Method for synthesizing chiral cyclic ether from hydroxy ketone, chiral cyclic ether and application of chiral cyclic ether

Abstract

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

Description

Technical Field

[0001] The present application relates to the technical field of chemical synthesis, and in particular to a method for synthesizing chiral cyclic ethers by using hydroxyketone, the chiral cyclic ethers and applications thereof. Background Art

[0002] Chiral cyclic ether fragments are widely present in biologically active compounds and natural products, such as nonacticacid, dideoxyinosine, cladosporin, empagliflozin, (+)-quinine and other biologically active molecules, all of which carry chiral cyclic ether fragments. In addition, chiral cyclic ethers can also be used as intermediates for many clinical drug molecules, such as larotrectinib and faropenem medoxomil. Therefore, chiral cyclic ethers have important uses in the field of bioactive substances and drug synthesis, and have great application value.

[0003] In the past two decades, with the development of asymmetric reduction methods for ketones, various chiral cyclic ethers can be synthesized by chiral transfer reactions using chiral alcohols with terminal hydroxyl or terminal chlorine, respectively. However, due to the limited methods for catalytic reduction of alkyl ketones, it is difficult to produce aliphatic substituted chiral ethers via chiral transfer methods.

[0004] In 1988, Nicolaou's group developed a method to synthesize cyclic ethers using hydroxyketones as starting materials, via Lewis acid catalysis and silicon-hydrogen conditions. Since then, this method has been widely used in the synthesis of natural products and drug molecules. However, the cyclic ethers synthesized so far are racemic or the chirality produced is controlled by the substrate, and the reducing agent used is a stoichiometric silicon-hydrogen compound. In comparison, asymmetric hydrogenation has higher atom economy and is more in line with the concept of green chemistry. Therefore, it is of great significance to use asymmetric hydrogenation methods to generate a series of chiral cyclic ethers. Summary of the invention

[0005] The purpose of the present application is to provide a method for synthesizing chiral cyclic ethers using hydroxyketones, chiral cyclic ethers and applications thereof.

[0006] In order to achieve the above objectives, this application adopts the following technical solutions:

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

[0008]

[0009] Wherein, in formula I and formula II, R represents an unsubstituted benzyl group, a benzyl group in which at least one hydrogen is substituted, 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 the present application discloses the chiral cyclic ether obtained by the synthesis method of the present application.

[0014] Another aspect of the present application discloses the use of the chiral cyclic ether obtained by the synthesis method of the present application in the preparation of biologically active compounds.

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

[0016] The present application provides a method for asymmetric hydrogenation of hydroxy ketones, using chiral Ir / N-Me Zhaophos efficient asymmetric catalytic hydrogenation method to reduce hydroxy ketone derivatives and synthesize chiral cyclic ether derivatives. The reaction system is simple and easy to operate. The chiral cyclic ether synthesized by the method of asymmetric catalytic hydrogenation has a high optical purity and can be used as an intermediate for a variety of drug molecules and bioactive molecules, with good application prospects. In addition, the hydrogenation method has excellent chemical selectivity and enantioselectivity. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 It is a schematic diagram of a method for asymmetric hydrogenation of hydroxy ketone involved in a specific embodiment of the present application.

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

[0019] Figure 3 This is the carbon nuclear magnetic resonance spectrum of the product II-a involved in the examples of the present application.

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

[0021] Figure 5 This is the carbon nuclear magnetic resonance spectrum of the product II-j involved in the examples of this application.

[0022] Figure 6 This is the hydrogen nuclear magnetic resonance spectrum of the product II-q involved in the examples of the present application.

[0023] Figure 7 This is the carbon nuclear magnetic resonance spectrum of the product II-q involved in the examples of the present application.

[0024] Figure 8 This is the hydrogen nuclear magnetic resonance spectrum of the product II-am involved in the examples of the present application.

[0025] Fig. 9 This is the carbon nuclear magnetic resonance spectrum of the product II-am involved in the examples of this application. DETAILED DESCRIPTION

[0026] The present invention is further described in detail below by specific embodiments in conjunction with the accompanying drawings. In the following embodiments, many detailed descriptions are intended to enable the present application to be better understood. However, those skilled in the art can easily recognize that some of the features can be omitted in different situations, or can be replaced by other materials and 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 for those skilled in the art, it is not necessary to describe these related operations in detail, and the related operations can be fully understood according to the description in the specification and the general technical knowledge in the art.

