A method for synthesizing chiral allene compounds from arenes and alkynes

Abstract

The application relates to the technical field of organic synthesis, and particularly relates to a method for synthesizing chiral diene compounds from aromatic hydrocarbons and alkynes. A simple aromatic hydrocarbon compound is designed to be in-situ constructed into an arylthianthrene onium salt under the action of an electrophilic activation reagent, then a palladium catalyst and a chiral ligand are used to catalyze the asymmetric Heck reaction of the arylthianthrene onium salt constructed in-situ and alkynes, so that a trisubstituted chiral diene compound is quickly and efficiently constructed. The method has mild conditions, a wide substrate range, excellent enantioselectivity and yield, and can introduce a chiral diene fragment into salicylate and indometacin which have anti-inflammatory and analgesic activities.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, and particularly relates to a method for synthesizing chiral diene compounds from arene and alkyne. BACKGROUND

[0002] Diene has attracted extensive attention of organic chemists due to its unique structure, reactivity and important structural unit and organic synthesis building block.

[0003] So far, about 150 natural products and pharmacologically active molecules containing diene skeleton have been isolated or synthesized, and diene containing axial chirality shows unique biological activity (Angew. Chem., Int. Ed.2012, 51, 2818).

[0004] Therefore, chemists have made great efforts to develop a simple method for synthesizing diene, especially optically pure diene compounds. β -H elimination reaction is one of the most important elementary reactions in transition metal chemistry, and is the key step of carbon-palladium bond quenching in Heck reaction. However, the enyl palladium is more prone to undergo protonation reaction, carbon halogenation reaction and competitive reaction such as tandem reaction. β -H elimination is an energy-unfavorable process, and enyl palladium is more prone to undergo protonation reaction, carbon halogenation reaction and competitive reaction such as tandem reaction. Therefore, it is a long-term challenge to synthesize diene by controlling this process in an enantioselective manner. Frantz group (J. Am. Chem. Soc. 2013, 135, 4970), Akira Masuno and Zhang Junliang group (J. Am. Chem. Soc. 2019, 141, 19246; Sci. Adv. 2023, 9, eadg1002) realized asymmetric β -H elimination reaction to synthesize chiral diene.

[0005] These methods rely on the pre-introduction of aromatic / olefin substrates containing different leaving groups, and the synthesis of substrates is complicated and inefficient. SUMMARY

[0006] The technical problem to be solved by the present application is to overcome the deficiencies of the prior art, and to provide a method for synthesizing chiral diene compounds from arene and alkyne, which uses thioxanthene-S-oxide (TTSO) to activate simple arene in situ, and then performs asymmetric Heck reaction with alkyne to develop a one-pot tandem asymmetric catalytic method, realizes direct, economical and efficient synthesis of chiral diene, and modifies precursor drugs with biological activity.

[0007] The present application provides a method for synthesizing chiral diene compounds from arene and alkyne, comprising the following steps:

[0008] S1, under inert atmosphere, dissolve the arene, thioxanthene-S-oxide in organic solvent 1 in a reaction vessel equipped with a magnetic stirrer to obtain a mixture, add electrophilic activation reagent to the mixture to react initially, then add base reagent 1 to stir and react, spin dry the solvent to obtain in-situ generated arylthioxanthium salt;

[0009] The structural formula of the arene is:

[0010] wherein R 1 , R 2 , R 3 and R 4 are any one of H, C1-C6 alkyl, C1-C10 alkoxy, 4-10 membered cycloalkyl, halogen, ester group, amino, heteroaryl;

[0011] S2, under inert atmosphere, pre-stir the palladium catalyst, chiral ligand and organic solvent 2 in a reaction vessel equipped with a magnetic stirrer, add the arylthioxanthium salt generated in-situ in S1, alkyne, base reagent 2, react at room temperature, after the reaction is completed, spin out the solvent under reduced pressure, and separate and purify by column chromatography to obtain the chiral diene compound.

[0012] Compared with the prior art, the present application has the following advantages:

[0013] The present application provides a method for synthesizing chiral diene compounds from arene and alkyne, which comprises the following steps: designing simple arene compounds to react with thioxanthene-S-oxide under the action of electrophilic activation reagent to construct arylthioxanthium salt in-situ, then catalyzing the arylthioxanthium salt constructed in-situ to react with alkyne by palladium catalyst and chiral ligand to construct trisubstituted chiral diene compounds quickly and efficiently. The method has mild conditions, wide substrate range, excellent enantioselectivity and yield, and can introduce chiral diene fragments into salicylate and indomethacin with anti-inflammatory and analgesic activity. BRIEF DESCRIPTION OF DRAWINGS

[0014] In order to more clearly illustrate the technical solutions of the present application or the prior art, the following will briefly introduce the drawings needed to be used in the embodiments or prior art description. Obviously, the drawings in the following description are some embodiments of the present application, and other drawings can also be obtained by those skilled in the art without creative labor.

[0015] Figure 1 The hydrogen spectrum of compound 3z prepared for example 28 is prepared;

[0016] Figure 2 The carbon spectrum of compound 3z prepared for example 28 is prepared; DETAILED DESCRIPTION

[0017] The yield in the examples of the present invention refers to the isolated yield. The method for determining the NMR yield is as follows: the crude product obtained by post-treatment is dissolved in deuterated chloroform, 0.1 mmol of dibromomethane (7 μL) is added as an internal standard, and after performing a crude NMR spectrum, the characteristic peak of hydrogen of dibromomethane is integrated as 1 to obtain the NMR yield of the target product.

[0018] Example 1

[0019] This embodiment provides a screening of a chiral ligand, palladium, solvent and base.

[0020] ① Screening of chiral ligands;

[0021] ;

[0022] Under an inert atmosphere, 5 mmol% Pd2(dba)3 (tris(dibenzylideneindeoxyacetone)dipalladium(0)), 15 mmol% chiral ligand, and 1 mL tetrahydrofuran (THF) were added to a 5 mL reaction tube equipped with a magnet and pre-stirred for 1 h. Then, 0.1 mmol arylthianthrenium salt 1a', 0.3 mmol 4-octyne 2a, and 0.2 mmol diisopropylethylamine (DIPEA) were added and reacted at 60°C for 12 h. After the reaction, the solvent was removed under reduced pressure to obtain the crude trisubstituted chiral allene 3a.

[0023] The structure of the chiral ligand is shown in Formula 1 below, wherein the yield of 3a shown in Formula 1 is obtained by 1 H NMR determination (with CH2Br2 (dibromomethane) as the internal standard), and the enantiomeric excess (ee%) value was determined by HPLC (high performance liquid chromatography);

[0024]

[0025] Formula 1

[0026] In the above formula 1 a Indicates room temperature;

[0027] ② Screening of palladium

[0028]

[0029] Under an inert atmosphere, 5 mmol% palladium, 15 mmol% L15, and 1 mL of THF were added to a 5 mL reaction tube equipped with a magnetic rod and pre-stirred for 1 h. 0.1 mmol of arylthianthrenium salt 1a', 0.3 mmol of 4-octyne 2a, and 0.2 mmol of DIPEA were added and reacted at room temperature for 12 h. After the reaction, the solvent was removed under reduced pressure to obtain the crude trisubstituted chiral allene 3a.

[0030] The results are shown in Table 1, wherein the yield of 3a shown in Table 1 was determined by HPLC. 1 H NMR measurement (with CH2Br2as an internal standard), and the ee value was determined by HPLC.

