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. 2025 Oct 10;4(2):135–142. doi: 10.1021/prechem.5c00087

Iridium-Catalyzed Regio- and Enantioselective Hydrogenation of 5‑Alkylidene Cyclopentenones

Haipeng Wei †,∥, Jinbao Ren †, Qianjia Yuan †,‡,*, Wei-Ping Deng ¶,∥,*, Wanbin Zhang †,*
PMCID: PMC12933482  PMID: 41756619

Abstract

The regio- and enantioselective hydrogenation of the CC bond in molecules with two or more CC bonds of the same type is very challenging but highly desirable. Herein, we report a regio- and enantioselective hydrogenation of 5-alkylidene cyclopentenones catalyzed by an Ir/BiphPHOX complex, delivering the corresponding mono- and double-hydrogenated products in excellent results, respectively (5-substituted cyclopentenones: up to 99% yield and 98% ee; 2,4-disubstituted cyclopentanones: up to 99% yield, 16:1 dr, and 99% ee). For the chiral 2,4-disubstituted cyclopentanones, the results of mechanistic studies indicated that both the exo- and endocyclic CC bonds of the substrate can be preferentially reduced with the exocyclic CC bond undergoing hydrogenation more readily. The ester group in the substrate plays an important role in improving the reactivity and controlling the stereoselectivity of the product. The reaction was successfully conducted on a gram-scale, and the hydrogenated product can be readily derivatized.

Keywords: asymmetric hydrogenation, regioselectivity, iridium, cyclopentenone, cyclopentanone

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Chiral cyclopentenones and 2,4-disubstituted cyclopentanone moieties are widely present in natural products and bioactive molecules, and are also very important building blocks. − In view of their broad significance, various synthetic methods have been developed for the preparation of these compounds. − For example, the well-known Pauson-Khand reaction ,− and Nazarov cyclization ,− could be used for the synthesis of chiral cyclopentenones. Compared with cyclopentenones, methods for preparing chiral 2,4-disubstituted cyclopentanones have not been widely reported, and the developed strategies are limited to enantioselective conjugate reduction and hydroacylation involving dynamic kinetic resolution. , In 2021, our group developed an enantioselective hydroacylation reaction, which could also deliver such compounds via alkene isomerization. Given the importance of chiral cyclopentenones and 2,4-disubstituted cyclopentanones and the structural diversity in the target molecules, it is highly desirable to develop new and efficient strategies for the construction of these compounds.

The transition-metal-catalyzed asymmetric hydrogenation reaction has been recognized as one of the most efficient approaches to chiral molecules, and in the past several decades, asymmetric hydrogenation has seen broad adoption in both academic research and industrial applications. − The research area of asymmetric hydrogenation mainly focuses on: 1) the enantioselective hydrogenation of substrates (alkene, imine and ketone) bearing only one CX (X = CR1R2, NR, O) bond (Figure a), and 2) the chem- and enantioselective hydrogenation of substrates bearing two different types of CX bond. ,, For example, the chem- and enantioselective hydrogenation of α,β-unsaturated ketones, which bear one CC bond and one CO bond, has attracted much attention and is well developed (Figure b). The regio- and enantioselective hydrogenation of the substrates bearing two CX bonds of the same type is challenging. Although some examples have been reported, the reported methods are limited to either selective monohydrogenation or double-hydrogenation of the CX bonds (Figure c). − Actually, there is only one example concerning the enantioselective monohydrogenation and double-hydrogenation of two CX bonds of the same type in the substrate, respectively, and which was mainly realized by controlling the reaction time.

1.

1

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Research progress in asymmetric hydrogenation and this work. (a) Enantioselective hydrogenation of substrates bearing only one CX bond (X = CR1R2, NR, O). (b) Chem- and enantioselective hydrogenation of substrates bearing two different types of CX bond. (c) Regio- and enantioselective hydrogenation of the substrates bearing two CX bonds of the same type. (d) This work: controlled chem-, regio- and enantioselective hydrogenation of 5-alkylidene cyclopentenones.

