Method for synthesizing chiral cyclic ether using hydroxy ketone, chiral cyclic ether and application thereof

Abstract

The application discloses a synthesis method of a chiral cyclic ether, the chiral cyclic ether and application of the chiral cyclic ether. The synthesis method comprises the following steps: reacting a compound shown in a structural formula I with hydrogen in the presence of a catalyst to obtain the chiral cyclic ether shown in a structural formula II. The synthesis method is simple in a reaction system, easy to operate and high in economic benefits.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of chemical synthesis, in particular to a method for synthesizing chiral cyclic ether by using hydroxy ketone, chiral cyclic ether and application thereof. BACKGROUND

[0002] Chiral cyclic ether fragments are widely present in biologically active compounds and natural products, such as Nonactic acid, Dideoxyinosine, Cladosporin, Empagliflozin, (+)-Quinine and other biologically active molecules. In addition, chiral cyclic ether can also be used as an intermediate of many clinical drug molecules, such as Larotrectinib and Faropenem medoxomil. Therefore, chiral cyclic ether has important use in the field of biologically active substances and drug synthesis, and has good application value.

[0003] In the past two decades, with the development of ketone asymmetric reduction method, various chiral cyclic ethers can be synthesized by using chiral alcohol and terminal hydroxyl or terminal chlorine for chiral transfer reaction respectively. However, due to the limited method of catalytic reduction of alkyl ketone, it is difficult to produce aliphatic substituted chiral ether by chiral transfer method.

[0004] In 1988, Nicolaou group developed a method for synthesizing cyclic ether by using hydroxy ketone as starting material, via Lewis acid catalysis and silicon hydrogen condition. Since then, this method has been widely used in the synthesis of natural products and drug molecules. However, since the development of this method, the synthesized cyclic ether is racemic or the chirality is controlled by the substrate, and the reducing agent used is stoichiometric silicon hydride. Compared with asymmetric hydrogenation, asymmetric hydrogenation has higher atom economy and is more in line with the concept of green chemistry. Therefore, it is of great significance to generate a series of chiral cyclic ethers by using asymmetric hydrogenation method. SUMMARY

[0005] The purpose of the present application is to provide a method for synthesizing chiral cyclic ether by using hydroxy ketone, chiral cyclic ether and application thereof.

[0006] In order to achieve the above purpose, the present application adopts the following technical scheme:

[0007] The present application discloses a method for synthesizing chiral cyclic ether by using hydroxy ketone, comprising: reacting a compound as shown in structural formula I with hydrogen gas in the presence of a catalyst to obtain the chiral cyclic ether as shown in structural formula II, and the reaction formula is as follows:

[0008]

[0009] In structural formulas I and II, R represents an unsubstituted benzyl group, a benzyl group with at least one hydrogen substituted group, or an alkyl group, and n is 0 or 1.

[0010] The catalyst is obtained by complexing a transition metal precursor with a ligand, wherein the transition metal precursor is [Ir(COD)Cl]2, and the ligand comprises the following structural formula:

[0011]

[0012] In the transition metal precursor, COD represents 1,5-cyclooctadiene; in the structural formula of the ligand, Ph represents phenyl and Me represents methyl.

[0013] Another aspect of this application discloses the chiral cyclic ethers obtained by the synthetic method of this application.

[0014] Another aspect of this application discloses the application of the chiral cyclic ethers obtained by the synthetic method of this application in the preparation of bioactive compounds.

[0015] Due to the adoption of the above technical solutions, the beneficial effects of this application are as follows:

[0016] This application provides an asymmetric hydrogenation method for hydroxyketones, using a chiral Ir / N-Me Zhaophos highly efficient asymmetric catalytic hydrogenation method to reduce hydroxyketone derivatives and synthesize chiral cyclic ether derivatives. The reaction system is simple and easy to operate. The chiral cyclic ethers synthesized by the asymmetric catalytic hydrogenation method yield products with high optical purity, which can serve as intermediates for various drug molecules and bioactive molecules, showing promising application prospects. Furthermore, this hydrogenation method exhibits excellent chemoselectivity and enantioselectivity. Attached Figure Description

[0017] Figure 1 This is a schematic diagram of an asymmetric hydrogenation method for hydroxyketones according to a specific embodiment of this application.

