4 and S5). Therefore, dispersion interaction between the substrate and ligands can be another factor.101 These geometrical features should promote the formation of the desired (R)-product. Remarkably, to examine the proposed role of the key NH group in experiments, the corresponding N-Me and N-CO2Me substrates were applied and found to be inactive in this catalytic hydrogenation (Scheme 2b). These combined DFT and experimental results support the key roles (electrostatic attraction and the least steric repulsion) of the N–H group on the substrate. Then, exchange of the product P from an intermediate E with a new H2 molecule can form an intermediate G, followed by thermodynamically unfavorable heterolytic H2 cleavage with the help of the MeSO3− anion to form unstable intermediates I and J as well as final addition of the protonated indole substrate to regenerate the active intermediate D (Scheme 2a). Our calculations suggest that this reaction catalyzed by the Rh catalyst is generally less favorable than the corresponding Ir catalyst, due to the unstable Rh(III)-dihydrogen intermediate H(Rh) (ΔGsoln = 33.7 kcal/mol) and presumably the formation of the stronger Ir(III)-H bond. Scheme 2 | (a) Proposed the possible mechanism for this Ir-catalyzed AH with the computed relative free energy (kcal/mol) of the key structures in solution by the SMD M06//B3LYP-D3 method. These relative free energies in solution for the Rh counterpart are also given in parenthesis. (b) Control experiment using the corresponding N-Me and N-CO2Me substrates. Download figure Download PowerPoint Furthermore, the Zhou group proposed another important mechanism102 for cationic Ir(I)-catalyzed hydrogenation of unsaturated carboxylic acids with a bidentate ligand involving a classical four-membered-ring olefin insertion step followed by reductive elimination without the protonation of the substrate. However, our calculations further showed that our current neutral Ir(I) catalyst with a bulky tridentate ZhaoPhos ligand strongly disfavors coordination of the indole substrate to the metal center in K (ΔGsoln = 22.4 kcal/mol) as well as the formation of the highly unstable Ir(III)-alkyl insertion product M (ΔGsoln = 55.1 kcal/mol, Scheme 3), due to the severe steric congestion. In addition, the direct (linear-form) hydride transfer to the neutral and unactivated indole substrate without forming the Ir–C bond (without the activation by the protonation) requires a very high barrier (ΔGsoln = 46.8 kcal/mol), partly due to the unfavorable loss of some aromaticity stability. These combined experimental and computational results highlight the important roles of the protonated indole substrate and outer-sphere reduction mechanism in this current Ir(I) system. Scheme 3 | Unfavorable direct linear-form hydride transfer step (top) and classical migratory insertion product (bottom) for the Ir-catalyzed hydrogenation of indole 1a with relative free energies (kcal/mol) by the SMD M06//B3LYP-D3 method. Download figure Download PowerPoint Synthetic utility To further evaluate the synthetic utility of this Ir-catalyzed AH, the gram-scale protocol of model substrate 1a was carried out smoothly even in the presence of 0.5 mol % catalyst loading, and the desired product 2a was easily obtained in 93% conversion, 90% yield, and 90% ee (Scheme 4). Scheme 4 | Gram-scale AH of model substrate 1a. Download figure Download PowerPoint Conclusion In summary, for the first time, we successfully developed a highly efficient Ir/bisphosphine-thiourea ligand ZhaoPhos catalytic system for the AH of challenging aryl-substituted unprotected indoles, 2-alkyl-substituted and 2,3-disubstituted unprotected indoles. A wide range of chiral indoline derivatives were generated with high yields and excellent stereoselectivities (75–99% yields, >20∶1 dr, and 86–99% ee). Moreover, the gram-scale hydrogenation was performed smoothly in this catalytic system. The anion-binding activation between the catalyst and unprotected indoles in situ-generating iminium ion by the assistance of Brønsted acid was proposed to play an important role in achieving high reactivity and excellent stereoselectivity. According to our DFT calculations and control experiment results, a possible catalytic mechanism was proposed for this Ir-catalyzed AH. Figure 1 | Computed lowest-energy enantiodetermining hydride-transfer transition states for the Ir-catalyzed hydrogenation of indole 1a with relative free energies (kcal/mol) by the SMD M06//B3LYP-D3 method. Relative distortion/interaction energies for TS-S (relative to TS-R) by the SMD M06//B3LYP-D3 method are also given. The key bond lengths (in angstrom) by the B3LYP-D3 and SMD B3LYP-D3 methods (in the parenthesis) are given. Unimportant hydrogen atoms are omitted for clarity. Download figure Download PowerPoint Footnote a For computational details and results, see Supporting Information. Supporting Information Supporting Information is available and includes additional experimental details. Conflict of Interest The authors declare no competing interests. Funding Information We are grateful for financial support from the National Natural Science Foundation of China (grant no. 22071187), the Natural Science Foundation of Jiangsu Province (grant no. BK20190213), the Shenzhen Nobel Prize Scientists Laboratory Project (grant no. C17783101), the Guangdong Provincial Key Laboratory of Catalysis (grant no. 2020B121201002), the Natural Science Foundation of Hubei Province (grant nos. 2020CFA036 and 2021CFA069), and the Scientific Research Project of Education Department of Hubei Province (grant no. B2020057). We are grateful to the High Performance Computing Center and the CHEM high performance supercomputer cluster (CHEM HPC) of the Southern University of Science and Technology. References 1. Southon I. W.; Buckingham J.Dictionary of Alkaloids; Chapman and Hall: New York, 1989. Google Scholar 2. Neuss N.; Neuss M. N.Therapeutic Use of Bisindole Alkaloids from Catharanthus. In The Alkaloids;Brossi A., Suffness M., Eds.; Academic Press: San Diego, CA, 1990; p 229. Google Scholar 3. Gueritte F.; Fahy J.The Vinca Alkaloids. In Anticancer Agent