[0027] In addition, the features, operations or characteristics described in the specification can be combined in any appropriate manner to form various implementations. At the same time, the steps or actions in the method description can also be interchanged or adjusted in a manner that is obvious to those skilled in the art. Therefore, the various sequences in the specification and the drawings are only for the purpose of clearly describing a certain embodiment and are not meant to be a required sequence, unless otherwise specified that a certain sequence must be followed.

[0028] In this application, for example, "Structural Formula Ia", "Structural Formula II-b", etc., are only used to distinguish the objects described and do not have any order or technical meaning.

[0029] Terminology explanation:

[0030] In the present application, "room temperature" refers to 25°C±2°C, R represents unsubstituted benzyl, benzyl or alkyl in which at least one hydrogen is substituted, DME represents ethylene glycol dimethyl ether, B(C6F5)3 represents trispentafluorophenylborane, iPr represents isopropyl, tBu represents tert-butyl, Et represents ethyl, NHBoc represents tert-butyloxycarbonylamino, 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 may include:

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

[0033] The reaction formula is as follows:

[0034]

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

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

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

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

[0039] In one 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 one embodiment, the reaction system further contains an organic solvent.

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

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

[0044] In one 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 one embodiment, the non-polar aprotic solvent includes but is not limited to at least one of n-hexane, ethylene dichloride, and dichloromethane.

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

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

[0048] In one embodiment, the Lewis acid includes but is not limited to at least one of trimethylsilyl chloride, cuprous chloride, copper trifluoromethanesulfonate, ferrous trifluoromethanesulfonate, ferric trifluoromethanesulfonate, bismuth trifluoromethanesulfonate, indium trifluoromethanesulfonate, zinc trifluoromethanesulfonate, erbium trifluoromethanesulfonate, silver trifluoromethanesulfonate, cerium trichloride, erbium trichloride, and tripentafluorophenylborane (chemical formula B(C6F5)3).

[0049] In one embodiment, the Lewis acid is trispentafluorophenylborane.

[0050] Figure 1 is a schematic diagram of a method for asymmetric hydrogenation of hydroxyketone according to a specific embodiment of the present application. In one embodiment, Figure 1 As shown, hydroxy ketones are asymmetrically hydrogenated by cyclic aliphatic oxocarbenium ions in the presence of catalysts Ir / L* and trispentafluorophenylborane to obtain chiral cyclic ethers, including chiral tetrahydrofuran and chiral tetrahydropyran. Figure 1 The yield of chiral tetrahydrofuran synthesized by the method shown is as high as 99%, and the enantiomeric ratio is as high as 96.5:3.5er; Figure 1 The yield of chiral tetrahydropyran synthesized by the method is as high as 83%, and the enantiomeric ratio is as high as 98.5:1.5er or greater than 20:1dr; the method has high yield and excellent stereoselectivity.

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

[0052]

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

[0054]

[0055] In one embodiment, the chiral cyclic ether represented by structural formula II includes 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-a At least one of v, wherein II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, II-i, II-i' are chiral tetrahydrofuran, 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 tetrahydropyrans:

[0056]

[0057] In one embodiment, the reaction is carried out in an inert gas atmosphere. It should be noted that the main purpose of introducing an inert gas into the reaction system in this application is to form an oxygen-free environment. If an oxygen-free environment can be ensured, an inert gas may not be used; in one implementation of this application, even if an inert gas is used, most of the entire reaction environment is still hydrogen, for example, more than 99% is hydrogen, and the rest is an inert gas.

[0058] In one 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 one embodiment, the hydrogen pressure is 5-80 atm.

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

[0061] In one embodiment, the amount of the catalyst used is 0.001 to 0.02 molar equivalents of the substrate represented by Formula I, preferably 0.002 molar equivalents.

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

[0063] This specific embodiment also provides a chiral cyclic ether obtained according to the above synthesis method.

[0064] This specific embodiment also provides an application of a chiral cyclic ether obtained according to the above synthesis method in the preparation of a biologically active compound. It should be noted that the present application uses a chiral Ir / N-Me Zhaophos efficient asymmetric catalytic hydrogenation method to reduce hydroxyketone derivatives to synthesize chiral cyclic ether derivatives, and the obtained product has high optical purity and can be used as an intermediate for many biologically active molecules.

[0065] In one embodiment, the biologically active compound may be a drug molecule.

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

[0067] In one embodiment, the drug molecules include DP receptor antagonists, 5-HT 2A Dual modulators of the 5-HT 2A and D3 receptors), (S)-δ-decalactone ((S)-δ-Decalactone).

