A process for the synthesis of chiral chlorohydrins or chiral cyclic ethers
By reacting the tetradentate ligand Ir/f-phamidol anion catalyst with hydrogen, the problem of difficult synthesis of chiral cyclic ethers in the prior art has been solved, realizing efficient and simple synthesis of chiral chlorools or chiral cyclic ethers, which is suitable for the production of drug molecular intermediates.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- SOUTHERN UNIVERSITY OF SCIENCE AND TECHNOLOGY
- Filing Date
- 2023-09-11
- Publication Date
- 2026-05-19
AI Technical Summary
Existing asymmetric hydrogenation methods for synthesizing chiral cyclic ethers suffer from difficulties in substrate synthesis, low catalytic efficiency, and the inability to obtain chiral cyclic ethers in a single reaction, which contradicts the concept of green economy.
Using a tetradentate ligand Ir/f-phamidol anionic catalyst, ω-chloroketone compounds react with hydrogen in the presence of the catalyst to efficiently synthesize chiral chlorools or chiral cyclic ethers in a one-step reaction. The reaction yield is as high as 99%, and the enantioselectivity is as high as 99%, using inexpensive and readily available raw materials and hydrogen as the hydrogen source.
This method enables the efficient synthesis of chiral chlorools or chiral cyclic ethers, simplifies the operation, improves catalytic efficiency and yield, is suitable for large-scale production, produces high-purity products, and is applicable to the synthesis of intermediates for various drug molecules.
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Figure CN117343031B_ABST
Abstract
Description
Technical Field
[0001] This application relates to the field of chiral chlorool or chiral cyclic ether synthesis technology, and in particular to a method for synthesizing chiral chlorool or chiral cyclic ether. Background Technology
[0002] Chiral chlorools and chiral cyclic ether fragments are widely found in biologically active compounds and natural products, and are key intermediates for many clinical drug molecules, making them valuable for applications in asymmetric catalysis.
[0003] In recent years, the enantioselective synthesis of chiral cyclic ethers has developed rapidly. However, existing asymmetric hydrogenation methods for synthesizing chiral cyclic ethers are limited by the difficulty of substrate synthesis, cannot obtain chiral cyclic ethers in a one-step reaction, have low catalytic efficiency, and violate the concept of green economy. Summary of the Invention
[0004] The purpose of this application is to provide a novel method for synthesizing chiral chloroalcohols or chiral cyclic ethers.
[0005] To achieve the above objectives, this application adopts the following technical solution:
[0006] One aspect of this application discloses a method for synthesizing a chiral chlorool or a chiral cyclic ether, comprising reacting a compound of structural formula I with hydrogen in the presence of a catalyst to obtain a chiral chlorool of structural formula II or a chiral cyclic ether of structural formula III.
[0007] The reaction formula is as follows:
[0008]
[0009] In structural formulas I, II, and III, Ar represents aryl, and n is 1 or 2;
[0010] The catalyst is obtained by complexing a ligand with a transition metal precursor, and the ligand contains the following structural formula;
[0011]
[0012] In the structural formula of the ligand, tBu represents tert-butyl; the transition metal precursor is [Ir(COD)Cl]2.
[0013] In this application, the transition metal precursor is the iridium precursor, COD refers to 1,5-cyclooctadiene, and the catalyst obtained by complexing the ligand with the transition metal precursor is the tetradentate ligand Ir / f-phamidol anion catalyst.
[0014] It should be noted that the synthetic method of this application uses a simple and easily synthesized tetradentate ligand Ir / f-phamidol anion catalyst, with inexpensive and readily available ω-chloroketone compounds (i.e., the compound shown in structural formula I) as substrates and hydrogen as the hydrogen source, to chemoselectively and divergently synthesize chiral chlorools or chiral cyclic ethers, achieving a reaction yield of up to 99% and an enantioselectivity of up to 99%. The synthetic method of this application can synthesize chiral chlorools or chiral cyclic ethers in a single step, is simple and easy to operate, and exhibits high catalytic efficiency, high yield, and high enantioselectivity. Furthermore, the raw materials used in the synthetic method of this application are inexpensive and readily available, resulting in low cost, and can better meet the needs of large-scale production of chiral chlorools or chiral cyclic ethers.
