Preparation method of chiral propargyl substituted aldehyde compound

Abstract

The invention discloses a preparation method of chiral propargyl substituted aldehyde compounds in the technical field of organic synthesis, which comprises the following steps: reacting propargyl acetate with aldehyde in a catalytic system of alkali, a palladium catalyst and a chiral ligand, and preparing a series of chiral propargyl substituted aldehyde compounds in a sealed tube in an inert argon environment; in the preparation method disclosed by the invention, the raw materials used in the reaction system, such as propargyl acetate and aldehyde, can be prepared by a simple method. According to the reaction, through continuous palladium catalytic oxidation addition, olefin migration insertion and reduction elimination, the chiral propargyl substituted aldehyde compound can be obtained through one-step conversion. The preparation method has the advantages of mild reaction conditions, wide substrate expansion range, simple preparation operation and the like; the chiral thiourea small-molecule catalyst can be converted into a series of important heterocyclic compounds and has important significance, and the chiral thiourea small-molecule catalyst can be further applied to asymmetric catalytic reaction and has excellent enantioselectivity.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for preparing chiral propargyl-substituted aldehyde compounds. Background Technology

[0002] Chiral all-carbon and quaternary carbon structural units are widely found in natural products, drug molecules, and organic materials. Due to the inherent steric hindrance of their tetrasubstituted stereocenters, the asymmetric catalytic construction of all-carbon and quaternary carbon chiral centers has always been an important research topic in organic synthetic chemistry. Furthermore, the α-position functionalization reaction of carbonyl compounds is one of the most effective and direct methods among these research areas.

[0003] The carbonyl group is one of the most important and multifunctional functional groups in organic synthesis. Carbonyl groups play a vital role in living organisms; for example, many important biomolecules in our bodies, such as glucose, ribose, and deoxyribose, all contain carbonyl groups. In the food and pharmaceutical industries, carbonyl groups have many important applications, such as formaldehyde and acetaldehyde, widely used as disinfectants and preservatives; the antitumor drug 5-azacytidine; and the chemotherapy drug topotecan hydrochloride. Drugs and natural products with carbonyl functional groups include:

[0004]

[0005] Since 1998, research groups have reported Pd-catalyzed α-arylation of cyclic ketones [(a) J. Åhman, JP Wolfe, MV Troutman, M. Palucki, SL Buchwald, J. Am. Chem. Soc. 1998, 120, 1918; (b) T. Hamada, A. Chieffi, J. Åhman, SL Buchwald, J. Am. Chem. Soc. 2002, 124, 1261; (c) X. Liao, Z. Weng, JF Hartwig, J. Am. Chem. Soc. 2008, 130, 195]. This approach has been widely extended to the α-arylation of other cyclic carbonyl compounds, such as lactones and lactams [(a) DJ Spielvogel, SL Buchwald, J. Am. Chem. Soc. 2002, 124, 195]. 3500; (b)AM Taylor, RA Altman, SL Buchwald, J. Am. Chem. Soc. 2009, 131,9900; (c) CI Jette, I. Geibel, S. Bachman, M. Hayashi, S. Sakurai, H.Shimizu, JB Morgan, BM Stoltz, Angew. Chem. Int. Ed. 2019, 58, 4297].

[0006] In 2018, Professor Wenjun Tang's research group in the Department of Organic Chemistry at Shanghai Jiao Tong University successfully achieved the asymmetric α-arylation reaction of cyclic ketones using a chiral monophosphine ligand developed by their group, Pd(OAc)₂ as a catalyst, and toluene as a solvent. They were able to obtain cyclic ketone compounds with all-carbon quaternary carbon chiral centers with excellent enantioselectivity (X. Rao, N. Li, H. Bai, C. Dai, Z. Wang, W. Tang. Angew. Chem. Int. Ed. 2018, 57, 12328). The specific reaction formula is as follows:

[0007]

[0008] In 2008, Stephen L. Buchwald's research group at MIT reported the first metal-catalyzed asymmetric α-arylation reaction of aldehydes, yielding a series of cyclic aldehydes with quaternary carbon chiral centers in high yield and with high enantioselectivity (J. Garca-Fortanet, SL Buchwald. Angew. Chem. 2008, 120, 8228); the specific reaction formula is as follows:

[0009]

[0010] Despite significant progress in the asymmetric α-arylation of cyclic ketones, lactones, and lactams, the enantioselective α-arylation of acyclic carbonyl compounds lags far behind due to the in-situ generation of Z / E enol intermediates leading to opposite enantiomers. In 2021, Professor Junliang Zhang's research group at Fudan University successfully achieved palladium-catalyzed asymmetric α-arylation of α-alkyl-α-aryl disubstituted aldehydes with aryl bromides using their Sadphos chiral ligand. This reaction provides an efficient and mild route to obtain aldehydes with all-carbon quaternary carbon chiral centers, yielding the corresponding aldehydes with excellent yields and enantioselectivity (Z. Pan, W. Li, S. Zhu, F. Liu, H.-H. Wu, J. Zhang.Angew. Chem. Int. Ed. 2021, 60, 18542); the specific reaction formula is as follows:

[0011]

[0012] The asymmetric α-functionalization of acyclic aldehydes has been a long-standing challenge due to the high reactivity of carbonyl compounds, leading to various competing side reactions. Furthermore, palladium-catalyzed asymmetric α-propynylation of carbonyl groups has not yet been achieved. Therefore, palladium-catalyzed asymmetric α-propynylation of aldehydes presents a significant challenge. To further explore synthetic strategies for aldehydes with chiral all-carbon quaternary carbon centers of great importance, this patent aims to achieve the synthesis of a series of structurally diverse aldehydes with high enantioselectivity through the synergistic regulation of chiral ligands, metal catalysts, and solvents. Summary of the Invention

[0013] To address the shortcomings of existing technologies for preparing chiral propargyl-substituted aldehyde compounds, this invention provides a method for preparing chiral propargyl-substituted aldehyde compounds. The chiral propargyl-substituted aldehyde compounds are generated by using an easily prepared aldehyde compound and propargyl acetate. These compounds possess potential biological and pharmacological activities, further laying a solid foundation for the screening of bioactive molecular drugs.