[0018] Figure 2 This is the hydrogen nuclear magnetic resonance spectrum of product II-a involved in the embodiments of this application.

[0019] Figure 3 This is the carbon NMR spectrum of product II-a involved in the embodiments of this application.

[0020] Figure 4 This is the hydrogen nuclear magnetic resonance spectrum of product II-j involved in the embodiments of this application.

[0021] Figure 5 This is the carbon NMR spectrum of product II-j involved in the embodiments of this application.

[0022] Figure 6 NMR spectrum of hydrogen of product II-q related to the embodiments of the present application.

[0023] Figure 7 NMR spectrum of carbon of product II-q related to the embodiments of the present application.

[0024] Figure 8 NMR spectrum of hydrogen of product II-am related to the embodiments of the present application.

[0025] Figure 9 NMR spectrum of carbon of product II-am related to the embodiments of the present application. DETAILED DESCRIPTION

[0026] The application will be further described in details by specific embodiments in conjunction with the accompanying drawings. In the following embodiments, many details are described in order to make the present application better understood. However, one skilled in the art can easily recognize that some features can be omitted in different cases, or can be replaced by other materials or methods. In some cases, some operations related to the present application are not shown or described in the specification in order to avoid the core part of the present application being overwhelmed by too much description, and it is not necessary to describe these related operations in detail for one skilled in the art according to the description in the specification and general technical knowledge in the art.

[0027] In addition, the features, operations or characteristics described in the specification can be combined in any appropriate way to form various embodiments. At the same time, the steps or actions in the method description can also be sequentially adjusted or adjusted in a manner that one skilled in the art can easily see. Therefore, the various sequences in the specification and drawings are only for the purpose of clearly describing a certain embodiment, and do not mean that the sequence is necessary, unless otherwise stated that a certain sequence must be followed.

[0028] In the present application, for example, "structural formula I-a", "structural formula II-b" and the like are only used to distinguish the described objects, and do not have any sequence or technical meaning.

[0029] Explanation of terms:

[0030] In the present application, "room temperature" refers to 25℃±2℃, R represents an unsubstituted benzyl group, a benzyl group substituted with at least one hydrogen, or an alkyl group, DME represents ethylene glycol dimethyl ether, B(C6F5)3 represents tri(pentafluorophenyl)borane, iPr represents isopropyl, tBu represents tert-butyl, Et represents ethyl, NHBoc represents tert-butoxycarbonylamino, DIBAL-H represents diisobutylaluminum hydride, RuCl3 represents ruthenium trichloride, NaIO4 represents sodium periodate, and H2 represents hydrogen.

[0031] According to a first aspect, the present application discloses a method for synthesizing a chiral cyclic ether, which can include:

[0032] In the presence of a catalyst, a compound of structural formula I is reacted with hydrogen to obtain a chiral compound of structural formula II;

[0033] The reaction is as follows:

[0034]

[0035] In structural formula I and II, R represents an alkyl group;

[0036] In an embodiment, the catalyst is obtained by complexing a ligand with a transition metal precursor.

[0037] In an embodiment, the transition metal precursor of the catalyst is [Ir(COD)Cl]2.

[0038] In an embodiment, in the catalyst used for asymmetric hydrogenation, the metal iridium precursor is [Ir(COD)Cl]2, and the ligand L* used is N-Mezhaophos structure. It should be noted that the Ir / N-Me Zhaophos catalyst selected by the present application has high catalytic activity and enantiomeric selectivity.