[0015] It is understood that the key to this application lies in the efficient asymmetric catalytic hydrogenation method using chiral Ir / f-phamidol complexes to reduce ω-chloroketone derivatives, thereby divergently synthesizing chiral chlorools represented by structural formula II or chiral cyclic ethers represented by structural formula III. The uses of the synthesized chiral chlorools and chiral cyclic ethers can be referenced from existing technologies; for example, they can serve as intermediates for various drug molecules. In one implementation of this application, larotrectinib can be synthesized from the chiral chlorool represented by formula II-o, and AMPK agonists can be synthesized from the chiral cyclic ether represented by formula III-e. Therefore, the synthetic method of this application, utilizing asymmetric hydrogenation to efficiently develop the divergent synthesis of chiral chlorools or chiral cyclic ethers from ω-chloroketones, has significant practical implications.
[0016] In one implementation of this application, the asymmetric hydrogenation reaction is carried out in an aprotic solvent, and a chiral chlorool of structural formula II is generated under weakly basic conditions, while a chiral cyclic ether of structural formula III is generated under strongly basic conditions.
[0017] In one implementation of this application, the aprotic solvent for generating the chiral chloroalcohol represented by structural formula II is selected from at least one of tetrahydrofuran, dichloromethane, dichloroethane, toluene, and ethylene glycol dimethyl ether.
[0018] Preferably, the weakly basic conditions are formed by adding at least one of cesium carbonate and potassium carbonate to an aprotic solvent. It is understood that, within the inventive concept of this application, other inorganic bases that form weakly basic conditions may also be used.
[0019] In one implementation of this application, the aprotic solvent for generating the chiral cyclic ether represented by structural formula III is selected from at least one of toluene, dichloromethane, dichloroethane, dioxane, tetrahydrofuran, and n-hexane.
[0020] Preferably, the strong alkaline conditions are formed by adding at least one of sodium hydroxide and potassium hydroxide to an aprotic solvent. It is understood that, within the inventive concept of this application, other inorganic bases that form strong alkaline conditions may also be used.
[0021] In one implementation of this application, the amount of base used is 0.1 to 3.0 molar equivalents of the compound shown in structural formula I.
[0022] In one implementation of this application, Ar in structural formulas I, II and III is selected from unsubstituted phenyl, at least one hydrogen-substituted phenyl, five-membered heterocycle or more heterocycles.
[0023] In one implementation of this application, when n=1, Ar is selected from the following groups in structural formulas I, II, and III.
[0024]
[0025] When n = 2, Ar is selected from the following groups.
[0026]
[0027] In one implementation of this application, the chiral chlorool represented by structural formula II is at least one of II-a to II-r;
[0028]
[0029] The chiral cyclic ether represented by structural formula III is at least one of III-a to III-r;
[0030]
[0031] In one implementation of this application, the pressure of the hydrogen gas in the asymmetric hydrogenation reaction is 40-80 atm. For example, the hydrogen gas pressure can be 40 atm, 50 atm, 60 atm, 70 atm, or 80 atm.
[0032] In one implementation of this application, the amount of catalyst used in the asymmetric hydrogenation reaction is 0.001-0.01 molar equivalents of the compound shown in structural formula I, preferably 0.001 molar equivalents.
[0033] In one implementation of this application, the temperature of the asymmetric hydrogenation reaction is room temperature.
[0034] In one implementation of this application, the asymmetric hydrogenation reaction is carried out in an oxygen-free environment.
[0035] In one implementation of this application, the oxygen-free environment is an inert gas atmosphere.
[0036] In one implementation of this application, the inert gas is at least one of nitrogen, helium, neon, argon, krypton, and xenon.
[0037] In one implementation of this application, the inert gas is nitrogen.
[0038] It should be noted that the inert gas introduced into the reaction system in this application is mainly to form an oxygen-free environment. If an oxygen-free environment can be ensured, the inert gas may not be used. In one implementation of this application, even if an inert gas is used, the majority of the reaction environment is still hydrogen, for example, more than 99% hydrogen, and the remainder is inert gas.
