π-π Interactions-Directed Asymmetric Hydrogenation of Sterically Unbiased Aromatic Ketones

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π-π Interactions-Directed Asymmetric Hydrogenation of Sterically Unbiased Aromatic Ketones

https://doi.org/10.21203/rs.3.rs-4881221/v1

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Transition metal-catalyzed asymmetric hydrogenation of ketones has been well established; however, the asymmetric hydrogenation of sterically unbiased ketones remains a formidable challenge, due to the difficulty in control of enantioselectivity. Herein, we have developed a highly practical and efficient protocol for the asymmetric hydrogenation of sterically unbiased aromatic ketones, and a series of chiral cyclic diaryl alcohols, including the key intermediate of Baloxavir (super Tamiflu), with up to 99% yield and up to 99% ee. Mechanistic investigations indicate that iridium precursor [Ir(COD)Cl]₂ could undergo an intramolecular oxidative C-H activation with the oxa-spirocyclic ligand to produce a highly rigid butterfly-shaped complex which is responsible for achieving high enantioselectivity, and X-ray diffraction analysis indicate that the ligand behaves as a tetradentate PNNC ligand, which could inhibit the toxicity of the sulfur-containing substrate to the catalyst. Preliminary DFT calculations and NCI analysis demonstrated that π-π interactions between the substrate and catalyst played a key role in the control of enantioselectivity. Furthermore, the synthetic potential of our catalytic system was verified by the gram-scale asymmetric hydrogenation, and Baloxavir intermediate was obtained with retention of enantioselectivity.

Physical sciences/Chemistry/Catalysis/Asymmetric catalysis

Physical sciences/Chemistry/Chemical synthesis/Asymmetric synthesis

In the past few decades, great progress has been made in the field of asymmetric catalysis, and a wide variety of chiral ligands and catalysts have emerged, which greatly promoted the development of this field.^1–5 Asymmetric hydrogenation is a crucial method for constructing molecular chirality, both in the laboratory and in industry.^6–19 The key to enantioselectivity in asymmetric hydrogenation is the addition of metal-hydride species to the prochiral center of the substrate from either the Re-face or Si-face. This facial selectivity is based on the recognition of the prochiral center of the substrate by the chiral ligand (Fig. 1a). Typically, the greater the difference between the two sides of the prochiral center, the more efficiently the chiral catalyst can control the facial selectivity. Over the past few decades, the asymmetric hydrogenation of sterically biased ketones, such as aryl alkyl ketones and ortho-substituted aromatic ketones, has been well-established, with many catalytic systems developed (Fig. 1a).^20–22 However, the asymmetric hydrogenation of sterically unbiased ortho-unsubstituted aromatic ketones has not been well solved due to the formidable challenge of distinguishing the structurally similar aromatic groups.^23–26 This limitation has significantly inhibited the further applications of asymmetric hydrogenation in medicinal chemistry and the pharmaceutical industry.^27–29