[0031] Table 1

[0032]

[0033] ③Screening of solvents

[0034]

[0035] Under an inert atmosphere, 5 mmol% Pd2(dba)3, 15 mmol% L15 and 1 mL of solvent were pre-stirred in a 5 mL reaction tube with a magnet for 1 h, 0.1 mmol arylthianthrenium salt 1a', 0.3 mmol 4-octyne 2a and 0.2 mmol DIPEA were added, and the reaction was carried out at room temperature for 12 h. After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product of trisubstituted chiral allene 3a.

[0036] The results are shown in Table 2, wherein the yield of 3a shown in Table 2 was determined by HPLC. 1 H NMR measurement (with CH2Br2as an internal standard), and the ee value was determined by HPLC.

[0037] Table 2

[0038]

[0039] ④Screening of bases

[0040]

[0041] Under an inert atmosphere, 5 mmol% Pd2(dba)3, 15 mmol% L16 and 1 mL of THF were pre-stirred in a 5 mL reaction tube with a magnet for 1 h, 0.1 mmol arylthianthrenium salt 1a', 0.3 mmol 4-octyne 2a and 0.2 mmol base were added, and the reaction was carried out at room temperature. After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product of trisubstituted chiral allene 3a.

[0042] The results are shown in Table 3, wherein the yield of 3a shown in Table 3 was determined by HPLC. 1 H NMR measurement (with CH2Br2as an internal standard), and the ee value was determined by HPLC.

[0043] Table 3

[0044]

[0045] Example 2

[0046] The embodiment provides a method for synthesizing a chiral diene compound from an aromatic hydrocarbon and an alkyne, and specific steps are as follows: under an inert atmosphere, 0.1 mmol of toluene 1a, 0.12 mmol of thioxanthene-S-oxide (TTSO) and 1 mL of acetonitrile are added into a 5 mL reaction tube provided with a magnet, and then 0.12 mmol of Tf2O is added into the reaction tube under -20 o C, and the reaction is continued for 20 min; the reaction tube is placed at room temperature, and 0.12 mmol of Tf2O is added into the reaction tube under room temperature, and the reaction is continued for 20 min; the reaction tube is placed at room temperature, and a base is added into the reaction tube under room temperature, and the reaction is continued for 2 h; the solvent is dried and removed to obtain an in-situ generated aryl thioxanthene onium salt 1a';

[0047] Under an inert atmosphere, 5 mmol% of Pd2(dba)3, 15 mmol% of L16 and 0.5 mL of THF are pre-stirred in a 5 mL reaction tube provided with a magnet for 1 h, and then 0.1 mmol of the in-situ generated aryl thioxanthene onium salt 1a', 0.3 mmol of 4-octyne 2a, 0.2 mmol of DIPEA, 0.2 mmol of NaOAc and 0.5 mL of THF are added into the reaction tube, and the reaction is continued for 22 h under room temperature; after the reaction is completed, the solvent is dried and removed under reduced pressure to obtain a trisubstituted chiral diene 3a crude product.

[0048] The results are shown in Table 4, wherein the yield of 3a shown in Table 4 is determined by H NMR (CH2Br2 as an internal standard), and the ee value is determined by HPLC. 1 H NMR (CH2Br2 as an internal standard), and the ee value is determined by HPLC.

[0049] Table 4

[0050]

[0051] In Table 4 above, a The reaction time represents 36 h;

[0052] .

[0053] Embodiment 3

[0054] The embodiment provides a method for synthesizing a chiral diene compound from an aromatic hydrocarbon and an alkyne, and specific steps are as follows: under an inert atmosphere, 0.3 mmol of toluene 1a, 0.36 mmol of thioxanthene-S-oxide and 1.5 mL of acetonitrile are added into a 5 mL reaction tube provided with a magnet, and then 0.36 mmol of Tf2O is added into the reaction tube under -20 o C, and the reaction is continued for 20 min; the reaction tube is placed at room temperature, and 0.12 mmol of Tf2O is added into the reaction tube under room temperature, and the reaction is continued for 20 min; the reaction tube is placed at room temperature, and a base is added into the reaction tube under room temperature, and the reaction is continued for 2 h; the solvent is dried and removed to obtain an in-situ generated aryl thioxanthene onium salt 1a';

[0055] In a 5 mL reaction tube equipped with a magnetic bar, 5 mmol% Pd2(dba)3, 15 mmol% L16 and 1 mL THF were pre-stirred for 1 h under inert atmosphere, then arylthianthrenium salt 1a’ was added in situ, 0.9 mmol 4-octyne 2a, 0.6 mmol DIPEA, 0.6 mmol NaOAc and 1 mL THF were added, and the reaction was stirred at room temperature for 36 h. After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure, and the product 3a was separated by column chromatography (petroleum ether) with an isolation yield of 84%, 91% ee, and in the form of an oil.

[0056] ;

[0057] The specific data of the chromatography, hydrogen spectrum, carbon spectrum and mass spectrum detection of product 3a are as follows:

[0058] HPLC conditions: Chiralpak OD-H, Hexane, 0.5 mL / min, 254 nm; tr(major) = 11.34 min, tr (minor) = 14.36 min.

[0059] 1 H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 7.9Hz, 2H), 5.58 – 5.52 (m, 1H), 2.43 – 2.36 (m, 2H), 2.34 (s, 3H), 2.17 – 2.10(m, 2H), 1.58 (h, J = 7.2 Hz, 2H), 1.08 (t, J = 7.4 Hz, 3H), 1.00 (t, J = 7.3Hz, 3H)。

[0060] 13 C NMR (100 MHz, CDCl3) δ 203.4, 136.1, 134.9, 129.1, 125.9, 106.0,95.9, 32.4, 22.5, 21.4, 21.2, 14.2, 13.8。

[0061] HRMS (EI): calculated for C 15 H 20 [M] +: 200.1560; Found: 200.1563.

[0062] Example 4

[0063] The procedure and conditions were the same as in Example 3, except that the starting material was tert-butylbenzene 1b. The product 3b was isolated by column chromatography (petroleum ether) in 88% yield, 90% ee as an oil.

[0064] ;

[0065] The specific data from the chromatographic, hydrogen, carbon and mass spectral analyses of product 3b are as follows:

[0066] HPLC conditions: Chiralpak OD-H, Hexane, 0.1 mL / min, 250 nm; tr(major) = 36.74 min, tr (minor) = 44.27 min.

[0067] 1 H NMR (400 MHz, CDCl3) δ 7.36 (s, 4H), 5.58 – 5.52 (m, 1H), 2.46 –2.33 (m, 2H), 2.18 – 2.11 (m, 2H), 1.60 (h, J = 7.4 Hz, 2H), 1.33 (s, 9H),1.09 (t, J = 7.4 Hz, 3H), 1.01 (t, J = 7.3 Hz, 3H)。

[0068] 13 C NMR (100 MHz, CDCl3) δ 203.5, 149.4, 134.9, 125.7, 125.3, 105.9,96.0, 34.6, 32.3, 31.5, 22.6, 21.4, 14.2, 13.8。

[0069] HRMS (EI): calculated for C 18 H 26 [M] + : 242.2029; Found: 242.2027.

[0070] Example 5

[0071] The operation process and conditions were the same as those in Example 3, except that the starting material was cyclohexylbenzene 1c. Product 3c was isolated by column chromatography (petroleum ether) with an isolated yield of 86% and 92% ee in the form of an oil.