[0039] Another aspect of this application discloses the chiral chlorools or chiral cyclic ethers obtained by the synthetic method of this application.
[0040] It should be noted that, compared with existing synthetic chiral chloroalcohols or chiral cyclic ethers, the synthetic method of this application, due to its high reaction yield and high enantioselectivity, results in chiral chloroalcohols or chiral cyclic ethers with higher purity, making them more suitable for drug molecule synthesis and thus improving the efficiency and quality of drug molecule synthesis. Therefore, from a chiral perspective, the enantioselectivity of the chiral chloroalcohols or chiral cyclic ethers of this application is as high as 99%, which is fundamentally different from existing synthetic chiral chloroalcohols or chiral cyclic ethers.
[0041] Due to the adoption of the above technical solutions, the beneficial effects of this application are as follows:
[0042] The synthetic method described in this application utilizes a simple and readily synthesizable chiral Ir / f-phamidol complex for highly efficient asymmetric catalytic hydrogenation to reduce ω-chloroketones. This allows for the one-step, divergent synthesis of chiral chlorools represented by structural formula II or chiral cyclic ethers represented by structural formula III. The method is simple, easy to operate, and exhibits high catalytic efficiency, high yield, and high enantioselectivity. The raw materials used in this synthetic method are inexpensive and readily available, resulting in low cost. This provides a new approach and route for the large-scale production of chiral chlorools or chiral cyclic ethers. Attached Figure Description
[0043] Figure 1 This is the 1H NMR spectrum of the chiral chloroalcohol shown in Example II-a of this application;
[0044] Figure 2 This is the carbon NMR spectrum of the chiral chloroalcohol shown in Example II-a of this application;
[0045] Figure 3 This is the 1H NMR spectrum of the chiral chloroalcohol shown in Example II-o of this application;
[0046] Figure 4This is the carbon NMR spectrum of the chiral chloroalcohol shown in Example II-o of this application;
[0047] Figure 5 This is the 1H NMR spectrum of the chiral cyclic ether shown in Example III-a of this application;
[0048] Figure 6 This is the carbon NMR spectrum of the chiral cyclic ether shown in Example III-a of this application;
[0049] Figure 7 This is the 1H NMR spectrum of the chiral cyclic ether shown in Example III-e of this application;
[0050] Figure 8 This is the carbon NMR spectrum of the chiral cyclic ether shown in Example III-e of this application. Detailed Implementation
[0051] The present invention will now be described in further detail with reference to specific embodiments and accompanying drawings. In the following embodiments, many details are described to facilitate a better understanding of the present application. However, those skilled in the art will readily recognize that some features may be omitted in different situations, or may be replaced by other materials or methods. In some cases, certain operations related to the present application are not shown or described in the specification. This is to avoid obscuring the core parts of the present application with excessive description. For those skilled in the art, detailed description of these related operations is not necessary; the relevant operations can be fully understood based on the description in the specification and general technical knowledge in the art.
[0052] Furthermore, the features, operations, or characteristics described in the specification can be combined in any suitable manner to form various embodiments. At the same time, the steps or actions in the method description can be rearranged or adjusted in a manner obvious to those skilled in the art. Therefore, the various orders in the specification and drawings are only for the clear description of a particular embodiment and do not imply a necessary order, unless otherwise stated that a particular order must be followed.
[0053] The serial numbers assigned to components in this application, such as "Structure I", "Structure II", "Structure III", etc., are only used to distinguish the described objects and have no sequential or technical meaning.
[0054] Terminology Explanation:
[0055] In this application, "room temperature" means 25℃±2℃.
[0056] In this application, Ar represents an aryl group, such as an unsubstituted phenyl group, a phenyl group with at least one hydrogen substituted group, a five-membered heterocycle, or a heterocycle with more than five members.
[0057] In this application, THF represents 1,4-epoxybutane, also known as tetrahydrofuran.
[0058] In this application, Toluene represents toluene.