Our group has focused on asymmetric hydrogenation for many years, − and our developed axis-unfixed biphenylphosphine-oxazoline (BiphPHOX) has shown excellent results in iridium-catalyzed asymmetric hydrogenation of several challenging substrates, especially for the hydrogenation of five-membered exo-α,β-unsaturated compounds. − To address the challenges of regio- and stereoselectivity in the asymmetric hydrogenation of substrates containing two CX bonds of the same type, and considering the importance of chiral cyclopentenones and 2,4-disubstituted cyclopentanone, we designed an Ir/BiphPHOX complex-catalyzed chem-, regio-, and enantioselective hydrogenation of 5-alkylidene cyclopentenones (Figure , this work). Based on our previous work, we conceived that the exocyclic CC bond should be reduced easily, but control of the endocyclic CC bond to be retained is challenging, because our developed Ir/BiphPHOX complex could also realize the hydrogenation of the CC bond of endocyclic α,β-unsaturated ketones. Moreover, since the efficient asymmetric hydrogenation of exo- and endocyclic CC bonds usually require different catalysts, ,, it is also challenging to obtain the double-hydrogenated products, 2,4-disubstituted cyclopentanones, with excellent diastereoselectivities and enantioselectivities with a single catalyst.

To optimize the reaction conditions, 3-methyl 5-benzylidene cyclopentenone 1a was selected as the model substrate (Table ). Notably, the Ding group reported the enantioselective hydrogenation of the exocyclic CC bond in 3-methoxy 5-benzylidene cyclopentenone, a key step in the total synthesis of (−)-Crinipellins. First, the BiphPHOX ligands with different substituents on the oxazoline ring were examined (Table , entries 1–3). To our delight, the reaction proceeded very well and delivered the exocyclic CC bond being hydrogenated product 2a with excellent enantioselectivities (96–98% ee), only a trace amount of the exo- and endocyclic CC bonds both being hydrogenated product 3a was observed (2a:3a = 95:5). Then, the ligand iPr-BiphPHOX (L1) was chosen for further optimization of the reaction conditions. When the reaction time was shortened to 12 h, 96% conversion was obtained, and the regioselectivity and enantioselectivity of the product were not affected (entry 4). The product 2a was obtained exclusively (2a:3a > 99:1) and with 98% ee when the reaction was performed at 10 °C, but the reaction proceeded with a lower 81% conversion (entry 5). It is exciting that the reaction proceeded in full conversion and provided the product 2a exclusively (2a:3a > 99:1) and with 98% ee when the reaction was carried out under a hydrogen pressure of 50 bar at 10 °C for 24 h (entry 6). In addition, the solvent for the reaction was also examined, better results were not obtained (entry 7).

1. Reaction Condition Screening .

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entry solvent L conv. (%) 2a:3a ee (%)
1 DCM L1 99 95:5 98
2 DCM L2 93 95:5 96
3 DCM L3 99 95:5 97
4 DCM L1 96 95:5 98
5 DCM L1 81 >99:1 98
6 DCM L1 99 >99:1 98
7 o-xylene L1 41 >99:1 97
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a

Reaction conditions: 1a (0.2 mmol) and [Ir­(L)­COD]­BArF (1 mol %) in DCM (2 mL) under H2 (20 bar) at room temperature for 24 h.

b

Determined by 1H NMR analysis of the crude reaction mixture.

c

Determined by chiral HPLC.

d

12 h.

e

10 °C.

f

H2 (50 bar), 10 °C. BArF = tetrakis­[3,5-bis­(trifluoromethyl)­phenyl]­borate.