[0014] The objective of this invention is achieved as follows: a method for preparing a chiral propargyl-substituted aldehyde compound, characterized by comprising:

[0015] Under argon conditions, a one-pot propargylation reaction of aldehydes with propargyl acetate was catalyzed using a catalytic condition consisting of a base, a palladium catalyst, and a chiral ligand. Chiral propargyl-substituted aldehyde compounds were prepared in a sealed tube under an inert argon atmosphere. The compounds shown in Formula I and Formula II were both reacted in an organic solvent. The chiral propargyl-substituted aldehyde compounds prepared are shown in Formula III.

[0016]

[0017] R 1 Substituents are selected from Where R = H, Ph, i Pr, t Bu, OMe, F, Cl, CF3, CN, COOMe, , , , ;R 2 , R 3 Substituents are selected from Me, , , , ;R 4 Substituents are selected from , , , H, Me, t Bu, Ph, OMe, F, Cl; R 5 The substituents are selected from Me, Et, and Bn.

[0018] Further, the specific steps are as follows:

[0019] Step 1) In the deoxygenated and dehydrated tube, add propargyl acetate, aldehyde, base, palladium catalyst and chiral ligand. The amount of solvent added should meet the requirement that the molar concentration of aldehyde is 0.1-0.2 mol / L. Then place the tube in the module and heat it.

[0020] Step 2: After the reaction is complete, the chiral propargyl substituted aldehyde compound is obtained by separation and purification using column chromatography.

[0021] Furthermore, the molar ratio of the compound shown in Formula I to the compound shown in Formula II, the base, the palladium catalyst, and the chiral ligand is 1:1~2:1.5~2.5:0.02~0.06:0.02~0.08.

[0022] Furthermore, the alkali is selected from one or more of potassium tert-butoxide, lithium tert-butyl, potassium carbonate, sodium carbonate, and cesium carbonate.

[0023] Furthermore, the palladium catalyst is one or more of the following: allyl palladium chloride dimer, tris(dibenzylidene acetone) dipalladium, (2,2'-bipyridine) palladium dichloride, palladium acetate, 1,5-cyclooctadiene palladium dichloride, and tris(dibenzylidene acetone) dipalladium chloroform adduct.

[0024] Furthermore, the chiral ligand is one or more of L1, L2, L3, L4, L5, L6, L7, L8, and L9;

[0025] .

[0026] Furthermore, the organic solvent used in the reaction is selected from one or more of toluene, cyclohexane, mesitylene, acetonitrile, 1,2-dichloroethane, tert-butyl methyl ether, and ethanol.

[0027] Furthermore, the reaction is carried out in the following order: first, palladium catalyst, chiral ligand and organic solvent are added and stirred for 30 ± 5 min, then the compound shown in Formula I, the compound shown in Formula II and the base are added, and then the reaction is carried out in a deoxygenation process.

[0028] Furthermore, the reaction temperature in step 1) is 40-90°C. o C, the reaction time is 15-48 h.

[0029] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0030] Starting from readily available aldehydes (compounds shown in Formula I) and propargyl acetate (compounds shown in Formula II), a novel chiral propargyl-substituted aldehyde compound was synthesized via a palladium-catalyzed one-pot reaction to construct CC, representing a groundbreaking achievement. The preparation method disclosed in this invention is highly efficient, has a broad substrate scope, and the resulting chiral propargyl-substituted aldehyde compounds possess potential biological and pharmacological activities, laying a solid foundation for further screening of bioactive molecular drugs. Detailed Implementation

[0031] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0032] In the following examples, except for compounds I and II, all were commercially available (palladium dichloride, 1,5-cyclooctadiene palladium dichloride, cesium carbonate, (2,2'-bipyridine) palladium dichloride, and tert-butyl methyl ether were from Anhui Zesheng Technology Co., Ltd.

[0033] The preparation method of compound I can be found in Z. Pan, W. Li, S. Zhu, F. Liu, H.-H. Wu, J. Zhang. Angew. Chem. Int. Ed. 2021, 60, 18542.

[0034] The preparation method of compound II can be found in Jiao, Z.; Shi, Q.; Zhou, JS Angew. Chem., Int. Ed. 2017, 56, 14567.

[0035] Example 1

[0036] Preparation: (S)-5-(4-methoxyphenyl)-2,3,3-trimethyl-2-phenylpent-4-enal

[0037] ;

[0038] Method 1: In a 10 mL sealed tube, first add (2,2'-bipyridine)palladium dichloride (0.012 mmol, 4.0 mg), L9 (0.015 mmol, 14.0 mg), and tert-butyl methyl ether (2.0 mL). After stirring for 30 min, add cesium carbonate (0.6 mmol, 195.5 mg), 2-phenylpropanal (0.45 mmol, 60.4 mg), and 4-(4-methoxyphenyl)-2-methylbut-3-yn-2-ylacetate (0.3 mmol, 69.7 mg). Finally, purge the reaction system with argon gas, seal the reaction tube, and place it at 50°C. o After heating and stirring in heating module C for 24 hours, the product was purified by column chromatography to obtain 79.4 mg of a yellow solid with a melting point of 79-82°C. o C, yield 86%, 94% ee.

[0039] The product structure characterization data are as follows:

[0040] 1H NMR (CDCl3, 400 MHz) δ 10.18 (s, 1H), 7.44 (d, J = 7.6 Hz, 2H), 7.38-7.28 (m, 5H), 6.83 (d, J = 8.8 Hz, 2H), 3.81 (s, 3H), 1.63 (s, 3H), 1.33(s, 3H), 1.30(s, 3H).

[0041] 13 C NMR (CDCl3, 100 MHz) δ 203.1, 158.6, 131.4, 130.4, 130.1, 128.2,127.8, 123.5, 113.2, 95.4, 83.3, 57.4, 55.2, 37.2, 25.9 (2C), 17.1;

[0042] Method 2: In a 10 mL sealed tube, first add tris(dibenzylacetone)palladium (0.004 mmol, 2.7 mg), L9 (0.015 mmol, 9.3 mg), and tert-butyl methyl ether (2.0 mL). After stirring for 30 min, add cesium carbonate (0.4 mmol, 130.3 mg), 2-phenylpropanal (0.3 mmol, 40.3 mg), and 4-(4-methoxyphenyl)-2-methylbut-3-yn-2-ylacetate (0.2 mmol, 46.5 mg). Finally, purge the reaction system with argon gas, seal the reaction tube, and place it at 50°C. o After heating and stirring in heating module C for 24 hours, the product was purified by column chromatography to obtain 46.4 mg of a yellow solid with a melting point of 79-82°C. o C, yield 76%, 93% ee.

