Iridium-Catalyzed Asymmetric Hydrogenation of Unsaturated

Article pubs.acs.org/accounts

Iridium-Catalyzed Asymmetric Hydrogenation of Unsaturated Carboxylic Acids Shou-Fei Zhu*,† and Qi-Lin Zhou*,†,‡ †

State Key Laboratory and Institute of Elemento-Organic Chemistry and ‡Collaborative Innovation Center of Chemical Science and Engineering, College of Chemistry, Nankai University, Tianjin 300071, China

CONSPECTUS: Chiral carboxylic acid moieties are widely found in pharmaceuticals, agrochemicals, flavors, fragrances, and health supplements. Although they can be synthesized straightforwardly by transition-metal-catalyzed enantioselective hydrogenation of unsaturated carboxylic acids, because the existing chiral catalysts have various disadvantages, the development of new chiral catalysts with high activity and enantioselectivity is an important, long-standing challenge. Ruthenium complexes with chiral diphosphine ligands and rhodium complexes with chiral monodentate or bidentate phosphorus ligands have been the predominant catalysts for asymmetric hydrogenation of unsaturated acids. However, the efficiency of these catalysts is highly substrate-dependent, and most of the reported catalysts require a high loading, high hydrogen pressure, or long reaction time for satisfactory results. Our recent studies have revealed that chiral iridium complexes with chiral spiro-phosphine-oxazoline ligands and chiral spirophosphine-benzylamine ligands exhibit excellent activity and enantioselectivity in the hydrogenation of α,β-unsaturated carboxylic acids, including α,β-disubstituted acrylic acids, trisubstituted acrylic acids, α-substituted acrylic acids, and heterocyclic α,β-unsaturated acids. On the basis of an understanding of the role of the carboxy group in iridium-catalyzed asymmetric hydrogenation reactions, we developed a carboxy-group-directed strategy for asymmetric hydrogenation of olefins. Using this strategy, we hydrogenated several challenging olefin substrates, such as β,γ-unsaturated carboxylic acids, 1,1-diarylethenes, 1,1-dialkylethenes, and 1-alkyl styrenes in high yield and with excellent enantioselectivity. All these iridium-catalyzed asymmetric hydrogenation reactions feature high turnover numbers (up to 10000) and turnover frequencies (up to 6000 h−1), excellent enantioselectivities (greater than 95% ee with few exceptions), low hydrogen pressure (99% ee). Conversion is substantially improved by the addition of a basic additive to the reaction mixture. For instance, the addition 989

DOI: 10.1021/acs.accounts.7b00007 Acc. Chem. Res. 2017, 50, 988−1001

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Accounts of Chemical Research

Various α-alkylcinnamic acid derivatives 5 were hydrogenated by using catalyst (Sa,S)-3c. Excellent enantioselectivities (>96% ee) were obtained for all substrates regardless of the steric and electronic properties of the substituent on the phenyl ring of the substrates (Scheme 2). The hydrogenation was very fast, and turnover frequencies as high as 800 h−1 were achieved. The hydrogenation of α-isopropylcinnamic acid derivative 5b catalyzed by (Sa)-3f proceeds smoothly even at very low catalyst loading (0.01 mol %, Scheme 3). The reaction affords a 95% yield of acid (R)-6b, a key intermediate in the synthesis of the new blood-pressure-lowering drug aliskiren, with a turnover number (TON) of 9700 and an ee of 95%. By using catalyst 3f, we also accomplished the hydrogenation of α-arylcinnamic acids 9 under ambient hydrogen pressure with a low catalyst loading (as low as 0.01 mol %) to provide 2,3-diarylpropionic acids 10 in high yield with excellent enantioselectivity (up to 99% ee, Scheme 4).18 With asymmetric hydrogenation of an α-arylcinnamic acid as a key step, the enantioselective synthesis of (S)-equol, an important soy isoflavonoid metabolite with phytoestrogenic activity and potential use in menopausal hormone replacement therapy, was accomplished in six steps in 48.4% overall yield starting from commercially available starting materials (Scheme 5). The asymmetric hydrogenation of α-oxymethylcinnamic acids 11 provides straightforward access to chiral α-benzyl-β2hydroxy carboxylic acids 12, which are useful building blocks in the syntheses of various pharmaceuticals and natural products (Scheme 6). However, previously reported catalysts for the asymmetric hydrogenation of α-oxymethylcinnamic acids show only low to moderate enantioselectivity or low yield. With catalyst (Sa)-3f, high activity (TON up to 2000) and excellent enantioselectivity (96−99.5% ee) were achieved in the hydrogenation of α-oxymethylcinnamic acids.19 Using this efficient hydrogenation as a key step, we accomplished a concise, enantioselective total synthesis of the natural product homoisoflavone, which has significant antibacterial activity. Tiglic acid and various derivatives 13 were also hydrogenated to produce corresponding carboxylic acids 14 with excellent enantioselectivity by using (Sa,S)-3d as a catalyst and Cs2CO3 as a basic additive (Scheme 7).17 A higher catalyst loading was needed when a bulky group was introduced into either the α-position or the β-position of the substrate.