[0059] In this application, Bpin represents tert-butyl dicarbonate.
[0060] Chiral chlorools and chiral cyclic ether fragments are widely found in biologically active compounds and natural products. Compared to mature and efficient asymmetric hydrogenation techniques for unsaturated ketones, the enantioselective synthesis of chiral cyclic ethers has also developed rapidly in recent years. Examples include intramolecular cyclization of chiral diols catalyzed by Lewis or Brønsted acids; iron-catalyzed asymmetric hydroboration followed by intramolecular cyclization; and manganese-catalyzed C… sp 3 -H oxidation enables the kinetic resolution of cyclic ethers; asymmetric addition to oxonium ions; and asymmetric cyclization of alkenes by oxygen atoms.
[0061] As shown in the following structure, since most chiral bioactive molecules such as AMPK agonists, T13326, Faropenem medoxomil, and Laricericinol contain chiral cyclic ether fragments, and chiral chlorools are important intermediates for the drug Iarotrectinib, it is of great practical significance to efficiently develop ω-chloroketones for the divergent synthesis of chiral chlorools and chiral cyclic ether derivatives using asymmetric hydrogenation.
[0062]
[0063] Therefore, this application creatively proposes a method for synthesizing chiral chlorools or chiral cyclic ethers, comprising reacting the compound of structural formula I with hydrogen in the presence of a catalyst to obtain the chiral chlorool of structural formula II or the chiral cyclic ether of structural formula III.
[0064] The reaction formula is as follows:
[0065]
[0066] In structural formulas I, II, and III, Ar represents aryl, and n is 1 or 2;
[0067] The catalyst is obtained by complexing a ligand with a transition metal precursor, and the ligand contains the following structural formula;
[0068]
[0069] In the structural formula of the ligand, tBu represents tert-butyl; the transition metal precursor is [Ir(COD)Cl]2.
[0070] This application utilizes a highly efficient asymmetric catalytic hydrogenation method using chiral Ir / f-phamidol complexes to reduce ω-chloroketone derivatives, and to divergently synthesize chiral chlorool derivatives shown in structural formula II and chiral cyclic ether derivatives shown in structural formula III. The resulting products have high optical purity and can serve as intermediates for many bioactive molecules.
[0071] For example, the chiral chlorool shown in structural formula II and the chiral cyclic ether shown in structural formula III were synthesized from the compound shown in structural formula I via asymmetric hydrogenation divergent synthesis, and Larotrectinib and AMPK agonists were synthesized using this as a key step. The synthetic route is as follows:
[0072]
[0073] Therefore, the chiral chlorool represented by II-o synthesized in this application can be used as an intermediate to further synthesize larotrectinib; the chiral cyclic ether represented by III-e synthesized in this application can be used to further synthesize AMPK agonists.
[0074] The catalyst of this application, namely the chiral catalyst, is synthesized by means of: stirring the metallic iridium precursor [Ir(COD)Cl]2 and 1.2 equivalents of the ligand f-phamidol together in an isopropanol solution for 10 hours, and then rotary evaporating the solution to obtain the crude product as the catalyst required for the reaction.
[0075] In the following examples, the reaction temperature is room temperature, the inert gas is nitrogen, but the reaction atmosphere is more than 99% hydrogen.
[0076] Example
[0077] In the presence of a catalyst, the compound shown in structural formula I reacts with hydrogen to yield a chiral chlorool shown in structural formula II or a chiral cyclic ether shown in structural formula III. This example synthesizes various chiral chlorools shown in structural formula II and chiral cyclic ethers shown in structural formula III, with the following chemical reaction formulas:
[0078]
[0079] In structural formulas I, II, and III, Ar represents an aryl group. Depending on the desired product, Ar can be an unsubstituted phenyl group, a phenyl group with at least one hydrogen substituted group, a five-membered heterocycle, or a heterocycle with five or more members. n is 1 or 2. The catalyst is obtained by complexing a ligand with a transition metal precursor. The ligand contains the following structural formula.
[0080]
[0081] In the structural formula of the ligand, tBu represents tert-butyl; the transition metal precursor is [Ir(COD)Cl]2.