[0072] ;

[0073] The specific data of the chromatographic, hydrogen, carbon and mass spectrometric detection of product 3c are as follows:

[0074] HPLC conditions: Chiralpak OD-H, Hexane, 0.5 mL / min, 254 nm; tr(major)= 9.05 min, tr(minor) = 11.71 min.

[0075] 1 H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 8.1Hz, 2H), 5.57 – 5.51 (m, 1H), 2.54 – 2.46 (m, 1H), 2.44 – 2.33 (m, 2H), 2.18 – 2.10 (m, 2H), 1.90 – 1.85 (m, 4H), 1.76 (d, J = 12.1 Hz, 1H), 1.59 (h, J =7.4 Hz, 2H), 1.48 – 1.46 (m, 5H), 1.09 (t, J = 7.4 Hz, 3H), 1.01 (t, J = 7.3 Hz, 3H).

[0076] 13 C NMR (100 MHz, CDCl3) δ 203.4, 146.4, 135.3, 126.9, 125.9, 106.1,96.0, 44.5, 34.6, 32.4, 27.1, 26.4, 22.6, 21.4, 14.2, 13.8.

[0077] HRMS(EI): calculated for C 20 H 28 [M] + : 268.2186; Found: 268.2187.

[0078] Example 6

[0079] The procedure and conditions were the same as Example 3, except that the starting material was 1-phenyl-2-pyrrolidinone 1d. The product 3d was isolated by column chromatography (petroleum ether: ethyl acetate = 3-10:1) in 72% isolated yield, 93% ee as an oil.

[0080] ;

[0081] The specific data of the product 3d from chromatography, hydrogen spectrum, carbon spectrum and mass spectrum detection are as follows:

[0082] HPLC conditions: Chiralpak OD-H, Hexane / iPrOH = 98 / 2, 0.7 mL / min, 250nm; tr (major) = 33.47 min, tr (minor) = 37.67 min.

[0083] 1 H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 8.7 Hz, 2H), 7.39 (d, J = 8.6Hz, 2H), 5.56 – 5.53 (m, 1H), 3.84 (t, J = 7.0 Hz, 2H), 2.59 (t, J = 8.1 Hz,2H), 2.43 – 2.30 (m, 2H), 2.18 – 2.08 (m, 4H), 1.55 (h, J = 7.4 Hz, 2H), 1.06(t, J = 7.4 Hz, 3H), 0.98 (t, J = 7.3 Hz, 3H)。

[0084] 13 C NMR (100 MHz, CDCl3) δ 203.6, 174.2, 137.8, 134.0, 126.3, 119.9,105.7, 96.2, 48.9, 32.8, 32.3, 22.5, 21.3, 18.1, 14.1, 13.7。

[0085] HRMS (EI): calculated for C 18 H 23 NO [M]+ : 269.1774; Found: 269.1776.

[0086] Example 7

[0087] The procedure and conditions were the same as in Example 3, except that the starting material was methyl phenylacetate 1e. The product 3e was isolated by column chromatography (petroleum ether: ethyl acetate = 50-200:1) in 71% isolated yield, 92% ee as an oil.

[0088] ;

[0089] The specific data from the chromatography, hydrogen spectrum, carbon spectrum and mass spectrum of the product 3e are as follows:

[0090] HPLC conditions: Chiralpak OD-H, Hexane / iPrOH = 99.8 / 0.2, 1.0 mL / min, 254 nm; tr (major) = 22.58 min, tr (minor) = 26.68 min.

[0091] 1 H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 8.1Hz, 2H), 5.58 – 5.52 (m, 1H), 3.69 (s, 3H), 3.61 (s, 2H), 2.43 – 2.32 (m,2H), 2.17 – 2.10 (m, 2H), 1.57 (h, J = 7.4 Hz, 2H), 1.07 (t, J = 7.4 Hz, 3H),1.00 (t, J = 7.3 Hz, 3H)。

[0092] 13 C NMR (100 MHz, CDCl3) δ 203.6, 172.2, 136.8, 132.0, 129.3, 126.2,105.9, 96.2, 41.0, 32.3, 22.5, 21.4, 14.1, 13.7。

[0093] HRMS (EI): calculated for C 17 H 22 O2 [M]+ : 258.1614; Found: 258.1615.

[0094] Example 8

[0095] The procedure and conditions were the same as Example 3 except that the starting material was 2-fluoroanisole 1f. The product 3f was isolated by column chromatography (petroleum ether: ethyl acetate = 50-200: 1) in 69% isolated yield, 94% ee as an oil.

[0096] ;

[0097] The specific data of the product 3f from the chromatography, hydrogen spectrum, fluorine spectrum, carbon spectrum and mass spectrum detection are as follows:

[0098] HPLC conditions: Chiralpak OD-H, Hexane, 1.0 mL / min, 254 nm; tr(major) = 8.72 min, tr (minor) = 10.93 min.

[0099] 1 H NMR (400 MHz, CDCl3) δ 7.18 – 7.12 (m, 1H), 7.09 (d, J = 8.7 Hz,1H), 6.90 (t, J = 8.7 Hz, 1H), 5.58 – 5.55 (m, 1H), 3.88 (s, 3H), 2.38 – 2.28(m, 2H), 2.16 – 2.09 (m, 2H), 1.58 – 1.51 (m, 2H), 1.07 (t, J = 7.4 Hz, 3H),0.99 (t, J = 7.3 Hz, 3H)。

[0100] 13 C NMR (100 MHz, CDCl3) δ 203.2, 152.6 (d, J 1 = 243.1 Hz), 146.3 (d, J 2 = 11.1 Hz), 131.3 (d, J 3 = 5.8 Hz), 121.3 (d, J 3 = 3.2 Hz), 113.9 (d, J 2 =19.1 Hz), 113.3 (d, J4 = 1.9 Hz), 105.2 (d, J 4 = 1.9 Hz), 96.6, 56.5, 32.3, 22.5, 21.3, 14.1, 13.7.

[0101] 19 F NMR (376 MHz, CDCl3) δ -136.6.

[0102] HRMS (EI): calculated for C 15 H 19 FO [M] + : 234.1420; Found: 234.1421.

[0103] Example 9

[0104] The operation process and conditions were the same as those in Example 3, except that the raw material was 1 g of 2-chloroanisole, and 3 g of the product was separated by column chromatography (petroleum ether: ethyl acetate = 100-200:1) with an isolated yield of 63%, 92% ee, and was in the form of an oil.

[0105] ;

[0106] The specific data of the chromatographic, hydrogen, carbon and mass spectrometric detection of product 3g are as follows:

[0107] HPLC conditions: Chiralpak OD-H, Hexane, 0.5 mL / min, 254 nm; tr(major) = 22.14 min, tr(minor) = 26.15 min.

[0108] 1 H NMR (400 MHz, CDCl3) δ 7.40 (s, 1H), 7.24 (d, J = 8.6 Hz, 1H), 6.86(d, J = 8.6 Hz, 1H), 5.59 – 5.53 (m, 1H), 3.88 (s, 3H), 2.38 – 2.27 (m, 2H), 2.16 – 2.09 (m, 2H), 1.54 (h, J = 7.4 Hz, 2H), 1.06 (t, J = 7.4 Hz, 3H), 0.98(t, J = 7.3 Hz, 3H).