Table 1. Asymmetric Hydrogenation of α-Methylcinnamic Acid, 5a

entry

[Ir]

additive

time (h)

conv. (%)

yield (%)

ee (%)a

1 2 3 4 5 6 7 8 9d 10 11

(Sa,S)-3a (Ra,S)-3a (Sa,S)-3b (Sa,S)-3c (Sa,S)-3c (Sa,S)-3d (Sa,S)-3e (Sa)-3f (Sa,S)-3c (S)-7 (Ra)-8

none none none none NEt3 NEt3 NEt3 NEt3 NEt3 NEt3 NEt3

24 24 24 24 0.5 2 3 8 4 24 24

15 c 29 58 100 100 100 100 100 5 15

b b b b 99 98 99 97 98 b b

82 b 76 >99 >99 >99 >99 >99 >99 b b

a

The absolute configuration of the product is S. bNot determined. cNo reaction. dPH2 = 1 atm.

of 0.5 equiv of NEt3 results in full conversion within 30 min and excellent enantioselectivity (entry 5). The basic additive converts the substrate to the anionic form, which coordinates more readily to the iridium catalyst. Unlike the P−Ar group, the substituent on the oxazoline ring of the catalyst has a negligible influence on the conversion and enantioselectivity of the reaction (entries 5−8). Catalyst (Sa,S)-3c catalyzes the hydrogenation of α-methylcinnamic acid under ambient hydrogen pressure (entry 9). That iridium catalysts with other chiral phosphine-oxazoline ligands, such as (S)-7 and (Sa)-8, give very low conversions (entries 10 and 11) clearly demonstrates the vital role of the chiral spiro backbone in the enantioselective hydrogenation of α-methylcinnamic acid.

Scheme 2. Iridium-Catalyzed Asymmetric Hydrogenation of α-Alkylcinnamic Acids

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Accounts of Chemical Research Scheme 3. Synthesis of a Key Intermediate of Aliskiren

protease inhibitor rupintrivir, was prepared by using this asymmetric hydrogenation protocol (Scheme 10).

Scheme 4. Iridium-Catalyzed Asymmetric Hydrogenation of α-Arylcinnamic Acids

2.2. 2,3,3-Trisubstituted Acrylic Acids

In contrast to the asymmetric hydrogenation of unsaturated carboxylic acids bearing a di- or trisubstituted olefin, the asymmetric hydrogenation of unsaturated carboxylic acids with a tetrasubstituted olefin cannot be readily achieved. The challenges arise mainly from steric hindrance around the olefin moiety. We succeeded in enantioselectively hydrogenating acrylic acids 20, which have tetrasubstituted olefins, by using chiral iridium catalyst (Sa,S)-3c (Scheme 11).22 The reaction provides a direct catalytic route to chiral carboxylic acids 21 with α-aryl, α-alkyl, α-aryloxy, or α-alkyloxy substituents.

