Chiral 1, 4-diyne compound and synthesis method thereof

Abstract

The invention provides a preparation method of a chiral 1, 4-diyne compound, which comprises the following step: in a solvent, in the presence of a copper catalyst, a bisoxazoline ligand and an oxidizing agent, reacting a compound containing a fragment II with a compound containing a fragment III to obtain a compound as shown in a formula I. The invention further provides a preparation method of the chiral 1, 4-diyne compound. The method disclosed by the invention is high in yield, wide in substrate universality, good in functional group compatibility, mild in reaction condition and simple to operate.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a chiral 1,4-diyne compound and its synthesis method. Background Technology

[0002] Chiral 1,4-diyne compounds are important building blocks for drug discovery and organic synthesis. For example, in the design of ribonucleotide reductase inhibitor molecules, diyne fragments are considered a viable structural component (WO / 2017 / 209155, 2017, A1). Furthermore, simple transformations of chiral 1,4-diyne compounds can yield structural components of chiral dienes and alkynes substituted or fully alkylated chiral tertiary carbon compounds widely found in natural products and active pharmaceutical molecules. For example: phorbasin C (McNally, M.; Capon, RJJ Nat. Prod. 2001, 64, 645-647.), arachidonic acid ethanolamide (AEA) analogs with rCB1 activity (Liu, Y.; Ji, L.; Eno, M.; Kudalkar, S.; Li, A.-L.; Nikas, SPetc. J. Med. Chem. 2018, 61, 8639-8657), sex pheromones (Bello, JE; McElfresh, JS; Millar, JG Proc. Natl. Acad. Sci. USA 2015, 112, 1077-1082), 6-methylphenylthiazide (Beifuss, U.; Tietze, M.; S.; Deppenmeier, U. Angew. Chem., Int. Ed. 2000, 39, 2470-2472), and thromboxane synthase inhibitor CGS23005 (Bhagwat, SS; Gude, C.; Boswell, C.; Contardo, N.; Cohen, DS; Dotson, R.; Mathis, J.; Lee, W.; Furness, P.; Zoganas, HJ Med. Chem. 1992, 35, 4373-4383), etc. Therefore, developing methods for synthesizing these compounds is of great significance.

[0003] In recent decades, 1,4-diyne compounds have been extensively studied. However, these reactions have mainly focused on the synthesis of racemic 1,4-diynes through various methods, with very few reports on the synthesis of chiral 1,4-diynes. In 2016, Aaron Aponick reported the asymmetric synthesis of amino-1,4-diynes using the nucleophilic addition of alkynyl copper species to imines, which could not be synthesized for diynes of common alkanes (Paioti, PHS; Abboud, KA; Aponick, AJAm. Chem. Soc. 2016, 138, 2150-2153). In 2019, Liu Xinyuan reported the Sonogashira coupling of alkynyl bromides and alkynes to obtain the corresponding chiral 1,4-diyne. This work yielded only three diyne products (Dong, X.-Y.; Zhang, Y.-F.; Ma, C.-L.; Gu, Q.-S.; Wang, F.-L.; Li, Z.-L.; Jiang, S.-P.; Liu, X.-Y. Nat. Chem. 2019, 11, 1158-1166). In 2024, Liu Xiaohua reported the asymmetric bifunctionalization of enyne substrates under light conditions to obtain a product containing a 1,4-diyne structure (Xin, S.; Liao, J.; Tang, Q.; Feng, X.; Liu, X. Chem. Sci. 2024, 15, 18557-18563). Nevertheless, there is still a significant gap in the understanding of reactions that yield chiral 1,4-diyne compounds through functionalization following CH extraction.

[0004] Therefore, there is an urgent need in this field to develop a novel catalytic strategy that is simple to operate, has universal substrates, good functional group compatibility, and high product yield, in order to achieve efficient and controllable synthesis of chiral 1,4-diyne compounds. Summary of the Invention

[0005] The present invention aims to provide a novel catalytic strategy that is simple to operate, has broad substrate applicability, excellent functional group compatibility, and high product yield, so as to achieve efficient and controllable synthesis of chiral 1,4-diyne compounds.

[0006] In a first aspect of the invention, a chiral 1,4-diyne compound is provided, the compound having the structure shown in Formula I:

[0007]

[0008] Among them, R 1 For C1-C 20 Alkyl group, with one, two or three R radicals 1-1 Replacement C1-C 20 Alkyl, C6-C 10The aryl group may be surrounded by one, two, or three R groups. 1-2 Replacement C6-C 10 Aryl, C1-C containing heteroatoms 20 Alkyl alkanes, C4-C 10 Heteroaryl or C4-C substituted with one, two or three alkyl groups 10 Mixed aromatics;

[0009] R 1-1 Independently halogen, hydroxyl, -O-CO-R 1-1-1 -COOCH3, C6-C 10 aryl, with 1, 2 or 3 R 1-1-3 Replacement C6-C 10 The aryl group, substituted or unsubstituted heteroatom, is a 5-10 membered heteroaryl group selected from one, two or three of N, O and S, with one, two or three heteroatoms; C3-C8 cycloalkyl; -OTBS; wherein, the substitution refers to one or more H atoms on the heteroaryl group being replaced by groups selected from the following group:

[0010] C1-C6 alkyl groups;

[0011] R 1-1-1 It is an alkyl group or -(CH2). n R 1-1-1-a n can be 0, 1, 2, 3, 4, or 5;

[0012] R 1-1-1-a C6-C, whether substituted or not 10 Aryl, terminal alkenes, terminal alkynes, "5-10 membered heteroaryl groups with one, two, or three heteroatoms selected from N, O, and S, and having one, two, or three heteroatoms", and "5-10 membered heteroaryl groups with one, two, or three heteroatoms substituted by one, two, or three heteroatoms selected from N, O, and S, and having one, two, or three heteroatoms". Wherein, substitution refers to the substitution of one or more H on the aryl or heteroaryl group by a group selected from the group consisting of: nitro, phenyl, halogen;

[0013] R 1-1-3 It is an alkyl group, a halogen, or a C1-C3 haloalkyl group;

[0014] R 1-2 Halogen, C1-C 20 Alkyl, trifluoromethyl;

[0015] R 2 For H, C1-C 20 Alkyl group, with one, two or three R radicals 2-1 Replacement C1-C 20 Alkyl, C3-C6 cycloalkyl, C6-C10 The aryl group may be surrounded by one, two, or three R groups. 2-2 Replacement C6-C 10 Aryl, C1-C containing heteroatoms 20 Alkyl alkanes, C6-C 10 Heteroaryl groups or 1, 2 or 3 R groups 2-3 Replacement C6-C 10 Mixed aromatics;

[0016] R 2-1 Independently for C6-C 10 Aryl, halogen, with 1, 2 or 3 R 2-1-1 Replacement C6-C 10 Aryl, "5-10 membered heteroaryl with one, two or three heteroatoms selected from N, O and S, and having one, two or three heteroatoms", C3-C8 cycloalkyl; -OCH3, -CH(OCH2CH3)2;

[0017] R 2-1-1 For C1-C 20 Alkyl, trifluoromethyl, -OCH3;

[0018] R 2-2 and R 2-3 Each independently is C1-C 20 Alkyl, C1-C6 alkoxy, trifluoromethyl;

[0019] [Si] represents 1, 2, or 3 Cl-C atoms. 20 Alkyl groups or 1, 2 or 3 C6-C 10 Aryl silicon-based.

[0020] In another preferred embodiment, the R 1 For C1-C 20 Alkyl group, with one, two or three R radicals 1-1 Replacement C1-C 20 alkyl;

[0021] R 1-1 Independently halogen, hydroxyl, -O-CO-R 1-1-1 C6-C 10 aryl, with 1, 2 or 3 R 1-1-3 Replacement C6-C 10 The terms are: aryl, substituted or unsubstituted "5-10 membered heteroaryl with one, two or three heteroatoms selected from N, O and S, and having one, two or three heteroatoms", C3-C8 cycloalkyl, -OTBS; wherein the substitution refers to one or more H atoms on the heteroaryl group being replaced by groups selected from the following group: C1-C6 alkyl;

[0022] R1-1-1 It is an alkyl group or -(CH2). n R 1-1-1-a n can be 0, 1, 2, 3, 4, or 5;

[0023] R 1-1-3 It is an alkyl group, a halogen, or a C1-C3 haloalkyl group;

[0024] R 1-1-1-a C6-C, whether substituted or not 10 Aryl, terminal alkenes, terminal alkynes, "5-10 membered heteroaryl groups with one, two, or three heteroatoms selected from N, O, and S, and having one, two, or three heteroatoms", and "5-10 membered heteroaryl groups with one, two, or three heteroatoms substituted by one, two, or three heteroatoms selected from N, O, and S, and having one, two, or three heteroatoms". The substitution refers to the substitution of one or more H atoms on the aryl or heteroaryl group by a group selected from the group consisting of: nitro, phenyl, and halogen.

[0025] In another preferred embodiment, the R 2 For H, C1-C 20 Alkyl group, with one, two or three R radicals 2-1 Replacement C1-C 20 Alkyl, C3-C6 cycloalkyl, C6-C 10 The aryl group may be surrounded by one, two, or three R groups. 2-2 Replacement C6-C 10 Aryl, C6-C 10 Mixed aromatics;

[0026] R 2-1 Independently halogen, C1-C6 alkoxy group, -CH(OCH2CH3)2;

[0027] R 2-2 For C1-C 20 Alkyl, C1-C6 alkoxy, trifluoromethyl.

[0028] In another preferred embodiment, R 2-1 Independently for C6-C 10 Aryl, halogen, -OCH3, -OEt, -CH(OCH2CH3)2.

[0029] In another preferred embodiment, the R 1 Selected from the following group: methyl, Preferably methyl,

[0030] In another preferred embodiment, the R 2Selected from the following group: H, phenyl, C3-C6 cycloalkyl, C1-C10 alkyl,

[0031] In another preferred embodiment, [Si] is Preferred In another preferred embodiment, the compound represented by Formula I has a structure selected from the group consisting of:

[0032]

[0033]

[0034] In a second aspect of the present invention, a method for preparing a chiral 1,4-diyne compound as described in the first aspect is provided, the method comprising the steps of: reacting a compound containing fragment II and a compound containing fragment III in a solvent in the presence of a copper catalyst, a bisoxazoline ligand and an oxidant to obtain a chiral 1,4-diyne compound of formula I.

[0035]

[0036] The bisoxazoline ligand is:

[0037] R 3 It can be phenyl or hydrogen;

[0038] R 4 Independently, it is a C1-C6 alkyl group, hydrogen, and Ar is C6-C. 10 aryl, with 1, 2 or 3 R 4-1 Replacement C6-C 10 aryl, "a 5-15 membered heteroaryl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or surrounded by one, two, or three R 4-2 The substituted heteroatoms are selected from one, two, or three of N, O, and S, and are 5-15 membered heteroaryl groups with one, two, or three heteroatoms.

[0039] R 4-1 It is independently C1-C6 alkyl, halogen, or C1-C6 alkoxy;

[0040] R 4-2 Independently, it is a C1-C6 alkyl group;

[0041] R 5 Independently C1-C6 alkyl, hydrogen; Ar is C6-C 10 aryl, with 1, 2 or 3 R 5-1 Replacement C6-C 10aryl, "a 5-15 membered heteroaryl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or surrounded by one, two, or three R 5-2 The substituted heteroatoms are selected from one, two, or three of N, O, and S, and are 5-15 membered heteroaryl groups with one, two, or three heteroatoms.