[0109] 13 C NMR (100 MHz, CDCl3) δ 203.2, 153.6, 131.5, 127.9, 125.1, 122.6,112.0, 105.0, 96.6, 56.4, 32.3, 21.3, 14.1, 13.7.

[0110] HRMS (EI): calculated for C 15 H 19 ClO [M] + : 250.1119; Found: 250.1121. Example

[0111] The procedure and conditions were the same as Example 3, except that the starting material was 2-bromoanisole 1h. The product 3h was isolated by column chromatography (petroleum ether: ethyl acetate = 100-200:1) in 66% isolated yield, 92% ee as an oil.

[0112] ;

[0113] The specific data of the chromatography, hydrogen spectrum, carbon spectrum and mass spectrum of the product 3h are as follows:

[0114] HPLC conditions: Chiralpak OD-H, Hexane, 0.5 mL / min, 254 nm; tr(major) = 16.66 min, tr (minor) = 19.98 min.

[0115] 1 H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 1.8 Hz, 1H), 7.29 (dd, J = 8.5,1.8 Hz, 1H), 6.84 (d, J = 8.6 Hz, 1H), 5.60 – 5.53 (m, 1H), 3.88 (s, 3H),2.38 – 2.27 (m, 2H), 2.16 – 2.09 (m, 2H), 1.55 (h, J = 7.5 Hz, 2H), 1.06 (t, J = 7.4 Hz, 3H), 0.99 (t, J = 7.3 Hz, 3H)。

[0116] 13 C NMR (100 MHz, CDCl3) δ 203.2, 154.5, 131.9, 130.9, 125.9, 111.9,111.8, 104.9, 96.9, 56.5, 32.3, 22.5, 21.3, 14.1, 13.7.

[0117] HRMS (EI): calculated for C 15 H 19 BrO [M] + : 294.0614; Found: 294.0617.

[0118] Example 11

[0119] The procedure and conditions were the same as in Example 3, except that the starting material was ethyl 2-methoxybenzoate li, and the product 3i was isolated by column chromatography (petroleum ether: ethyl acetate = 20-200: 1) in 53% isolated yield, 92% ee, as an oil.

[0120] ;

[0121] The specific data of the chromatography, hydrogen spectrum, carbon spectrum and mass spectrum of the product 3i are as follows:

[0122] HPLC conditions: Chiralpak OD-H, Hexane / iPrOH = 99 / 1, 1.0 mL / min, 250nm; tr (major) = 7.87 min, tr (minor) = 8.96 min.

[0123] 1 H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 2.2 Hz, 1H), 7.48 (dd, J = 8.7,2.3 Hz, 1H), 6.91 (d, J = 8.7 Hz, 1H), 5.53 – 5.58 (tt, J = 6.0, 2.9 Hz, 1H),4.36 (q, J = 7.1 Hz, 2H), 3.88 (s, 3H), 2.43 – 2.29 (m, 2H), 2.16 – 2.09 (m,2H), 1.55 (h, J= 7.4 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H), 1.06 (t, J = 7.4 Hz,3H), 0.99 (t, J = 7.3 Hz, 3H)。

[0124] 13 C NMR (100 MHz, CDCl3) δ 203.2, 166.6, 157.8, 130.8, 130.0, 128.8,120.5, 112.3, 105.2, 96.5, 60.9, 56.3, 32.3, 22.5, 21.3, 14.4, 14.1, 13.8.

[0125] HRMS (EI): calculated for C 18 H 24 O3 [M] + : 288.1720; Found: 288.1714.

[0126] Example 12

[0127] The procedure and conditions were the same as in Example 3, except that the starting material was 1,2,3,4-tetrahydronaphthalene 1j, and the product 3j was isolated by column chromatography (petroleum ether) in 80% isolated yield, 88% ee, as an oil.

[0128] ;

[0129] The specific data for the chromatography, hydrogen spectrum, carbon spectrum and mass spectrum of the product 3j are as follows:

[0130] HPLC conditions: Chiralpak OD-H, Hexane, 0.5 mL / min, 254 nm; tr(major) = 9.85 min, tr (minor) = 11.11 min.

[0131] 1 H NMR (400 MHz, CDCl3) δ 7.18 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H), 7.03(d, J = 8.0 Hz, 1H), 5.57 – 5.52 (m, 1H), 2.78 (d, J= 6.0 Hz, 4H), 2.45 –2.34 (m, 2H), 2.19 – 2.12 (m, 2H), 1.85 – 1.78 (m, 4H), 1.59 (h, J = 7.4 Hz, 2H), 1.10 (t, J = 7.4 Hz, 3H), 1.02 (t, J = 7.3 Hz, 3H)。

[0132] 13 C NMR (100 MHz, CDCl3) δ 203.4, 137.0, 135.5, 135.0, 129.2, 126.5,123.4, 106.1, 95.8, 32.5, 29.7, 29.3, 23.5, 22.6, 21.4, 14.2, 13.8.

[0133] HRMS (EI): calculated for C 18 H 24 [M] + : 240.1873; Found: 240.1876.

[0134] Example 13

[0135] The procedure and conditions were the same as in Example 3, except that the starting materials were methyl 3-phenylpropanoate 1k and 3-hexynyl 2b, and the product 3k was isolated by column chromatography (petroleum ether: ethyl acetate = 30-200: 1) in 86% yield, 81% ee as an oil.

[0136] ;

[0137] The specific data of the chromatography, hydrogen spectrum, carbon spectrum and mass spectrum of the product 3k are as follows:

[0138] HPLC conditions: Chiralpak OJ-H, Hexane / iPrOH = 99 / 1, 0.5 mL / min, 250nm; tr (major) = 22.40 min, tr (minor) = 20.84 min.

[0139] 1 H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.1 Hz, 2H), 7.15 (d, J= 8.1Hz, 2H), 5.54 – 5.47 (m, 1H), 3.68 (s, 3H), 2.94 (t, J = 7.8 Hz, 2H), 2.63(t, J = 7.8 Hz, 2H), 2.45 – 2.36 (m, 2H), 1.77 (d, J = 7.0 Hz, 3H), 1.14 (t, J = 7.3 Hz, 3H).

[0140] 13 C NMR (100 MHz, CDCl3) δ 204.4, 173.5, 138.7, 135.8, 128.3, 126.2, 106.7, 89.6, 51.7, 35.8, 30.7, 23.0, 14.6, 12.7.

[0141] HRMS (EI): calculated for C 16 H 20 O2 [M] + : 244.1458; Found: 244.1462.

[0142] Example 14

[0143] The operation process and conditions were the same as those in Example 3, except that the starting materials were methyl 3-phenylpropionate 1k and 5-decyne 2c. The product 31 was isolated by column chromatography (petroleum ether:ethyl acetate = 30-200:1) with an isolated yield of 54% and 89% ee, and was an oil.

[0144] ;

[0145] The specific data of the chromatographic, hydrogen, carbon and mass spectrometric detection of product 3l are as follows:

[0146] HPLC conditions: Chiralpak OD-H, Hexane / iPrOH = 99.5 / 0.5, 1.0 mL / min, 250 nm; tr (major) = 18.34 min, tr (minor) = 26.29 min.