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

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

[0070] In one embodiment, the chiral cyclic ether shown in the structural formula II-aj can be used to synthesize DP receptor antagonists, 5-HT 2A And D3 receptor dual modulator, the reaction formula is as follows:

[0071]

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

[0073] In one embodiment, (S)-δ-decalactone can be synthesized from a hydroxyketone derivative represented by structural formula I-al and a chiral cyclic ether represented by structural formula II-al, and the reaction formula is as follows:

[0074]

[0075] The present application provides an asymmetric hydrogenation method for synthesizing chiral tetrahydrofuran or chiral tetrahydropyran from Ir-catalyzed hydroxyketone, and can achieve dynamic kinetic resolution and construct chiral tetrahydropyran with two continuous stereocenters. The method uses a simple and easy-to-synthesize bisphosphine-thiourea ligand N-Me ZhaoPhos as a ligand, [Ir(COD)Cl]2 as a metal precursor, hydroxyketone as a substrate, tris-pentafluorophenylborane as an acid additive, ethylene glycol dimethyl ether as a solvent, and hydrogen as a hydrogen source to chemically selectively 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 hydrogenated product can be used as an intermediate for a variety of drug molecules and has important application prospects.

[0076] The present application is further described in detail below by specific examples. The following examples are only further described for the present application and should not be construed as limiting the present application. It should be noted that the reagents, test kits, instruments, etc. used in the examples are all commercially available, and the operating steps are carried out according to the instructions or the general operating steps in the art.

[0077] Example

[0078] (1) Preparation of Catalyst

[0079] In ethylene glycol dimethyl ether solution, the metal iridium precursor [Ir(COD)Cl]2 and 2.1 equivalents 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 the chiral cyclic ether shown in structural formula II

[0081] Under an inert gas atmosphere, a hydroxyketone derivative I (0.1 mmol) was added to a hydrogenation bottle, followed by Ir / N-MeZhaophos catalyst (0.002 mmol), trispentafluorophenylborane (5.11 mg, 0.01 mmol), and deoxyethylene glycol dimethyl ether (0.5 mL), and then transferred to a pressure autoclave (the inert gas in the reaction chamber may or may not be present, 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, and the hydrogen was slowly released. The solvent was dried to obtain a crude product II, which was subsequently separated and purified by column chromatography to obtain a clean product II.

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

[0083] pass 1 H NMR and 13 C NMR spectrum was used to confirm the structure of the hydrogenated product, conduct yield analysis, and determine the er value (enantiomeric ratio) of the product.

[0084] In this embodiment, a variety of chiral cyclic ethers were synthesized, including products shown in structural formula 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, and the structures of the products and their yields and enantiomeric ratios are as follows:

[0085]

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

[0087] This example schematically lists the specific synthesis steps of some products and their product structures, yields and enantioselectivity detection and analysis data, as follows:

[0088] a) Synthesis of the chiral cyclic ether represented by structural formula II-a, namely (R)-2-benzyltetrahydrofuran

[0089] In an inert gas (nitrogen) atmosphere, add hydroxyketone derivative Ia (17.8 mg, 0.1 mmol) to a hydrogenation bottle, then add Ir / N-Me Zhaophos catalyst (0.002 mmol), trispentafluorophenylborane (5.11 mg, 0.01 mmol), deoxyethylene glycol dimethyl ether (0.5 mL), and then transfer to a pressure autoclave (the inert gas in the reaction chamber is optional, more than 99% is hydrogen), set the hydrogen pressure (10 atm), react at 0 ° C for 72 hours, slowly release hydrogen, spin dry the solvent to obtain a crude product II-a, and then separate and purify by column chromatography to obtain a clean product II-a. Colorless oil, 15.6 mg, 96% yield; 95.5:4.5er; (c 0.41, CH2Cl2); 1 H NMR (400MHz, CDCl3) δ7.33–7.28(m,2H),7.26–7.20(m,3H),4.09(p,J=6.6Hz,1H),3.92(q,J=7.6,6.9Hz,1H),3.7 9–3.74(m,1H),2.95(dd,J=13.5,6.4Hz,1H),2.77(dd,J=13.6,6.5Hz,1H),1.98–1.82(m,3H),1.63–1.54(m,1H); 13 CNMR(100MHz, CDCl3)δ139.1,129.3,128.4,126.3,80.2,68.1,42.1,31.1,25.7; HRMS(ESI-TOF):Calcd for C 11 H 15 O + [M+H] + :163.1117, found 163.1116. Among them, Figure 2 is the hydrogen nuclear magnetic resonance spectrum of the product II-a involved in the examples of the present application, Figure 3 This is the carbon nuclear magnetic resonance spectrum of the product II-a involved in the examples of the present application.