Non-covalent bond interactions (NCI), which have showed wide impact in material science,³⁰ medicinal chemistry,³¹ biology³² etc., could not only control the stereoselectivity of chemical reactions, but also have great influence on the chemical selectivity,^33–35 and have been developed as an important element of ligand design.^36–41 Hydrogen-bond interactions,^38,42–44 ion-pair interactions,^45–47 ion-binding interactions,^48,49 and hydrophobic effect⁵⁰ have been widely used in organocatalysis, transition metal catalysis and enzyme catalysis.⁵¹ In recent years, scientists have gradually realized the importance of non-covalent π interactions in the regulation of chemical reactions, and it has been applied in the design of catalysts and chiral ligands.^37,52,53 The non-covalent π interactions can be divided into anionic π-interactions,⁵⁴ cationic π-interactions,⁵² XH-π interactions, ^55–59 lone pair electron π-interactions⁶⁰ and π-π interactions (Fig. 1b), of which, the C‒H···π interactions⁶¹ has been an important controlling factor in the enantiocontrol of asymmetric hydrogenation (Fig. 1c).⁵⁵ According to the orientation of aromatic ring, π-π interactions can be divided into four types: parallel, parallel displaced, edge-to-face and T-shaped (Fig. 1b).^62,63 Despite the wide application of π-π interactions in medicinal chemistry and material science,^64–69 examples using π-π interactions to control the selectivity of chemical reaction are rare, ^34,53,70 probably due to the fact that π-π interactions is very sensitive to the steric hindrance. For example, the π-π interactions in toluene is much weaker than that of benzene, which can be verified by the high freezing point of toluene compared with benzene. In 2010, Swager and Houk⁷¹ found that by tuning the π-π interactions between the two reactants, the selectivity of the Diels-Alder reaction could be modulated. In 2022, the long-pursued dihydroxylation-based kinetic resolution was achieved by Xu and coworkers⁷⁰ via the collective cooperation of a lone pair-π interactions and a π-π stacking interactions. In 2020, Liu and coworker reported the asymmetric hydrogenation of quinoline by manganese catalysis, where the π-π interactions between ligand and substrate was proposed to be the key point of the enantiocontrol (Fig. 1c).⁷² In 2023, cobalt-catalyzed asymmetric transfer hydrogenation of ketones was realized by Zuo and coworker.⁷³ DFT calculations indicated that by changing the charge of cobalt center, CH-π interactions and π-π interactions could selectively operate to control the configuration of chiral alcohol product (Fig. 1c). Herein, we disclose a highly efficient π-π interactions-directed asymmetric hydrogenation of sterically unbiased aromatic ketones enabled a well-defined butterfly-shaped tetradentate iridium catalyst (Fig. 1d).

Baloxavir marboxil,⁷⁴ a third-generation anti-influenza drug, was first marketed in Japan in 2018. It is the first new anti-influenza drug with an innovative mechanism of action approved by the FDA in nearly 20 years. Compared to Tamiflu, a single dose of Baloxavir marboxil can significantly shorten the duration of illness, while Tamiflu requires continuous use for 5 days. Additionally, Baloxavir marboxil is effective against a wide range of influenza viruses and has preventive effects. Its sales and clinical feedback indicate it is a promising chiral anti-influenza drug with excellent market potential. According to the retrosynthetic analysis of Baloxavir marboxil depicted in Scheme 1,⁷⁵ chiral cyclic diaryl alcohol 2a is a key intermediate of Baloxavir marboxil, however, the chiral recognition problem for the asymmetric hydrogenation of cyclic diaryl ketone 1a remain unsolved, the development of efficient protocol for the asymmetric hydrogenation of 1a is highly desirable, which could significantly reduce the production cost of Baloxavir marboxil.

We targeted cyclic diaryl ketone 1a as substrate for asymmetric hydrogenation. As a continuation of our long-term investigations in asymmetric hydrogenation, herein, we disclose our breakthrough in asymmetric hydrogenation: the π-π interactions directed highly practical and enantioselective hydrogenation of sterically unbiased aromatic ketones, which was enabled by a highly rigid butterfly-shaped PNNC iridium catalyst generated via intramolecular C-H activation (Fig. 1d)

We initiated our investigations by using 1a as the model substrate of asymmetric hydrogenation, and the results were depicted in Scheme 2. Inspired by our recent works,⁷⁶ we firstly evaluated the effects of the ruthenium(II)-diphosphine-diamine catalyst (Cat1)^77,78 and ferrocene based chiral phosphine ligands such as f-phamidol (L1),^6,7 and f-amphol (L2)^79,80 employing [Ir(COD)Cl]₂ as metal precursor, and Cs₂CO₃ (10 mol%) as base and iPrOH as solvent in the presence of 60 atm H₂ was used. Unfortunately, the Cat1 only achieves trace conversion with 0.5% ee, and for L1 and L2 only 35% and 50% ee were achieved respective combining with low to moderate conversions. Oxa-spirocyclic tridentate PNN ligand O-SpiroPAP (L3) ^13,81 were also tested, and 98% conversion and 73% ee were achieved. Ph-O-SpiroPAP (L4) could only give 42% conversion and 34% ee. Almost full conversion was achieved with DTBM-O-SpiroPAP (L5) as ligand, and the ee was improved to 76%. The conversion and ee were dropped to 33% and 52% respectively with O-SpiroSAP (L6).¹³ We next examined the ligands bearing a modified pyridine moiety with MeOH as solvent at a substrate-to-catalyst ratio of 1000, however, very poor enantioselectivity was provided with the ligand containing 6-Me pyridine (L7) and 3-MeO pyridine moiety (L8). For the quinoline-containing ligand L9, no reaction occurred. To our great surprise, excellent result of 99% conversion and 96% ee were delivered with L10 as ligand (termed as O-SpiroPABQ), which bears a benzoquinoline moiety. It should be noted that the enantioselectivity was further improved to 98% with L11 (Ph-O-SpiroPABQ) as ligand, indicating that the benzoquinoline moiety probably plays a very important role in the control of enantioselectivity.