[0042] R 5-1 It is independently C1-C6 alkyl, halogen, or C1-C6 alkoxy;

[0043] R 5-2 Independently, it is a C1-C6 alkyl group;

[0044] R 6 Independently, it is a C1-C6 alkyl group, hydrogen, and Ar is C6-C. 10 aryl, with 1, 2 or 3 R 6-1 Replacement C6-C 10 aryl, "a 5-15 membered heteroaryl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or surrounded by one, two, or three R 6-2 The substituted heteroatoms are selected from one, two, or three of N, O, and S, and are 5-15 membered heteroaryl groups with one, two, or three heteroatoms.

[0045] R 6-1 It is independently C1-C6 alkyl, halogen, or C1-C6 alkoxy;

[0046] R 6-2 Independently, it is a C1-C6 alkyl group;

[0047] R 7 Independently, it is a C1-C6 alkyl group, hydrogen, and Ar is C6-C. 10 aryl, with 1, 2 or 3 R 7-1 Replacement C6-C 10 aryl, "a 5-15 membered heteroaryl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or surrounded by one, two, or three R 7-2 The substituted heteroatoms are selected from one, two, or three of N, O, and S, and are 5-15 membered heteroaryl groups with one, two, or three heteroatoms.

[0048] R 7-1 It is independently C1-C6 alkyl, halogen, or C1-C6 alkoxy;

[0049] R 7-2 Independently, it is a C1-C6 alkyl group;

[0050] Among them, R 1 and R2 The definition is as stated in the first aspect.

[0051] In another preferred embodiment, the compound containing fragment II is a compound represented by formula II: The R mentioned 1 As stated in the first aspect.

[0052] In another preferred embodiment, the compound represented by Formula II is selected from any of the following compounds:

[0053]

[0054]

[0055] Preferred

[0056]

[0057]

[0058] In another preferred embodiment, the compound containing fragment III is a compound represented by formula III, wherein the compound represented by formula III is selected from any of the following compounds: Preferably:

[0059] In another preferred embodiment, the oxazoline ligand is any of the following compounds:

[0060]

[0061] Preferably:

[0062]

[0063] In another preferred embodiment, the solvent is selected from one or more of the following group: halogenated hydrocarbon solvents, nitrile solvents, benzene solvents, and amide solvents; the benzene solvent is preferably perfluorobenzene; the nitrile solvent is preferably acetonitrile; the amide solvent is preferably N,N-dimethylacetamide; preferably, the solvent is a benzene solvent, a nitrile solvent, or a mixture of halogenated hydrocarbon solvents and amide solvents.

[0064] In another preferred embodiment, the volume ratio of the mixed solvent is nitrile solvent: amide solvent = (1-10):(1-5), preferably 10:1, 1:5 or 5:1; more preferably 5:1.

[0065] In another preferred embodiment, the amount of solvent used is conventional for such reactions in the art; preferably, the concentration of the compound containing fragment II in the solvent is 0.01 to 5.00 mol / L (e.g., 0.625, 0.5, or 2.00 mol / L), more preferably 0.50 to 1.00 mol / L.

[0066] In another preferred embodiment, the copper catalyst is selected from one or more of the following group: cuprous acetate, cuprous iodide, copper tetraacetonitrile tetrafluoroborate, di(acetylacetone)copper and cuprous chloride; preferably copper acetate and cuprous chloride.

[0067] In another preferred embodiment, the molar ratio of the copper catalyst to the compound containing segment II is (1-50):100; preferably (1-10):100; for example, 1:100 or 5:100.

[0068] In another preferred embodiment, the molar ratio of the bisoxazoline ligand to the compound containing fragment II is (0.01-0.75):1, for example, 0.1:1 or 0.2:1.

[0069] In another preferred embodiment, the molar ratio of the copper catalyst to the bisoxazoline ligand is 1:(0.5-3), for example 1:2 or 1:1.2.

[0070] In another preferred embodiment, the oxidant is selected from the group consisting of: Preferably, the oxidant is

[0071] In another preferred embodiment, the base is a base conventional for such reactions in the art, and preferably, the oxidant is lithium carbonate.

[0072] In another preferred embodiment, the molar ratio of the oxidant to the compound containing fragment II is (1.0 to 5.0):1, preferably (1.0 to 3.0):1, for example, 1.2:1, 2:1 or 3:1; preferably 3:1.

[0073] In another preferred embodiment, the molar ratio of the compound containing fragment III to the compound containing fragment II is (1.0 to 100):1, more preferably (2.5 to 10):1, for example 2.5:1 or 3:1.

[0074] In another preferred embodiment, the temperature of the coupling reaction is a temperature conventional for such reactions in the art; preferably, the reaction temperature is -20 to 60°C; for example, room temperature.

[0075] In another preferred embodiment, the progress of the coupling reaction is monitored using conventional detection methods in the art (e.g., TLC, HPLC, HNMR), preferably with the disappearance or cessation of reaction of the compound containing fragment II as the endpoint of the reaction.

[0076] In another preferred embodiment, the addition reaction time is 1 to 168 hours, preferably 12 to 108 hours, for example 24 hours, 36 hours, 48 ​​hours, 64 hours or 96 hours; more preferably 96 hours.

[0077] In another preferred embodiment, the coupling reaction further includes the following post-processing steps: direct concentration and purification.

[0078] In another preferred embodiment, the reactants for the coupling reaction are the solvent, the copper catalyst, the bisoxazoline ligand, the oxidant, the compound containing fragment II, and the compound containing fragment III.

[0079] In another preferred embodiment, "room temperature" refers to 10–30°C.

[0080] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0081] Figure 1 The molecular ellipsoid of compound I-36 is shown. Detailed Implementation

[0082] Through extensive and in-depth research and numerous experimental screenings, the inventors have unexpectedly developed a novel synthetic method for chiral 1,4-diyne compounds. This invention employs a specific copper catalytic system, using commercially available trimethoxysilyne / alkynylboronic ester as the alkynyl source, to efficiently and with high enantioselectivity construct chiral 1,4-diyne skeletons under mild conditions. This method utilizes readily available raw materials, is simple to operate, and exhibits excellent substrate versatility and functional group compatibility. The resulting products can be rapidly converted into pharmaceutical active molecules and natural product skeletons as key intermediates, providing an efficient and practical new strategy for the precise synthesis of chiral functional molecules. Based on this, the inventors have completed this invention.

[0083] Terminology Explanation

[0084] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Furthermore, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe this invention.

[0085] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0086] The term "alkyl" refers to an alkyl group having a specified number of carbon atoms (e.g., C1 to C2). 20 Or C1~C 10 Alkyl groups are straight-chain or branched saturated hydrocarbon groups. Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, etc.

[0087] The term "alkoxy" refers to the group R. Z -O-, where R Z It is an alkyl group as defined above.

[0088] The term "aryl" refers to an aryl group having a specified number of carbon atoms (e.g., C6-C). 10 Aromatic rings are cyclic groups consisting solely of carbon atoms, which may be monocyclic or polycyclic, and at least one of the rings is aromatic. Aromatic rings include, but are not limited to, benzene rings and naphthalene rings.

[0089] The term "heteroaryl" refers to a cyclic group having a specified number of ring atoms (e.g., 5-15 or 5-10), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one, two, or three of N, O, and S), which can be monocyclic or polycyclic, and at least one ring is aromatic. The heteroaryl group is attached to the rest of the molecule via a carbon atom or a heteroatom; it can be attached to the rest of the molecule via a ring with or without heteroatoms. Heteroaryl groups include, but are not limited to, furan rings, pyrrole rings, thiophene rings, pyrazole rings, imidazole rings, oxazole rings, thiazole rings, pyridine rings, pyrimidine rings, indole rings, and benzopyrrole rings.

[0090] The term "cycloalkyl" refers to a saturated monocyclic cyclic group consisting only of carbon atoms and having a specified number of carbon atoms (e.g., C3 to C8). Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0091] In structural fragments This refers to the connection between this structural segment and other segments in the molecule through this site. For example, It refers to cyclohexyl.

[0092] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0093] The reagents and raw materials used in this invention are all commercially available.

[0094] Ar is defined as described in any of the claims of this invention.

[0095] In one embodiment of the present invention, C1-C 20 The alkyl group is a C1-C6 alkyl group; for example, methyl, ethyl, propyl, butyl, or hexyl.

[0096] In one embodiment of the present invention, C1-C 10 The alkyl group is a C1-C6 alkyl group, preferably methyl, ethyl, propyl or butyl; more preferably methyl or ethyl.

[0097] In one embodiment of the present invention, the C6-C 10 The aryl group is either phenyl or naphthyl.

[0098] In one embodiment of the present invention, the C3-C8 cycloalkyl group is a monocyclic C3-C8 cycloalkyl group, preferably a C3-C6 monocyclic cycloalkyl group; for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; and for another example, cyclohexyl.

[0099] In one embodiment of the present invention, the halogen is fluorine, chlorine, bromine or iodine; preferably chlorine.

[0100] In one embodiment of the present invention, the 5-10 member heteroaryl group is a monocyclic or bicyclic heteroaryl group, preferably a 5-membered monocyclic heteroaryl group.

[0101] In one embodiment of the present invention, the 5-10 member heteroaryl group, for example,

[0102] In one embodiment of the present invention, C1-C 10 The alkoxy group is a C1-C6 alkoxy group; preferably a methoxy group.

[0103] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0104] 1. In this invention, a specific copper catalyst system is used to achieve the precise construction of the chiral 1,4-diyne skeleton with high anti-catalyst selectivity and high yield, effectively controlling the stereoconfiguration of the product.

[0105] 2. In this invention, commercially available trimethoxysilyne / alkynylboronic ester is used as the alkynyl source, which reacts efficiently with allene substrates under mild conditions. The raw materials are readily available and have good stability, which greatly reduces the complexity of the process and the production cost.

[0106] 3. The preparation method of the present invention is applicable to allenes and functionalized alkynes with various substitution types, and shows good compatibility with sensitive functional groups such as ethers, esters, halogens, and nitrogen-containing heterocycles, providing an effective tool for complex molecular modification.

[0107] 4. The chiral 1,4-diyne product prepared by this invention can be used as a key intermediate and can be rapidly converted into bioactive drug molecules and natural product skeletons, greatly expanding the application prospects of this method in synthetic chemistry and drug development.