[0090] b) Synthesis of the chiral cyclic ether represented by structural formula II-j, namely (R)-2-phenethyltetrahydro-2H-pyran (i.e. (R)-2-phenethyltetrahydro-2H-pyran)

[0091] In an inert gas (nitrogen) atmosphere, add hydroxyketone derivative Ij (20.6 mg, 0.1 mmol) to a hydrogenation bottle, then add Ir / N-Me Zhaophos catalyst (0.002 mmol), trispentafluorophenylborane (5.11 mg, 0.01 mmol), deoxyethylene glycol dimethyl ether (0.5 mL), and then transfer to a pressure autoclave (the inert gas in the reaction chamber is optional, more than 99% is hydrogen), set the hydrogen pressure (10 atm), react at 20 ° C for 72 hours, slowly release hydrogen, spin dry the solvent to obtain a crude product II-j, and then separate and purify by column chromatography to obtain a clean product II-j. Colorless oil, 18.3 mg, 96% yield; 96:4er; (c 0.70, CH2Cl2); 1 H NMR (600MHz, CDCl3) δ7.29–7.26(m,2H),7.20–7.17(m,3H),4.02–4.00(m,1H),3.42(td,J=11.7,2.4Hz,1H),3.27–3.22(m,1H),2.77(ddd, J=14.8,10.0,5.4Hz,1H),2.66(ddd,J=13.8,9.8,6.8Hz,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 (150MHz, CDCl3) δ142.6,128.6,128.4,125.8,77.1,68.6,38.4,32.1,31.9,26.4,23.7; HRMS (ESI-TOF):Calcd for C 13 H 17 + [M+H-H2O] + :173.1325, found 173.1323. Among them, Figure 4 is the hydrogen nuclear magnetic resonance spectrum of the product II-j involved in the examples of this application, Figure 5 The embodiments of the present application relate to the carbon nuclear magnetic resonance spectrum of product II-j.

[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 (i.e., (R)-9-(4-(2-(tetrahydro-2H-pyran-2-yl)ethyl)phenyl)-9H-carbazole)

[0093] In an inert gas (nitrogen) atmosphere, add hydroxyketone derivative Iq (37.1 mg, 0.1 mmol) to a hydrogenation bottle, then add Ir / N-Me Zhaophos catalyst (0.002 mmol), trispentafluorophenylborane (5.11 mg, 0.01 mmol), deoxyethylene glycol dimethyl ether (0.5 mL), and then transfer to a pressure autoclave (the inert gas in the reaction chamber is optional, more than 99% is hydrogen), set the hydrogen pressure (10 atm), react at 20 ° C for 72 hours, slowly release hydrogen, spin dry the solvent to obtain a crude product II-q, and then separate and purify by column chromatography to obtain a clean product II-q. Colorless oil, 32.7 mg, 92% yield; 95.5:4.5er; (c 1.22, CH2Cl2); 1 H NMR(600MHz, CDCl3)δ8.17(d,J=7.8Hz,2H),7.49–7.48(m,2H),7.44–7.42(m,6H),7 .30(ddd,J=7.9,5.0,3.1Hz,2H),4.09–4.07(m,1H),3.50(td,J=11.7,2.3Hz,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 (150MHz, CDCl3) δ142.0,141.1,135.4,130.0,127.1,126.0,123.4,120.4, 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. Among them, Figure 6 is the hydrogen nuclear magnetic resonance spectrum of the product II-q involved in the examples of the present application, Figure 7 This is the carbon nuclear magnetic resonance spectrum of the product II-q involved in the examples of the present application.

[0094] d) Synthesis of chiral cyclic ether represented by structural formula II-am: (R)-1-phenyl-2-((R)-tetrahydro-2H-pyran-2-yl)acetone (i.e., (R)-1-phenyl-2-((R)-tetrahydro-2H-pyran-2-yl)propan-1-one)

