Asymmetric catalytic synthesis method and application of chiral azido tertiary alcohol and azolylene compound

Abstract

The application relates to an asymmetric catalytic synthesis method and application of chiral azido tertiary alcohol and azulenic compound. The method is characterized in that under an air atmosphere, a racemic azido tertiary alcohol compound ((+ / -) I) and tri (4-methylphenyl) phosphorus (II) are reacted in toluene by taking chiral tartaric acid derivative phosphoric acid C1, a spirochiral phosphoric acid C2 or octahydroazulene phosphoric acid C3 as a chiral catalyst, the reaction is carried out at 30 DEG C for 17-72 hours, and target chiral azido tertiary alcohol compound (I) and chiral azulenic compound (III) are obtained through separation and purification. S I) and chiral azulenic compound (III) can be used for synthesizing chiral ligand IV, and deuterium water can be added in the reaction system to be used for synthesizing chiral deuterated azulenic compound (D-III).

Description

Technical Field

[0001] This invention belongs to the field of asymmetric catalytic synthesis technology, specifically relating to an asymmetric catalytic synthesis method and its application for chiral azaethynyl tertiary alcohols and aza-allenes. Background Technology

[0002] Imine-containing aza-aromatic hydrocarbons (such as pyridine and quinoline) are widely found in natural products, pharmaceuticals, catalysts, and functional materials. Many of these aza-aryl ethynyl tertiary alcohols possess biological activity, and their synthesis methods include: nucleophilic addition of alkynyl reagents to ketones, nucleophilic addition of aza-aryl ketones, and coupling of ethynyl tertiary alcohols with aza-aromatic hydrocarbon derivatives. However, there are currently no reports on the enantioselective synthesis of chiral aza-aryl ethynyl tertiary alcohols. This may be due to the strong nucleophilicity of the nitrogen atom in aza-aromatic hydrocarbons, which easily interferes with catalytic cycles, making it incompatible with current strategies.

[0003] On the other hand, aryl or alkyl-substituted propargyl tertiary alcohols have been used to construct a large number of useful compounds, achieving remarkable success in the enantioselective synthesis of axially chiral allenes. For example, the research groups of Sun Jianwei and Li Wenjun have successively developed chiral allenes. Acid-catalyzed reactions of racemic propargyl alcohols with various nucleophiles have enabled the synthetic transformation of multi-substituted chiral allenes. In 2019, Asahi Akira's research group reported on the synthesis of chiral Pd complexes and achiral allenes. Under acid catalysis, highly enantioselective synthesis of ethynyl tertiary alcohols was achieved through kinetic resolution, but none of them were chiral ethynyl tertiary alcohols substituted with aza-aromatic hydrocarbons.

[0004] Based on the above, this invention patent utilizes chiral phosphoric acid to preferentially act on nitrogen-containing aromatic hydrocarbons to enhance their electron-withdrawing ability, and in the chiral... Under the induction of an acid catalyst, phosphorus-containing compounds readily undergo nucleophilic addition to one of the isomers of azeotylenyl tertiary alcohols, followed by a deoxygenation-protonation process, thereby achieving the kinetic resolution of racemic azeotylenyl tertiary alcohols and simultaneously completing the asymmetric catalytic synthesis of azeoline compounds. If deuterium water is added to the reaction system, chiral deuterated azeoline compounds can be synthesized; chiral azeotylenyl tertiary alcohols can also be used for the synthesis of chiral ligands. Summary of the Invention

[0005] The purpose of this invention is to overcome the shortcomings of existing technologies and provide an asymmetric catalytic synthesis method for chiral azeotropic tertiary alcohols and azeotropic allenes, along with their applications. This method uses simple substrates, operates under mild conditions, involves no heavy metals, exhibits good atom economy, and achieves high yields. It yields two classes of highly enantioselective azeotropic aromatic compounds in a single step, and the chiral azeotropic tertiary alcohols can also be used for the synthesis of chiral ligands.

[0006] To achieve the above objectives, the present invention adopts the following technical solution:

[0007] An asymmetric catalytic synthesis method for chiral azaethynyl tertiary alcohols and aza-alkenes is described below:

[0008] In an air atmosphere, racemic azirethynyl tertiary alcohol compound (±)-I and tris(4-tolyl)phosphine II were reacted in toluene with chiral tartaric acid-derived phosphoric acid C1, spirocyclic chiral phosphoric acid C2, or octahydronaphthyl phosphate C3 as chiral catalysts at 20–30 °C until complete reaction. The target chiral azirethynyl tertiary alcohol compound SI and chiral azirethynyl allene compound III were obtained by separation and purification.