Tremendous effort has been devoted to the asymmetric hydrogenation of α-aryloxy- and α-alkoxy-substituted α,βunsaturated acids, but success has been limited.6d,20 Catalysts (Sa,S)-3e and (Sa,S)-3c show high efficiency in the asymmetric hydrogenation of α-alkoxy- and α-aryloxy-substituted α,βunsaturated acids 15 and 17 (Schemes 8 and 9, respectively).21 Under mild reaction conditions, a broad range of α-aryloxy and α-alkoxy substituted α,β-unsaturated acids were hydrogenated in excellent yields (90−97%) and exceptional enantioselectivities (96−99.8% ee) and TONs up to 10000. α-Hydroxy carboxylic acid 19, a key intermediate in the syntheses of rhinovirus

2.3. 2-Substituted Acrylic Acids

The asymmetric hydrogenation of α-arylacrylic acids is highly useful for the synthesis of well-known nonsteroidal antiinflammatory drugs such as ibuprofen and naproxen, and thus this reaction has been studied extensively.5,6 However, chiral ruthenium catalysts generally require high hydrogen pressure

Scheme 5. Total Synthesis of (S)-Equol

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Accounts of Chemical Research Scheme 6. Iridium-Catalyzed Asymmetric Hydrogenation of α-Oxymethylcinnamic Acids and Synthesis of (S)(+)-Homoisoflavone

With catalyst (Sa)-4c, various α-aryl- and α-alkylacrylic acids can be hydrogenated to the corresponding chiral carboxylic acids, including ibuprofen, naproxen, and flurbiprofen, in excellent yields (97−99%) and enantioselectivities (94−98% ee, Scheme 12).

Scheme 7. Iridium-Catalyzed Asymmetric Hydrogenation of Tiglic Acid Derivatives

2.4. Heterocyclic α,β-Unsaturated Carboxylic Acids

The transition-metal-catalyzed enantioselective hydrogenation of unsaturated heterocyclic carboxylic acids is a direct approach to chiral heterocyclic acids, which are present in various pharmaceuticals. However, efficient catalysts for the asymmetric hydrogenation of cyclic α,β-unsaturated carboxylic acids are rare. Highly enantioselective hydrogenations of unsaturated N-heterocyclic acids and O-heterocyclic acids have been realized with (Sa)-3f and (Sa,S)-3c as catalysts, respectively (Schemes 13 and 14).23 A concise synthesis of (R)-tiagabine, a γ-aminobutyric acid reuptake inhibitor for the treatment of epilepsy, was accomplished by hydrogenation of unsaturated acid 24a (Scheme 15). The CC double bond conjugated to the carboxy group of 24a is hydrogenated smoothly, whereas the double bond conjugated to the two thiophenes remains intact. This excellent chemoselectivity is another merit of chiral spiro-iridium catalysts 3.

for high enantioselectivity, while the rhodium catalysts show modest TONs or turnover frequencies. Iridium catalysts 3 with chiral spiro-phosphine-oxazoline ligands also show unsatisfactory catalytic activity and enantioselectivity in the hydrogenation of α-arylacrylic acid 22a (Table 2, entries 1−4). Novel iridium catalysts 4 (Scheme 1), which have chiral SpiroBAP ligands, were developed and found to be effective for the asymmetric hydrogenation of α-substituted acrylic acids, exhibiting extremely high reaction rates (turnover frequencies of up to 6000 h−1) and excellent enantioselectivity (Table 2, entry 7).15 Increasing the bulk of the P-aryl group in catalysts 4 increases their activity and enantioselectivity (compare entries 5−7), with catalyst 4c giving the best result. The loading of catalyst (Sa)-4c can be reduced to 0.01 mol % without diminishing the conversion or enantioselectivity of the reaction, although a longer reaction time is required (entry 9). However, a catalyst with an N-methyl group, (Sa)-4d, does not give complete reaction (entry 8).