By designing and synthesizing a series of chiral oxa-spirocyclic ligands and continuously optimizing the reaction conditions, we have increased the ee value of this hydrogenation reaction from 74–98%. The TON of the reaction has also been significantly improved, making it possible to apply the catalytic system to industrial asymmetric synthesis of chiral intermediates of Baloxavir. Next, we evaluated the effects of other conditions such as solvents and bases at a substrate to catalyst ratio of 2000 and the results were summarized in Table 1. Protic solvents such as EtOH, iPrOH and tBuOH could not give better results, 77% conversion and 91% ee of 2a were produced (Table 1, entry 2), < 5% conversion was observed in iPrOH and tBuOH (Table 1, entries 2 and 3). Aprotic solvents such as DCM, toluene, ethyl acetate, THF and dioxane were also screened and only toluene could give 54% conversion and 86% ee (Table 1, entry 6), DCM, ethyl acetate, THF and dioxane were ineffective for the current reaction (Table 1, entries 5 and 7–9). With MeOH as the best solvent, the effect of base on the reaction was evaluated. Full conversions were achieved with bases such as Na₂CO₃, K₂CO₃, KOH, tBuOK, and MeOK, and 96% ee were achieved with Na₂CO₃ and tBuOK as base, 95% ee were achieved with K₂CO₃, KOH, and MeOK as base (Table 1, entries 10–14). At a substrate-to-catalyst ratio of 5000, the enantioselectivity was retained for tBuOK (Table 1, entry 16), whereas, the enantioselectivity was dropped to 93% with Na₂CO₃ or tBuONa as base (Table 1, entries 15 and 17). The conversion and enantioselectivity dropped sharply to 15% and 54% at a substrate-to-catalyst ratio of 5000 (Table 1, entry 18), so ligand L10 was identified as the best ligand instead of L11.

Table 1. Evaluation of the effects of solvents and bases on the current reaction

Entry	Solvent	Base	Conv. (%)^a	Ee (%)^b
1	MeOH	Cs₂CO₃	99	96
2	EtOH	Cs₂CO₃	77	91
3	iPrOH	Cs₂CO₃	< 5	--
4	tBuOH	Cs₂CO₃	< 5	--
5	DCM	Cs₂CO₃	< 5	--
6	toluene	Cs₂CO₃	54	86
7	EtOAc	Cs₂CO₃	< 5	--
8	THF	Cs₂CO₃	< 5	--
9	dioxane	Cs₂CO₃	< 5	--
10	MeOH	Na₂CO₃	99	96
11	MeOH	K₂CO₃	99	95
12	MeOH	KOH	99	95
13	MeOH	tBuOK	99	96
14	MeOH	MeOK	99	95
15^c	MeOH	Na₂CO₃	81	93
16^c	MeOH	tBuOK	79	94
17^c	MeOH	tBuONa	86	93
18^c,d	MeOH	tBuOK	15	54

Reaction conditions: 1a (0.20 mmol), [Ir(COD)Cl]₂ (0.1 µmol), ligand (0.22 µmol), base (0.02 mmol), solvent (1 mL), H₂ (80 atm), rt, 24 h; ^a Determined by ¹H NMR analysis of the crude reaction mixture; ^b Determined by HPLC analysis using a chiral stationary phase; ^c S/C = 5000. ^d L11 was used as ligand.

With the optimal conditions in hand, some cyclic diaryl ketones were prepared and tested, and the results were shown in Scheme 3. Ir/O-SpiroPABQ system could indeed act as the highly efficient catalyst. To our delight, for substrates bearing halide, methoxy, methyl or trifluoromethyl group, the corresponding chiral cyclic diaryl alcohols were obtained with high yields and excellent enantioselectivities (2b–2k, 94–99% yield and 76–98% ee), including 5 examples of oxa-heterocyclic products (2l–2p, 99% yield and 93–99% ee) and an example of sulfone-containing heterocyclic diaryl alcohol (2q, 99% yield and 88% ee). The catalytic system was also compatible with alkyl aryl ketone substrate, and the asymmetric hydrogenation of acetophenone 1r could produce the desired product with quantitative yield and high enantioselectivity (2r, 99% yield and 94% ee).