[0043] Method 3: In a 10 mL sealed tube, first add (2,2'-bipyridine)palladium dichloride (0.008 mmol, 4.0 mg), L9 (0.015 mmol, 9.3 mg), and 1,2-dichloroethane (2.0 mL). After stirring for 30 min, add cesium carbonate (0.4 mmol, 130.3 mg), 2-phenylpropanal (0.3 mmol, 40.3 mg), and 4-(4-methoxyphenyl)-2-methylbut-3-yn-2-ylacetate (0.2 mmol, 46.5 mg). Finally, purge the reaction system with argon gas, seal the reaction tube, and place it at 50°C. oIn heating module C, the mixture was heated and stirred for 24 hours. The product was purified by column chromatography to obtain 24.5 mg of a yellow solid with a melting point of 79-82°C. o C, yield 40%, 83% ee.

[0044] Method 4: In a 10 mL sealed tube, first add (2,2'-bipyridine)palladium dichloride (0.008 mmol, 4.0 mg), L9 (0.015 mmol, 9.3 mg), and tert-butyl methyl ether (2.0 mL). After stirring for 30 min, add sodium tert-butoxide (0.4 mmol, 38.4 mg), 2-phenylpropanal (0.3 mmol, 40.3 mg), and 4-(4-methoxyphenyl)-2-methylbut-3-yn-2-yl acetate (0.2 mmol, 46.5 mg). Finally, purge the reaction system with argon gas, seal the reaction tube, and place it at 50°C. o In heating module C, the mixture was heated and stirred for 24 hours. The product was purified by column chromatography to obtain 17.4 mg of a yellow solid with a melting point of 79-82°C. o C, yield 28%, 93% ee.

[0045] Example 2

[0046] Preparation: (S)-2,3,3-trimethyl-2,5-diphenylpent-4-enal

[0047] ;

[0048] In a 10 mL sealed tube, (2,2'-bipyridine)palladium dichloride (0.012 mmol, 4.0 mg), L9 (0.015 mmol, 14.0 mg), and tert-butyl methyl ether (2.0 mL) were first added. After stirring for 30 min, cesium carbonate (0.6 mmol, 195.5 mg), 2-phenylpropanal (0.45 mmol, 60.4 mg), and 2-methyl-4-phenylbut-3-yn-2-ylacetate (0.3 mmol, 60.7 mg) were added. Finally, the reaction system was evacuated, purged with argon, and the reaction tube was sealed and placed at 50°C. o In heating module C, the product was heated and stirred for 24 hours. The product was then purified by column chromatography to obtain a yellow oily substance with a yield of 86% and an ee of 94%.

[0049] The product structure characterization data are as follows:

[0050] 1H NMR (CDCl3, 400 MHz) δ 10.18 (s, 1H), 7.44 (d, J = 7.6 Hz, 2H), 7.38-7.28 (m, 5H), 6.83 (d, J = 8.8 Hz, 2H), 3.81 (s, 3H), 1.63 (s, 3H), 1.32(s, 3H), 1.30(s, 3H).

[0051] 13 C NMR (CDCl3, 100 MHz) δ 203.1, 158.6, 131.4, 130.4, 130.1, 128.2,127.8, 123.5, 113.2, 95.4, 83.3, 57.4, 55.2, 37.2, 25.9 (2C), 17.1;

[0052] Example 3

[0053] Preparation: (S)-5-(4-chlorophenyl)-2,3,3-trimethyl-2-phenylpent-4-enal

[0054] ;

[0055] In a 10 mL sealed tube, (2,2'-bipyridine)palladium dichloride (0.012 mmol, 4.0 mg), L9 (0.015 mmol, 14.0 mg), and tert-butyl methyl ether (2.0 mL) were first added. After stirring for 30 min, cesium carbonate (0.6 mmol, 195.5 mg), 2-phenylpropanal (0.45 mmol, 60.4 mg), and 4-(4-chlorophenyl)-2-methylbut-3-yn-2-yl acetate (0.3 mmol, 71.0 mg) were added. Finally, the reaction system was evacuated, purged with argon, and the reaction tube was sealed and placed at 50 °C. o In heating module C, the product was heated and stirred for 24 hours. The product was then purified by column chromatography to obtain a yellow solid with a yield of 71% and an ee of 94%.

[0056] The product structure characterization data are as follows:

[0057] 1 H NMR (CDCl3, 400 MHz) δ 10.01 (s, 1H), 7.35-7.27 (m, 4H), 7.25-7.16(m, 5H), 1.56 (s, 3H), 1.25 (s, 3H), 1.23 (s, 3H);

[0058] 13 C NMR (CDCl3, 100 MHz) δ 202.8, 138.4, 133.8, 132.6, 129.0, 128.5,127.9, 127.4, 122.0, 96.3, 82.2, 58.0, 37.1, 25.9, 25.8, 17.0;

[0059] Example 4

[0060] Preparation: (S)-2,3,3-trimethyl-5-(naphth-2-yl)-2-phenylpent-4-enal

[0061] ;

[0062] In a 10 mL sealed tube, (2,2'-bipyridine)palladium dichloride (0.012 mmol, 4.0 mg), L9 (0.015 mmol, 14.0 mg), and tert-butyl methyl ether (2.0 mL) were first added. After stirring for 30 min, cesium carbonate (0.6 mmol, 195.5 mg), 2-phenylpropanal (0.45 mmol, 60.4 mg), and 2-methyl-4-(naphthyl-2-yl)but-3-en-2-yl acetate (0.3 mmol, 75.7 mg) were added. Finally, the reaction system was evacuated, purged with argon, and the reaction tube was sealed and placed at 50°C. o In heating module C, the product was heated and stirred for 24 hours. The product was then purified by column chromatography to obtain a yellow solid with a yield of 70% and an ee of 90%.