[0039] In an embodiment, the ligand of the catalyst comprises the following structural formula:

[0040] Ph represents a phenyl group, and Me represents a methyl group.

[0041] In an embodiment, the reaction system further contains an organic solvent.

[0042] In an embodiment, the organic solvent is a polar protic or aprotic solvent and a non-polar aprotic solvent.

[0043] In an embodiment, the polar protic solvent includes but is not limited to at least one of methanol, ethanol, and isopropanol.

[0044] In an embodiment, the polar aprotic solvent includes but is not limited to at least one of tetrahydrofuran, ethyl acetate, diethyl ether, methyl tert-butyl ether, cyclopentyl methyl ether, and ethylene glycol dimethyl ether.

[0045] In an embodiment, the non-polar aprotic solvent includes but is not limited to at least one of n-hexane, dichloroethane, and dichloromethane.

[0046] In an embodiment, the reaction system contains a Lewis acid or a Bronsted acid.

[0047] In an embodiment, the Bronsted acid includes, but is not limited to, at least one of hydrochloric acid, methanesulfonic acid, trifluoroacetic acid, acetic acid, d-camphorsulfonic acid.

[0048] In an embodiment, the Lewis acid includes, but is not limited to, at least one of trimethylchlorosilane, cuprous chloride, copper triflate, ferrous triflate, iron triflate, bismuth triflate, indium triflate, zinc triflate, erbium triflate, silver triflate, cerium trichloride, erbium trichloride, tris(pentafluorophyl)borane (chemical formula B(C6F5)3).

[0049] In an embodiment, the Lewis acid is tris(pentafluorophyl)borane.

[0050] Figure 1 A schematic diagram of the asymmetric hydrogenation method of the hydroxy ketone involved in the present embodiment is shown in FIG. 1. In an embodiment, as shown in FIG. 1, the hydroxy ketone is asymmetrically hydrogenated by a cyclic aliphatic oxocarbenium ion in the presence of a catalyst Ir / L* and tris(pentafluorophyl)borane to obtain a chiral cyclic ether, including a chiral tetrahydrofuran and a chiral tetrahydropyran. In an embodiment, the chiral tetrahydrofuran is synthesized by the method shown in FIG. 2, with a yield of up to 99% and an enantiomeric ratio of up to 96.5:3.5 er. In an embodiment, the chiral tetrahydropyran is synthesized by the method shown in FIG. 3, with a yield of up to 83% and an enantiomeric ratio of up to 98.5:1.5 er or a diastereomeric ratio of more than 20:1 dr, with high yield and excellent stereoselectivity. Figure 1 Figure 1 Figure 1

[0051] In an embodiment, when n = 0, R is selected from the following groups:

[0052]

[0053] In an embodiment, when n = 1, R is selected from the following groups:

[0054]

[0055] ​​​In an embodiment, the chiral cyclic ether of structural formula II includes at least one of II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, II-i, II-i', II-j, II-k, II-l, II-m, II-n, II-o, II-p, II-q, II-r, II-s, II-t, II-u, II-v, II-w, II-x, II-y, II-z, II-aa, II-ab, II-ac, II-ad, II-ae, II-af, II-ag, II-ah, II-ai, II-aj, II-ak, II-al, II-am, II-an, II-ao, II-ap, II-aq, II-ar, II-as, II-at, II-au, and II-av as shown below, wherein II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, II-i, II-i' are chiral tetrahydrofuran, and II-j, II-k, II-l, II-m, II-n, II-o, II-p, II-q, II-r, II-s, II-t, II-u, II-v, II-w, II-x, II-y, II-z, II-aa, II-ab, II-ac, II-ad, II-ae, II-af, II-ag, II-ah, II-ai, II-aj, II-ak, II-al, II-am, II-an, II-ao, II-ap, II-aq, II-ar, II-as, II-at, II-au, and II-av are chiral tetrahydropyran:

[0056]

[0057] In an embodiment, the reaction is carried out in an inert gas atmosphere. It should be noted that the inert gas is introduced into the reaction system in the present application, mainly to form an oxygen-free environment. If an oxygen-free environment can be ensured, the inert gas can also not be used. In an implementation manner of the present application, even if the inert gas is used, most of the reaction environment is still hydrogen, for example, more than 99% is hydrogen, and the rest is inert gas.