[0082] The synthetic method for the chiral chlorool shown in structural formula II is as follows:
[0083] Under an inert gas atmosphere, 0.1 mmol of the ω-chloroketone derivative shown in structural formula I was added to a hydrogenation flask, followed by 0.76 mg of the chiral Ir / f-phamidol complex and 1.0 × 10⁻⁶ mg of 1.0 × 10⁻⁶ ppm. -3 mmol, cesium carbonate 33 mg, 0.1 mmol, deoxytetrahydrofuran 0.5 mL, and then transferred to a pressure vessel. The inert gas in the reaction chamber was nitrogen, and the reaction atmosphere was more than 99% hydrogen. The hydrogen pressure was set to 60 atm, and the reaction was carried out at 25°C for 48 h. Hydrogen was slowly released, and 1.0 mL of ethyl acetate was added for dilution. The solution was quenched with 2.0 mL of water, and the organic phase was separated. The aqueous phase was washed twice with 2.0 mL of ethyl acetate. The organic phases were combined, dried with anhydrous sodium sulfate, and the solvent was evaporated to obtain the crude product. The crude product was then purified by column chromatography to obtain a clean chiral chlorool with the structure shown in formula II.
[0084] The synthetic method for the chiral cyclic ether shown in structural formula III is as follows:
[0085] Under an inert gas atmosphere, 0.2 mmol of the ω-chloroketone derivative shown in structural formula I was added to a hydrogenation flask, followed by 1.52 mg of a chiral Ir / f-phamidol complex and 2.0 × 10⁻⁶ ppm of hydrogenated gas. -3 mmol, sodium hydroxide 24 mg, 0.6 mmol, deoxytoluene 1.0 mL, and then transferred to a pressure vessel. The inert gas in the reaction chamber was nitrogen, and the reaction atmosphere was more than 99% hydrogen. The hydrogen pressure was set to 60 atm, and the reaction was carried out at 25°C for 48 h. Hydrogen was slowly released, diluted with 1.5 mL of ethyl acetate, quenched with 3.0 mL of water, and the organic phase was separated. The aqueous phase was washed twice with 3.0 mL of ethyl acetate, the organic phases were combined, dried with anhydrous sodium sulfate, and the solvent was evaporated to obtain the crude product. The crude product was then purified by column chromatography to obtain a clean chiral cyclic ether with the structure shown in formula III.
[0086] When n=1, in this example, the ω-chloroketone derivatives of structural formula I with Ar as the following group are used respectively, and the chiral chlorools shown in II-a to II-q are synthesized in sequence according to the aforementioned “Synthesis method of chiral chlorools shown in structural formula II”; and the chiral cyclic ethers shown in III-a to III-q are synthesized in sequence according to the aforementioned “Synthesis method of chiral cyclic ethers shown in structural formula III”.
[0087]
[0088] When n=2, this example uses the ω-chloroketone derivative of structural formula I with Ar as the following group, and synthesizes the chiral chlorool shown in II-r according to the aforementioned "synthetic method of chiral chlorool shown in structural formula II"; and synthesizes the chiral cyclic ether shown in III-r according to the aforementioned "synthetic method of chiral cyclic ether shown in structural formula III".
[0089]
[0090] The ω-chloroketone derivatives shown in the above structural formula I for different Ar structures are still numbered in the order from a to r, and are numbered from Ia to Ir. The ω-chloroketone when n=2 is Ir.