[0108] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0109] Example 1: Preparation method of chiral 1,4-diyne under different ligand conditions

[0110] General operating procedure: In a 10 mL reaction tube, add the corresponding bisoxazoline ligand (0.004 mmol, 2 mol%), CuOAc (0.24 mg, 0.002 mmol, 1 mol%), and NF-1 (196.8 mg, 0.6 mmol, 3.0 equiv.). Then, add hexafluorobenzene (PhF6), N,N-dimethylacetamide (0.5 mL, v / v 5:1), Li₂CO₃ (44.4 mg, 0.6 mmol, 3.0 equiv.), compound III-1 (133.4 mg, 0.6 mmol, 3.0 equiv.), and allene shown in formula II-1 (40.8 mg, 0.2 mmol, 1.0 equiv.). Stir the reaction at room temperature for 48 hours. After the reaction is complete, concentrate the solution. Separate the product by rapid column chromatography (petroleum ether) to obtain the target product. The bisoxazoline ligand is selected from the following group:

[0111]

[0112] Example 2III-1: Preparation method of chiral 1,4-diyne in different solvents as alkynyl sources

[0113]

[0114] General operating procedure: In a 10 mL reaction tube, add the following solvents sequentially: bisoxazoline ligand L7 (3.6 mg, 0.004 mmol, 2 mol%), CuOAc (0.24 mg, 0.002 mmol, 1 mol%), and NF-1 (196.8 mg, 0.6 mmol, 3.0 equiv.). Then add N,N-dimethylacetamide (0.02 mL), Li₂CO₃ (44.4 mg, 0.6 mmol, 3.0 equiv.), compound III-1 (133.4 mg, 0.6 mmol, 3.0 equiv.), and allene (48.8 mg, 0.2 mmol, 1.0 equiv.) as shown in Table 1. Stir the reaction at room temperature for 48 hours. After the reaction is complete, filter and concentrate. Separate the target product by rapid column chromatography (petroleum ether).

[0115] Table 1: Reaction Solvent and Product Yield

[0116]

[0117]

[0118] Example 3: Preparation method of chiral 1,4-diyne under different amounts of DMAc (N,N-dimethylacetamide)

[0119]

[0120] General operating procedure: In a 10 mL reaction tube, add the following solvents sequentially: bisoxazoline ligand L7 (3.6 mg, 0.004 mmol, 2 mol%), CuOAc (0.24 mg, 0.002 mmol, 1 mol%), and NF-1 (196.8 mg, 0.6 mmol, 3.0 equiv.); solvent PhF6 (0.4 mL); DMAc (N,N-dimethylacetamide, added according to Table 2 below); Li₂CO₃ (44.4 mg, 0.6 mmol, 3.0 equiv.); compound III-1 (133.4 mg, 0.6 mmol, 3.0 equiv.); and allene shown in formula II-1 (0.2 mmol, 1.0 equiv.). Stir the reaction at room temperature for 48 hours. After the reaction is complete, filter and concentrate. Separate the target product by rapid column chromatography (petroleum ether).

[0121] Table 2: Amount of DMAc (N,N-dimethylacetamide) added

[0122]

[0123]

[0124] Note: a L8 is a ligand.

[0125] Example 4: Preparation of chiral 1,4-diyne under different NF reagent conditions

[0126]

[0127] General operating procedure: In a 10 mL reaction tube, add the following solvents sequentially: bisoxazoline ligand L7 (3.6 mg, 0.004 mmol, 2 mol%), CuOAc (0.24 mg, 0.002 mmol, 1 mol%), and NF (0.6 mmol, 3.0 equiv.); solvent PhF6 (0.4 mL); Li₂CO₃ (44.4 mg, 0.6 mmol, 3.0 equiv.); compound III-1 (133.4 mg, 0.6 mmol, 3.0 equiv.); and allene (0.2 mmol, 1.0 equiv.) as shown in formula II-1. Stir the reaction at room temperature for 96 hours. After the reaction is complete, filter and concentrate. Separate the target product by rapid column chromatography (petroleum ether). The NF reagent is selected from the following group:

[0128]

[0129] Example 5: Preparation method of chiral 1,4-diyne under different catalyst dosages

[0130]

[0131] General operating procedure: In a 10 mL reaction tube, bisoxazoline ligand L8, CuOAc, and NF-2 (220.4 mg, 0.6 mmol, 3.0 equiv.) were added sequentially, followed by solvent PhF6 (0.4 mL), Li₂CO₃ (44.4 mg, 0.6 mmol, 3.0 equiv.), compound III-1 (133.4 mg, 0.6 mmol, 3.0 equiv.), and allene (0.2 mmol, 1.0 equiv.) as shown in formula II-1. The reaction was stirred at 10 °C for 96 hours. After the reaction was completed, the mixture was filtered and concentrated. The target product was obtained by rapid column chromatography (petroleum ether). The amounts of different copper catalysts used are shown in Table 3.

[0132] Table 3: Dosage of copper catalyst

[0133] entry copper catalyst ligands product(%) ee(%) 1 1.0％ 2.0％ 51％ 97％ 2 2.0％ 4.0％ 56％ 97％ 3 3.0％ 6.0％ 66％ 97％ 4 4.0％ 8.0％ 74％ 97％ 5 5.0％ 10.0％ 77％ 97％ 6 5.0％ 7.5％ 77％ 97％ 7 5.0％ 6.0％ 77％ 97％

[0134] Example 6III-2: Preparation of chiral 1,4-diyne in different solvents using alkynyl groups as a source

[0135]

[0136] General operating procedure: In a 10 mL reaction tube, bisoxazoline ligand L8 (11.2 mg, 0.004 mmol, 2 mol%), CuOAc (1.2 mg, 0.002 mmol, 1 mol%), and NF-2 (220.4 mg, 0.6 mmol, 3.0 equiv.) were added sequentially with solvent (0.48 mL), Li₂CO₃ (44.4 mg, 0.6 mmol, 3.0 equiv.), compound III-1 (115.2 mg, 0.6 mmol, 3.0 equiv.), and allene (52.8 mg, 0.2 mmol, 1.0 equiv.) as shown in formula II-2. The reaction was stirred at 10 °C for 96 hours. After the reaction was completed, the product was filtered, concentrated, and separated by rapid column chromatography (petroleum ether) to obtain the target product. The solvents used and the yields in this experiment are shown in Table 4.

[0137] Table 4: Reaction Solvent and Product Yield

[0138]

[0139]

[0140] Example 7III-1: Preparation method of chiral 1,4-diyne as an alkynyl source

[0141]

[0142] General operating procedure: In a 10 mL reaction tube, bisoxazoline ligand L8 (11.2 mg, 0.012 mmol, 6 mol%), CuOAc (1.2 mg, 0.005 mmol, 5 mol%), and NF-2 (0.6 mmol, 3.0 equiv.) were added sequentially to a solvent (0.48 mL), followed by Li₂CO₃ (44.4 mg, 0.6 mmol, 3.0 equiv.), compound III-1 (133.4 mg, 0.6 mmol, 3.0 equiv.), and allene (48.8 mg, 0.2 mmol, 1.0 equiv.) as shown in formula II-1. The reaction was stirred at 10 °C for 96 hours. After the reaction was complete, the mixture was filtered and concentrated. The target product was obtained by rapid column chromatography (petroleum ether).

[0143] Example 8III-2: Preparation method of chiral 1,4-diyne as alkynyl source

[0144]

[0145] General operating procedure: In a 10 mL reaction tube, the following solvents were added sequentially: bisoxazoline ligand L8 (11.2 mg, 0.012 mmol, 6 mol%), CuOAc (1.2 mg, 0.005 mmol, 5 mol%), and NF-2 (220.4 mg, 0.6 mmol, 3.0 equiv.); Li₂CO₃ (44.4 mg, 0.6 mmol, 3.0 equiv.); compound III-2 (133.4 mg, 0.6 mmol, 3.0 equiv.); and allene (48.8 mg, 0.2 mmol, 1.0 equiv.) as shown in formula II-2. The reaction was stirred at 10 °C for 96 hours. After the reaction was complete, the mixture was filtered and concentrated. The target product was obtained by rapid column chromatography (petroleum ether).

[0146] The compounds prepared using the method of the present invention and their characterization data are shown below. The list of compounds is shown in Table 6.

[0147] Table 6: Compounds of the present invention

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154] I-1

[0155]

[0156] The reaction was carried out according to the general operating procedure in Example 7, and column chromatography (petroleum ether) yielded a colorless oily liquid. (51 mg, 74% yield, 97% ee). [α] D 27.4 -12.12(c 0.3, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.67-7.66(m,2H),7.44-7.30(m,8H),3.67(t,J=6.8Hz,1H),1.8 7-1.82(m,2H),1.60-1.56(m,2H),1.42-1.29(m,4H),0.97-0.87(m,3H),0.43(s,6H). 13C NMR (100MHz, CDCl3) δ 137.3, 133.7, 131.7, 129.3, 128.2, 128.0, 127.8, 123.2, 106.3, 87.6, 83.3, 81.2, 35.8, 31.2, 26.5, 25.0, 22.5, 14.0, -0.8. HRMS: m / z (EI) Calculated values: C 24 H 28 Si + [M] + 344.1955, Measured value: 344.1960. HPLC (OD-H, n-hexane / isopropanol = 99.5 / 0.5, flow rate 0.65 mL / min) Detection wavelength: 214 nm, retention time: 6.133 min (major) and 6.737 min (secondary).

[0157] I-3

[0158]

[0159] The reaction was carried out according to the general operating procedure in Example 7, and column chromatography (petroleum ether) yielded a colorless oily liquid. (67 mg, 88% yield, 94% ee). [α] D 27.2 -4.73 (c 0.63, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.68-7.67(m,2H),7.46-7.31(m,8H),3.66(t,J=6.4Hz,1H),1. 90-1.79(m,6H),1.63-1.61(m.2H)1.56-1.53(m,3H),1.19-1.10(m,2H),0.44(s,6H). 13 C NMR (100MHz, CDCl3) δ 137.3, 133.7, 131.7, 129.3, 128.2, 128.0, 127.8, 123.3, 106.4, 87.7, 83.4, 81.2, 39.6, 35.1, 33.4, 32.7, 25.24, 25.17, -0.8. HRMS: m / z (EI) Calculated values: C 26 H 30 Si + [M] + 370.2111, Measured value: 370.2114. HPLC (OD-H, n-hexane / isopropanol = 99.5 / 0.5, flow rate 0.65 mL / min) Detection wavelength: 214 nm, retention time: 6.342 min (major) and 7.204 min (secondary).

[0160] I-4

[0161]

[0162] The reaction was carried out according to the general operating procedure in Example 7, and column chromatography (petroleum ether) yielded a colorless oily liquid. (64 mg, 87% yield, 98% ee). [α] D 26.9 -4.46 (c 0.83, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.70-7.69(m,2H),7.49 -7.46(m,2H),7.42 -7.41(m,3H),7.34-7.32(m,3H),3.72(t,J=6.4Hz,1H),3.59(t,J=6.4Hz,2H),1.89-1.85(m,4H),1.82-1.77(m,2H),0.47(s,6H). 13 CNMR (100MHz, CDCl3) δ 137.1, 133.7, 131.7, 129.4, 128.2, 128.1, 127.8, 123.0, 105.7, 87.1, 83.8, 81.5, 44.7, 34.9, 32.0, 24.9, 24.2, -0.8. HRMS: m / z (EI) Calculated value: C 23 H 25 ClSi + [M] + 364.1409, Measured value: 364.1403. HPLC (OD-H, n-hexane / isopropanol = 99.5 / 0.5, flow rate 0.65 mL / min) Detection wavelength: 214 nm, retention time: 13.100 min (major) and 21.929 min (secondary).