With the optimized reaction conditions in hand (standard conditions A, Table , entry 6), the substrate scope for this reaction was investigated (Table ). In general, the reaction showed good functional group tolerance, and provided the corresponding hydrogenated products with excellent yields and enantioselectivities. When R1 was a phenyl group without a substituent or had an electron-withdrawing or electron-donating group at various positions on the ring, the substrates were suitable for the reaction and gave the hydrogenated products with excellent yields and enantioselectivities (2a-2m, 95–99% yields, 92–98% ee). When R1 was a 3,4-dimethyphenyl, 3,4-methylenedioxyphenyl or β-naphthyl group, the corresponding hydrogenated products were also obtained in excellent yields and enantioselectivities (2n-2p, 96–97% yields, 94–96% ee). The substrate with an α-naphthyl group gave the corresponding product 2q in 95% yield with 80% ee. Substrates with R1 as a heterocyclic substituent (e.g., 2-furanyl, 2-thiophenyl, 4-(2-fluorine)­pyridinyl) were also examined for the reaction, however, poor results were obtained (please see the Supporting Information for details). For the substrates with an aliphatic group of R1, the reaction also proceeded very well and delivered the desired hydrogenated products in quantitative yields and with high enantioselectivities (2r, 99% yield, 95% ee; 2s, 99% yield, 83% ee). The substrates bearing different R2 or R3 groups were also examined in the reaction. When R2 was an alkyl or phenyl group, the corresponding hydrogenated products were obtained in quantitative yields with excellent enantioselectivities (2t-2v, 99% yields, 95–98% ee). The substrate with R3 as a methyl group, could be reduced to give product 2w in 99% yield and with 91% ee. When both R2 and R3 were methyl or phenyl groups, the desired products were obtained with excellent results (2x, 99% yield, 97% ee; 2y, 99% yield, 97% ee). The regio- and enantioselective hydrogenation of 6-benzyliene cyclohexenone was also realized under the optimized reaction conditions, and the corresponding hydrogenated product 2z was obtained in 99% yield with 64% ee. In addition, when both R2 and R3 were hydrogenated, the double-hydrogenated product was obtained. The absolute configuration of 2v was assigned to be S by single X-ray diffraction, and the other products were then assigned accordingly.

2. Substrate Scope for the Preparation of Chiral Cyclopentenones .

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a

Reaction conditions: 1 (0.2 mmol) and [Ir­(L1)­COD]­BArF (1 mol %) in DCM (2 mL) under H2 (50 bar) at 10 °C for 24 h. Isolated yield.

In view of the importance of the chiral 2,4-disubstituted cyclopentanones, we turned our attention to the preparation of such compounds via asymmetric hydrogenation of both the exo- and endocyclic CC bonds of 5-alkylidene cyclopentenones. First, the reaction was carried out under 50 bar of H2 at 60 °C with substrate 1a. The reaction proceeded with consumption of the starting material; however, the desired double-hydrogenated product 3a was obtained in only 8% yield (Table , entry 1). Increasing the catalyst loading from 1 to 5 mol % gave the product 3a in quantitative yield and with 1:1 dr, and in excellent enantioselectivities (entry 2). Then the substituent group R2 of the substrate was modified. To our delight, when the R2 group was an ester (4a), the desired hydrogenated product 5a was obtained in 99% yield with 12:1 dr and 99% ee (entry 3). When the R2 group was the benzoyl group (4b), the reaction proceeded well, and gave the hydrogenated product 5b in 99% yield and with 4:1 dr and 95% ee (entry 4). The reaction also proceeded well with a lower catalyst loading (1 mol %) at room temperature and provided the product 5a with excellent results (99% yield, 12:1 dr and 99% ee) (entry 5).

3. Optimization of the Double Hydrogenation Reaction Conditions .

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entry substrate conv. (%) yield (%) dr ee (%)
1 1a, R2 = Me >99 3a, 8% – –
2 1a, R2 = Me >99 3a, 99% 1:1 95/98
3 4a, R2 = MeO2C >99 5a, 99% 12:1 99
4 4b, R2 = PhC(O) >99 5b, 99% 4:1 95
5 4a, R2 = MeO2C >99 5a, 99% 12:1 99
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a

Reaction conditions: 1 or 4 (0.2 mmol), [Ir­(L1)­COD]­BArF (5 mol %) in DCM (2 mL) under H2 (50 bar) at 60 °C for 24 h.

b

Isolated yield.

c

Determined by 1H NMR analysis of the crude reaction mixtures.

d

Determined by chiral HPLC.

e

[Ir­(L1)­COD]­BArF (1 mol %) was used.

f

It is difficult to determine which of these ee values specifically corresponds to which of the two different diastereomers.

g

[Ir­(L1)­COD]­BArF (1 mol %) was used and the reaction was carried out at room temperature.