To investigate the structure of iridium catalyst, O-SpiroPABQ L10 was synthesized according to the procedures in previous literature⁸¹ (Scheme 4). The reductive amination of 3 and 4 could product ligand L10 with 88% yield. Coordination of ligand L10 with [Ir(COD)Cl]₂ in the presence of 40 atm H₂ at 45 ^oC could form iridium complex 5 with 92% yield. We have characterized the iridium complex 5 by NMR and HRMS. The Ir − H resonance appears at − 23.4 ppm in CDCl₃ (d, J = 17.3 Hz, 1H) and ³¹P NMR: 14.64 ppm. To our surprise, only the NMR signal of one hydride was found. The crystal structure of 5 suitable for X-ray analysis was also cultivated, and the structure was finally unambiguously determined by X-ray diffraction (CCDC Number: 2262718), verifying the formation of Ir-C bond via C-H activation (Scheme 4). The unique butterfly-shaped structure of 5 was probably responsible for the high enantioselectivity observed in the asymmetric hydrogenation of 1. Afterward, we conducted control experiments using complex 5 as catalyst, and the results were consistent with the reaction by in situ generated catalyst.

A plausible catalytic cycle for the current reaction was also proposed (Scheme 5a), Firstly, in situ coordination of the metal precursor and ligand combined with a C-H bond activation process forms complex 5, which was further transformed to catalyst A in the presence of H₂ under basic conditions. The metal-hydride of the catalyst adds to the ketone carbonyl via a six-membered ring transition state TS1 to form intermediate B, which coordinates with H₂ to form intermediate C. Heterolytic cleavage of hydrogen results in the formation of product 2a and regenerating catalyst A. To investigate the origin of enantioselectivity, density functional theory (DFT) calculations were also performed with 1a as model substrate and L10 as ligand.^6,82–84 The calculated Gibbs energy profiles for the reaction mechanism are shown in Scheme 5. Our calculations indicate that the hydrogenation of ketone takes place through the six-membered ring transition state TS1 and TS2, which involve hydride transfer from the Ir center to carbon. The interactions between Na and O play significant role in these transition states. In TS1, a chiral catalytic pocket is formed by the C‒H activation of the ligand,⁸⁵ where the substrate must distort to the butterfly-shaped structure to adapt the catalytic pocket. The reaction barrier of this hydrogenation step is 12.7 kcal/mol to afford the main product 2a, and is 17.8 kcal/mol for the enantiomer (Scheme 5b).

To explain the origin of the energy difference between TS1 and TS2, Wheeler’s energy decomposition analysis was carried out (Fig. 2). The result indicated that the energy difference mainly came from the distortion energy of the substrate molecule and interactions between the substrate and catalyst. In TS1, the dihedral angel (∠1234) of the free substrate (173.2°) distorted to 149.1°, while this dihedral angel in TS2 is 145.9°, indicating that the substrate requires greater structural distortion in TS2 to adapt the catalytic pocket. Structure analysis also shows that the distance of Na···O interactions in TS1 is 2.215 Å, shorter than that of 2.410 Å in TS2, implying the strong interactions between substrate and catalyst in TS1. In addition, two C‒H···π interactions (2.688 Å and 2.745 Å) is observed in TS1, indicating better noncovalent interactions compared with the C‒H···π interactions (2.664 Å) in TS2. Furthermore, the distance of the π-π interactions in TS1 is 3.485 Å, shorter than that of 3.507 Å in TS2. These non-covalent interactions including Na···O interactions and π-π stacking could be visualized from the NCI plot (Fig. 2).

To demonstrate the scalability and synthetic potential of this hydrogenation method for enantioselective synthesis of the key intermediate of Baloxavir, a scale-up reaction has been performed with S/C = 3000, and 981 mg of 2a was obtained with 98% yield and 96% ee (Scheme 6).