[0147] 1 H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.1 Hz, 2H), 7.14 (d,J = 7.8 Hz, 2H), 2.62(t, J = 7.8 Hz, 2H), 2.62(t, J = 7.8 Hz, 2H), 2.43 – 2.34 (m, 2H), 2.09 (q, J = 7.0 Hz, 2H), 1.57 –1.45 (m, 4H), 1.44 – 1.36 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H), 0.92 (d, J = 7.2Hz, 3H)。

[0148] 13 C NMR (100 MHz, CDCl3) δ 203.9, 173.5, 138.6, 135.8, 128.3, 126.2,105.3, 94.3, 51.7, 35.8, 31.5, 30.7, 30.4, 29.9, 22.8, 22.7, 14.1, 14.0。

[0149] HRMS (EI): calculated for C 20 H 28 O2 [M] + : 300.2084; Found: 300.2084.

[0150] Example 15

[0151] The procedure and conditions were the same as in Example 3, except that the starting materials were methyl 3-phenylpropanoate 1k and 2,9-dimethyl-5-decyne 2d. The product 3m was isolated by column chromatography (petroleum ether: ethyl acetate = 30-200: 1) in 73% isolated yield with 93% ee as an oil.

[0152] ;

[0153] The specific data of the chromatography, hydrogen spectrum, carbon spectrum and mass spectrum of the product 3m are as follows:

[0154] HPLC conditions: Chiralpak OD-H, Hexane / iPrOH = 99.5 / 0.5, 1.0 mL / min, 250 nm; tr (major) = 16.99 min, tr (minor) = 23.20 min.

[0155] 1 H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.0Hz, 2H), 5.47 – 5.40 (m, 1H), 3.68 (s, 3H), 2.94 (t, J = 7.8 Hz, 2H), 2.63(t, J = 7.8 Hz, 2H), 2.44 – 2.34 (m, 2H), 2.01 (t, J = 7.0 Hz, 2H), 1.79 –1.70 (m, 1H), 1.68 – 1.63 (m, 1H), 1.43 (q, J = 7.3 Hz, 2H), 0.98 (d, J = 6.6Hz, 3H), 0.97 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.6 Hz, 6H)。

[0156] 13 C NMR (100 MHz, CDCl3) δ 204.2, 173.5, 138.6, 135.7, 128.3, 126.2,104.9, 93.1, 51.7, 38.8, 37.4, 35.8, 30.7, 28.8, 28.0, 27.9, 22.7, 22.6,22.5。

[0157] HRMS (EI): calculated for C 22 H 32 O2 [M] + : 328.2397; Found: 328.2401.

[0158] Example 16

[0159] The procedure and conditions were the same as in Example 3, except that the starting materials were methyl 3-phenylpropanoate 1k and 6-dodecyne 2e. The product 3n was isolated by column chromatography (petroleum ether: ethyl acetate = 30-200: 1) in 77% isolated yield, 92% ee as an oil.

[0160] ;

[0161] The specific data of the product 3n from the chromatography, hydrogen spectrum, carbon spectrum and mass spectrum detection are as follows:

[0162] HPLC conditions: Chiralpak OD-H, Hexane / iPrOH = 99.5 / 0.5, 1.0 mL / min, 250 nm; tr (major) = 19.13 min, tr (minor) = 24.56 min.

[0163] 1 H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 7.9 Hz, 2H), 7.14 (d, J = 7.9Hz, 2H), 5.52 – 5.44 (m, 1H), 3.68 (s, 3H), 2.93 (t, J = 7.8 Hz, 2H), 2.63(t, J = 7.8 Hz, 2H), 2.45 – 2.32 (m, 2H), 2.11 (q, J = 6.9 Hz, 2H), 1.58 –1.50 (m, 2H), 1.48 – 1.32 (m, 8H), 0.96 – 0.86 (m, 6H).

[0164] 13 C NMR (100 MHz, CDCl3) δ 203.8, 173.5, 138.6, 135.8, 128.3, 126.1,105.4, 94.5, 51.7, 35.8, 31.8, 31.7, 30.7, 30.1, 29.0, 27.8, 22.7, 22.5,14.2, 14.1.

[0165] HRMS (EI): calculated for C 22 H 32 O2 [M] +: 328.2400; Found: 328.2404.

[0166] Example 17

[0167] The procedure and conditions were the same as Example 3, except that the starting materials were methyl 3-phenylpropionate Ik and 7-tetradecynyl 2f. The product 3o was isolated by column chromatography (petroleum ether: ethyl acetate = 30-200: 1) in 75% isolated yield, 94% ee as an oil.

[0168] ;

[0169] The specific data of the product 3o from the chromatography, hydrogen spectrum, carbon spectrum and mass spectrum detection are as follows:

[0170] HPLC conditions: Chiralpak OD-H, Hexane / iPrOH = 99.5 / 0.5, 1.0 mL / min, 250 nm; tr (major) = 18.94 min, tr (minor) = 24.42 min.

[0171] 1 H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0Hz, 2H), 5.52 – 5.43 (m, 1H), 3.68 (s, 3H), 2.94 (t, J = 7.8 Hz, 2H), 2.63(t, J = 7.8 Hz, 2H), 2.43 – 2.33 (m, 2H), 2.11 (q, J = 7.0 Hz, 2H), 1.57 –1.46 (m, 4H), 1.41 – 1.31 (m, 10H), 0.90 (t, J = 5.8 Hz, 6H)。

[0172] 13 C NMR (100 MHz, CDCl3) δ 203.8, 173.5, 138.6, 135.9, 128.3, 126.2,105.4, 94.5, 51.7, 35.8, 31.9, 31.6, 30.7, 30.2, 29.3, 29.2, 28.2, 22.8,22.6, 14.2, 14.2。

[0173] HRMS (ESI): calculated for C 24 H 36 O2Na [M+Na] + : 379.2608; Found:379.2608.

[0174] Example 18

[0175] The procedure and conditions were the same as in Example 3, except that the starting material was methyl 3-phenylpropanoate 1k and 8-hexadecyn-2g, and the product 3p was isolated by column chromatography (petroleum ether: ethyl acetate = 30-200: 1) in 77% isolated yield, 94% ee as an oil.

[0176] ;

[0177] The specific data of the product 3p from chromatography, hydrogen spectrum, carbon spectrum and mass spectrum detection are as follows:

[0178] HPLC conditions: Chiralpak OD-H, Hexane / iPrOH = 99.5 / 0.5, 1.0 mL / min, 250 nm; tr (major) = 19.20 min, tr (minor) = 24.84 min.

[0179] 1 H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0Hz, 2H), 5.51 – 5.44 (m, 1H), 3.68 (s, 3H), 2.94 (t, J = 7.8 Hz, 2H), 2.63(t, J = 7.8 Hz, 2H), 2.43 – 2.33 (t, J = 7.4 Hz, 2H), 2.11 (q, J = 7.0 Hz,2H), 1.57 – 1.44 (m, 4H), 1.39 – 1.24 (m, 14H), 1.91 – 0.87 (m, 6H).

[0180] 13C NMR (100 MHz, CDCl3) δ 203.8, 173.5, 138.6, 135.9, 128.3, 126.2, 105.4, 94.5, 51.7, 35.8, 32.1, 31.9, 30.7, 30.2, 29.6, 29.5, 29.4, 29.3, 29.1, 28.2, 22.9, 22.8, 14.2, 14.2.

[0181] HRMS (ESI): calculated for C 26 H 40 O2Na [M+Na] + : 407.2921; Found:407.2920.