[0058] In an embodiment, the inert gas includes, but is not limited to, at least one of nitrogen (N2), helium (He), neon (Ne), argon (Ar), krypton (Kr), and xenon (Xe).

[0059] In an embodiment, the hydrogen pressure is 5-80 atm.

[0060] In an embodiment, the amount of Lewis acid used in the reaction system is 0.1 molar equivalent of the substrate of formula I.

[0061] In one embodiment, the amount of catalyst is 0.001 to 0.02 molar equivalent of the substrate of formula I, preferably 0.002 molar equivalent.

[0062] In one embodiment, the reaction temperature is 0°C or 20°C or room temperature.

[0063] The specific embodiment also provides a chiral cyclic ether obtained by the above-mentioned synthesis method.

[0064] The specific embodiment also provides an application of the chiral cyclic ether obtained by the above-mentioned synthesis method in the preparation of a bioactive compound. It should be noted that the present application uses the chiral Ir / N-Me Zhaophos high-efficiency asymmetric catalytic hydrogenation method to reduce the hydroxy ketone derivative, synthesize the chiral cyclic ether derivative, and the obtained product has high optical purity and can be used as an intermediate of many bioactive molecules.

[0065] In one embodiment, the bioactive compound can refer to a drug molecule.

[0066] In one embodiment, the key chiral compound II obtained by asymmetric hydrogenation of the present application is a key intermediate of many chiral drug molecules.

[0067] In one embodiment, the drug molecule includes at least one of a DP receptor antagonist, a 5-HT 2A and D3 receptor dual modulator, (S)-delta-Decalactone. 2A

[0068] In one embodiment, the present application can synthesize the key chiral intermediate II-aj of the DP receptor antagonist by asymmetric hydrogenation.

[0069] In one embodiment, the present application can synthesize the key chiral intermediate II-aj of the 5-HT 2A and D3 receptor by asymmetric hydrogenation.

[0070] In one embodiment, the DP receptor antagonist, the 5-HT 2A and D3 receptor dual modulator can be synthesized by the chiral cyclic ether shown in structural formula II-aj, and the reaction formula is as follows:

[0071]

[0072] In one embodiment, the present application can synthesize the key chiral intermediate II-al of (S)-delta-Decalactone by asymmetric hydrogenation.​

[0073] In one embodiment, (S)-delta-decalactone can be synthesized from hydroxy ketone derivative shown in structural formula I-al and chiral cyclic ether shown in structural formula II-al, and the reaction formula is as follows:

[0074]

[0075] The application provides an Ir-catalyzed synthesis of chiral tetrahydrofuran or chiral tetrahydropyran from hydroxy ketone, which can realize dynamic kinetic resolution and asymmetric hydrogenation to construct chiral tetrahydropyran with two consecutive stereogenic centers. The method uses N-Me ZhaoPhos, a simple and easy-to-synthesize bisphosphine-thiourea ligand, as a ligand, [Ir(COD)Cl]2 as a metal precursor, hydroxy ketone as a substrate, triphenylborane as an acid additive, ethylene glycol dimethyl ether as a solvent, and hydrogen as a hydrogen source to chemoselectively synthesize chiral cyclic ether compounds. The reaction yield is as high as 99%, and the enantiomeric ratio is as high as 98.5:1.5. The product after hydrogenation can be used as an intermediate of various drug molecules, and has important application prospect.