3. CARBOXY-GROUP-DIRECTED ASYMMETRIC HYDROGENATION OF OLEFINS 3.1. β,γ-Unsaturated Acids

The asymmetric hydrogenation of β,γ-unsaturated acids provides an ideal route for the preparation of carboxylic acids with

Scheme 8. Iridium-Catalyzed Asymmetric Hydrogenation of α-Alkoxy Cinnamic Acids

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Accounts of Chemical Research Scheme 9. Iridium-Catalyzed Asymmetric Hydrogenation of α-Aryloxy Cinnamic Acids and α-Aryloxy Butenoic Acids

Scheme 10. Asymmetric Synthesis of a Key Intermediate of Rupintrivir

Table 2. Asymmetric Hydrogenation of α-(4-Isobutylphenyl)acrylic Acid, 22a

Scheme 11. Iridium-Catalyzed Asymmetric Hydrogenation of 2,3,3-Trisubstituted Acrylic Acids

a chiral center at the γ-position, which are important intermediates in the synthesis of various natural products. However, efficient catalysts for this reaction are rare.5a,6e Iridium catalyst (Sa,S)-3h, which has an α-naphthylmethyl group on the oxazoline ring, efficiently catalyzes the asymmetric hydrogenation of β,γ-unsaturated acids, including 4-alkyl-4-aryl-3-butenoic acids to yield saturated carboxylic acids 29 in up to 97% ee (Scheme 16).24 Mechanistic studies showed that the carboxy group of substrate acts as an anchor by coordinating to the

a

entry

[Ir]

time

conv. (%)

1 2 3 4 5 6 7 8 9a

(Sa,S)-3c (0.25 mol %) (Sa,S)-3d (0.25 mol %) (Sa,S)-3e (0.25 mol %) (Sa)-3f (0.25 mol %) (Ra)-4a (0.1 mmol %) (Sa)-4b (0.1 mmol %) (Sa)-4c (0.1 mmol %) (Sa)-4d (0.1 mmol %) (Sa)-4c (0.01 mol %)

24 h 24 h 24 h 10 h 2h 1h 10 min 18 h 8h

36 33 51 100 100 100 100 44 100

ee (%) 45 42 67 84 94 96 98 98 97

(R) (R) (R) (R) (S) (R) (R) (R) (R)

Used 5 equiv of NEt3 as additive, 60 °C.

iridium and facilitates the hydrogenation. The carboxy-groupdirected asymmetric hydrogenation of olefins provides a new strategy for remote control of the enantioselectivity of the reaction. With this asymmetric hydrogenation as the key step, 993


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Accounts of Chemical Research Scheme 12. Iridium-Catalyzed Asymmetric Hydrogenation of α-Substituted Acrylic Acids

Scheme 13. Iridium-Catalyzed Asymmetric Hydrogenation of α,β-Unsaturated N-Heterocyclic Acids

Scheme 15. Synthesis of (R)-Tiagabine

double-bonded carbons are similar in size, as is the case for 1,1-dialkylethenes and 1,1-diarylethenes, and thus the enantioselectivity of the hydrogenation of such substrates is low. However, the asymmetric hydrogenation of these two types of olefins has been achieved by means of the carboxy-group-directed strategy with chiral iridium catalysts 3.25 With (Sa)-3i and (Sa,S)-3g, a variety of chiral diarylethanes 31 and chiral γ-methyl fatty acids 33, which are core structures of many biologically active compounds, were prepared by asymmetric hydrogenation of substrates 30 and 32, respectively, in high yields and excellent enantioselectivities (Schemes 18−20). The carboxy group of the substrates, which acts as a directing group and increases the enantioselectivity of the hydrogenation reaction, can subsequently be removed

concise total syntheses of the natural products (R)-aristelegoneA, (R)-curcumene, and (R)-xanthorrhizol were accomplished (Scheme 17). 3.2. 1,1-Dialkylethenes and 1,1-Diarylethenes