[0182] Example 19

[0183] The procedure and conditions were the same as in Example 3, except that the starting materials were methyl 3-phenylpropanoate 1k and 1,8-dichloro-4-octyne 2h, and the product 3q was isolated by column chromatography (petroleum ether: ethyl acetate = 30-200:1) in 51% isolated yield, 88% ee as an oil.

[0184] ;

[0185] The specific data of the product 3q from the chromatography, hydrogen spectrum, carbon spectrum and mass spectrum detection are as follows:

[0186] HPLC conditions: Chiralpak OD-H, Hexane / iPrOH = 99 / 1, 1.0 mL / min, 250nm; tr (major) = 12.60 min, tr (minor) = 11.24 min.

[0187] 1 H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.1 Hz, 2H), 7.16 (d, J = 8.1Hz, 2H), 5.60 – 5.53 (m, 1H), 3.67 (s, 3H), 3.62 (t, J = 6.7 Hz, 4H), 2.94(t, J = 7.8 Hz, 2H), 2.64 – 2.55 (m, 6H), 2.03 (p, J = 6.9 Hz, 2H).

[0188] 13 C NMR (100 MHz, CDCl3) δ 204.4, 173.4, 139.5, 134.3, 128.6, 126.3,105.6, 91.7, 51.8, 44.8, 43.9, 35.7, 32.6, 30.9, 30.7, 27.2.

[0189] HRMS (ESI): calculated for C 18 H 22 Cl2O2Na [M+Na] + : 363.0890; Found:363.0890.

[0190] Example 20

[0191] The procedure and conditions were the same as Example 3, except that the starting materials were methyl 3-phenylpropanoate 1k and 1,8-diphenyl-4-octyne 2i, and the product 3r was isolated by column chromatography (petroleum ether: ethyl acetate = 30-200:1) in 84% isolated yield, 94% ee as an oil.

[0192] ;

[0193] The specific data of the product 3r from the chromatography, hydrogen spectrum, carbon spectrum and mass spectrum detection are as follows:

[0194] HPLC conditions: Chiralpak OD-H, Hexane / iPrOH = 99 / 1, 1.0 mL / min, 250nm; tr (major) = 18.82 min, tr (minor) = 21.63 min.

[0195] 1 H NMR (400 MHz, CDCl3) δ 7.33 – 7.27 (m, 4H), 7.25 – 7.20 (m, 8H),7.13 (d, J = 8.0 Hz, 2H), 5.60 – 5.53 (m, 1H), 3.71 (s, 3H), 2.96 (t, J = 7.8Hz, 2H), 2.82 (t, J = 7.4 Hz, 2H), 2.71 (t, J = 7.7 Hz, 2H), 2.65 (t, J= 7.8 Hz, 2H), 2.49 (q, J = 7.2 Hz, 2H), 2.45 – 2.38 (m, 2H), 1.90 – 1.79 (m, 2H).

[0196] 13 C NMR (100 MHz, CDCl3) δ 203.9, 173.5, 142.5, 141.8, 138.8, 135.3,128.7, 128.6, 128.4, 128.4, 128.3, 126.1, 126.0, 125.8, 105.6, 94.1, 51.7,35.8, 35.7, 31.1, 30.7, 29.7, 29.5.

[0197] HRMS (ESI): calculated for C 30 H 32 O2Na [M+Na] + : 447.2295; Found:447.2286.

[0198] Example 21

[0199] The procedure and conditions were the same as in Example 3, except that the starting materials were methyl 3-phenylpropanoate 1k and 1,8-dibenzyloxy-4-octyne 2j, and the product 3s was isolated by column chromatography (petroleum ether: ethyl acetate = 10-200:1) in 82% isolated yield, 91% ee as an oil.

[0200] ;

[0201] The specific data of the product 3s from the chromatography, hydrogen spectrum, carbon spectrum and mass spectrum detection are as follows:

[0202] HPLC conditions: Chiralpak OD-H, Hexane / iPrOH = 75 / 25, 0.5 mL / min,254 nm; tr (major) = 15.12 min, tr (minor) = 16.06 min.

[0203] 1 H NMR (400 MHz, CDCl3) δ 7.37 – 7.29 (m, 12H), 7.13 (d, J= 8.0 Hz, 2H), 5.60 – 5.53 (m, 1H), 4.53 (s, 4H), 3.69 (s, 3H), 3.63 (t, J = 6.6 Hz, 2H), 3.57 (t, J = 6.3 Hz, 2H), 2.95 (t, J = 7.8 Hz, 2H), 2.64 (t, J = 7.8 Hz, 2H), 2.53 – 2.50 (m, 2H), 2.44 (q, J = 6.6 Hz, 2H), 1.89 (p, J = 7.0 Hz, 2H).

[0204] 13 C NMR (100 MHz, CDCl3) δ 204.2, 173.4, 138.9, 138.6, 135.2, 128.4,128.3, 127.7, 127.7, 127.6, 127.6, 126.2, 105.5, 91.6, 73.1, 73.0, 70.0,69.9, 51.7, 35.7, 30.6, 29.8, 28.3, 26.5.

[0205] HRMS (ESI): calculated for C 32 H 36 O4Na [M+Na] + : 507.2506; Found:507.2492.

[0206] Example 22

[0207] The procedure and conditions were the same as Example 3, except that the starting materials were methyl 3-phenylpropanoate 1k and 2,2'-(4-octyn-1,8-diyl)bis(isoindoline-1,3-dione) 2k. The product 3t was isolated by column chromatography (petroleum ether: ethyl acetate = 3-20:1) in 81% isolated yield, 93% ee as an oil.

[0208] ;

[0209] The specific data of the product 3t from the chromatography, hydrogen spectrum, carbon spectrum and mass spectrum detection are as follows:

[0210] HPLC conditions: Chiralpak OD-H, Hexane / iPrOH = 70 / 30, 0.8 mL / min, 254 nm; tr (major) = 26.34 min, tr (minor) = 24.01 min.

[0211] 1 H NMR (400 MHz, CDCl3) δ 7.82 – 7.76 (m, 4H), 7.72 – 7.59 (m, 4H),7.13 (d, J = 7.4 Hz, 2H), 6.91 (d, J = 7.4 Hz, 2H), 5.56 – 5.46 (m, 1H), 3.82(t, J = 6.7 Hz, 2H), 3.69 (t, J = 7.0 Hz, 2H), 3.65 (d, J = 1.3 Hz, 3H), 2.82(t, J = 7.8 Hz, 2H), 2.62 – 2.47 (m, 4H), 2.43 – 2.30 (m, 2H), 1.84 (p, J =7.1 Hz, 2H)。

[0212] 13 C NMR (100 MHz, CDCl3) δ 204.1, 173.4, 168.4, 168.3, 138.9, 133.9,133.8, 132.3, 132.2, 128.2, 126.0, 123.3, 123.2, 105.5, 91.8, 51.7, 37.9,37.6, 35.6, 30.6, 28.4, 27.2, 27.0.

[0213] HRMS (ESI): calculated for C 34 H 30 N2O6Na [M+Na] + : 585.1997; Found:585.1998.

[0214] Example 23

[0215] The operating procedures and conditions were the same as in Example 3, except that the starting materials were 3-phenylpropionic acid methyl ester 1k and di-tert-butyl-4-octynoate 2l, and the product 3u was isolated by column chromatography (petroleum ether: ethyl acetate = 10-50:1) in 33% isolated yield, 80% ee, as an oil.