[0009]

[0010] In formulas (±)-Ⅰ, SI, and Ⅲ, Ar represents aryl compounds containing different substituents and of different types; Alkyl represents alkyl compounds containing different substituents and of different types.

[0011] Specifically, the molar ratio of racemic azirtylenol (±)-I to tris(4-tolyl)phosphine II is 1:1.2, the amount of chiral phosphoric acid C1, C2 or C3 added is preferably 10-20% of the molar amount of racemic azirtylenol (±)-I, the solvent is toluene, the temperature is 30°C, and the reaction time is 17-72 hours.

[0012] Preferably, Ar is R3 and R4 are each independently selected from one of H, Cl, F, Br, Me, MeO, and OTf, and R1 is... L1 is H, Cl, F, Br, Me, MeO, or CF3, and R2 is... Or a C1-C6 alkyl group, where L2 is H, Me, or MeO.

[0013] The chiral azirethynyl tertiary alcohols and azirenes obtained by the above-described asymmetric catalytic synthesis method, specifically, the chiral azirethynyl tertiary alcohols have the structure of the above-described general formula S-1, and the azirenes have the structure of the above-described general formula III, where Ar is... R3 and R4 are each independently selected from one of H, Cl, F, Br, Me, MeO, and OTf, and R1 is... L1 is H, Cl, F, Br, Me, MeO, or CF3, R2 is Or a C1-C6 alkyl group, where L2 is H, Me, or MeO.

[0014] In the preparation process of this application, deuterium water can also be added to the reaction system. The amount of deuterium water added is 100 times the molar amount of the azirynyl tertiary alcohol compound (±)–I, thereby obtaining the deuterated compound D-III.

[0015] The application of the above-mentioned chiral azinoethynyl tertiary alcohol compounds in the synthesis of catalyst ligands is as follows: Compound S-1 and solvent are added to a reaction flask, followed by the addition of azidotrimethylsilane. The mixture is stirred at 100°C until the reaction is complete. After the reaction is finished, ethyl acetate and water are added, and the organic layer is separated. Subsequently, the organic layer is further extracted with water, dried with anhydrous sodium sulfate, filtered, and then separated by column chromatography to obtain the final product. The molar ratio of compound S-1 to azidotrimethylsilane is 1:3, the preferred solvent is DMF, and the concentration of compound S-1 in the solvent is 0.1 mol / L.

[0016] Compared with the prior art, the beneficial effects of the method of the present invention are as follows:

[0017] This invention utilizes chiral phosphoric acid to preferentially act on nitrogen-containing aromatic hydrocarbons in the reaction, thereby enhancing their electron-withdrawing ability, and in the chiral... Under the induction of an acid catalyst, phosphorus-containing compounds readily undergo nucleophilic addition to one isomer of azaethynyl tertiary alcohol, followed by a deoxygenation-protonation process, thereby achieving the kinetic resolution of racemic azaethynyl tertiary alcohols and simultaneously completing the asymmetric catalytic synthesis of azahexenes. Adding deuterium water to the reaction system can facilitate the preparation of chiral deuterated azahexenes; chiral azaethynyl tertiary alcohols can also be used for the synthesis of chiral ligands. The reaction conditions are mild, with no heavy metal involvement, good atom economy, stability, high efficiency, simple operation, environmental friendliness, broad substrate range, high product conversion rate, and good enantioselectivity. Compared with existing synthetic methods, the most significant feature of this invention is that it achieves the asymmetric catalytic synthesis of chiral azaethynyl tertiary alcohols and azahexenes in a single step through the kinetic resolution of racemic substrates. This method is green and environmentally friendly, and has significant potential for widespread application. Detailed Implementation

[0018] The technical solution of the present invention will be further described in detail below with reference to the embodiments, but the scope of protection of the present invention is not limited thereto.

[0019] In the examples described below, the chiral spirocyclic phosphates C1, C2, or C3 were purchased from Daicel.