Under the optimized reaction conditions (standard conditions B: Table , entry 5), the substrate scope for preparing 2,4-disubstituted cyclopentanones 5 was examined (Table ). When the R1 group of substrates 4 was a phenyl ring without a substituent or possessed an electron-withdrawing or electron-donating group at the para- or meta-positions of the phenyl ring, the corresponding products were obtained in quantitative yields and with good diastereoselectivities and excellent enantioselectivities (5a and 5c-5g, 99% yield, 9:1–12:1 dr, 96–99% ee). Substrates with a substituent at the ortho-position of the phenyl ring could also give the desired products with good results (5h, 99% yield, 6:1 dr and 84% ee; 5i, 99% yield, 10:1 dr and 93% ee). When the R1 group was 2-naphthyl, the desired product 5j was obtained in 99% yield and with 9:1 dr and 97% ee. Finally, a substrate with R1 as a methyl group was examined, and the corresponding hydrogenated product 5k was obtained in 99% yield and with 16:1 dr and 96% ee. The absolute configuration of 5c was assigned to be (2S, 4S) by single X-ray diffraction, and the other products 5 were then assigned accordingly.

4. Substrate Scope for the Preparation of 2,4-Disubstituted Cyclopentanones .

graphic file with name pc5c00087_0007.jpg

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a

Reaction conditions: 4 (0.2 mmol) and [Ir­(L1)­COD]­BArF (1 mol %) in DCM (2 mL) under H2 (50 bar) at room temperature for 24 h. Isolated yield.

To verify the reaction efficiency, a gram-scale reaction was carried out with a low catalyst loading (0.1 mol %), and the desired product 2a was obtained in 97% yield and with 98% ee (Figure a). Next, the derivatizations of the hydrogenated product 2a were carried out (Figure b). The product 2a could undergo a palladium-catalyzed 1,4-addition reaction, delivering the product 6, containing a quaternary stereocenter, in 74% yield with 12:1 dr and 98% ee. Furthermore, the epoxidation product 7 was obtained in 99% yield and with >20:1 dr and 86% ee in the presence of H2O2. Finally, the developed catalytic system was also applied to the hydrogenation of substrate 8, which possesses three CC bonds, including a disubstituted alkene. As a result, the reaction proceeded well and provided the product 9, with retention of the disubstituted alkene, in 89% yield and with 96% ee.

2.

2

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Gram-scale reaction, derivatization of the product, and the applications. (a) Gram-scale reaction. (b) Derivatization of the product and the applications.

To gain insight into the reaction pathway and the origin of the stereochemistry of the 2,4-disubstituted cyclopentanones, control experiments were designed and carried out (Figure ). First, the reaction was carried out under D2 (10 bar) for 48 h, and hydrogenated products d 3-2a and d 5-5a were obtained in 95% yield, respectively (Figure a). To further determine how the D atom was introduced to the hydrogenated products, the product 2a was subjected to the above reaction conditions, and compound 2a was recovered in 99% yield and no deuterated 2a was detected (Figure a, bottom). These results indicate that benzyl H/D exchange occurs via C–H activation prior to reduction of the exocyclic CC bond. To investigate the origin of the stereochemistry of the products, 2,4-disubstituted cyclopentanones, a control experiment was performed with substrate 4j under modified reaction conditions to obtain the possible reaction intermediates (Figure b). The reaction ceased in 1 h, affording 53% conversion, and the hydrogenated products 5j, 5j’ and 5j’’ were obtained in 1.7:1.8:1 (5j: 9:1 dr, 98% ee; 5j’’: 72% ee). These results indicated that both the exo- and endocyclic CC bonds of the substrates can be preferentially reduced. Furthermore, we also tried to determine the enantioselectivity of the intermediate 5j’, however, it is very prone to racemization during purification. In addition, to further investigate potential racemization of the intermediate 5j’ through keto–enol tautomerization during the reaction, the reaction was performed in the presence of D2O. The reaction proceeded similarly to the above experiment, affording products 5j:5j’:5j’’ in a ratio of 1.6:1.8:1. Notably, no d-5j’ was detected, demonstrating that the intermediate 5j’ generated in situ does not racemize during the reaction.

3.

3

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Control experiments and the proposed reaction pathway. (a) Deuterium-labeling experiments. (b) Experiments to determine the possible intermediates. (c) Stereochemical model for the asymmetric hydrogenation of the endocyclic CC bond in substrate 4. (d) Proposed reaction pathway for the H/D exchange and the asymmetric hydrogenation.