[0216] ;

[0217] The specific data of the chromatography, hydrogen spectrum, carbon spectrum and mass spectrum detection of product 3u are as follows:

[0218] HPLC conditions: Chiralpak OD-H, Hexane / iPrOH = 75 / 25, 0.8 mL / min, 254 nm; tr (major) = 5.77 min, tr (minor) = 5.45 min.

[0219] 1 H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 8.0Hz, 2H), 5.68 – 5.61 (m, 1H), 3.66 (s, 3H), 3.02 (d, J = 7.2 Hz, 2H), 2.93(t, J = 7.8 Hz, 2H), 2.69 – 2.65 (m, 2H), 2.61 (t, J = 7.8 Hz, 2H), 2.51 –2.43 (m, 2H), 1.45 (s, 9H), 1.45 (s, 9H).

[0220] 13 C NMR (100 MHz, CDCl3) δ 204.4, 173.4, 172.6, 170.7, 139.5, 134.4,128.5, 126.3, 106.0, 89.6, 81.1, 80.4, 51.7, 36.4, 35.8, 33.9, 30.7, 28.3,28.2, 24.9.

[0221] HRMS (ESI): calculated for C 26 H 36 O6Na [M+Na] +: 467.2405; Found: 467.2405.

[0222] Example 24

[0223] The procedure and conditions were the same as in Example 3, except that the starting materials were (2-methoxyethyl)benzene 1 1 and cyclododecatriene 2m. The product 3v was isolated by column chromatography (petroleum ether: ethyl acetate = 50-200: 1) in 52% isolated yield, 87% ee as an oil.

[0224] ;

[0225] The specific data from the chromatography, hydrogen spectrum, carbon spectrum and mass spectrum of the product 3v are as follows:

[0226] HPLC conditions: Chiralpak OD-H, Hexane, 1.0 mL / min, 254 nm; tr(major) = 11.46 min, tr (minor) = 14.01 min.

[0227] 1 H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 8.1Hz, 2H), 5.24 (t, J = 6.8 Hz, 1H), 3.60 (t, J = 7.1 Hz, 2H), 3.36 (s, 3H),2.87 (t, J = 7.1 Hz, 2H), 2.68 - 2.60 (m, 1H), 2.48 (t, J = 12.9 Hz, 1H),2.28 - 2.23 (m, 2H), 1.74 - 1.65 (m, 2H), 1.58 - 1.39 (m, 8H), 1.24 - 1.15(m, 3H), 1.11 - 1.00 (m, 1H).

[0228] 13C NMR (100 MHz, CDCl3) δ 206.2, 137.2, 135.0, 128.9, 126.4, 102.7, 91.9, 73.8, 58.8, 36.0, 28.5, 27.2, 27.0, 26.2, 25.7, 23.6, 22.8, 22.3, 21.9.

[0229] HRMS (ESI): calculated for C 21 H 30 ONa [M+Na] + : 321.2189; Found:321.2189.

[0230] Example 25

[0231] The procedure and conditions were the same as Example 3, except that the starting materials were 2,6-dimethylanisole 1m and cyclotetradecyne 2n. The product 3w was isolated by column chromatography (petroleum ether: ethyl acetate = 100-300: 1) in 80% isolated yield with 92% ee as an oil.

[0232] ;

[0233] The specific data of the product 3w from the chromatography, hydrogen spectrum, carbon spectrum and mass spectrum detection are as follows:

[0234] HPLC conditions: Chiralpak OD-H, Hexane, 1.0 mL / min, 254 nm; tr(major) = 7.09 min, tr (minor) = 9.10 min.

[0235] 1 H NMR (400 MHz, CDCl3) δ 7.04 (s, 2H), 5.49 – 5.42 (m, 1H), 3.72 (s, 3H), 2.47 – 2.41 (m, 1H), 2.39 – 2.33 (m, 1H), 2.29 (s, 6H), 2.23 – 2.08 (m, 2H), 1.65 – 1.60 (m, 1H), 1.57 – 1.53 (m, 1H), 1.48 – 1.29 (m, 18H).

[0236] 13C NMR (100 MHz, CDCl3) δ 204.0, 155.8, 133.3, 130.6, 126.5, 105.3,94.4, 59.8, 30.4, 28.9, 28.7, 28.6, 28.0, 27.8, 27.5, 27.2, 27.1, 27.0, 26.7,26.6, 16.4.

[0237] HRMS (ESI): calculated for C 24 H 37 O [M+H] + : 341.2839; Found: 341.2830.

[0238] Example 26

[0239] The procedure and conditions were the same as in Example 3, except that the starting materials were 3-phenylpropionic acid methyl ester 1k and cyclotetradecyne 2n, and the product 3x was isolated by column chromatography (petroleum ether: ethyl acetate = 100-300: 1) in 76% isolated yield, 90% ee as an oil.

[0240] ;

[0241] The specific data of the product 3x from the chromatography, hydrogen spectrum, carbon spectrum and mass spectrum detection are as follows:

[0242] HPLC conditions: Chiralpak OD-H, Hexane / iPrOH = 99.5 / 0.5, 1.0 mL / min,250 nm; tr (major) = 26.98 min, tr (minor) = 30.64 min.

[0243] 1 H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0Hz, 2H), 5.52 – 5.43 (m, 1H), 3.68 (s, 3H), 2.94 (t, J = 7.8 Hz, 2H), 2.63(t, J= 7.8 Hz, 2H), 2.50 – 2.41 (m, 1H), 2.40 – 2.31 (m, 1H), 2.25 – 2.07(m, 2H), 1.65 – 1.53 (m, 3H), 1.50 – 1.28 (d, J = 21.0 Hz, 17H)。

[0244] 13 C NMR (100 MHz, CDCl3) δ 204.2, 173.5, 138.7, 136.0, 128.3, 126.2,105.5, 94.7, 51.7, 35.8, 30.7, 30.2, 28.8, 28.6, 28.5, 28.0, 27.7, 27.5,27.2, 27.1, 27.0, 26.7, 26.6.

[0245] HRMS (ESI): calculated for C 25 H 36 O2Na [M+Na] + : 391.2608; Found:391.2607.

[0246] Example 27

[0247] The procedure and conditions were the same as in Example 3, except that the starting material was methyl 2-(l-(4-chlorobenzoyl)-5-methoxy-2-methyl-lH-indol-3- yl)acetate ln, and the product 3y was isolated by column chromatography (petroleum ether: ethyl acetate = 5-100: 1) in 54% isolated yield, 93% ee as an oil.

[0248] ;

[0249] The specific data of the product 3y from the chromatography, hydrogen spectrum, carbon spectrum and mass spectrum detection are as follows:

[0250] HPLC conditions: Chiralpak IE, Hexane / iPrOH = 97 / 3, 0.5 mL / min, 250nm; tr (major) = 33.83 min, tr (minor) = 32.55 min.

[0251] 1 H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.4 Hz, 2H), 7.45 (d,J = 8.4 Hz, 2H), 6.92 (s, 1H), 6.66 (s, 1H), 5.21 - 5.13 (m, 1H), 3.86 (s, 3H), 3.70 (s, 3H), 3.67 (s, 2H), 2.45 (s, 3H), 2.30 - 2.18 (m, 2H), 2.00 - 1.88 (m, 2H), 1.37 - 1.29 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H), 0.84 (t, J = 7.3 Hz, 3H).