In the asymmetric hydrogenation of CC double bonds, chiral induction arises from differentiation of the prochiral faces of the double bond by the catalyst. Differentiation of the re and si faces is difficult if the substituents attached to the

Scheme 14. Iridium-Catalyzed Asymmetric Hydrogenation of α,β-Unsaturated O-Heterocyclic Acids

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Accounts of Chemical Research Scheme 16. Iridium-Catalyzed Asymmetric Hydrogenation of 4-Alkyl-4-aryl-3-butenoic Acids

Scheme 17. Syntheses of (R)-Aristelegone-A, (R)-Curcumene, and (R)-Xanthorrhizol

Scheme 18. Carboxy-Group-Directed Asymmetric Hydrogenation of 1,1-Diarylethenes

Scheme 19. Carboxy-Group-Directed Asymmetric Hydrogenation of 1,1-Diarylethenes

easily (Scheme 21) or transformed to other useful functional groups (Scheme 22). 995


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Accounts of Chemical Research Scheme 20. Carboxy-Group-Directed Asymmetric Hydrogenation of 1,1-Dialkylethenes

Scheme 23. Carboxy-Group-Directed Asymmetric Hydrogenation of 1-Alkylstyrenes

and enantioselectively in high overall yields by using this catalytic asymmetric hydrogenation as a key step. 3.3. 1-Alkylstyrenes

4. MECHANISTIC STUDIES The mechanism of iridium-catalyzed asymmetric hydrogenation of olefins depends strongly on the catalyst and the substrate.7,9,27 Two major pathways have been proposed: an Ir(I)/ Ir(III) cycle and an Ir(III)/Ir(V) cycle (Scheme 24). Note that migratory insertion intermediate B-1 is involved in both cycles. In the Ir(I)/Ir(III) cycle, B-1 directly undergoes reductive

The strategy of using a carboxy group as a directing group has been extended to the asymmetric hydrogenation of 1-alkylstyrenes 34 catalyzed by (Sa)-3f, which produces compounds with a chiral benzylmethyl center (Scheme 23).26 Chemoselective hydrogenation of various dienes was achieved without isomerization of the terminal CC double bond, and (S)-curcudiol and (S)-curcumene were synthesized concisely Scheme 21. One-Pot Preparation of Chiral Diarylethanes

Scheme 22. Transformations of Carboxylic Groups

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Accounts of Chemical Research Scheme 24. Two Possible Mechanisms for Iridium-Catalyzed Hydrogenation of Olefins

Scheme 25. Preparation of Migratory Insertion Intermediate 37

Scheme 26. Transformations of 37

elimination that gives the hydrogenation product and regenerates the Ir(I) catalyst. In contrast, in the Ir(III)/Ir(V) cycle, B-1 undergoes a further oxidative addition of hydrogen to give

an Ir(V) intermediate, from which the hydrogenation product forms by means of reductive elimination accompanied by regeneration of the Ir(III) catalyst. Migratory insertion 997


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Accounts of Chemical Research Scheme 27. Gibbs Energy Profile Calculated for the Hydrogenation of Sodium α-Methyl Cinnamate

intermediate B-1 is particularly valuable for mechanistic studies because it contains both of the activated reaction components (hydrogen and the olefin substrate) and can therefore provide evidence for understanding chiral induction by the catalyst. However, because the intermediate contains highly active M−H and M−C bonds, it is unstable and difficult to isolate and characterize. The high stability of the chiral spiro-iridium catalysts under hydrogenation conditions13 allows trapping of the active intermediates. For example, the hydrogenation of α-methylcinnamic acid catalyzed by catalyst (Sa)-3j, which has a triflate counterion, was used as a model reaction for a mechanistic study (Scheme 25).28 First, iridium dihydride species 36 was prepared by treating a solution of (Sa)-3j in methanol with 1 atm of hydrogen at room temperature. Sodium (E)-2-methyl-3phenyl acrylate was then added to the reaction mixture at 25 °C to generate migratory insertion intermediate 37. Both 36 and 37 were fully characterized by NMR spectroscopy and highresolution mass spectrometry. In contrast, an Ir-dihydride-olefin