[0063] The product structure characterization data are as follows:

[0064] 1 H NMR (CDCl3, 400 MHz) δ 10.21 (s, 1H), 7.93 (s, 1H), 7.83-7.78 (m,3H), 7.52-7.45 (m, 5H), 7.40 (t, J = 7.2 Hz, 2H), 7.34 (t, J = 7.2 Hz, 1H), 1.70 (s, 3H), 1.40 (s, 3H), 1.38 (s, 3H);

[0065] 13C NMR (CDCl3, 100 MHz) δ 203.1, 138.6, 132.9, 132.5, 131.0, 129.0,128.4, 127.8, 127.7, 127.6, 127.3, 126.4 (2C), 120.7, 95.6, 83.7, 58.0, 37.2,26.0, 25.9, 17.0;

[0066] Example 5

[0067] Preparation: (S)-2,3,3-trimethyl-2-phenyl-5-(thiophen-2-yl)pent-4-enal

[0068] ;

[0069] In a 10 mL sealed tube, (2,2'-bipyridine)palladium dichloride (0.012 mmol, 4.0 mg), L9 (0.015 mmol, 14.0 mg), and tert-butyl methyl ether (2.0 mL) were first added. After stirring for 30 min, cesium carbonate (0.6 mmol, 195.5 mg), 2-phenylpropanal (0.45 mmol, 60.4 mg), and 2-methyl-4-(thiophen-2-yl)but-3-yn-2-yl acetate (0.3 mmol, 62.5 mg) were added. Finally, the reaction system was evacuated, purged with argon, and the reaction tube was sealed and placed at 50 °C. o In heating module C, the product was heated and stirred for 24 hours. The product was then purified by column chromatography to obtain a yellow oily substance with a yield of 80% and an ee of 91%.

[0070] The product structure characterization data are as follows:

[0071] 1 H NMR (CDCl3, 400 MHz) δ 10.11 (s, 1H), 7.44-7.37 (m, 4H), 7.34-7.30(m, 1H), 7.21 (dd, J1 = 5.2 Hz, J2 = 1.2 Hz, 1H), 7.14 (dd, J1 = 3.6 Hz, J2 =0.8 Hz, 1H), 6.97 (dd, J1 = 5.2 Hz, J2 = 3.6 Hz, 1H), 1.65 (s, 3H), 1.35 (s,3H), 1.33 (s, 3H);

[0072] 13C NMR (CDCl3, 100 MHz) δ 202.8, 138.4, 131.1, 128.9, 127.9, 127.3,126.8, 126.3, 123.5, 99.1, 76.6, 57.9, 37.4, 25.7 (2C), 16.9;

[0073] Example 6

[0074] Preparation: (S)-5-cyclopropyl-2,3,3-trimethyl-2-phenylpent-4-enal

[0075] ;

[0076] In a 10 mL sealed tube, (2,2'-bipyridine)palladium dichloride (0.012 mmol, 4.0 mg), L9 (0.015 mmol, 14.0 mg), and tert-butyl methyl ether (2.0 mL) were first added. After stirring for 30 min, cesium carbonate (0.6 mmol, 195.5 mg), 2-phenylpropanal (0.45 mmol, 60.4 mg), and 4-cyclopropyl-2-methylbut-3-yn-2-yl acetate (0.3 mmol, 49.9 mg) were added. Finally, the reaction system was evacuated, purged with argon, and the reaction tube was sealed and placed at 50°C. o In heating module C, the product was heated and stirred for 24 hours. The product was then purified by column chromatography to obtain a yellow oily substance with a yield of 55% and an ee of 95%.

[0077] The product structure characterization data are as follows:

[0078] 1 H NMR (CDCl3, 400 MHz) δ 10.04 (s, 1H), 7.30-7.18 (m, 5H), 1.46 (s,3H), 1.18-1.11 (m, 4H), 1.08 (s, 3H), 0.68-0.63 (m, 2H), 0.55-0.51 (m, 2H);

[0079] 13 C NMR (CDCl3, 100 MHz) δ 204.0, 139.0, 128.9, 127.6, 127.0, 86.3,80.6, 57.6, 36.4, 26.2, 26.1, 16.9, 8.0 (2C), -0.5;

[0080] Example 7

[0081] Preparation: (S)-2-phenyl-2-(4-(phenylethynyl)tetrahydro-2H-pyran-4-yl)propionaldehyde

[0082] ;

[0083] In a 10 mL sealed tube, (2,2'-bipyridine)palladium dichloride (0.012 mmol, 4.0 mg), L9 (0.015 mmol, 14.0 mg), and tert-butyl methyl ether (2.0 mL) were first added. After stirring for 30 min, cesium carbonate (0.6 mmol, 195.5 mg), 2-phenylpropanal (0.45 mmol, 60.4 mg), and 4-(phenylethynyl)tetrahydro-2H-pyran-4-ylacetate (0.3 mmol, 73.3 mg) were added. Finally, the reaction system was evacuated, purged with argon, and the reaction tube was sealed and placed at 50°C. o In heating module C, the product was heated and stirred for 24 hours. The product was then purified by column chromatography to obtain a yellow solid with a yield of 72% and an ee of 93%.

[0084] The product structure characterization data are as follows:

[0085] 1 H NMR (CDCl3, 400 MHz) δ 10.05 (s, 1H), 7.44-7.37 (m, 6H), 7.35-7.32(m, 4H), 3.90-3.87 (m, 4H), 1.97-1.86 (m, 2H), 1.70 (s, 3H), 1.65-1.62 (m,2H);

[0086] 13 C NMR (CDCl3, 100 MHz) δ 202.1, 137.4, 131.4, 129.2, 128.3, 128.1,127.9, 127.6, 123.1, 90.9, 87.6, 64.8 (2C), 58.2, 41.3, 32.8, 32.6, 16.5;

[0087] Example 8

[0088] Preparation: (S)-2-(4-methoxyphenyl)-2,3,3-trimethyl-5-phenylpent-4-enal

[0089] ;

[0090] In a 10 mL sealed tube, (2,2'-bipyridine)palladium dichloride (0.012 mmol, 4.0 mg), L9 (0.015 mmol, 14.0 mg), and tert-butyl methyl ether (2.0 mL) were first added. After stirring for 30 min, cesium carbonate (0.6 mmol, 195.5 mg), 2-(4-methoxyphenyl)propanal (0.45 mmol, 73.9 mg), and 2-methyl-4-phenylbut-3-yn-2-ylacetate (0.3 mmol, 60.7 mg) were added. Finally, the reaction system was evacuated, purged with argon, and the reaction tube was sealed and placed at 50°C. o In heating module C, the product was heated and stirred for 24 hours. The product was then purified by column chromatography to obtain a yellow solid with a yield of 74% and an ee of 93%.