[0095] In an inert gas (nitrogen) atmosphere, add hydroxyketone derivative I-am (23.4 mg, 0.1 mmol) to a hydrogenation bottle, then add Ir / N-Me Zhaophos catalyst (0.002 mmol), trispentafluorophenylborane (5.11 mg, 0.01 mmol), deoxyethylene glycol dimethyl ether (0.5 mL), and then transfer to a pressure autoclave (inert gas in the reaction chamber is optional, more than 99% is hydrogen), set hydrogen pressure (10 atm), react at room temperature for 72 hours, slowly release hydrogen, spin dry the solvent to obtain a crude product II-am, and then separate and purify by column chromatography to obtain a clean product II-am. Colorless oil, 17.0 mg, 78% yield; 97.5:2.5er,>20:1dr; (c 0.28, CH2Cl2); 1 H NMR (600MHz, CDCl3) δ7.99–7.97(m,2H),7.55–7.52(m,1H),7.46–7.44(m,2H ),3.85–3.83(m,1H),3.69(ddd,J=10.9,8.3,2.1Hz,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=7.0Hz,3H); 13 C NMR (150MHz, CDCl3) δ204.1,137.6,132.9,128.6,128.6,80.0,68.8,46.3,28.8,26.2,23.6,13.5; HRMS (ESI-TOF): Calcd for C 14 H 18 NaO2 + [M+Na] + :241.1199,found241.1197.Among them, Figure 8 is the hydrogen nuclear magnetic resonance spectrum of the product II-am involved in the examples of this application, Fig. 9 This is the carbon nuclear magnetic resonance spectrum of the product II-am involved in the examples of this application.

[0096] In summary, the method for synthesizing the chiral cyclic ether of this embodiment has a simple reaction system, is easy to operate, and has the advantages of high catalytic efficiency, high yield, and high product enantioselectivity.

[0097] The above contents are further detailed descriptions of the present application in combination with specific implementation methods, and it cannot be determined that the specific implementation of the present application is limited to these descriptions. For ordinary technicians in the technical field to which the present application belongs, several simple deductions or substitutions can be made without departing from the concept of the present application.

Claims

1. A method for synthesizing chiral cyclic ethers using hydroxyketones, characterized in that: include: In the presence of Ir / N-Me Zhaophos catalyst, the compound shown in structural formula I reacts with hydrogen to obtain the chiral cyclic ether shown in structural formula II. The reaction formula is as follows: In the structural formula I and the structural formula II, R represents an unsubstituted benzyl group, a benzyl group in which at least one hydrogen is substituted, or an alkyl group, and n is 0 or 1.

2. The method according to claim 1, characterized in that 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: In the transition metal precursor, COD represents 1,5-cyclooctadiene; in the structural formula of the ligand, Ph represents phenyl, and Me represents methyl; Preferably, the amount of the catalyst is 0.001 to 0.02 molar equivalents of the compound represented by structural formula I; Preferably, the amount of the catalyst used is 0.002 molar equivalent of the compound represented by structural formula I.

3. The method according to claim 1, characterized in that The reaction system further contains an organic solvent, which is a polar protic solvent, an aprotic solvent, or a non-polar aprotic solvent; Preferably, the polar protic solvent comprises at least one of methanol, ethanol and isopropanol; Preferably, the polar aprotic solvent comprises at least one of tetrahydrofuran, ethyl acetate, diethyl ether, methyl tert-butyl ether, cyclopentyl methyl ether and ethylene glycol dimethyl ether; Preferably, the non-polar aprotic solvent comprises at least one of n-hexane, ethylene dichloride and dichloromethane.

4. The method according to claim 3, characterized in that The reaction system also contains Lewis acid and / or Bronsted acid; Preferably, the Lewis acid comprises at least one of trimethylsilyl chloride, cuprous chloride, copper trifluoromethanesulfonate, ferrous trifluoromethanesulfonate, ferric trifluoromethanesulfonate, bismuth trifluoromethanesulfonate, indium trifluoromethanesulfonate, zinc trifluoromethanesulfonate, erbium trifluoromethanesulfonate, silver trifluoromethanesulfonate, cerium trichloride, erbium trichloride and trispentafluorophenylborane; Preferably, the Bronsted acid includes at least one of hydrochloric acid, methanesulfonic acid, trifluoroacetic acid, acetic acid and dextrorotatory camphorsulfonic acid.

5. The method according to claim 4, characterized in that The amount of Lewis acid used in the reaction system is 0.1 molar equivalent of the compound shown in structural formula I.

6. The method according to claim 1, characterized in that The reaction is carried out in an inert gas atmosphere, the reaction temperature is 0° C. to 30° C., and the hydrogen pressure during the reaction is 5 atm to 80 atm.

7. The method according to any one of claims 1 to 6, characterized in that: When n=0, R is selected from the following groups: When n=1, R is selected from the following groups:

8. The method according to claim 7, characterized in that The chiral cyclic ether shown in structural formula II includes at least one of the compounds shown in structural formulas 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:

9. A chiral cyclic ether synthesized by the method according to any one of claims 1 to 8.

10. Use of the chiral cyclic ether according to claim 9 in the preparation of biologically active compounds.

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