[0252] 13 C NMR (100 MHz, CDCl3) δ 203.5, 171.5, 168.3, 153.9, 139.4, 135.9, 134.0, 131.4, 130.6, 129.5, 129.2, 124.7, 115.9, 112.5, 105.1, 100.2, 92.5, 56.1, 52.3, 35.0, 30.4, 22.3, 21.5, 13.9, 13.5, 13.3.

[0253] HRMS (ESI): calculated for C 28 H 30 ClNO4Na [M+Na] + : 502.1756; Found:502.1754.

[0254] Example 28

[0255] The procedure and conditions were the same as in Example 3, except that the starting material was salicin pentaacetate lo, and the product 3z was isolated by column chromatography (petroleum ether: ethyl acetate = 5-100: 1) with an isolated yield of 68%, 93% ee, as an oil.

[0256] ;

[0257] The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection chart of the product 3z are shown in Figure 1 and 2 , and the specific data of its chromatography, hydrogen spectrum, carbon spectrum and mass spectrum detection are as follows:

[0258] HPLC conditions: Chiralpak IE, Hexane / iPrOH = 90 / 10, 0.5 mL / min, 254 nm; tr (major) = 59.11 min, tr (minor) = 63.05 min.

[0259] 1 H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 2.3 Hz, 1H), 7.28 (dd, J = 8.6,2.3 Hz, 1H), 7.02 (d, J = 8.6 Hz, 1H), 5.56 – 5.51 (m, 1H), 5.32 – 5.24 (m,2H), 5.20 – 5.14 (m, 1H), 5.11 – 5.08 (m, 1H), 5.05 – 4.98 (m, 2H), 4.27 (dd, J = 12.3, 5.1 Hz, 1H), 4.17 (dd, J = 12.3, 2.5 Hz, 1H), 3.87 – 3.78 (m, 1H),2.40 – 2.30 (m, 2H), 2.14 – 2.11 (m, 3H), 2.08 – 2.05 (m, 8H), 2.03 (d, J =2.9 Hz, 6H), 1.54 (h, J = 7.4 Hz, 2H), 1.05 (t, J = 7.4 Hz, 3H), 0.97 (t, J =7.3 Hz, 3H)。

[0260] 13 C NMR (100 MHz, CDCl3) δ 203.4, 170.8, 170.7, 170.3, 169.5, 169.4,153.3, 133.4, 127.3, 126.8, 126.1, 116.3, 105.3, 99.7, 96.3, 72.8, 72.1,71.2, 68.5, 62.0, 61.4, 32.3, 22.4, 21.3, 21.0, 20.7, 20.6, 14.1, 13.7。

[0261] HRMS (ESI): calculated for C 31 H 40 O 12 K [M+K] + : 643.2152; Found:643.2139.

[0262] The above description is only the preferred embodiment of the application, not any limitation of the application. Any simple modification, change and equivalent change of the above embodiment according to the technical essence of the application are still within the protection scope of the technical solution of the application.

Claims

1. A method for synthesizing a chiral allene compound from an aromatic hydrocarbon and an alkyne, characterized in that: The following steps are involved: S1. Under an inert atmosphere, in a reaction vessel equipped with a magnet, an aromatic hydrocarbon and thianthrene-S-oxide are dissolved in an organic solvent 1 to obtain a mixture, an electrophilic activating reagent is added to the mixture for a preliminary reaction, and then an alkaline reagent 1 is added and stirred to react, and the solvent is spin-dried to obtain an in situ generated aryl thianthrene salt; The structural formula of the aromatic hydrocarbon is: , Among them, R 1 、R 2 、R 3 and R 4 Any one of H, C1-C6 alkyl, C1-C10 alkoxy, 4-10 membered cycloalkyl, halogen or amino; The structural formula of the thianthrene-S-oxide is: ； The electrophilic activation reagent is Tf2O, and the alkaline reagent 1 is Cs2CO3, Na2CO3, NaHCO3, K2CO3 or DIPEA; S2. Under an inert atmosphere, a palladium catalyst, a chiral ligand, and an organic solvent 2 are added to a reaction vessel equipped with a magnet and pre-stirred. The arylthianthrenium salt, alkyne, and alkaline reagent 2 generated in situ in S1 are added and reacted at room temperature. After the reaction is completed, the solvent is removed under reduced pressure and separated and purified by column chromatography to obtain a chiral allene compound. The palladium catalyst is any one of Pd2(dba)3·CHCl3, Pd(dba)2, Pd(PPh3)4, Pd(TFA)2, Pd(OAc)2 or Pd2(dba)3; The structural formula of the chiral ligand is: ； Among them, R 7 Selected from H, methyl, 、 or Any of; Ar is phenyl, 4-methoxyphenyl, 、 、 、 、 、 or Any of; The reaction equation for synthesizing chiral allene compounds from aromatic hydrocarbons and alkynes is: 。 2. The method for synthesizing a chiral allene compound from aromatic hydrocarbons and alkynes according to claim 1, wherein: The organic solvent 1 in S1 is acetonitrile, and the amount ratio of the aromatic hydrocarbon, thianthrene-S-oxide, organic solvent 1, electrophilic activator and alkaline reagent 1 is 0.3 mmol: 0.36 mmol: 1.5 mL: 0.36 mmol: 0.6 mmol.

3. The method for synthesizing chiral allene compounds from aromatic hydrocarbons and alkynes according to claim 1, characterized in that: The steps of the preliminary reaction described in S1 are: o C for 20 min, then moved to room temperature and continued to react for 20 min; the stirring reaction time was 2 h.

4. The method for synthesizing chiral allene compounds from aromatic hydrocarbons and alkynes according to claim 1, characterized in that: The organic solvent 2 in S2 is THF, PhMe, DCM, EA, ( i -Pr)2O or Dioxane, the alkyne is 3-hexyne, 4-octyne, 5-decyne, 2,9-dimethyl-5-decyne, 6-dodecyne, 7-tetradecyne, 8-hexadecyne, 1,8-dichloro-4-octyne, 1,8-diphenyl-4-octyne, 1,8-dibenzyloxy-4-octyne, 2,2'-(4-octyne-1,8-diyl)bis(isoindoline-1,3-dione), di-tert-butyl-4-octynoate, cyclododecyne or cyclopentadecyne Any one, the alkaline reagent 2 is any one of DIPEA, NaOAc, CsF, Na3PO4, Na2CO3, NaOAc / DIPEA, CsF / DIPEA, Na2CO3 / DIPEA or Na3PO4 / DIPEA. If the alkaline reagent 2 is any one of NaOAc / DIPEA, CsF / DIPEA, Na2CO3 / DIPEA or Na3PO4 / DIPEA, the mixing ratio thereof is 1:

1.

5. The method for synthesizing chiral allene compounds from aromatic hydrocarbons and alkynes according to claim 1, characterized in that: The amount ratio of the palladium catalyst, chiral ligand, organic solvent 2, arylthianthrenium salt, alkyne and base reagent 2 described in S2 is 0.015 mmol: 0.045 mmol: 2 mL: 0.3 mmol: 0.9 mmol: 0.6 mmol.

6. The method for synthesizing chiral allene compounds from aromatic hydrocarbons and alkynes according to claim 1, characterized in that: The pre-stirring time in S2 is 1 h, the reaction time at room temperature is 36 h, and the separation agent for column chromatography separation is petroleum ether or petroleum ether / ethyl acetate in a ratio of 3 to 300:1.

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