[0091] The product structure characterization data are as follows:

[0092] 1 H NMR (CDCl3, 400 MHz) δ 10.11 (s, 1H), 7.40-7.35 (m, 4H), 7.31-7.29(m, 3H), 6.90 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H), 1.62 (s, 3H), 1.33 (s, 3H),1.31 (s, 3H);

[0093] 13 C NMR (CDCl3, 100 MHz) δ 203.1, 158.6, 131.4, 130.4, 130.1, 128.2,127.8, 123.5, 113.2, 95.4, 83.3, 57.4, 55.2, 37.2, 25.9 (2C), 17.1;

[0094] Example 9

[0095] Preparation: (S)-2-(2,3-dihydrobenzofuran-5-yl)-2,3,3-trimethyl-5-phenylpent-4-enal

[0096] ;

[0097] In a 10 mL sealed tube, (2,2'-bipyridine)palladium dichloride (0.012 mmol, 4.0 mg), L9 (0.015 mmol, 14.0 mg), and tert-butyl methyl ether (2.0 mL) were first added. After stirring for 30 min, cesium carbonate (0.6 mmol, 195.5 mg), 2-(2,3-dihydrobenzofuran-5-yl)propionaldehyde (0.45 mmol, 79.3 mg), and 2-methyl-4-phenylbut-3-yn-2-yl acetate (0.3 mmol, 60.7 mg) were added. Finally, the reaction system was evacuated, purged with argon, and the reaction tube was sealed and placed at 50 °C. o In heating module C, the product was heated and stirred for 24 hours. The product was then purified by column chromatography to obtain a yellow oily substance with a yield of 76% and an ee of 93%.

[0098] The product structure characterization data are as follows:

[0099] 1 H NMR (CDCl3, 600 MHz) δ 9.98 (s, 1H), 7.30-7.29 (m, 2H), 7.22-7.17(m, 4H), 7.07 (d, J = 8.4 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 4.49 (t, J = 9.0Hz, 2H), 3.12 (t, J = 8.4 Hz, 2H), 1.52 (s, 3H), 1.24 (s, 3H), 1.23 (s, 3H);

[0100] 13 C NMR (CDCl3, 150 MHz) δ 203.0, 159.2, 131.4, 130.2, 128.8, 128.2,127.7, 126.5, 125.6, 123.6, 108.5, 95.6, 83.2, 71.3, 57.6, 37.1, 29.8, 25.9(2C), 17.3;

[0101] Example 10

[0102] Preparation: (R)-2,3,3-trimethyl-2-(1-methyl-1H-indol-3-yl)-5-phenylpent-4-enal

[0103] ;

[0104] In a 10 mL sealed tube, (2,2'-bipyridine)palladium dichloride (0.012 mmol, 4.0 mg), L9 (0.015 mmol, 14.0 mg), and tert-butyl methyl ether (2.0 mL) were first added. After stirring for 30 min, cesium carbonate (0.6 mmol, 195.5 mg), 2-(1-methyl-1H-indol-3-yl)propionaldehyde (0.45 mmol, 84.3 mg), and 2-methyl-4-phenylbut-3-yn-2-yl acetate (0.3 mmol, 60.7 mg) were added. Finally, the reaction system was evacuated, purged with argon, and the reaction tube was sealed and placed at 80°C. o In heating module C, the product was heated and stirred for 24 hours. The product was then purified by column chromatography to obtain a yellow solid with a yield of 45% and an ee of 86%.

[0105] The product structure characterization data are as follows:

[0106] 1 H NMR (CDCl3, 400 MHz) δ 10.14 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.39-7.36 (m, 2H), 7.33-7.28 (m, 4H), 7.24-7.20 (m, 2H), 7.08 (t, J = 7.2 Hz,1H), 3.80 (s, 3H), 1.78 (s, 3H), 1.47 (s, 3H), 1.41 (s, 3H);

[0107] 13 C NMR (CDCl3, 100 MHz) δ 202.8, 136.8, 131.4, 129.3, 128.2, 127.7,127.3, 123.6, 121.7, 121.4, 119.3, 111.4, 109.4, 96.0, 83.2, 55.9, 37.6,32.9, 26.4, 26.3, 17.9;

[0108] Example 11

[0109] Preparation: (S)-1-(2-methyl-4-phenylbut-3-yn-2-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxaldehyde

[0110] ;

[0111] In a 10 mL sealed tube, (2,2'-bipyridine)palladium dichloride (0.012 mmol, 4.0 mg), L9 (0.015 mmol, 14.0 mg), and tert-butyl methyl ether (2.0 mL) were first added. After stirring for 30 min, cesium carbonate (0.6 mmol, 195.5 mg), 1,2,3,4-tetrahydronaphthalene-1-carboxaldehyde (0.45 mmol, 72.1 mg), and 2-methyl-4-phenylbut-3-yn-2-yl acetate (0.3 mmol, 60.7 mg) were added. Finally, the reaction system was evacuated, purged with argon, and the reaction tube was sealed and placed at 50°C. o In heating module C, the product was heated and stirred for 24 hours. The product was then purified by column chromatography to obtain a colorless oily substance with a yield of 86% and an ee of 94%.