[0076] The application will be further described in detail below through specific examples. The following examples are only for further description of the application, and should not be understood as limiting the application. It should be noted that the reagents, kits, instruments and the like used in the examples are all commercially available, and the operation steps are carried out according to the instructions or general operation steps in the art.

[0077] Examples

[0078] (1) Preparation of catalyst

[0079] In ethylene glycol dimethyl ether solution, the metal iridium precursor [Ir(COD)Cl]2 and 2.1 equivalent of the ligand N-MeZhaophos were placed together and stirred for 10 minutes to obtain a clear yellow solution, which was the catalyst required for the reaction.

[0080] (2) Synthesis of chiral cyclic ether shown in structural formula II

[0081] Under an inert gas atmosphere, hydroxy ketone derivative I (0.1 mmol) was added to a hydrogenation bottle, then Ir / N-MeZhaophos catalyst (0.002 mmol), triphenylborane (5.11 mg, 0.01 mmol), and deoxygenated ethylene glycol dimethyl ether (0.5 mL) were added, and then transferred to a pressure tank (the inert gas in the reaction chamber can be present or absent, and more than 99% is hydrogen), the hydrogen pressure was set (10 atm), and the reaction was carried out at 0°C or 10°C or room temperature for 72 h, the hydrogen was slowly released, the solvent was rotary evaporated, and the crude product II was obtained, which was then separated and purified by column chromatography to obtain the pure product II.

[0082] (3) Product structure, yield and enantioselectivity detection

[0083] By 1 H NMR and 13 The hydrogenation product structure was determined by H NMR and C NMR spectra, yield analysis was performed, and the er value (enantiomeric ratio) of the product was determined.

[0084] In this embodiment, a plurality of chiral cyclic ethers were synthesized, including products represented by structural formulae II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, II-i, II-i’, II-j, II-k, II-l, II-m, II-n, II-o, II-p, II-q, II-r, II-s, II-t, II-u, II-v, II-w, II-x, II-y, II-z, II-aa, II-ab, II-ac, II-ad, II-ae, II-af, II-ag, II-ah, II-ai, II-aj, II-ak, II-al, II-am, II-an, II-ao, II-ap, II-aq, II-ar, II-as, II-at, II-au, and II-av, the structure of each product and its yield and enantiomeric ratio results are as follows:

[0085]

[0086] It should be noted that the above content indicates that the first structural formula is product II-a, the yield thereof is 96%, and the enantiomeric ratio thereof is 95.5:4.5; the second structural formula is product II-b, the yield thereof is 95%, and the enantiomeric ratio thereof is 95:5, and the yield and enantiomeric ratio of other products are sequentially referred to in the above content and will not be described in detail one by one here.

[0087] In this embodiment, the specific synthesis steps of some products and the product structure, yield, and enantioselectivity detection analysis data thereof are listed here schematically and are as follows:

[0088] a) Synthesis of chiral cyclic ether represented by structural formula II-a, (R)-2-benzyltetrahydrofuran (i.e., (R)-2-Benzyltetrahydrofuran)

[0089] Inert atmosphere (nitrogen) in a hydrogenation flask, add hydroxy ketone derivative I-a (17.8 mg, 0.1 mmol), then add Ir / N-Me Zhaophos catalyst (0.002 mmol), triphenylborane (5.11 mg, 0.01 mmol), deoxygenated ethylene glycol dimethyl ether (0.5 mL), then transfer to a pressure tank (inert gas in the reaction chamber can or can not be, more than 99% is hydrogen), set the hydrogen pressure (10 atm), 0°C for 72h, slow release of hydrogen, spin dry the solvent to obtain the crude product II-a, followed by column chromatography separation and purification to obtain the clean product II-a. Colorless oil, 15.6 mg, 96% yield; 95.5:4.5er; (c 0.41, CH2Cl2); 1 H NMR (400 MHz, CDCl3) δ 7.33-7.28 (m, 2H), 7.26-7.20 (m, 3H), 4.09 (p, J = 6.6 Hz, 1H), 3.92 (q, J = 7.6, 6.9 Hz, 1H), 3.79-3.74 (m, 1H), 2.95 (dd, J = 13.5, 6.4 Hz, 1H), 2.77 (dd, J = 13.6, 6.5 Hz, 1H), 1.98-1.82 (m, 3H), 1.63-1.54 (m, 1H); 13 CNMR (100 MHz, CDCl3) δ 139.1, 129.3, 128.4, 126.3, 80.2, 68.1, 42.1, 31.1, 25.7; HRMS (ESI-TOF): Calcd for C 11 H 15 O + [M+H] + :163.1117, found 163.1116. wherein, Figure 2 is the nuclear magnetic resonance hydrogen spectrum of the product II-a involved in the examples of the present application, Figure 3 is the nuclear magnetic resonance carbon spectrum of the product II-a involved in the examples of the present application.