The intermediate 5j’’ was obtained with moderate enantioselectivity (72% ee), while the product 5j exhibited good stereoselectivity (9:1 dr, 98% ee). These results demonstrate that double-hydrogenated products obtained through sequential hydrogenation (exocyclic CC bond first, followed by endocyclic bond) show better stereoselectivity. In contrast, the intermediate 5j’’ (resulting from hydrogenation of the endocyclic CC bond) with moderate enantioselectivity leads to the double-hydrogenated product 5j in poor diastereoselectivity, and intermediates 5j’ and 5j’’ were obtained in a ratio of 1.8:1. It was speculated that the exocyclic CC bond underwent hydrogenation more readily. Furthermore, substrate 1a gave the 2,4-disubstituted cyclopentanone 3a in 1:1 dr under a higher reaction temperature (Table , entry 2). These results indicated that the ester group plays an important role in improving the reactivity and controlling the stereoselectivity of the product. The effect of the ester group on the chiral induction and stereochemistry in the asymmetric hydrogenation of the endocyclic CC bond in substrate 4 can be explained by the favored and disfavored intermediates (Figure c).

In the favored intermediate A, the carbonyl group on the ring is positioned away from the isopropyl group on the oxazoline, giving the major enantiomer (S)-5″. In disfavored intermediate B, steric interaction between the carbonyl group and the isopropyl group destabilized the intermediate. It is worth noting that, compared to the reduction of the exocyclic CC bond, substrate 4 exhibits a less favorable binding mode for endocyclic CC bond reduction.

In addition, a possible reaction pathway for the H/D exchange and asymmetric hydrogenation was provided (Figure d). ,− First, Ir­(III)-complex I was generated from Ir­(I)-complex via oxidative addition with D2. Then, complex I coordinated with the carbonyl of substrate 1a through a hydrogen bond to form complex II, where steric accessibility directs benzylic C­(sp2)-H activation, yielding the five-membered metallacycle III. Subsequently, H/D exchange in metallacycle III occurred and gave complex IV. The complex I was then regenerated, producing the deuterium-labeled intermediate d 1-1a, which subsequently underwent asymmetric hydrogenation. Finally, the hydrogenated product d 3-2a was obtained through the selective hydrogen addition to the CC bond via complexes V and VI, and with the regeneration of complex I.

In summary, an efficient iridium-catalyzed regio- and enantioselective hydrogenation of 5-alkylidene cyclopentenones was realized using the axis-unfixed biphenylphosphine-oxazoline ligand (BiphPHOX). When the substituents at the C3 position of the substrates were alkyl or phenyl groups, the hydrogenated products, 5-substituted cyclopentenones, were obtained in excellent yields and with excellent enantioselectivities (up to 99% yield and 98% ee). Furthermore, substrates bearing an ester group at the C3 position delivered the double hydrogenated products, 2,4-disubstituted cyclopentanones, in excellent results (up to 99% yield, up to 16:1 dr and 99% ee). In addition, a gram-scale reaction was also carried out, delivering the hydrogenated product in excellent yield with no erosion in enantioselectivity, and the hydrogenated product can be readily derivatized. For the chiral 2,4-disubstituted cyclopentanones, the results of mechanistic studies indicated that both the exo- and endocyclic CC bonds of the substrates can be preferentially reduced, with the exocyclic CC bond undergoing hydrogenation more readily and the ester group in the substrate playing an important role in improving the reactivity and controlling the stereoselectivity of the product.

Supplementary Material

pc5c00087_si_001.pdf (17.7MB, pdf)

Acknowledgments

This work was supported by National Key R&D Program of China (2023YFA1506400), National Natural Science Foundation of China (22361132533), Natural Science Foundation of Shanghai (24ZR1439600), Shanghai Municipal Science and Technology Major Project, and Zhengzhou Industrial Technology Research Institute of Shanghai Jiao Tong University (ZZHC-2025-001) for financial support. The authors thank the Instrumental Analysis Center of SJTU for characterization.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/prechem.5c00087.

  • Experimental procedures and characterization data for all reactions and products, including 1H and 13C NMR spectra, 19F NMR spectra, HRMS, HPLC and X-ray crystal structures of 2v and 5c (PDF)

Deposition Numbers 2023015 and 2070418 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via the joint Cambridge Crystallographic Data Centre (CCDC) and Fachinformationszentrum Karlsruhe Access Structures service.

The authors declare no competing financial interest.

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