[0112] The product structure characterization data are as follows:

[0113] 1 H NMR (CDCl3, 400 MHz) δ 10.07 (s, 1H), 8.32 (d, J = 7.6 Hz, 1H), 7.37-7.34 (m, 2H), 7.28-7.23 (m, 3H), 7.20-7.11 (m, 2H), 7.06 (d, J = 7.6 Hz,1H), 2.63-2.60 (m, 2H), 2.43-2.38 (m, 1H), 1.89-1.82 (m, 1H), 1.60-1.53 ​​(m,1H), 1.37-1.30 (m, 4H), 1.07 (s, 3H);

[0114] 13 C NMR (CDCl3, 100 MHz) δ 202.7, 140.7, 134.2, 131.4, 129.6, 129.5,128.3, 128.0, 126.8, 125.9, 123.3, 95.8, 84.2, 56.9, 37.9, 30.9, 26.7, 26.3,25.2, 21.0;

[0115] Example 12

[0116] Preparation: (S)-2-benzyl-2-(4-methoxyphenyl)-3,3-dimethyl-5-phenylpent-4-enal

[0117] ;

[0118] In a 10 mL sealed tube, (2,2'-bipyridine)palladium dichloride (0.012 mmol, 4.0 mg), L9 (0.015 mmol, 14.0 mg), and tert-butyl methyl ether (2.0 mL) were first added. After stirring for 30 min, cesium carbonate (0.6 mmol, 195.5 mg), 2-(4-methoxyphenyl)-3-phenylpropanal (0.45 mmol, 108.1 mg), and 2-methyl-4-phenylbut-3-yn-2-ylacetate (0.3 mmol, 60.7 mg) were added. Finally, the reaction system was evacuated, purged with argon, and the reaction tube was sealed and placed at 50°C. o In heating module C, the product was heated and stirred for 24 hours. The product was then purified by column chromatography to obtain a yellow solid with a yield of 61% and an ee of 78%.

[0119] The product structure characterization data are as follows:

[0120] 1 H NMR (CDCl3, 400 MHz) δ 10.03 (s, 1H), 7.47-7.44 (m, 4H), 7.37-7.32(m, 3H), 7.12-7.05 (m, 3H), 6.97-6.94 (m, 2H), 6.87 (d, J = 8.8 Hz, 2H),3.89-3.75 (m, 5H), 1.38 (s, 3H), 1.35 (s, 3H);

[0121] 13 C NMR (CDCl3, 100 MHz) δ 204.0, 158.5, 137.0, 131.4, 131.4, 130.3,128.3, 127.9, 127.9, 127.5, 126.1, 123.4, 113.0, 95.2, 84.1, 61.4, 55.1,38.6, 37.5, 26.8, 26.2;

[0122] The invention will be further described below in conjunction with its application scenarios.

[0123] Application Example 1

[0124] Oxygen-containing heterocycles are ubiquitous in natural products, and compounds containing this fragment often exhibit good biological activity and are widely used in new drug development. Therefore, the oxygen-containing heterocyclic compounds derived from chiral aldehydes using this invention through a simple procedure are of great significance.

[0125] ;

[0126] a) In a 50 mL round-bottom flask equipped with a magnetic stirrer, (S)-5-(4-methoxyphenyl)-2,3,3-trimethyl-2-phenylpent-4-enal (306.2 mg, 1.0 mmol, 1.0 equivalent), NaBH4 (75.66 mg, 2.0 mmol, 2.0 equivalent), and THF (8 mL) were added. The resulting mixture was stirred at room temperature for 2 hours. After the reaction was complete (monitored by TLC), 2 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was collected. The collected organic phase was concentrated under vacuum, and the residue was purified by column chromatography to give intermediate S1 in 82% yield, 94% ee.

[0127] b) An intermediate S1 (254.1 mg, 0.82 mmol, 1.0 equivalence), K2CO3 (340.0 mg, 3.0 mmol, 3.0 equivalence), AgOAc (410.6 mg, 3.0 mmol, 3.0 equivalence), I2 (624.3 mg, 3.0 mmol, 3.0 equivalence), and MeCN (15 mL) were added to a 50 mL round-bottom flask equipped with a magnetic stir bar. The resulting mixture was stirred overnight at room temperature. After the reaction was complete (monitored by TLC), the mixture was concentrated under vacuum, and the residue was purified by column chromatography to a white solid, 52% yield, 94% ee.

[0128] (S)-5-iodo-6-(4-methoxyphenyl)-3,4,4-trimethyl-3-phenyl-3,4-dihydro-2H-pyran

[0129] ;

[0130] 1 H NMR (CDCl3, 400 MHz) δ 7.44 (d, J = 8.4 Hz, 2H), 7.37-7.34 (m, 4H), 7.30-7.28 (m, 1H), 6.91 (d, J = 8.8 Hz, 2H), 4.82 (d, J = 14.4 Hz, 1H), 4.01(d, J = 10.0 Hz, 1H), 3.84 (s, 3H), 1.53 (s, 3H), 1.25 (s, 3H), 0.90 (s, 3H);

[0131] 13C NMR (CDCl3, 100 MHz) δ 159.7, 151.7, 143.0, 131.7, 131.0, 127.9,127.2, 126.7, 113.2, 90.5, 71.6, 55.3, 42.9, 42.4, 28.0, 27.3, 19.2;

[0132] Application Example 2

[0133] ;

[0134] c) In a 10 mL sealed tube equipped with a magnetic stir bar, (S)-5-(4-methoxyphenyl)-2,3,3-trimethyl-2-phenylpent-4-enal (91.9 mg, 0.3 mmol, 1.0 equivalent), sodium chlorite (81.4 mg, 0.9 mmol, 3 equivalent), H₂O₂ (51.0 mg, 1.5 mmol, 5 equivalent), n-butanol (2 mL), and ethanol (2 mL) were added. The resulting mixture was stirred at room temperature for 24 hours. After the reaction was complete (monitored by TLC), the reaction mixture was extracted with ethyl acetate. Subsequently, the mixture was concentrated under vacuum, and the residue was purified by column chromatography to give intermediate S2 in 73% yield, 94% ee.

[0135] d) An intermediate S2 (70.6 mg, 0.219 mmol, 1.0 equivalent), indium(III) bromide (15.5 mg, 0.0438 mmol, 0.2 equivalent), and toluene (2 mL) were added to a 10 mL sealed tube equipped with a magnetic stir bar. The resulting mixture was stirred at 90°C for 24 hours. After the reaction was complete (monitored by TLC), the mixture was concentrated under vacuum, and the residue was purified by column chromatography to a white solid, 82% yield, 94% ee.