[0163] I-5

[0164]

[0165] The reaction was carried out according to the general operating procedure in Example 7, and column chromatography (petroleum ether) yielded a colorless oily liquid. (61 mg, 86% yield, 98% ee). [α] D 25.0 -6.40 (c 0.40, CHCl3). 1H NMR (400MHz, CDCl3) δ7.43-7.42(m,2H),7.30-7.29(m,3H),3.63(t,J=6.8Hz,1H),3. 55(t,J=6.8Hz,2H),1.85-1.78(m,4H),1.66-1.49(m,4H),0.95(s,9H),0.11(s,6H). 13 C NMR (100MHz, CDCl3) δ 131.7, 128.2, 128.0, 123.2, 104.6, 87.6, 83.8, 81.2, 44.9, 35.6, 32.4, 26.3, 26.1, 24.8, 16.6, -4.6. HRMS: m / z (FI) Calculated values: C 22 H 31 ClSi + [M] + 358.1878, Measured value: 358.1875. HPLC (OD-H, n-hexane / isopropanol = 99.5 / 0.5, flow rate 0.65 mL / min) Detection wavelength: 214 nm, retention time: 7.221 min (major) and 8.617 min (secondary).

[0166] I-6

[0167]

[0168] The reaction was carried out according to the general operating procedure in Example 7, and column chromatography (petroleum ether) yielded a colorless oily liquid. (54 mg, 95% yield, 95% ee). [α] D 28.2 -7.68 (c 0.56, CHCl3). 1 H NMR(400MHz, CDCl3)δ7.44-7.42(m,2H),7.30 -7.27(m,3H),3.62(t,J=6.8Hz,1H),3.56(t,J=6.8Hz,2H),1.84-1.79(m,4H),1.61-1.57(m,2H),1.54-1.49(m,2H),0.18(s,9H). 13 C NMR (100MHz, CDCl3) δ 131.7, 128.2, 128.0, 123.2, 104.0, 87.5, 85.5, 81.3, 44.9, 35.6, 32.4, 26.3, 26.1, 24.8, 0.0. HRMS: m / z (EI) Calculated values: C 19 H 25 ClSi + [M] +316.1409, Measured value: 16.1403. HPLC (OD-H, n-hexane / isopropanol = 99.5 / 0.5, flow rate 0.65 mL / min) Detection wavelength: 214 nm, retention time: 7.987 min (major) and 9.767 min (secondary).

[0169] I-7

[0170]

[0171] The reaction was carried out according to the general operating procedure in Example 7, and column chromatography (petroleum ether) yielded a colorless oily liquid. (64 mg, 81% yield, 94% ee). [α] D 24.6 +1.11 (c 1.90, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.67-7.65(m,4H),7.45-7.42(m,2H),7.40-7.37(m, 6H),7.31-7.30(m,3H),3.80-3.73(m,3H),2.01-1.88(m,4H),0.70(s,3H). 13 C10 NMR (100MHz, CHCl3) δ 135.4, 134.5, 131.7, 129.6, 128.2, 128.1, 127.9, 123.2, 107.6, 87.0, 82.2, 81.7, 62.3, 32.1, 30.1, 25.0, -2.0. HRMS: m / z (FI) Calculated values: C10 27 H 26 OSi + [M] + 394.1747, Measured value: 394.1753. HPLC (OD-H, n-hexane / isopropanol = 90 / 10, flow rate 0.65 mL / min), detection wavelength: 214 nm, retention time: 11.671 min (major) and 13.958 min (secondary).

[0172] I-8

[0173]

[0174] The reaction was carried out according to the general operating procedure in Example 7, and column chromatography (petroleum ether) yielded a colorless oily liquid. (46 mg, 64% yield, 94% ee). [α] D 24.9 -4.88 (c 0.4, CHCl3). 1H NMR(400MHz, CDCl3)δ7.65-7.63(m,2H),7.45 -7.42(m,2H),7.38-7.36(m,3H),7.32-7.29(m,3H),4.33(t,J=6.4Hz,2H ),3.84(t,J=7.2Hz,1H),2.17(q,J=6.4Hz,2H),2.06(s,3H),0.43(s,6H), 13 C NMR (100MHz, CDCl3) δ 170.9, 136.9, 133.7, 131.7, 129.4, 128.2, 127.9, 122.8, 104.7, 86.2, 84.3, 81.9, 61.6, 34.8, 22.1, 20.9, -0.8. HRMS: m / z (FI) Calculated values: C 23 H 24 O2Si + [M] + 360.1547, Measured value: 360.1540. HPLC (OD-H, n-hexane / isopropanol = 99.5 / 0.5, flow rate 0.65 mL / min), detection wavelength: 214 nm, retention time: 23.346 min (major) and 23.346 min (secondary).

[0175] I-9

[0176]

[0177] The reaction was carried out according to the general operating procedure in Example 7, and column chromatography (petroleum ether) yielded a colorless oily liquid. (46 mg, 64% yield, 94% ee). [α] D 26.2 -1.28 (c 1.6, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.76-7.74(m,2H),7.53-7.52(m,2H),7.46-7.45(m,3H),7.37-7.31(m,5H),7 .29-7.26(m,3H),3.72(t,J=6.8Hz,1H),2.99(t,J=7.6Hz,2H),2.23(q,J=7.6Hz,2H),0.52(s,6H). 13C NMR (100MHz, CDCl3) δ 141.0, 137.1, 133.7, 131.7, 129.4, 128.6, 128.5, 128.2, 128.1, 127.8, 126.1, 123.1, 105.8, 87.1, 84.0, 81.8, 37.5, 33.0, 24.4, -0.8. HRMS: m / z (EI) Calculated values: C 27 H 26 Si + [M] + 378.1798, Measured value: 378.1797. HPLC (OD-H, n-hexane / isopropanol = 99.5 / 0.5, flow rate 0.65 mL / min), detection wavelength: 214 nm, retention time: 12.050 min (major) and 13.421 min (secondary).

[0178] I-10

[0179]

[0180] The reaction was carried out according to the general operating procedure in Example 7, and column chromatography (petroleum ether) yielded a colorless oily liquid. (55 mg, 71% yield, 94% ee). [α] D 27.0 -13.73 (c 1.9, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.71-7.68(m,2H),7.49-7.46(m,2H),7.41-7.39(m,3H),7.33-7.32(m,3H),7.16-7 -12(m,4H),3.66(t,J=7.2Hz,1H),2.90(t,J=7.6Hz,2H),2.35(s,3H),2.16(q,J=7.6Hz,2H),0.46(s,6H). 13 C NMR (100MHz, CDCl3) δ137.8,137.2,135.5,133.7,131.7,129.4,129.1,128.5,1 28.2,128.1,127.8,123.2,105.9,87.2,83.9,81.7,37.6,32.5,24.3,21.0,-0.8 . HRMS:m / z(FI) calculated value: C 28 H 28 Si + [M] +392.1955, Measured value: 392.1952. HPLC (OD-H, n-hexane / isopropanol = 99.5 / 0.5, flow rate 0.65 mL / min), detection wavelength: 214 nm, retention time: 10.092 min (major) and 11.239 min (secondary).

[0181] I-11

[0182]

[0183] The reaction was carried out according to the general operating procedure in Example 7, and column chromatography (petroleum ether) yielded a colorless oily liquid. (77 mg, 94% yield, 95% ee). [α] D 27.5 -1.48 (c 0.86, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.69-7.67(m,2H),7.47-7.45(m,2H),7.40-7.39(m,3H),7.33-7.28(m,5H),7 .25-7.15(m,2H),3.64(t,J=7.2Hz,1H),2.88(t,J=7.6Hz,2H),2.14(q,J=7.6Hz,2H),0.46(s,6H). 13 CNMR (100MHz, CDCl3) δ 139.4, 137.1, 133.7, 131.9, 131.7, 129.9, 129.4, 128.5, 128.2, 128.1, 127.9, 123.0, 105.5, 86.9, 84.2, 81.9, 37.2, 32.3, 24.3, -0.8. HRMS: m / z (EI) Calculated value: C 27 H 25 ClSi + [M] + 412.1409, Measured value: 412.1412. HPLC (OD-H, n-hexane / isopropanol = 99.5 / 0.5, flow rate 0.65 mL / min), detection wavelength: 214 nm, retention time: 9.542 min (major) and 10.712 min (secondary).

[0184] I-12

[0185]

[0186] The reaction was carried out according to the general operating procedure in Example 7, and column chromatography (petroleum ether) yielded a colorless oily liquid. (77 mg, 94% yield, 95% ee). [α] D 27.3-8.21 (c 1.5, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.72-7.69(m,2H),7.52-7.41(m,9H),7.35-7.33(m,3H),3 .68(t,J=6.8Hz,1H),3.00(t,J=7.6Hz,2H),2.19(q,J=7.6Hz,2H),0.48(s,6H). 13 C NMR (100MHz, CDCl3) δ141.9,137.0,133.7,132.0,131.7,130.8(q,J=32.2Hz,),129.4,128.9,128.23,128.20,127.9, 125.3(q,J=3.8Hz),124.2(q,J=270.6Hz),123.0(q,J=3.7Hz),122.9,105.3,86.7,84.4,82.0,37.1,32.8,24.4,-0.9. 19 F NMR (376MHz, CDCl3) δ -62.5(s). HRMS: m / z (EI) Calculated value: C 28 H 25 F3Si + [M] + 446.1672, Measured value: 446.1679. HPLC (OD-H, n-hexane / isopropanol = 99.5 / 0.5, flow rate 0.65 mL / min), detection wavelength: 214 nm, retention time: 9.429 min (major) and 10.987 min (secondary).

[0187] I-13

[0188]

[0189] The reaction was carried out according to the general operating procedure in Example 7, and column chromatography (petroleum ether) yielded a colorless oily liquid. (61 mg, 75% yield, 99% ee). [α] D 28.0 -11.47 (c 0.59, CHCl3). 1H NMR (400MHz, CDCl3) δ8.24-8.21(m,1H),7.95-7.93(m,1H),7.82-7.77(m,3H),7.58-7.54(m,4H),7.50-7.47 (m,5H),7.40-7.38(m,3H),3.85(t,J=6.8Hz,1H),3.49(t,J=8.0Hz,2H),2.37(q,J=8.4Hz,2H),0.57(s,6H). 13 C NMR (100MHz, CDCl3) δ 137.1, 137.0, 133.9, 133.7, 131.8, 131.7, 129.4, 128.8, 128.2, 128.1, 127.9, 127.0, 126.4, 125.9, 125.54, 125.51, 123.7, 123.1, 105.7, 87.1, 84.2, 81.9, 36.7, 30.2, 24.9, -0.8. HRMS: m / z (FI) Calculated values: C 31 H 28 Si + [M] + 428.1955, Measured value: 428.1952. HPLC (OD-H, n-hexane / isopropanol = 99.5 / 0.5, flow rate 0.65 mL / min), detection wavelength: 214 nm, retention time: 21.471 min (scan) and 24.700 min (major).

[0190] I-14

[0191]

[0192] The reaction was carried out according to the general operating procedure in Example 7, and column chromatography (petroleum ether) yielded a colorless oily liquid. (64 mg, 83% yield, 92% ee). [α] D 26.6 -11.83 (c 0.81, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.71-7.70(m,2H),7.50-7.48(m,2H),7.43-7.42(m,3H),7.34-7.33(m,3H),7.19-7.17(m,1H),6. 98-6.96(m,1H),6.89(d,J=8.0Hz,1H),3.76(t,J=7.2Hz,1H),3.18(t,J=7.6Hz,2H),2.24(q,J=6.8Hz,2H),0.49(s,6H). 13C NMR (100MHz, CDCl3) δ 143.4, 137.1, 133.7, 131.7, 129.4, 128.2, 128.1, 127.9, 126.9, 124.8 123.4, 123.1, 105.4 86.8, 84.2, 81.9, 37.5, 27.1, 24.2, -0.8. HRMS: m / z (EI) Calculated values: C 25 H 24 SSi + [M] + 384.1362, Measured value: 384.1360. HPLC (OD-H, n-hexane / isopropanol = 99.5 / 0.5, flow rate 0.65 mL / min), detection wavelength: 214 nm, retention time: 12.275 min (major) and 14.179 min (secondary).