[0090] b) synthesis of chiral cyclic ether represented by structural formula II-j - (R)-2-phenethyltetrahydro-2H-pyran

[0091] In a hydrogenation flask, hydroxy ketone derivative I-j (20.6 mg, 0.1 mmol) was added, followed by Ir / N-Me Zhaophos catalyst (0.002 mmol), tri- pentafluorophenylborane (5.11 mg, 0.01 mmol), deoxygenated ethylene glycol dimethyl ether (0.5 mL), then transferred to a pressure tank (inert gas in the reaction chamber can or can not be present, more than 99% is hydrogen), set the hydrogen pressure (10 atm), 20 °C for 72 h, slowly release the hydrogen, spin dry the solvent to obtain the crude product II-j, and then separated and purified by column chromatography to obtain the pure product II-j. Colorless oil, 18.3 mg, 96% yield; 96:4 er; (c 0.70, CH2Cl2); 1 H NMR (600 MHz, CDC13) δ 7.29 - 7.26 (m, 2H), 7.20 - 7.17 (m, 3H), 4.02 - 4.00 (m, 1H), 3.42 (td, J = 11.7, 2.4 Hz, 1H), 3.27 - 3.22 (m, 1H), 2.77 (ddd, J = 14.8, 10.0, 5.4 Hz, 1H), 2.66 (ddd, J = 13.8, 9.8, 6.8 Hz, 1H), 1.85 - 1.79 (m, 2H), 1.71 - 1.65 (m, 1H), 1.62 - 1.54 (m, 3H), 1.52 - 1.43 (m, 2H); 13 C NMR (150 MHz, CDC13) δ 142.6, 128.6, 128.4, 125.8, 77.1, 68.6, 38.4, 32.1, 31.9, 26.4, 23.7; HRMS (ESI-TOF): Calcd for C 13 H 17 + [M+H-H20] + : 173.1325, found 173.1323. wherein, Figure 4 is the nuclear magnetic resonance hydrogen spectrum of product II-j involved in the examples of the present application, Figure 5 is the nuclear magnetic resonance carbon spectrum of product II-j involved in the examples of the present application.

[0092] c) Synthesis of chiral cyclic ether represented by structural formula II-q - (R)-9-(4-(2-(tetrahydro-2H-pyran-2-yl)ethyl)phenyl)-9H-carbazole