[0091] The yields and enantioselectivity (ee) of the chiral chlorools represented by structural formula II and the chiral cyclic ethers represented by structural formula III synthesized in this example were analyzed using nuclear magnetic resonance (NMR). Specifically, chiral chlorools represented by II-a to II-r and chiral cyclic ethers represented by III-a to III-r were synthesized in this example. The structures, yields, and ee results of each product are as follows:
[0092]
[0093]
[0094] The detailed synthesis and NMR analysis of some chiral chlorools and chiral cyclic ethers are as follows:
[0095] (1) Synthesis of the chiral chlorool (R)-4-chloro-1-phenylbutan-1-ol shown in II-a
[0096] Under an inert gas atmosphere, 18.2 mg (0.1 mmol) of the ω-chloroketone derivative shown in Ia was added to a hydrogenation flask, followed by 0.76 mg (1.0 × 10⁻⁶) of the chiral Ir / f-phamidol complex. -3 mmol, cesium carbonate 33 mg, 0.1 mmol, deoxytetrahydrofuran 0.5 mL, and then transferred to a pressure vessel. The inert gas in the reaction chamber was nitrogen, and the reaction atmosphere was more than 99% hydrogen. The hydrogen pressure was set to 60 atm, and the reaction was carried out at 25°C for 48 h. Hydrogen was slowly released, and 1.0 mL of ethyl acetate was added for dilution. The solution was quenched with 2.0 mL of water, and the organic phase was separated. The aqueous phase was washed twice with 2.0 mL of ethyl acetate. The organic phases were combined, dried with anhydrous sodium sulfate, and the solvent was evaporated to obtain the crude chiral chlorool shown in II-a. The crude product was then purified by column chromatography to obtain the clean chiral chlorool shown in II-a.
[0097] The obtained 18.2 mg of chiral chlorohydrin (II-a) was a colorless oil. Nuclear magnetic resonance analysis showed a yield of 99% and an ee of >99%. 1 H NMR(400MHz,Chloroform-d)δ7.30-7.24(m,4H),7.23-7.18(m,1H),4.61(t,J= 8Hz,1H),3.52-3.42(m,2H),1.92(s,1H),1.87-1.77(m,3H),1.75-1.68(m,1H); 13 C NMR (150MHz, CDCl3) δ144.42, 128.68, 127.86, 125.91, 74.01, 45.08, 36.26, 29.03; HRMS (ESI-TOF): Calcd for C10H14ClO + [M+H] + :185.0733, found 185.0811. Its proton NMR spectrum is as follows: Figure 1 As shown, the carbon NMR spectrum is as follows: Figure 2 As shown.
[0098] (2) Synthesis of II-o chiral chlorool (R)-4-chloro-1-(2,5-difluorophenyl)butan-1-ol
[0099] Under an inert gas atmosphere, 18.2 mg (0.1 mmol) of the ω-chloroketone derivative shown in Io was added to a hydrogenation flask, followed by 0.76 mg (1.0 × 10⁻⁶) of the chiral Ir / f-phamidol complex. -3 mmol, cesium carbonate 33 mg, 0.1 mmol, deoxytetrahydrofuran 0.5 mL, and then transferred to a pressure vessel. The inert gas in the reaction chamber was nitrogen, and the reaction atmosphere was more than 99% hydrogen. The hydrogen pressure was set to 60 atm, and the reaction was carried out at 25°C for 48 h. Hydrogen was slowly released, and 1.0 mL of ethyl acetate was added for dilution. The solution was quenched with 2.0 mL of water, and the organic phase was separated. The aqueous phase was washed twice with 2.0 mL of ethyl acetate. The organic phases were combined, dried with anhydrous sodium sulfate, and the solvent was evaporated to obtain the crude chiral chlorool shown in II-o. The crude product was then purified by column chromatography to obtain the clean chiral chlorool shown in II-o.
[0100] The obtained chiral chlorool (II-O) was a colorless oily substance, 19.3 mg, and the NMR analysis results showed 88% yield and 98% ee. 1H NMR(600MHz,Chloroform-d)δ7.20-7.18(m,1H),7.00-6.96(m,1H),6.94-6.91(m ,1H),5.04-5.03(m,1H),3.61-3.55(m,2H),2.03-2.03(m,1H),1.98-1.83(m,4H); 13 C NMR(150MHz,Chloroform-d)δ159.14(dd,J=242.5,2.2Hz),155.54(dd,J=240.9,2.5Hz),133.30(dd,J=16.0,6.9Hz),116.57(d d, J=25.0, 8.6Hz), 115.39 (dd, J=24.4, 8.7Hz), 113.86 (dd, J=24.9, 4.9Hz), 67.44, 44.90, 35.22, 28.76; HRMS (ESI-TOF): Calcd for C 10 H 11 ClF2NaO + [M+Na] + :243.0364, found243.0356. Its proton NMR spectrum is as follows: Figure 3 As shown, the carbon NMR spectrum is as follows: Figure 4 As shown.