[0193] I-15

[0194]

[0195] The reaction was carried out according to the general operating procedure in Example 7, and column chromatography (petroleum ether) yielded a colorless oily liquid. (57 mg, 75% yield, 92% ee). [α] D 26.4 -5.40 (c 0.6, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.68-7.67(m,2H),7.47-7.45(m,2H),7.40-7.39(m,3H),7.32-7.31(m,3H),5.93(d,J=2.4H z,1H),5.87(s,1H),3.72(t,J=6.8Hz,1H),2.90(t,J=7.2Hz,2H),2.28(s,3H),2.17(q,J=7.2Hz,2H),0.45(s,6H). 13 C NMR (100MHz, CDCl3) δ 152.7, 150.7, 137.1, 133.7, 131.7, 129.4, 128.2, 128.1, 127.8, 123.1, 106.2, 105.9, 105.6, 86.9, 84.0, 81.7, 34.2, 25.4, 24.4, 13.5, -0.8. HRMS: m / z (EI) Calculated values: C 26 H 26 OSi + [M] +382.1747, Measured value: 382.1745. HPLC (OD-H, n-hexane / isopropanol = 99.5 / 0.5, flow rate 0.65 mL / min), detection wavelength: 214 nm, retention time: 5.829 min (scan) and 6.137 min (major).

[0196] I-16

[0197]

[0198] The reaction was carried out according to the general operating procedure in Example 7, and column chromatography (petroleum ether / ethyl acetate) yielded a colorless oily liquid. (71 mg, 86% yield, 91% ee). [α] D 26.3 -6.73 (c 2.20, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.66-7.65(m,2H),7.45-7.44(m,2H),7.39-7.38(m,3H),7.32-7.31(m,3H),4.35(t,J=6.0Hz,2H),3.85(t,J=7.2Hz ,1H),2.47(t,J=7.2Hz,2H),2.26(td,J=6.8,2.4Hz,2H),2.19(q,J=6.4Hz,2H),1.98(t,J=2.4Hz,1H),1.87(q,J=7.2Hz,2H),0.44(s,6H). 13 CNMR (100MHz, CHCl3) δ 172.9, 136.9, 133.7, 131.7, 129.4, 128.2, 127.9, 122.8, 104.6, 86.1, 84.3, 83.2, 81.9, 69.2, 61.5, 34.7, 32.8, 23.5, 22.0, 17.8, -0.8. HRMS: m / z (FI) Calculated value: C 27 H 28 O2Si + [M] + 412.1853, Measured value: 412.1860. HPLC (OD-H, n-hexane / isopropanol = 90 / 10, flow rate 0.65 mL / min), detection wavelength: 214 nm, retention time: 20.004 min (scan) and 20.892 min (major).

[0199] I-17

[0200]

[0201] The reaction was carried out according to the general operating procedure in Example 7, and column chromatography (petroleum ether / ethyl acetate) yielded a colorless oily liquid. (68 mg, 82% yield, 88% ee). [α] D 25.8 -7.63 (c 2.60, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.66-7.64(m,2H),7.46-7.43(m,2H),7.40-7.35(m,3H)7.32-7.30(m,3H),5.83-5.73(m,1H),5.05–4.98(m,2H),4.34(t ,J=6.0Hz,2H),3.85(t,J=7.2Hz,1H),2.34(t,J=7.2Hz,2H),2.18(q,J=6.4Hz,2H),2.10(q,J=6.8Hz,2H),1.75(q,J=7.6Hz,2H),0.44(s,6H). 13 C10 NMR (100MHz, CHCl3) δ 173.4, 137.6, 136.9, 133.7, 131.7, 129.4, 128.2, 127.9, 122.8, 115.4, 104.7, 86.1, 84.3, 81.9, 61.4, 34.8, 33.5, 33.0, 24.0, 22.0, -0.8. HRMS: m / z (FI) Calculated values: C10 27 H 30 O2Si + [M] + 414.2010, Measured value: 414.2012. HPLC (OD-H, n-hexane / isopropanol = 95 / 5, flow rate 0.65 mL / min), detection wavelength: 214 nm, retention time: 8.350 min (snapshot) and 8.896 min (major).

[0202] I-18

[0203]

[0204] The reaction was carried out according to the general operating procedure in Example 8, and column chromatography (petroleum ether) yielded a colorless oily liquid. (47 mg, 71% yield, 90% ee). [α] D 23.6 -22.19 (c 2.8, CHCl3). 1H NMR (400MHz, CDCl3) δ7.68-7.67(m,4H),7.44-7.36(m,6H),3.42(td,J=6.4,1.6Hz,1H ),1.80(q,J=7.2Hz,2H),1.34-1.21(m,1H),1.11(t,J=7.2Hz,3H),0.79-0.66(m,7H). 13 C NMR (100MHz, CDCl3) δ 135.7, 134.5, 129.5, 127.9, 127.8, 108.8, 84.7, 81.2, 72.9, 29.4, 26.1, 11.3, 8.1, -0.5, -2.0. HRMS: m / z (EI) Calculated values: C 23 H 24 Si + [M] + 328.1642, Measured value: 328.1648. HPLC (OD-H, n-hexane / isopropanol = 99.5 / 0.5, flow rate 0.65 mL / min), detection wavelength: 214 nm, retention time: 6.350 min (major) and 6.567 min (secondary).

[0205] I-19

[0206]

[0207] The reaction was carried out according to the general operating procedure in Example 8, and column chromatography (petroleum ether) yielded a colorless oily liquid. (51 mg, 71% yield, 94% ee). [α] D 24.6 -0.24(c 0.3, CHCl3).δ7.68-7.61(m,4H),7.43-7.32(m,6H),3.46-3.37(m,1H),2.18(t,J=7.2Hz,2H),1.78(p,J=7 .2Hz,2H),1.56-1.48(m,2H),1.44-1.24(m,4H),1.10(t,J=7.2Hz,3H),0.89(t,J=7.2Hz,3H),0.67(s,3H). 13 CNMR (100MHz, CDCl3) δ 135.7, 134.5, 129.5, 127.8, 109.0, 81.8, 81.0, 77.6, 31.0, 29.4, 28.5, 26.1, 22.2, 18.7, 14.0, 11.3, -1.9. HRMS: m / z (EI) Calculated values: C 25 H 30 Si + [M] +358.2111, Measured value: 358.2116. HPLC (OD-H, n-hexane / isopropanol = 100 / 0, flow rate 0.65 mL / min), detection wavelength: 214 nm, retention time: 13.612 min (major) and 17.204 min (secondary).

[0208] I-20

[0209]

[0210] The reaction was carried out according to the general operating procedure in Example 8, and column chromatography (petroleum ether) yielded a colorless oily liquid. (40 mg, 72% yield, 96% ee). [α] D 23.1 +26.69 (c 0.7, CHCl3). 1 H NMR(400MHz,CDCl3)δ7.65-7.63(m,4H),7.41 -7.34(m,6H),3.52-3.33(m,1H),1.83(d,J=2.4Hz,3H),1.81-1.73(m,2H),1.09(t,J=7.2Hz,3H),0.68(s,3H). 13 C NMR (100MHz, CDCl3) δ 135.6, 134.5, 129.5, 127.8, 108.7, 81.2, 29.4, 26.0, 11.3, 3.6, -1.9. HRMS: m / z (EI) Calculated values: C 21 H 22 Si + [M] + 302.1491, Measured value: 302.1480. HPLC (OD-H, n-hexane / isopropanol = 99.5 / 0.5, flow rate 0.65 mL / min), detection wavelength: 214 nm, retention time: 7.412 min (major) and 8.037 min (secondary).

[0211] I-21

[0212]

[0213] The reaction was carried out according to the general operating procedure in Example 8, and column chromatography (petroleum ether) yielded a colorless oily liquid. (61 mg, 83% yield, 91% ee). [α] D 24.0 -2.92 (c 0.70, CHCl3). 1H NMR (400MHz, CDCl3) δ7.67-7.65(m,4H),7.42-7.36(m,6H),3.67(t,J=6.0Hz,2H),3.43(t,J=6.8Hz,1H ),2.42-2.38(m,2H),1.97(p,J=6.4Hz,2H),1.79(p,J=7.2Hz,2H),1.11(t,J=7.2Hz,3H),0.70(s,3H). 13 C NMR (100MHz, CDCl3) δ135.5,134.5,129.5,127.9,108.5,81.3,79.6,78.9,43.7,31.4,29.3,26.0,16.2,11.3,-2.0.

[0214] HRMS:m / z (DRAT) calculated value: C 23 H 26 ClSi + [M+H] + 365.1487, Measured value: 365.1486. ​​HPLC (OD-H, n-hexane / isopropanol = 99.5 / 0.5, flow rate 0.65 mL / min), detection wavelength: 214 nm, retention time: 8.845 min (major) and 8.896 min (secondary).

[0215] I-22

[0216]

[0217] The reaction was carried out according to the general operating procedure in Example 8, and column chromatography (petroleum ether) yielded a colorless oily liquid. (47 mg, 67% yield, 95% ee). [α] D 25.3 +0.67 (c 1.40, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.66-7.64(m,4H),7.42-7.35(m,6H),4.13(d,J=2.0Hz,2H),3.51( t,J=6.8Hz,1H),3.39(s,3H),1.82(q,J=7.2Hz,2H),1.12(t,J=7.2Hz,3H),0.69(s,3H). 13 C10 NMR (100MHz, CHCl3) δ 135.4, 134.5, 129.6, 127.9, 107.6, 84.3, 81.8, 60.0, 57.4, 29.0, 26.1, 11.3, -2.0. HRMS: m / z (DRAT) Calculated values: ... 22 H28 NOSi + [M+NH4] + 350.1935, Measured value: 350.1934. HPLC (OD-H, n-hexane / isopropanol = 99.5 / 0.5, flow rate 0.65 mL / min), detection wavelength: 214 nm, retention time: 10.308 min (major) and 10.308 min (secondary).

[0218] I-23

[0219]

[0220] The reaction was carried out according to the general operating procedure in Example 8, and column chromatography (petroleum ether) yielded a colorless oily liquid. (65 mg, 83% yield, 98% ee). [α] D 25.0 +2.34 (c 1.30, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.65-7.64(m,4H),7.38-7.37(m,6H),5.31(s,1H),3.76-3.75(m,2H),3. 62-3.53(m,3H),1.84(p,J=7.2Hz,2H),1.24-1.23(m,6H),1.12(t,J=7.2Hz,3H),0.68(s,3H). 13 C10 NMR (100MHz, CHCl3) δ 135.4, 134.4, 129.6, 127.9, 106.9, 91.3, 83.4, 82.2, 76.9, 60.8, 28.8, 26.0, 15.1, 11.3, -2.0. HRMS: m / z (DRAT) Calculated values: ... 25 H 34 NO2Si + [M+NH4] + 408.2353, Measured value: 408.2352. HPLC (OD-H, n-hexane / isopropanol = 99.5 / 0.5, flow rate 0.65 mL / min), detection wavelength: 214 nm, retention time: 9.158 min (major) and 9.842 min (secondary).