[0093] Inert gas (nitrogen) atmosphere, in a hydrogenation bottle, add hydroxy ketone derivative I-q (37.1 mg, 0.1 mmol), then add Ir / N-Me Zhaophos catalyst (0.002 mmol), triphenylborane (5.11 mg, 0.01 mmol), deoxygenated ethylene glycol dimethyl ether (0.5 mL), then transfer to a pressure tank (inert gas in the reaction chamber can or can not be, more than 99% is hydrogen), set the hydrogen pressure (10 atm), 20 ℃ for 72 h, slowly release the hydrogen, spin dry the solvent to obtain the crude product II-q, and then purified by column chromatography to obtain the pure product II-q. Colorless oil, 32.7 mg, 92% yield; 95.5:4.5 er; (c 1.22, CH2Cl2); 1 H NMR (600 MHz, CDCl3) δ 8.17 (d, J = 7.8 Hz, 2H), 7.49-7.48 (m, 2H), 7.44-7.42 (m, 6H), 7.30 (ddd, J = 7.9, 5.0, 3.1 Hz, 2H), 4.09-4.07 (m, 1H), 3.50 (td, J = 11.7, 2.3 Hz, 1H), 3.38-3.33 (m, 1H), 2.96-2.91 (m, 1H), 2.83-2.78 (m, 1H), 1.97-1.92 (m, 1H), 1.91-1.87 (m, 1H), 1.84-1.79 (m, 1H), 1.69-1.61 (m, 2H), 1.58-1.51 (m, 2H), 1.42-1.36 (m, 1H); 13 C NMR (150 MHz, CDCl3) δ 142.0, 141.1, 135.4, 130.0, 127.1, 126.0, 123.4, 120.4, 119.8, 109.9, 77.1, 68.7, 38.4, 32.2, 31.7, 26.3, 23.7; HRMS (ESI-TOF): Calcd for C 25 H 26 NO + [M+H] + :356.2009, found 356.2005. wherein, Figure 6 is the nuclear magnetic resonance hydrogen spectrum of product II-q involved in the examples of the present application, Figure 7 is the nuclear magnetic resonance carbon spectrum of product II-q involved in the examples of the present application.

[0094] d) synthesis of chiral cyclic ether shown in structural formula II-am - (R)-1-phenyl-2-((R)-tetrahydro-2H-pyran-2-yl)propan-1-one

[0095] In a hydrogenation flask, under inert gas (nitrogen) atmosphere, add hydroxy ketone derivative I-am (23.4 mg, 0.1 mmol), then add Ir / N-Me Zhaophos catalyst (0.002 mmol), tri-phenylborane (5.11 mg, 0.01 mmol), deoxygenated ethylene glycol dimethyl ether (0.5 mL), then transfer to a pressure tank (inert gas in the reaction chamber can or can not be present, more than 99% is hydrogen), set the hydrogen pressure (10 atm), react at room temperature for 72 h, slowly release hydrogen, spin dry the solvent to obtain crude product II-am, and then separate and purify to obtain clean product II-am by column chromatography. Colorless oil, 17.0 mg, 78% yield; 97.5:2.5 er, >20:1 dr; (c 0.28, CH2Cl2); 1 H NMR (600 MHz, CDC13) δ 7.99 - 7.97 (m, 2H), 7.55 - 7.52 (m, 1H), 7.46 - 7.44 (m, 2H), 3.85 - 3.83 (m, 1H), 3.69 (ddd, J = 10.9, 8.3, 2.1 Hz, 1H), 3.60 - 3.55 (m, 1H), 3.40 - 3.36 (m, 1H), 1.89 - 1.87 (m, 1H), 1.76 - 1.73 (m, 1H), 1.57 - 1.53 (m, 1H), 1.52 - 1.49 (m, 1H), 1.48 - 1.45 (m, 1H), 1.36 - 1.29 (m, 1H), 1.11 (d, J = 7.0 Hz, 3H); 13 C NMR (150 MHz, CDC13) δ 204.1, 137.6, 132.9, 128.6, 128.6, 80.0, 68.8, 46.3, 28.8, 26.2, 23.6, 13.5; HRMS (ESI-TOF): Calcd for C 14 H 18 NaO2 + [M+Na] + : 241.1199, found 241.1197. Wherein, Figure 8 is the nuclear magnetic resonance hydrogen spectrum of product II-am involved in the examples of the present application, Figure 9 is the nuclear magnetic resonance carbon spectrum of product II-am involved in the examples of the present application.