complex identified as an intermediate in the hydrogenation of an unfunctionalized substrate does not undergo migratory insertion in the absence of H2,29 which implies that the mechanism of Ir-catalyzed hydrogenation is highly catalyst- and substrate-dependent. When a solution of intermediate 37 in methanol is heated at 65 °C, dimer 38 forms instead of the hydrogenation product. However, 37 smoothly produces hydrogenation product 39 under 1 atm of hydrogen at 25 °C within 0.5 h (Scheme 26). Both 38 and 39 catalyze the hydrogenation of α-methylcinnamic acid. Under 1 atm of deuterium, 37 affords a hydrogenation product with 50% deuterium at the newly formed C−H bond at the β-position, which implies that the hydrogen involved in the reductive elimination step comes partially from hydrogen gas. These experimental results clearly suggest that the Ir(III) in 37 undergoes an oxidative addition to form Ir(V), which then releases the hydrogenation product by reductive elimination. Therefore, these experimental results rule out the Ir(I)/Ir(III) cycle and strongly support the involvement of the 998


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Scheme 28. An Overall Catalytic Cycle of Iridium-Catalyzed Asymmetric Hydrogenation of Sodium α-Methyl Cinnamate

Ir(III)/Ir(V) cycle in the iridium-catalyzed hydrogenation of olefins. Density functional theory calculations were performed with the goal of understanding the details of the processes involved in the hydrogenation reaction. Calculation of the enantioselectivity-determining step, that is, conversion of 36 to 37 (Scheme 27a), indicates that the energy of transition state TS-S is 4.3 kcal/mol lower than that of transition state TS-R. This result suggests perfect enantioselectivity for the S product, which is consistent with the experimental data (99% ee). Density functional theory calculations also provide insight into the formation and reactions of the Ir(V) intermediate (Scheme 27b). Interestingly, the Ir(V) intermediate cannot be obtained via TS-42/43; the calculations suggest an alternative pathway involving recombination of the H−H bond to give a new Ir(III) intermediate (43a). Only after the H−H bond of 43a rotates by 72° to give 43b can the oxidative addition take place smoothly with a low energy barrier (1.5 kcal/mol) to afford Ir(V) intermediate 43c. This high-valence intermediate readily undergoes a reductive elimination via transition structure TS-III/V with an 11.6 kcal/mol energy barrier. In contrast, the direct reductive elimination from 37 has a much higher energy barrier (16.9 kcal/mol). The unexpected hydrogen rearrangement sequence from 43a to 43c also explains the deuterium distribution in the product of the deuteration experiment shown in Scheme 26. In the reductive elimination from 43c, only the hydrogen or the deuterium in the N−O−C−Ir plane can participate in the reaction. Because the N−O−C−Ir plane in 43c contains one hydrogen and one deuterium, the reductive elimination reaction must give a product containing 50% D at the newly formed C−H bond at the β-position.

Taken together, these results suggest that the overall catalytic cycle for the iridium-catalyzed hydrogenation of sodium α-methyl cinnamate is as shown in Scheme 28. First, active dihydride intermediate 36 undergoes a migratory insertion reaction with the carboxylate substrate to give intermediate 37. In addition, the carboxy anion of the substrate can also join two molecules of Ir(III) species 36 to form dimeric intermediate 38. Intermediate 37 is further oxidized by hydrogen to Ir(V) species 43c, which undergoes reductive elimination to afford the hydrogenation product. The carboxy group of the hydrogenation product can also serve as a bridging ligand to link two molecules of 36 to generate dimer 39. Intermediates 36−39 and 40s have been unequivocally identified experimentally. The structures of Ir(V) intermediate 43c and Ir(III) intermediate 44 were determined by means of density functional theory calculations. It is worth mentioning that the carboxy group of the substrates plays a critical role in iridium-catalyzed asymmetric hydrogenation reactions. No hydrogenation reaction occurs when the corresponding esters are used in place of the acids. As suggested by the mechanistic study, the carboxy group anchors the substrate to the iridium center and initiates the reaction. Moreover, the carboxy group stabilizes the active intermediates and permits isolation and characterization of the migratory insertion intermediate.