In conclusion, we have developed a highly practical and efficient asymmetric hydrogenation of sterically unbiased aromatic ketones and a series of chiral cyclic diaryl alcohols, including the key intermediate of Baloxavir, with high yields and excellent enantioselectivities. Mechanistic investigations indicate that iridium precursor [Ir(COD)Cl]₂ could undergo an oxidative C-H activation with ligand L10 to produce a butterfly-shaped complex which is responsible for achieving high enantioselectivity, and ligand L10 behaves as a tetradentate PNNC ligand in the current reaction. Preliminary DFT calculations and NCI analysis demonstrated that π-π interactions between the substrate and catalyst played a key role in the control of enantioselectivity.

Representative procedure of asymmetric hydrogenation of 1b

The substrate dibenzo[b,e]thiepin-11(6H)-one (1b, 22.6 mg, 0.1 mmol), Na₂CO₃ (1.06 mg, 0.01 mmol.) were added into a 5 mL hydrogenation vessel. 1.0 mL anhydrous EtOH was added as solvent and a solution of L10/[Ir(COD)Cl]₂ in anhydrous Toluene (50 µL) was added via an injection port. Then the vessel was placed in an autoclave, closed it and moved it out from golvebox. The autoclave quickly purged with hydrogen gas for three times, then pressurized to 80 atm H₂. hen released pressure carefully. The solution of reaction mixture was purified by a flash chromatography on a silica gel with ethyl acetate and the solvent was removed under reduced pressure. The ee value was determined by chiral HPLC analysis. The yield value was determined by NMR. The absolute configurations were assigned by analogy.

Additional information

Supporting Information is available and includes [Experimental procedures, spectral data and NMR spectra for all compounds (PDF)].

Competing interests

The authors declare no competing interests.

Author contributions

J.S. and R.X. contributed equally to this work. J.S. and R.X. contributed to the conception and design of the experiments. J.S. and R.X. performed the experiments and analyzed the data. L.W., D.L. and M.Z. synthesized several substrates. F.H. carried out the X-ray analysis of the catalyst. G.-Q.C. and X.Z. directed the project. H.H. and S.N. performed the DFT calculations. J.S., R.X. and G.-Q.C. co-wrote the manuscript.

Acknowledgement

X. Zhang is indebted to the financial support from the National Key R&D Program of China (2021YFA1500200), National Natural Science Foundation of China (No. 21991113), Chemistry and Chemical Engineering Guangdong Laboratory (Grant nos. 2011006 and 2132013) and Innovative Team of Universities in Guangdong Province (No. 2020KCXTD016). G.-Q. Chen gratefully acknowledges the National Natural Science Foundation of China (No. 22171129), Shenzhen Science and Technology Innovation Committee (JCYJ20210324104202007) and the Guangdong Basic and Applied Basic Research Foundation (2022B1515020055) for financial support. The authors acknowledge the assistance of SUSTech Core Research Facilities. We gratefully acknowledge the Center for Computational Science and Engineering at Southern University of Science and Technology (SUSTech) for the support of computational work.

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Schemes 1 to 6 are available in the Supplementary Files section

There is NO Competing Interest.

Scheme1.png
Scheme 1. Baloxavir and its retrosynthetic analysis
Scheme2.png
Scheme 2. Screen of ligands for the asymmetric hydrogenation. Reaction condition: 1a (0.10 mmol), [Ir(COD)Cl]₂ (0.25 µmol), ligand (0.55 µmol), Cs₂CO₃ (0.01 mmol), solvent (1 mL), H₂ (60 atm), rt, 12 h; the conversion was determined by ¹H NMR analysis of the crude reaction mixture, and the enantioselectivity was determined by HPLC analysis using a chiral stationary phase; ^athe reaction was conducted with MeOH as solvent at S/C = 1000 for 24 h.
Scheme3.png
Scheme 3. Substrate Scope of Cyclic Diaryl Ketones
Scheme4.png
Scheme 4. Synthesis of L10 and its iridium complex 5
Scheme5.png
Scheme 5. The proposed catalytic cycle and calculated Gibbs energy profiles (in kcal/mol).
Scheme6.png
Scheme 6. Gram scale experiment
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π-π Interactions-Directed Asymmetric Hydrogenation of Sterically Unbiased Aromatic Ketones

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