[0221] I-24

[0222]

[0223] The reaction was carried out according to the general operating procedure in Example 8, and column chromatography (petroleum ether) yielded a colorless oily liquid. (49 mg, 67% yield, 92% ee). [α] D22.9 +48.21(c 1.3,CHCl3). 1 H NMR (400MHz, CDCl3) δ7.68-7.64(m,4H),7.45-7.36(m,6H),7.29(d,J=7.2Hz,2H),7.27-7.20(m ,3H),3.51-3.46(m,1H),2.88(t,J=7.6Hz,2H),2.25(s,1H),2.12(q,J=7.2Hz,2H),0.71(s,3H). 13 C NMR (100MHz, CDCl3) δ 140.7, 135.3, 134.5, 129.7, 128.6, 128.5, 127.9, 126.1, 106.9, 82.6, 81.5, 69.9, 37.2, 32.8, 23.7, -2.0. HRMS: m / z (DRAT) Calculated values: C 26 H 28 NSi + [M+NH4] + 382.1986, Measured value: 382.1985. HPLC (OD-H, n-hexane / isopropanol = 100 / 0, flow rate 0.65 mL / min), detection wavelength: 214 nm, retention time: 6.554 min (major) and 6.883 min (secondary).

[0224] I-25

[0225]

[0226] The reaction was carried out according to the general operating procedure in Example 8, and column chromatography (petroleum ether) yielded a colorless oily liquid. (43 mg, 61% yield, 94% ee). [α] D 26.5 +2.95 (c 1.5, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.71-7.58(m,4H),7.44-7.36(m,6H),3.61-3.48(m,3H ),2.22(d,J=2.4Hz,1H)),1.88-1.80(m,4H),1.79-1.71(m,2H),0.70(s,3H). 13 CNMR (100MHz, CDCl3) δ 135.2, 134.5, 129.6, 127.9, 106.8, 82.5, 81.5, 7, 69.8, 44.6, 34.7, 31.9, 24.2, 24.1, -2.0. HRMS: m / z (DRAT) Calculated values: C 22 H27 Si + [M+NH4] + 368.1596, Measured value: 368.1596. HPLC (OD-H, n-hexane / isopropanol = 99.5 / 0.5, flow rate 0.65 mL / min), detection wavelength: 214 nm, retention time: 11.396 min (major) and 12.892 min (secondary).

[0227] I-26

[0228]

[0229] The reaction was carried out according to the general operating procedure in Example 8, and column chromatography (petroleum ether) yielded a colorless oily liquid. (54 mg, 72% yield, 95% ee). [α] D 23.3 -1.65 (c 0.90, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.68-7.66(m,4H),7.42-7.36(m,6H),3.47-3.46(m,1H),1.84(d,J=2.4Hz,3H),1.76(q,J=6.8Hz,2H),1.58 -1.52(m,2H),1.36-1.24(m,6H),0.91-0.89(m,3H),0.70(s,3H). 13 CNMR (100MHz, CHCl3) δ 135.6, 134.5, 129.5, 127.8, 109.0, 81.0, 76.9, 36.0, 31.7, 28.7, 26.8, 24.5, 22.6, 14.1, 3.6, -1.9. HRMS: m / z (FI) Calculated values: C 25 H 30 Si + [M] + 358.2111, Measured value: 358.2105. HPLC (OD-H, n-hexane / isopropanol = 100 / 0, flow rate 0.65 mL / min), detection wavelength: 214 nm, retention time: 25.046 min (major) and 25.046 min (secondary).

[0230] I-27

[0231]

[0232] The reaction was carried out according to the general operating procedure in Example 8, and column chromatography (petroleum ether) yielded a colorless oily liquid. (67 mg, 76% yield, 90% ee). [α] D 24.8+4.58 (c 2.10, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.69-7.67(m,4H),7.46-7.45(m,2H),7.42-7.36(m,6H),7.31-7.28(m,5H),7 .23-7.19(m,3H),3.70(t,J=7.2Hz,1H),2.94(t,J=7.6Hz,2H),2.19(q,J=7.2Hz,2H),0.72(s,3H). 13 CNMR (100MHz, CHCl3) δ 140.9, 135.4, 134.5, 131.7, 129.6, 128.6, 128.5, 128.2, 128.1, 127.9, 126.1, 123.1, 107.5, 87.0, 82.4, 81.9, 37.4, 33.0, 24.6, -2.0. HRMS: m / z (FI) Calculated values: C 32 H 28 Si + [M] + 440.1955, Measured value: 440.1949. HPLC (AD-H, n-hexane / isopropanol = 99.5 / 0.5, flow rate 0.5 mL / min), detection wavelength: 214 nm, retention time: 8.908 min (major) and 9.454 min (secondary).

[0233] I-28

[0234]

[0235] The reaction was carried out according to the general operating procedure in Example 8, and column chromatography (petroleum ether) yielded a colorless oily liquid. (56 mg, 56% yield, 91% ee). [α] D 25.2 -4.10 (c 1.00, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.69-7.67(m,5H),7.66-7.35(m,11H),7.32-7.30(m,6H),7. 29-7.21(m,3H)3.74(t,J=6.8Hz,1H),2.96(t,J=7.6Hz,2H),2.21(q,J=7.2Hz,2H). 13C10 NMR (100MHz, CHCl3) δ 140.9, 135.6, 133.6, 131.7, 129.9, 128.6, 128.5, 128.2, 128.1, 127.9, 126.1, 123.1, 109.0, 86.9, 82.0, 81.3, 37.4, 33.1, 24.7. HRMS: m / z (FI) Calculated values: C10 37 H 30 Si + [M] + :502.2111, Measured value: 502.2105. HPLC (AD-H, n-hexane / isopropanol = 99.5 / 0.5, flow rate 0.5 mL / min), detection wavelength: 214 nm, retention time: 9.450 min (scan) and 9.937 min (major).

[0236] I-29

[0237]

[0238] The reaction was carried out according to the general operating procedure in Example 8, and column chromatography (petroleum ether) yielded a colorless oily liquid. (33 mg, 44% yield, 95% ee). [α] D 25.1 +1.32 (c 0.50, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.69-7.67(m,4H),7.43-7.35(m,7H),7.21-7.15(m,2H),7.14-7.11(m,1 H),3.73(t,J=6.4Hz,1H),2.45(s,3H),1.97-1.90(m,2H),1.20(t,J=7.2Hz,3H),0.71(s,3H). 13 C10 NMR (100MHz, CHCl3) δ 140.3, 135.5, 134.5, 131.9, 129.6, 129.3, 128.0, 127.9, 125.4, 123.0, 108.1, 91.3, 81.7, 80.5, 29.3, 26.8, 20.6, 11.4, -1.9. HRMS: m / z (EI) Calculated values: ... 27 H 26 Si + [M] + 378.1798, Measured value: 378.1796. HPLC (OD-H, n-hexane / isopropanol = 99.5 / 0.5, flow rate 0.65 mL / min), detection wavelength: 214 nm, retention time: 8.633 min (major) and 9.507 min (secondary).

[0239] I-30

[0240]

[0241] The reaction was carried out according to the general operating procedure in Example 8, and column chromatography (petroleum ether) yielded a colorless oily liquid. (55 mg, 65% yield, 94% ee). [α] D 24.3 -3.02 (c 1.4, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.69-7.65(m,4H),7.41-7.30(m,10H),3.66(t,J=6.8Hz ,1H),1.90(p,J=7.2Hz,2H),1.31(s,9H),1.16(t,J=7.2Hz,3H),0.69(s,3H). 13 CNMR (101MHz, CDCl3) δ 135.6, 134.5, 131.4, 129.6, 127.9, 125.2, 120.2, 108.1, 86.5, 81.7, 81.6, 34.7, 31.2, 29.7, 29.3, 26.7, 11.4. HRMS: m / z (EI) Calculated values: C 30 H 32 Si + [M] + 420.2268, Measured value: 420.2269. HPLC (OD-H, n-hexane / isopropanol = 100 / 0, flow rate 0.65 mL / min), detection wavelength: 214 nm, retention time: 26.358 min (major) and 37.508 min (secondary).

[0242] I-31

[0243]

[0244] The reaction was carried out according to the general operating procedure in Example 8, and column chromatography (petroleum ether) yielded a colorless oily liquid. (55 mg, 65% yield, 94% ee). [α] D 23.4 +1.70 (c 0.9, CHCl3). 1H NMRδ7.68-7.67(m,4H),7.39 -7.38(m,6H),7.22(t,J=8.0Hz,1H),7.06-7.05(m,1H),7.01-6.95(m,1H),6.87(dd,J=8.4,2.4Hz, 1H), 3.81 (s, 3H), 3.68 (t, J = 6.4Hz, 1H), 1.92 (q, J = 7.2Hz, 2H), 1.18 (t, J = 7.4Hz, 3H), 0.71 (s, 3H). 13 C NMR (100MHz, CDCl3) δ 159.3, 135.5, 134.5, 129.6, 129.2, 127.9, 124.3, 124.2, 116.5, 114.7, 107.7, 87.1, 81.9, 81.4, 55.2, 29.2, 26.7, 11.4, -2.0. HRMS: m / z (DART) Calculated values: C 27 H 27 OSi + [M+H] + 395.1826, Measured value: 395.1824. HPLC (OD-H, n-hexane / isopropanol = 98 / 2, flow rate 0.65 mL / min), detection wavelength: 214 nm, retention time: 7.358 min (major) and 7.975 min (secondary).

[0245] I-32

[0246]

[0247] The reaction was carried out according to the general operating procedure in Example 8, and column chromatography (petroleum ether) yielded a colorless oily liquid. (63 mg, 76% yield, 96% ee). [α] D 25.7 +2.68 (c 0.72, CHCl3). 1 H NMR(400MHz, CDCl3)δ7.97(s,1H),7.82-7.76(m,3H),7.69-7.67(m,4H),7.51-7.47(m,3H),7.40 -7.36(m,6H),3.73(t,J=6.8Hz,1H),1.96(q,J=7.2Hz,2H),1.21(t,J=7.2Hz,3H),0.72(s,3H). 13C NMR (100MHz, CDCl3) δ 135.6, 134.5, 133.0, 132.7, 131.5, 129.6, 128.6, 127.9, 127.8, 127.7, 127.7, 126.5, 126.4, 120.6, 107.9, 87.6, 82.0, 81.9, 29.7, 29.3, 26.8, 11.4, -2.0. HRMS: m / z (FI) Calculated values: C 30 H 26 Si + [M] + 414.1798, Measured value: 414.1805. HPLC (OD-H, n-hexane / isopropanol = 99.5 / 0.5, flow rate 0.65 mL / min), detection wavelength: 214 nm, retention time: 12.846 min (major) and 17.196 min (secondary).