[0101] (3) Synthesis of the chiral cyclic ether (R)-2-phenyltetrahydrofuran shown in III-a
[0102] Under an inert gas atmosphere, 36.4 mg (0.2 mmol) of the ω-chloroketone derivative shown in Ia was added to a hydrogenation flask, followed by 1.56 mg (2.0 × 10⁻⁶ mmol) of the chiral Ir / f-phamidol complex. -3 mmol, sodium hydroxide 24 mg, 0.6 mmol, deoxytoluene 1.0 mL, and then transferred to a pressure vessel. The inert gas in the reaction chamber was nitrogen, and the reaction atmosphere was more than 99% hydrogen. The hydrogen pressure was set to 60 atm, and the reaction was carried out at 25°C for 48 h. Hydrogen was slowly released, and ethyl acetate 1.5 mL was added for dilution. The solution was quenched with 3.0 mL of water, and the organic phase was separated. The aqueous phase was washed twice with ethyl acetate 3.0 mL. The organic phases were combined, dried with anhydrous sodium sulfate, and the solvent was evaporated to obtain the crude chiral cyclic ether shown as III-a. The crude product was then purified by column chromatography to obtain the clean chiral cyclic ether shown as III-a.
[0103] The obtained chiral cyclic ether III-a was a colorless oily substance, 29.3 mg, and NMR analysis showed >99% yield; >99% ee; 1 H NMR(400MHz,Chloroform-d)δ7.35-7.31(m,4H),7.27-7.23(m,1H),4.90(t,J=7.2Hz,1H),4.10(dt,J= 8.3,6.8Hz,1H),3.94(dt,J=7.9,6.4Hz,1H),2.37-2.29(m,1H),2.05-1.96(m,2H),1.86-1.77(m,1H); 13 CNMR(100MHz, CDCl3)δ143.56,128.40,127.23,125.74,80.79,68.79,34.73,26.14; HRMS(ESI-TOF):Calcd for C 10 H 12 NaO + [M+Na] + :171.0786, found 171.0780. Its proton NMR spectrum is as follows: Figure 5 As shown, the carbon NMR spectrum is as follows: Figure 6 As shown.
[0104] (4) Synthesis of the chiral cyclic ether (R)-2-(4-bromophenyl)tetrahydrofuran shown in III-e
[0105] Under an inert gas atmosphere, 52.0 mg (0.2 mmol) of the ω-chloroketone derivative shown by Ie was added to a hydrogenation flask, followed by 1.56 mg (2.0 × 10⁻⁶ mmol) of the chiral Ir / f-phamidol complex. -3 mmol, sodium hydroxide 24 mg, 0.6 mmol, deoxytoluene 1.0 mL, and then transferred to a pressure vessel. The inert gas in the reaction chamber was nitrogen, and the reaction atmosphere was more than 99% hydrogen. The hydrogen pressure was set to 60 atm, and the reaction was carried out at 25°C for 48 h. Hydrogen was slowly released, and ethyl acetate 1.5 mL was added for dilution. The solution was quenched with 3.0 mL of water, and the organic phase was separated. The aqueous phase was washed twice with ethyl acetate 3.0 mL. The organic phases were combined, dried with anhydrous sodium sulfate, and the solvent was evaporated to obtain the crude chiral cyclic ether shown as III-e. The crude product was then purified by column chromatography to obtain the clean chiral cyclic ether shown as III-e.