5. CONCLUDING REMARKS The iridium-catalyzed asymmetric hydrogenation of unsaturated acids has significantly expanded the applications of chiral iridium catalysts. Compared with the well-established chiral ruthenium and rhodium catalysts, iridium catalysts 3 and 4 modified with chiral spiro-P,N-ligands afford chiral carboxylic 999


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(Grants 21532003, 21625204, and 21421062), the National Basic Research Program of China (2012CB821600), the “111” project (B06005) of the Ministry of Education of China, and the National Program for Support of Top-notch Young Professionals for financial support.

acids with excellent enantioselectivity from a broad range of substrates with low catalyst loading under mild reaction conditions, making the hydrogenation reaction of unsaturated carboxylic acids particularly suitable for practical use. Indeed, several chiral spiro-iridium catalysts have been used to prepare chiral carboxylic acids by hydrogenation of α,β-unsaturated carboxylic acids. For instance, Roche30 used chiral spiro-iridium catalysts 3 in the highly enantioselective hydrogenation reactions of α-alkoxycinnamic acid derivatives for the preparation of aleglitazar and R4940, chiral drug candidates for treatment of type 2 diabetes. Jiuzhou Pharmaceutical Co.31 efficiently synthesized silodosin, a selective α1-adrenergic receptor antagonist for treatment of benign prostatic hyperplasia, by asymmetric hydrogenation of α-methylcinnamic acid derivatives with catalysis by a chiral spiro-iridium catalyst 3. Lei and co-workers32 reported an efficient synthesis of trideuterated [5,24,25-D3](25S)-Δ7-dafachronic acid, a useful chemical tool for biological studies, by using 3-catalyzed asymmetric hydrogenation as a key step. The chiral iridium catalysts have become important in the asymmetric hydrogenation of unsaturated carboxylic acids and are attracting increasing attention.16,33 The unique catalytic mechanism exhibited by chiral iridium catalysts in the asymmetric hydrogenation of unsaturated carboxylic acids will undoubtedly inspire future studies on both the design of new chiral catalysts and the development of new hydrogenation reactions.

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REFERENCES

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Shou-Fei Zhu: 0000-0002-6055-3139 Qi-Lin Zhou: 0000-0002-4700-3765 Notes

The authors declare no competing financial interest. Biographies Shou-Fei Zhu received his Ph.D. degree in chemistry under the supervision of Prof. Qi-Lin Zhou at the Institute of Elemento-Organic Chemistry, Nankai University, in 2005. He then joined the faculty of the same institute and was promoted to full professor in 2013. He did postdoctoral research in the University of Tokyo with Prof. Eiichi Nakamura from 2012 to 2013. His research interests focus on organic synthesis, particularly on the catalytic reactions containing hydrogen transfer. Qi-Lin Zhou received his Ph.D. degree from Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, under the supervision of Prof. Yao-Zeng Huang in 1987. After postdoctoral research in Europe and United States, he joined the faculty of the Institute of Fine Chemicals, East China University of Science and Technology, in 1996. In 1999, he moved to the Institute of Elementoorganic Chemistry, Nankai University, as a Cheung Kong Scholar. He was elected as a member of Chinese Academy of Sciences in 2009. His current research interests include transition-metal-catalyzed reactions, asymmetric catalysis, and synthesis of biologically active compounds.

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ACKNOWLEDGMENTS We are indebted to co-workers, whose names are cited in the references, for their intellectual and experimental contributions. We thank the National Natural Science Foundation of China 1000


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Iridium-Catalyzed Asymmetric Hydrogenation of Unsaturated

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