[0096] In summary, the chiral cyclic ether synthesis method of the embodiment has the advantages of simple reaction system, simple operation, high catalytic efficiency, high yield, and high enantioselectivity of the product.

[0097] The above is a further detailed description of the present application in combination with specific embodiments, and the specific implementation of the present application cannot be limited to these descriptions. For ordinary skilled persons in the technical field to which the present application belongs, some simple deductions or replacements can be made without departing from the concept of the present application.

Claims

1. A method for synthesizing a chiral cyclic ether from a hydroxy ketone, characterized by, The application relates to a method for preparing a chiral cyclic ether of structural formula II by reacting a compound of structural formula I with hydrogen in the presence of an Ir / N-Me Zhaophos catalyst. The catalyst is obtained by complexing a transition metal precursor and a ligand, wherein the transition metal precursor is [Ir(COD)Cl]2, and the ligand is selected from the following structural formulae: ； In the transition metal precursor, COD represents 1,5-cyclooctadiene; in the structural formula of the ligand, Ph represents a phenyl group, and Me represents a methyl group; ， In structural formula I and structural formula II, n is 0 or 1; When n=0, R is selected from the following groups: When n=1, R is selected from the following groups: ； The chiral cyclic ether of structural formula II is selected from at least one of the following compounds of structural formulae II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, II-i, II-i', II-j, II-k, II-l, II-m, II-n, II-o, II-p, II-r, II-s, II-t, II-u, II-v, II-w, II-x, II-y, II-z, II-aa, II-af, II-ah, II-ai, II-aj, II-ak, II-al, II-am, II-an, II-ao, II-ap, II-aq, II-ar, II-as, II-at, II-au and II-av: ； The amount of the catalyst is 0.001 to 0.02 mole equivalents of the compound of structural formula I. 。 2. The method of claim 1, wherein, The amount of the catalyst is 0.002 mole equivalents of the compound of structural formula I.

3. The method of claim 2, wherein, The reaction system further contains an organic solvent, wherein the organic solvent is a polar protic solvent, a polar aprotic solvent or a non-polar aprotic solvent.

4. The method of claim 1, wherein, The polar protic solvent includes at least one of methanol, ethanol and isopropanol.

5. The method of claim 4, wherein, The polar aprotic solvent includes at least one of tetrahydrofuran, ethyl acetate, diethyl ether, methyl tert-butyl ether, cyclopentyl methyl ether and ethylene glycol dimethyl ether.

6. The method of claim 4, wherein, The non-polar aprotic solvent includes at least one of n-hexane, dichloroethane and dichloromethane.

7. The method of claim 4, wherein, The reaction system further contains a Lewis acid and / or a Bronsted acid.

8. The method of claim 4, wherein, The Lewis acid is selected from at least one of trimethylchlorosilane, cuprous chloride, copper triflate, ferrous triflate, ferric triflate, bismuth triflate, indium triflate, zinc triflate, erbium triflate, silver triflate, cerium trichloride, erbium trichloride and triphenylphosphine borane.

9. The method of claim 8, wherein, The Bronsted acid is selected from at least one of hydrochloric acid, methanesulfonic acid, trifluoroacetic acid, acetic acid and d-camphorsulfonic acid.

10. The method of claim 8, wherein, The amount of the Lewis acid in the reaction system is 0.1 mole equivalents of the compound of structural formula I.

11. The method of claim 8, wherein, The reaction is carried out in an inert gas atmosphere, the reaction temperature is 0-30 DEG C, and the hydrogen pressure in the reaction is 5-80 atm.

12. The method of claim 1, wherein, The chiral cyclic ether is a compound of structural formula II-aj or a compound of structural formula II-al, and the bioactive compound is selected from the following compounds:

13. Use of a chiral cyclic ether produced according to the process of any one of claims 1 to 12 for the preparation of a biologically active compound, characterized in that, ​ 、 、 。

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