[0020] Example 1

[0021] The specific preparation steps for (S)-1-phenyl-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol and (S)-1-phenyl-1-benzyl-3-(pyridin-2-yl)propadiene are as follows:

[0022]

[0023] Racemic 1-phenyl-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol 28.3 mg (0.1 mmol) and chiral phosphate C1 22.6 mg (0.02 mmol) were added to a 10 mL reaction flask, followed by 2.0 mL of toluene and 36.5 mg (0.12 mmol) of tris(4-tolyl)phosphide. The reaction flask was placed in a 30 °C incubator and stirred for 72 hours. After the reaction was completed (the reaction completion time was determined by monitoring the ee value of the tertiary alcohol of the substrate by HPLC), the mixture was directly separated by column chromatography (n-hexane / ethyl acetate 30-3:1) to obtain (S)-1-phenyl-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol 11.9 mg and (S)-1-phenyl-1-benzyl-3-(pyridin-2-yl)propadiene 11.6 mg.

[0024] (S)-1-Phenylacetyl-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol is a yellow solid with a yield of 40% and an optical purity of 91% ee. Its melting point is 145.3-146.0 °C, and its NMR data are as follows: 1 H NMR (600MHz, CDCl3) δ8.50–8.44(m,1H),7.61–7.52(m,3H),7.31–7.25(m, 3H),7.25–7.20(m,1H),7.20–7.11(m,6H),3.27–3.18(m,2H),3.05(s,1H). 13 C NMR (151MHz, CDCl3) δ 150.1, 143.7, 142.9, 136.3, 135.8, 131.2, 128.3, 128.0, 127.9, 127.4, 127.1, 125.8, 123.2, 91.5, 86.4, 73.6, 51.8. High-resolution data are: HRMS (ESI) m / z 300.1378 (M+H + ),calc.for C 21 H 18 NO + 300.1383.

[0025] (S)-1-Phenylon-1-benzyl-3-(pyridin-2-yl)propadiene is a yellow oil in yield of 43% and optical purity of 90% ee. NMR data are as follows: 1H NMR (600MHz, CDCl3) δ8.49–8.42(m,1H),7.51(td,J=7.7,1.7Hz,1H),7.42–7.37(m,2H),7.30(d,J=8.0Hz,1H),7. 27–7.20(m,4H),7.19–7.12(m,3H),7.09(t,J=7.4Hz,1H),7.02(m,1.0Hz,1H),6.61(t,J=2.4Hz,1H),3.88(m,2H). 13 C NMR (151MHz, CDCl3) δ 209.9, 154.3, 149.3, 138.8, 136.5, 134.8, 128.8, 128.6, 128.4, 127.5, 126.5, 126.4, 121.6, 121.4, 109.8, 99.3, 37.0. High-resolution data: HRMS (ESI) m / z 284.1431 (M+H + ),calc.for C 21 H 18 N + 284.1434.

[0026] Example 2

[0027] The reaction formulas for the synthesis of (S)-1-(4-fluorophenyl)-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol and (S)-1-(4-fluorophenyl)-1-benzyl-3-(pyridin-2-yl)propadiene are as follows:

[0028]

[0029] In this embodiment, the racemic 1-phenyl-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol from Example 1 was replaced with racemic 1-(4-fluorophenyl)-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol, and the other steps were the same as in Example 1, yielding 13.9 mg of (S)-1-(4-fluorophenyl)-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol and 12.9 mg of (S)-1-(4-fluorophenyl)-1-benzyl-3-(pyridin-2-yl)propadiene.

[0030] (S)-1-(4-fluorophenyl)-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol is a yellow solid with a yield of 44% and an optical purity of 91% ee. Its melting point is 133.0-134.1 °C. NMR data are as follows: 1H NMR(400MHz, CDCl3)δ8.49(m,1H),7.61(m,1H),7.55–7.48(m,2H),7.31(m,1H),7 .24–7.15(m,4H),7.12(m,2H),7.01–6.85(m,2H),3.30–3.12(m,2H),2.75(s,1H). 13 C NMR (151MHz, CDCl3) δ162.5 (d, J = 246.1Hz), 161.7, 149.9, 142.5, 139.5, 139.5, 136.6, 135.5, 132.2 (d, J = 10.3Hz), 131 .1,129.3(d,J=12.4Hz),128.0,127.7(d,J=8.2Hz),127.4,127.2,123.3,115.0(d,J=21.5Hz),91.7,86.2,73.2,51.9. 19 F NMR (565MHz, CDCl3) δ-115.0. High-resolution data are: HRMS (ESI) m / z 318.1284 (M+H + ),calc.for C 21 H 17 FNO + 318.1289.