[0248] I-33

[0249]

[0250] The reaction was carried out according to the general operating procedure in Example 8, and column chromatography (petroleum ether) yielded a colorless oily liquid. (47 mg, 64% yield, 96% ee). [α] D 24.8 +1.26 (c 0.8, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.70-7.63(m,4H),7.41-7.34(m,6H),7.25-7.17(m,2H),6.96(dd,J=5.2 ,3.6Hz,1H),3.70(t,J=6.0Hz,1H),1.90(q,J=7.2Hz,2H),1.17(t,J=7.2Hz,3H),0.70(s,3H). 13 C10 NMR (100MHz, CHCl3) δ 135.5, 134.5, 131.8, 129.6, 127.9, 126.8, 126.6, 123.3, 107.3, 91.1, 82.2, 74.8, 29.1, 26.9, 11.4, -1.9. HRMS: m / z (DART) Calculated values: ... 24 H 23 SSi + [M+H] +371.1284, Measured value: 371.1282. HPLC (OD-H, n-hexane / isopropanol = 99.5 / 0.5, flow rate 0.65 mL / min), detection wavelength: 214 nm, retention time: 10.208 min (major) and 12.296 min (secondary).

[0251] I-34

[0252]

[0253] The reaction was carried out according to the general operating procedure in Example 8, and column chromatography (petroleum ether) yielded a colorless oily liquid. (76 mg, 78% yield, 96% ee). [α] D 24.8 +1.26 (c 0.8, CHCl3). [α] D 25.2 -0.33 (c 1.60, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.69 -7.67(m,4H),7.58 -7.55(m,4H),7.43-7.36(m,6H),3.76(p,J=7.2,1H),1.92 -1.88(m,2H),1.65-1.63(m,2H),1.39-1.28(m,6H),0.92(q,J=7.2,3H),0.72(s,3H). 13 C NMR (100MHz, CHCl3) δ135.4,134.5,131.9,129.6,127.9,125.1(q),107.3,90.2,82.2,80.2,35.6,31.7,28.7,26.9,25.2,22.6,14.1,-2.0. 19 F NMR (376MHz, CDCl3) δ -62.8. HRMS: m / z (FI) Calculated value: C 31 H 31 F3Si + [M] + 488.2142, Measured value: 488.2146. HPLC (OD-H, n-hexane / isopropanol = 100 / 0, flow rate 0.65 mL / min), detection wavelength: 214 nm, retention time: 21.983 min (major) and 29.767 min (secondary).

[0254] I-35

[0255]

[0256] The reaction was carried out according to the general operating procedure in Example 8, and column chromatography (petroleum ether) yielded a colorless oily liquid. (47 mg, 60% yield, 92% ee). [α] D 28.1 -3.26 (c 0.6, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.69-7.67(m,2H),7.41-7.34(m 3H),7.33(d,J=8.0Hz,2H),7.28-7.26(m,2H),7.17 -7.12(m,4H),3.63(t,J=7.2Hz,1H),2.89(t,J=7.6Hz,2H),2.37(s,3H),2.13(q,J=7.2Hz,2H),0.45(s,6H). 13 C10 NMR (100MHz, CHCl3) δ 139.4, 138.2, 137.1, 133.7, 131.8, 131.6, 123.0, 129.4, 129.0, 128.5, 127.9, 119.9, 105.7, 86.1, 84.1, 82.0, 37.3, 32.3, 24.3, 21.5, -0.8. HRMS: m / z (FI) Calculated values: C10 28 H 27 Si + [M] + 426.1565, Measured value: 426.1570. HPLC (AD-H, n-hexane / isopropanol = 99.5 / 0.5, flow rate 0.65 mL / min), detection wavelength: 214 nm, retention time: 7.942 min (major) and 12.196 min (secondary).

[0257] I-36

[0258]

[0259] The reaction was carried out according to the general operating procedure in Example 8, and column chromatography (petroleum ether / ethyl acetate) yielded a colorless oily liquid. (55 mg, 74% yield, 86% ee). [α] D 23.3 +1.51 (c 0.6, CHCl3). 1 H NMR (400MHz, CDCl3) δ9.23 (s, 1H), 9.18 (s, 2H), 4.70-4.63 (m, 2H), 3.67 (d, J = 6.8Hz, 1H), 2.29–2.24 (m, 3H), 0.16 (s, 9H). 13C NMR (100MHz, CDCl3) δ 162.4, 148.7, 133.8, 129.5, 122.5, 101.5, 87.3, 81.0, 70.4, 64.0, 34.1, 21.4, -0.1. HRMS: m / z (FI) Calculated values: C 17 H 18 N2O6Si + [M] + 374.0929, Measured value: 374.0932. HPLC (OD-H, n-hexane / isopropanol = 70 / 30, flow rate 1.0 mL / min), detection wavelength: 214 nm, retention time: 11.921 min (major) and 18.796 min (secondary).

[0260] The single-crystal structure data of compound I-36 are shown in Table 5, and the molecular ellipsoid of the compound is shown in Table 5. Figure 1 As shown.

[0261] Table 5: I-36 Single Crystal Structure Data

[0262]

[0263]

[0264] I-37

[0265]

[0266] The reaction was carried out according to the general operating procedure in Example 8, and column chromatography (petroleum ether / ethyl acetate) yielded a colorless oily liquid. (54 mg, 52% yield, 90% ee). [α] D 23.5 +9.48 (c 1.1, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.67-7.54(m,6H),7.40-7.29(m,9H),4.35(t,J=6.4Hz,2H),3.63 -3.60(m,1H),3.18(t,J=7.2Hz,2H),2.92(t,J=7.6Hz,2H),2.19(d,J=2.8Hz,1H),2.11(q,J=6.8Hz,2H),0.41(s,6H). 13C NMR (100MHz, CDCl3) δ 171.7, 161.6, 145.4, 136.8, 135.2, 133.6, 132.4, 129.4, 129.0, 128.6, 128.5, 128.4, 128.0, 127.89, 127.86, 126.5, 104.0, 84.6, 80.8, 70.1, 61.7, 34.5, 31.0, 23.5, 21.2, -0.9. HRMS: m / z (ESI) Calculated values: C 33 H 32 NO3Si + [M+H] + 518.2146, Measured value: 518.2138. HPLC (OD-H, n-hexane / isopropanol = 95 / 5, flow rate 0.65 mL / min), detection wavelength: 214 nm, retention time: 5.554 min (major) and 6.054 min (secondary).

[0267] I-38

[0268]

[0269] The reaction was carried out according to the general operating procedure in Example 8, and column chromatography (petroleum ether / ethyl acetate) yielded a colorless oily liquid. (67 mg, 67% yield, 99% ee). [α] D 26.1 -6.55 (c 3.30, CHCl3). 1 H NMR(400MHz,CDCl3)δ7.65-7.64(m,2H),7.45 -7.44(m,5H),7.39-7.38(m,3H),4.41(t,J=6.0Hz,2H),4.15-4.05(m,4H),3.83(t ,J=7.2Hz,1H),3.36-3.29(m,1H),2.20(q,J=6.4Hz,2H),1.44(s,9H),0.44(s,6H). 13 C10 NMR (100MHz, CHCl3) δ 172.3, 156.0, 136.8, 133.6, 131.7, 129.4, 128.3, 128.2, 127.9, 122.7, 104.3, 85.9, 84.5, 82.0, 79.8, 62.3, 34.5, 32.0, 28.3, 22.0, -0.9. HRMS: m / z (FI) Calculated values: C10 30 H 35 NO4Si + [M] +502.2408, Measured value: 502.2399. HPLC (OD-H, n-hexane / isopropanol = 90 / 10, flow rate 0.65 mL / min), detection wavelength: 214 nm, retention time: 11.196 min (scan) and 12.033 min (major).

[0270] I-39

[0271]

[0272] The reaction was carried out according to the general operating procedure in Example 8, and column chromatography (petroleum ether / ethyl acetate) yielded a colorless oily liquid. (81 mg, 81% yield, 82% ee). [α] D 26.0 -14.27 (c 2.70, CHCl3). 1 H NMR (400MHz, CDCl3) δ8.06 (d, J = 8.8Hz, 1H), 7.66-7.60 (m, 4H), 7.43-7.37 (m, 5H), 7.30 -7.29(m,3H),4.68(t,J=6.4Hz,2H),3.94(t,J=7.2Hz,1H),2.36(q,J=6.8Hz,2H),0.43(s,6H). 13 C NMR (100MHz, CHCl3) δ 163.7, 148.6, 142.2, 139.0, 136.8, 133.63, 133.58, 131.74, 131.69, 129.4, 128.2, 128.2, 127.8, 127.8, 124.1, 122.7, 104.5, 86.0, 84.5, 82.0, 63.3, 34.5, 22.2, -0.9. HRMS: m / z (FI) Calculated values: C 27 H 24 BrNO2Si + [M] + 501.0754, Measured value: 501.0747. HPLC (OD-H, n-hexane / isopropanol = 90 / 10, flow rate 0.65 mL / min), detection wavelength: 214 nm, retention time: 17.050 min (scan) and 21.267 min (major).

[0273] Example 9: Synthesis of thromboxane synthase inhibitor CGS23305

[0274]

[0275] The procedure was performed according to the general steps described in Example 8, using II-3 (310 mg, 1.0 mmol), and column chromatography (petroleum ether / ethyl acetate) was used to obtain a colorless oily liquid IV (344 mg, 61% yield, 90% ee). [α] D 29.1 -0.96 (c 0.8, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.80 (d, J = 8.4H, 2H), 7.63-7.61 (m, 4H), 7.44 (d, J = 8.4H, 2H), 7.40 -7.35(m,6H),5.02(s(br),1H),3.69(s,3H),3.57(t,J=6.8Hz,1H),3.10(q,J=6.4Hz,2H ),2.56(t,J=7.2Hz,2H),2.36(td,J=6.4,4.4Hz,2H),2.05(q,J=6.8Hz,2H),0.69(s,3H). 13 C NMR (100MHz, CDCl3) δ 173.3, 139.1, 138.6, 135.0, 134.4, 129.7, 129.4, 128.4, 127.9, 106.6, 82.7, 79.5, 78.1, 51.8, 41.8, 31.0, 30.5, 23.8, 20.1, -2.1. HRMS: m / z (ESI) Calculated values: C 30 H 31 O4NClSSi + [M+H] + 564.1426, Measured value: 564.1422. HPLC (OD-H, n-hexane / isopropanol = 99.5 / 0.5, flow rate 0.65 mL / min) Detection wavelength: 214 nm Retention time: 17.375 min (semi) and 22.329 min (major).

[0276] A stir bar was placed in a 10 mL three-necked flask, and compound IV (112 mg, 0.2 mmol, 1.0 equiv.) was added and dissolved in methanol (1.0 mL). Pd / C (11.2 mg, 10 wt%) was then added, and the mixture was stirred for 24 hours under a hydrogen atmosphere. After the reaction was complete, the resulting solution was filtered, and the filtrate was concentrated under vacuum to obtain the crude product.