[0136] (R)-6-(4-methoxyphenyl)-3,4,4-trimethyl-3-phenyl-3,4-dihydro-2H-pyran-2-one

[0137] ;

[0138] 1 H NMR (CDCl3, 400 MHz) δ 7.58 (d, J = 8.4 Hz, 2H), 7.33-7.22 (m, 5H), 6.90 (d, J = 8.8 Hz, 2H), 5.39 (s, 1H), 3.83 (s, 3H), 1.71 (s, 3H), 1.18 (s,3H), 1.05 (s,3H);

[0139] 13 C NMR (CDCl3, 100 MHz) δ 173.3, 160.1, 146.8, 138.8, 128.0, 127.6,127.1, 125.8, 124.7, 113.8, 110.3, 55.3, 53.2, 37.9, 25.2, 24.9, 19.3;

[0140] Currently, organic small molecule catalysis has become a hot topic in asymmetric synthesis research. Organic small molecule catalysts have advantages such as simple operation, easy availability, low cost, stable storage, and environmental friendliness. Hydrogen bond activation, as an important pathway for electrophilic reagent activation in small molecule synthesis catalytic systems, has attracted widespread attention from organic chemists. Chiral thiourea catalysts are typical bifunctional organic small molecule catalysts that can provide two hydrogen bonds. The two nitrogen hydrogen atoms of thiourea can form two hydrogen bonds with substrates such as imines, aldehydes, ketones, and nitro groups, enhancing their electrophilicity; at the same time, the chiral fragment of thiourea and the interaction of nucleophiles improve enantioselectivity.

[0141] This invention provides a chiral thiourea catalyst prepared from the above-mentioned chiral propargyl-substituted aldehyde compounds through a simple reaction process, which has wide applications.

[0142] ;

[0143] R 1 Substituents are selected from Where R = H, Ph, i Pr, t Bu, OMe, F, Cl, CF3, CN, COOMe, , , , etc. R 2 , R 3 Substituents are selected from Me, , , , etc. R 4 Substituents are selected from , , , H, Me, t Bu, Ph, OMe, F, Cl, etc., R 5 Substituents such as Me, Et, and Bn are selected.

[0144] Application Example 3

[0145] 1-((1R,2R)-2-(dimethylamino)cyclohexyl)-3-((S)-5-(4-methoxyphenyl)-2,3,3-trimethyl-2-phenylpent-4-yn-1-yl)thiourea

[0146] ;

[0147] e) In a 50 mL round-bottom flask equipped with a magnetic stirrer, IV (1043.7 mg, 3.4 mmol, 1.0 equivalent), 2-methylpropane-2-sulfinamide (618.0 mg, 5.1 mmol, 1.5 equivalent), and THF (15 mL) were added. Then, Ti(OEt)4 (2416.7 mg, 8.5 mmol, 2.5 equivalent) was slowly added dropwise. The resulting mixture was stirred overnight at 50°C. After the reaction was complete (monitored by TLC), it was diluted with ethyl acetate and poured into brine with rapid stirring. The resulting suspension was filtered through diatomaceous earth and washed with ethyl acetate. The combined organic phases were dried over Na2SO4, and the solvent was removed under vacuum. The target crude product S3 could be used directly for the next step without column chromatography purification.

[0148] f) In a 50 mL round-bottom flask equipped with a magnetic stirrer, the crude product S3, NaBH4 (258.4 mg, 6.8 mmol, 2.0 equivalent), and THF (15 mL) were added. The resulting mixture was stirred overnight at room temperature. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with water and extracted with ethyl acetate (3 × 15 mL). The combined organic phases were dried over Na2SO4, and the solvent was removed under vacuum. The target crude product S4 could be used directly in the next step without column chromatography purification.

[0149] g) A 50 mL round-bottom flask equipped with a magnetic stirrer was used to add the crude product S4 and methanol (20 mL). Then, HCl (4 mol / L, soluble in 1,4-dioxane, 3 mL) was slowly added dropwise. The resulting mixture was stirred at room temperature for 0.5 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with saturated NaHCO3 solution and extracted with ethyl acetate (3 × 15 mL). The combined organic phases were dried over Na2SO4, the mixture was concentrated under vacuum, and the residue was purified by rapid silica gel column chromatography with ethyl acetate as eluent to give intermediate S5, 70% yield, 97% ee.

[0150] h) Take a dried Shrek tube (20 mL) equipped with a magnetic stir bar, add intermediate S5 (523.7 mg, 1.671 mmol), anhydrous dichloromethane (5 mL), and pyridine (197.75 mg, 2.5 mmol, 1.5 equivalents). Then slowly add phosgene (287.5 mg, 2.5 mmol, 1.5 equivalents). Stir the reaction mixture at room temperature for 2 hours, then connect the Shrek tube to a vacuum system and carefully remove volatile substances. The resulting pale yellow solid is dissolved in anhydrous dichloromethane (5 mL) under an argon atmosphere, and then the solvent is removed again under vacuum. This process is repeated twice to remove excess phosgene. The resulting residue is dissolved in dichloromethane (15 mL), and (1S,2S)-(+)-N,N-dimethylcyclohexane-1,2-diamine (460 μL, 3.0 mmol) is added, and stirred at room temperature for 1 hour. After the reaction was complete (monitored by TLC), the mixture was concentrated under vacuum, and the residue was purified by column chromatography to give a white solid with a yield of 42% and an ee of 96%.

[0151] 1 H NMR (CDCl3, 400 MHz) δ 7.47 (d, J = 7.6 Hz, 2H), 7.34-7.29 (m, 4H), 7.22 (t, J = 7.6 Hz, 1H), 6.80 (d, J = 8.8 Hz, 2H), 6.51 (s, 1H), 6.27 (s,1H), 4.37 (s, 2H), 3.77 (s, 3H), 3.39-3.26 (m, 2H), 2.08 (s, 6H), 1.78-1.71(m, 2H), 1.56-1.47 (m, 4H), 1.31-1.24 (m, 4H), 1.13-0.94 (m, 7H);

[0152] 13 C NMR (CDCl3, 100 MHz) δ 182.4, 159.0, 132.7, 128.7, 127.6, 126.6,115.8, 113.7, 94.1, 82.6, 66.6, 55.5, 55.2, 47.7, 39.8, 38.5, 32.6, 25.7,25.5, 24.7, 24.2, 22.0, 19.8;

[0153] Two reactions have been successfully catalyzed, and both yielded the target products in good yields and with excellent enantioselectivity.

[0154] .