[0106] The obtained III-e chiral ether was a colorless oily substance, 44.7 mg, and the NMR analysis results showed >99% yield; >99% ee; 1H NMR(600MHz,Chloroform-d)δ7.46-7.43(m,2H),7.22-7.20(m,2H),4.84(t,J=7.2Hz,1H),4. 10-4.06(m,1H),3.94-3.91(m,1H),2.35-2.28(m,1H),2.02-1.97(m,2H),1.77-1.71(m,1H); 13 C NMR (150MHz, CDCl3) δ142.71, 131.46, 127.46, 120.91, 80.12, 68.84, 34.76, 26.06; HRMS (ESI-TOF): Calcd forC 10 H 12 BrO + [M+H] + :227.0072, found 227.0065. Its proton NMR spectrum is as follows: Figure 7 As shown, the carbon NMR spectrum is as follows: Figure 8 As shown.
[0107] Therefore, this example demonstrates the efficient sequential synthesis of chiral chlorools (II-a to II-r) and chiral cyclic ethers (III-a to III-r) using ω-chloroketone derivatives represented by Ia to Ir. The synthetic method employed in this example utilizes inexpensive and readily available raw materials, is simple to operate, and leverages hydrogen as a green energy source, aligning with the principles of green development. Furthermore, it boasts advantages such as high catalytic efficiency, high yield, and high enantioselectivity. The chiral chlorool represented by structural formula II or the chiral cyclic ether represented by structural formula III synthesized in this example can be used for the synthesis of drug molecules such as AMPK agonists, Faropenem medoxomil, Laricericinol, and Larotrectinib, or for constructing the core framework of compounds with important biological activities.
[0108] The above description, in conjunction with specific embodiments, provides a further detailed explanation of this application and should not be construed as limiting the specific implementation of this application to these descriptions. Those skilled in the art to which this application pertains can make several simple deductions or substitutions without departing from the concept of this application.
Claims
1. A method for synthesizing a chiral cyclic ether, characterized in that: This includes reacting the compound of structural formula I with hydrogen in the presence of a catalyst to give the chiral cyclic ether of structural formula III. The reaction formula is as follows: In structural formulas I and III, Ar represents aryl, and n is 1 or 2; The catalyst is obtained by complexing a ligand with a transition metal precursor, and the ligand comprises the following structural formula; In the structural formula of the ligand, tBu represents tert-butyl; The transition metal precursor is [Ir(COD)Cl]2; In structural formulas I and III, when n=1, Ar is selected from the following groups: ； When n=2, Ar is selected from the following groups. 。 2. The synthesis method according to claim 1, characterized in that: The reaction is carried out in an aprotic solvent and, under strongly basic conditions, produces a chiral cyclic ether represented by structural formula III.
3. The synthesis method according to claim 2, characterized in that: The aprotic solvent for generating the chiral cyclic ether shown in structural formula III is selected from at least one of toluene, dichloromethane, dichloroethane, dioxane, tetrahydrofuran, and n-hexane.
4. The synthesis method according to claim 2, characterized in that: The strong alkaline conditions are formed by adding at least one of sodium hydroxide and potassium hydroxide to an aprotic solvent.
5. The synthesis method according to claim 2, characterized in that: The amount of the base used is 0.1 to 3.0 molar equivalents of the compound shown in structural formula I.
6. The synthesis method according to claim 1, characterized in that: In structural formulas I and III, Ar is selected from unsubstituted phenyl, at least one hydrogen-substituted phenyl, five-membered heterocycle, or more than five-membered heterocycle.
7. The synthesis method according to claim 1, characterized in that: The chiral cyclic ether represented by structural formula III is at least one of III-a to III-r; 。 8. The synthesis method according to any one of claims 1-7, characterized in that: In the reaction, the pressure of hydrogen gas is 40-80 atm.
9. The synthesis method according to any one of claims 1-7, characterized in that: In the reaction, the amount of catalyst used is 0.001-0.01 molar equivalents of the compound shown in structural formula I.
10. The synthesis method according to any one of claims 1-7, characterized in that: The reaction was carried out at room temperature.
11. The synthesis method according to claim 10, characterized in that: The reaction is carried out in an anaerobic environment.
12. The synthesis method according to claim 11, characterized in that: The oxygen-free environment is an inert gas atmosphere.
13. The synthesis method according to claim 12, characterized in that: The inert gas is at least one of nitrogen, helium, neon, argon, krypton, and xenon.