[0277] The crude product was transferred to a 10 mL three-necked flask, and 1 mL of dichloromethane was added. The mixture was stirred at 0 °C for 5 minutes. HBF4·Et2O (0.05 mL, 50% diethyl ether solution, 0.4 mmol) was slowly added dropwise at 0 °C. After the addition was complete, the mixture was stirred at this temperature for another 30 minutes. The reaction was quenched with 2.0 mL of saturated NaOH solution, and the aqueous phase was extracted with 2 mL × 3 of dichloromethane. The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the crude product. This crude product was then dissolved in a mixed solvent of tetrahydrofuran (0.5 mL) and methanol (0.5 mL), and NaHCO3 (100 mg, 1.2 mmol), KF (6.9 mg, 1.2 mmol), and 30% H2O2 aqueous solution (0.4 mL, 30%, 4.0 mmol) were added sequentially at 0 °C. The reaction mixture was then stirred at 30 °C for 1.5 hours. The reaction was quenched at 0 °C with saturated Na₂SO₃ solution (1.0 mL) and extracted with ethyl acetate (2 mL × 3). The combined organic phases were washed with saturated brine (2 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (5:1) as eluent to give alcohol V (64 mg, 82% - 90%) as a colorless solid. [α] D 29.3 -0.99 (c0.8, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.80(d,J=8.0Hz,2H),7.49(d,J=8.0Hz,2H),4.79(t,J=6.0Hz,1H),3.45(s,5H), 2.94(q,J=6.8Hz,2H),2.29(t,J=7.6Hz,2H),1.62-1.52(m,2H),1.50-1.44(m,4H).1.29-1.25(m,5H). 13 C NMR (100MHz, CDCl3) δ 174.4, 139.0, 138.6, 129.4, 128.5, 60.6, 51.6, 43.0, 36.1, 33.6, 32.7, 31.3, 29.6, 28.4, 23.2. HRMS: m / z (ESI) Calculated values: C 17 H 27 O5NClS + [M+H] + 392.1293, Measured value: 392.1288. HPLC (IC, n-hexane / isopropanol = 80 / 20, flow rate 0.65 mL / min) Detection wavelength: 214 nm, retention times: 40.983 min (semi) and 43.513 min (major).

[0278] Among them, the thromboxane synthase inhibitor CGS23305 can be synthesized from alcohol V according to the literature (J.Med.Chem.1992,35,4373).

[0279] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A chiral 1,4-diynic compound, characterized in that, The compound has a structure shown in formula I: in which R 1 is C1-C 20 alkyl, C1-C 1-1 alkyl substituted by 1, 2 or 3 R 20 , C6-C 10 aryl or C6-C 1-2 aryl substituted by 1, 2 or 3 R 10 , C1-C 20 alkyl containing heteroatoms, C4-C 10 heteroaryl or C4-C 10 heteroaryl substituted by 1, 2 or 3 alkyl; R 1-1 independently halogen, hydroxyl, -O-CO-R 1-1-1 , -COOCH3, C6-C 10 aryl, C6-C 1-1-3 substituted C6-C 10 aryl, substituted or unsubstituted "heteroatom selected from 1, 2 or 3 of N, O and S, 1, 2 or 3 of the number of heteroatoms, 5-10 membered heteroaryl", C3-C8cycloalkyl, -OTBS; wherein the substitution means that one or more H on the heteroaryl is substituted by a group selected from the group consisting of C1-C6alkyl; R 1-1-1 is alkyl or -(CH2) n R 1-1-1-a ; n is 0, 1, 2, 3, 4 or 5; R 1-1-1-a substituted or unsubstituted C6-C 10 aryl, terminal olefin, terminal alkyne, "5-10 membered heteroaryl having 1, 2, or 3 kinds of heteroatoms selected from the group consisting of N, O, and S, and having 1, 2, or 3 numbers of heteroatoms", "5-10 membered heteroaryl having 1, 2, or 3 kinds of heteroatoms selected from the group consisting of N, O, and S, and having 1, 2, or 3 numbers of heteroatoms, substituted with 1, 2, or 3 groups", "5-10 membered heteroaryl having 1, 2, or 3 kinds of heteroatoms selected from the group consisting of N, O, and S, and having 1, 2, or 3 numbers of heteroatoms, substituted with 1, 2, or 3 groups, wherein the groups are selected from the group consisting of nitro, phenyl, halogen, and the like", and the like. wherein, the substitution means that one or more H on the aryl or heteroaryl is replaced by a group selected from the group consisting of nitro, phenyl, halogen, and the like. R 1-1-3 is alkyl, halogen, C1-C3haloalkyl; R 1-2 halogen, C1-C 20 alkyl, trifluoromethyl; R 2 For H, C1-C 20 Alkyl group, with one, two or three R radicals 2-1 Replacement C1-C 20 Alkyl, C3-C6 cycloalkyl, C6-C 10 The aryl group may be surrounded by one, two, or three R groups. 2-2 Replacement C6-C 10 Aryl, C1-C containing heteroatoms 20 Alkyl alkanes, C6-C 10 Heteroaryl groups or 1, 2 or 3 R groups 2-3 Replacement C6-C 10 Mixed aromatics; R 2-1 independently C6-C 10 aryl, halogen, C1-C6alkyl substituted with 1, 2, or 3 R 2-1-1 substituted C6-C 10 aryl, "5-10 membered heteroaryl with 1, 2, or 3 heteroatoms selected from N, O, and S, the number of heteroatoms being 1, 2, or 3", C3-C8cycloalkyl; -OCH3, -CH(OCH2CH3)2; R 2-1-1 is C1-C 20 alkyl, trifluoromethyl, -OCH3; R 2-2 and R 2-3 each independently is C1-C 20 alkyl, C1-C6alkoxy, trifluoromethyl; [Si] is 1, 2 or 3 C1-C 20 alkyl or 1, 2 or 3 C6-C 10 aryl.

2. The compound of claim 1, wherein The R 1 For C1-C 20 Alkyl group, with one, two or three R radicals 1-1 Replacement C1-C 20 alkyl; R 1-1 independently halogen, hydroxyl, -O-CO-R 1-1-1 , C6-C 10 aryl, C6-C 1-1-3 aryl substituted with 1, 2 or 3 R 10 , 5-10 membered heteroaryl substituted or unsubstituted "heteroatoms selected from 1, 2 or 3 of N, O and S, number of heteroatoms is 1, 2 or 3", C3-C8 cycloalkyl, -OTBS; wherein the substitution means that one or more H on the heteroaryl is substituted with a group selected from the group consisting of C1-C6 alkyl; R 1-1-1 is alkyl or -(CH2) n R 1-1-1-a ; n is 0, 1, 2, 3, 4 or 5; R 1-1-3 is alkyl, halogen, C1-C3haloalkyl; R 1-1-1-a substituted or unsubstituted C6-C 10 aryl, terminal olefin, terminal alkyne, "5-10 membered heteroaryl having 1, 2, or 3 kinds of heteroatoms selected from the group consisting of N, O, and S, and having 1, 2, or 3 numbers of heteroatoms", "5-10 membered heteroaryl having 1, 2, or 3 kinds of heteroatoms selected from the group consisting of N, O, and S, and having 1, 2, or 3 numbers of heteroatoms, substituted with 1, 2, or 3 groups", wherein the substitution means that 1 or more H on the aryl or heteroaryl is replaced with a group selected from the group consisting of nitro, phenyl, halogen.

3. The compound of claim 1, wherein The R 2 For H, C1-C 20 Alkyl group, with one, two or three R radicals 2-1 Replacement C1-C 20 Alkyl, C3-C6 cycloalkyl, C6-C 10 The aryl group may be surrounded by one, two, or three R groups. 2-2 Replacement C6-C 10 Aryl, C6-C 10 Mixed aromatics; R 2-1 independently halogen, C1-C6alkoxy, -CH(OCH2CH3)2; R 2-2 is C1-C 20 alkyl, C1-C6alkoxy, trifluoromethyl.

4. The compound of claim 1, wherein The compound shown in formula I has a structure selected from the group consisting of:

5. A method for preparing a chiral 1,4-diyne compound as described in claim 1, characterized in that, The method comprises the step of: in the presence of a copper catalyst, a bisoxazoline ligand and an oxidant, reacting a compound containing fragment II and a compound containing fragment III in a solvent to obtain a chiral 1,4-diyn compound shown in formula I; The bisoxazoline ligand is: R 3 is phenyl or hydrogen; R 4 independently C1-C6alkyl, is hydrogen, Ar is C6-C 10 aryl, "heteroatoms selected from N, O and S, 1, 2 or 3 of which are heteroatoms, 5-15 membered heteroaryl having 1, 2 or 3 heteroatoms" or "heteroatoms selected from N, O and S, 1, 2 or 3 of which are heteroatoms, 5-15 membered heteroaryl having 1, 2 or 3 heteroatoms" substituted with 1, 2 or 3 R 4-1 substituted C6-C 10 aryl, "heteroatoms selected from N, O and S, 1, 2 or 3 of which are heteroatoms, 5-15 membered heteroaryl having 1, 2 or 3 heteroatoms" or "heteroatoms selected from N, O and S, 1, 2 or 3 of which are heteroatoms, 5-15 membered heteroaryl having 1, 2 or 3 heteroatoms" substituted with 1, 2 or 3 R 4-2 substituted "heteroatoms selected from N, O and S, 1, 2 or 3 of which are heteroatoms, 5-15 membered heteroaryl having 1, 2 or 3 heteroatoms"; R 4-1 independently C1-C6alkyl, halogen, or C1-C6alkoxy; R 4-2 independently C1-C6alkyl; R 5 independently C1-C6alkyl, hydrogen; Ar is C6-C 10 aryl, C6-C 5-1 substituted C6-C 10 aryl, "5-15 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, or 3 substituents" or "5-15 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, or 3 substituents" substituted with 1, 2, or 3 R 5-2 substituted "5-15 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, or 3 substituents"; R 5-1 independently C1-C6alkyl, halogen, or C1-C6alkoxy; R 5-2 independently C1-C6alkyl; R 6 independently C1-C6alkyl, is hydrogen, Ar is C6-C 10 aryl, C6-C 6-1 substituted C6-C 10 aryl, "5-15 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, the number of heteroatoms being 1, 2, or 3" substituted with 1, 2, or 3 R 6-2 substituted "5-15 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, the number of heteroatoms being 1, 2, or 3"; R 6-1 independently C1-C6alkyl, halogen, or C1-C6alkoxy; R 6-2 independently C1-C6alkyl; R 7 independently C1-C6alkyl, is hydrogen, Ar is C6-C 10 aryl, "heteroatoms selected from N, O, and S, 1, 2, or 3 in number, 5-15 membered heteroaryl, 1, 2, or 3 in number of heteroatoms" substituted with 1, 2, or 3 R 7-1 substituted C6-C 10 aryl, "heteroatoms selected from N, O, and S, 1, 2, or 3 in number, 5-15 membered heteroaryl, 1, 2, or 3 in number of heteroatoms" substituted with 1, 2, or 3 R 7-2 substituted "heteroatoms selected from N, O, and S, 1, 2, or 3 in number, 5-15 membered heteroaryl, 1, 2, or 3 in number of heteroatoms"; R 7-1 independently C1-C6alkyl, halogen, or C1-C6alkoxy; R 7-2 independently C1-C6alkyl; wherein R 1 and R 2 are as defined in claim 1.

6. The method of claim 5, wherein, The compound containing Fragment II is a compound of Formula II: The R 1 As in claim 1.

7. The method of claim 5, wherein, The compound containing fragment III is a compound shown in formula III, wherein the compound shown in formula III is any one compound selected from the group consisting of: Preferably:

8. The method of claim 5, wherein, The copper catalyst is selected from one or more of the group consisting of cuprous acetate, cuprous iodide, copper tetrafluoroborate tetraacetonitrile, copper bis(acetylacetone) and cuprous chloride; preferably cuprous acetate and cuprous chloride.

9. The method of claim 5, wherein, The molar ratio of the bisoxazoline ligand to the compound containing fragment II is (0.01-0.75):

1.

10. The method of claim 5, wherein, The molar ratio of the compound containing fragment III to the compound containing fragment II is (1.0-100):1, and further preferably (2.5-10):1.

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