[0155] Application Example 4

[0156] 1-((1R,2R)-2-(dimethylamino)cyclohexyl)-3-((S)-2,3,3-trimethyl-2,5-diphenylpent-4-tri-1-yl)thiourea

[0157]

[0158] 1 H NMR (CDCl3, 400 MHz) δ 7.45 (d, J = 7.6 Hz, 2H), 7.40-7.38 (m, 2H), 7.30 (t, J = 7.6 Hz, 2H), 7.25-7.19 (m, 4H), 6.08 (s, 1H), 4.53 (s, 1H),4.38-4.35 (m, 2H), 3.01 (s, 1H), 2.50 (s, 6H), 2.16 (d, J = 10.4 Hz, 1H),1.91-1.85 (m, 2H), 1.67 (d, J = 12.8 Hz, 1H), 1.56-1.55 (m, 5H), 1.31-1.24(m, 5H), 1.14-1.06 (m, 4H).

[0159] 13 C NMR (CDCl3, 100 MHz) δ 179.3, 131.4, 128.7, 128.0, 127.5, 127.4,126.5, 123.7, 95.9, 82.6, 65.6, 54.1, 49.7, 47.6, 38.8, 38.6, 32.6, 25.6,25.4, 24.4, 24.1, 23.4, 22.4, 19.5;

[0160] Two reactions have been successfully catalyzed, and both yielded the target products in good yields and with excellent enantioselectivity.

[0161] .

[0162] Application Example 5

[0163] 1-((1R,2R)-2-(dimethylamino)cyclohexyl)-3-((S)-2,3,3-trimethyl-5-(naphth-2-yl)-2-phenylpentan-4-yn-1-yl)thiourea

[0164]

[0165] 1 H NMR (CDCl3, 400 MHz) δ 7.92 (s, 1H), 7.77-7.71 (m, 3H), 7.51-7.40(m, 5H), 7.33 (t, J = 7.6 Hz, 2H), 7.23 (t, J = 7.2 Hz, 1H), 6.21 (s, 1H),4.55 (s, 1H), 4.42 (d, J = 12.0 Hz, 1H), 3.94 (s, 1H), 2.70 (s, 1H), 2.29 (s,6H), 2.13-2.07 (m, 1H), 1.81-1.76 (m, 2H), 1.64-1.56 (m, 4H), 1.30 (s, 3H), 1.21-0.99 (m, 7H).;

[0166] 13 C NMR (CDCl3, 100 MHz) δ 179.8, 132.8, 132.3, 130.9, 128.7, 128.5,127.6 (2C), 127.5, 127.4, 126.6, 126.2, 126.1, 121.0, 96.2, 83.0, 65.9, 47.7,39.1, 38.6, 32.6, 25.7, 25.4, 24.5, 24.1, 23.6, 22.2, 19.6;

[0167] Two reactions have been successfully catalyzed, and both yielded the target products in good yields and with excellent enantioselectivity.

[0168] .

[0169] The above description of the embodiments is only for the purpose of helping to understand the method and core ideas of the present invention. It should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A method for preparing a chiral propargyl-substituted aldehyde compound, characterized in that, include: Under argon conditions, a one-pot propargylation reaction of aldehydes with propargyl acetate was catalyzed using a catalytic condition consisting of a base, a palladium catalyst, and a chiral ligand. Chiral propargyl-substituted aldehyde compounds were prepared in a sealed tube under an inert argon atmosphere. The compounds shown in Formula I and Formula II were both reacted in an organic solvent. The chiral propargyl-substituted aldehyde compounds prepared are shown in Formula III. R 1 Substituents are selected from Where R = H, Ph, i Pr, t Bu, OMe, F, Cl, CF3, CN, COOMe, , , , ;R 2 , R 3 Substituents are selected from Me, , , , ;R 4 Substituents are selected from , , , H, Me, t Bu, Ph, OMe, F, Cl; R 5 The substituents are selected from Me, Et, and Bn.

2. The method for preparing a chiral propargyl-substituted aldehyde compound according to claim 1, characterized in that, The specific steps are as follows: Step 1) In the deoxygenated and dehydrated tube, add propargyl acetate, aldehyde, base, palladium catalyst and chiral ligand. The amount of solvent added should meet the requirement that the molar concentration of aldehyde is 0.1-0.2 mol / L. Then place the tube in the module and heat it. Step 2: After the reaction is complete, the chiral propargyl substituted aldehyde compound is obtained by separation and purification using column chromatography.

3. The method for preparing a chiral propargyl-substituted aldehyde compound according to claim 2, characterized in that, The molar ratio of the compound shown in Formula I to the compound shown in Formula II, and the molar ratio of base to palladium catalyst to chiral ligand is 1:1~2:1.5~2.5:0.02~0.06:0.02~0.

08.

4. The method for preparing a chiral propargyl-substituted aldehyde compound according to claim 2, characterized in that, The alkali is selected from one or more of potassium tert-butoxide, lithium tert-butyl, potassium carbonate, sodium carbonate, and cesium carbonate.

5. The method for preparing a chiral propargyl-substituted aldehyde compound according to claim 2, characterized in that, The palladium catalyst is one or more of the following: allyl palladium chloride dimer, tris(dibenzylidene acetone) dipalladium, (2,2'-bipyridine) palladium dichloride, palladium acetate, 1,5-cyclooctadiene palladium dichloride, and tris(dibenzylidene acetone) dipalladium chloroform adduct.

6. The method for preparing a chiral propargyl-substituted aldehyde compound according to claim 2, characterized in that, The chiral ligands are one or more of L1, L2, L3, L4, L5, L6, L7, L8, and L9; 7. The method for preparing a chiral propargyl-substituted aldehyde compound according to claim 2, characterized in that, The organic solvent used in the reaction is selected from one or more of toluene, cyclohexane, mesitylene, acetonitrile, 1,2-dichloroethane, tert-butyl methyl ether, and ethanol.

8. The method for preparing a chiral propargyl-substituted aldehyde compound according to claim 2, characterized in that, The reaction was carried out in the following order: first, palladium catalyst, chiral ligand and organic solvent were added and stirred for 30 ± 5 min, then the compound shown in Formula I, the compound shown in Formula II and the base were added, and the reaction was carried out in an argon atmosphere that had been deoxygenated.

9. The method for preparing a chiral propargyl-substituted aldehyde compound according to claim 2, characterized in that, The reaction temperature in step 1) is 40-90°C. o C, the reaction time is 15-48 h.

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