[0031] (S)-1-(4-fluorophenyl)-1-benzyl-3-(pyridin-2-yl)propadiene is a yellow oil with a yield of 43% and an optical purity of 93% ee. Its melting point is 133.0-134.1℃, and its NMR data are as follows: 1 H NMR (600MHz, CDCl3) δ8.50–8.44(m,1H),7.52(td,J=7.7,1.7Hz,1H),7.39–7.31(m,2H),7.28(d,J=7.9Hz,1H),7.24(d, J=7.5Hz,2H),7.21–7.14(m,2H),7.10(t,J=7.3Hz,1H),7.05–7.01(m,1H),6.94–6.86(m,2H),6.60(s,1H),3.86(m,2H). 13C NMR (151MHz, CDCl3) δ209.7, 162.3 (d, J = 247.1Hz), 161.5, 154.3, 149.6, 138.6, 136.7, 130.9, 128. 9,128.6,128.2(d,J=8.1Hz),126.7,121.7(d,J=39.1Hz),115.7(d,J=21.7Hz),109.0,99.4,37.3. 19 F NMR (565MHz, CDCl3) δ-114.7. High-resolution data are: HRMS (ESI) m / z 302.1338 (M+H + ),calc.for C 21 H 17 FN + 302.1340.

[0032] Example 3

[0033] The reaction formulas for the synthesis of (S)-1-(3-chlorophenyl)-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol and (S)-1-(3-chlorophenyl)-1-benzyl-3-(pyridin-2-yl)propadiene are as follows:

[0034]

[0035] In this embodiment, the racemic 1-phenyl-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol from Example 1 was replaced with racemic 1-(3-chlorophenyl)-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol. The reaction time was 48 hours, and the other steps were the same as in Example 1, yielding 14.7 mg of (S)-1-(3-chlorophenyl)-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol and 13.3 mg of (S)-1-(3-chlorophenyl)-1-benzyl-3-(pyridin-2-yl)propadiene.

[0036] (S)-1-(3-chlorophenyl)-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol is a yellow solid with a yield of 44% and an optical purity of 91% ee. Its melting point is 107.5–109.2 °C. NMR data are as follows: 1 H NMR (600MHz, CDCl3) δ8.34(d,J=5.3Hz,1H),7.55(d,J=7.6Hz,2H),7.28(t,J=7.4Hz,3H) ,7.23(t,J=7.2Hz,1H),7.18(m,4H),7.15–7.09(m,2H),3.24–3.20(m,2H),2.87(s,1H). 13C NMR (151MHz, CDCl3) δ 149.9, 145.9, 142.5, 136.5, 135.4, 134.2, 131.1, 129.5, 128.1, 128.0, 127.4, 127.3, 126.1, 124.3, 123.4, 91.2, 86.4, 73.0, 51.8. High-resolution data is: HRMS (ESI) m / z 334.0988 (M+H + ),calc.for C 21 H 17 ClNO + 334.0993.

[0037] (S)-1-(3-chlorophenyl)-1-benzyl-3-(pyridin-2-yl)propadiene is a yellow oil with a yield of 42% and an optical purity of 93% ee. NMR data are as follows: 1 H NMR (600MHz, CDCl3) δ8.47(d,J=4.8Hz,1H),7.53(td,J=7.7,1.6Hz,1H),7.37(s,1H),7.25(dd,J= 15.2,8.1Hz,4H),7.20–7.08(m,5H),7.05(dd,J=7.1,5.2Hz,1H),6.63(s,1H),3.91–3.79(m,2H). 13 C NMR (151MHz, CDCl3) δ 209.9, 154.0, 149.6, 138.4, 137.1, 136.7, 134.7, 129.9, 128.9, 128.6, 127.6, 126.7, 126.7, 124.7, 122.0, 121.7, 109.1, 99.8, 37.0. High-resolution data: HRMS (ESI) m / z 318.1040 (M+H + ), calc.forC 21 H 17 ClN + 318.1044.

[0038] Example 4

[0039] The reaction formulas for the synthesis of (S)-1-(2-methylphenyl)-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol and (S)-1-(2-methylphenyl)-1-benzyl-3-(pyridin-2-yl)propadiene are as follows:

[0040]

[0041] In this embodiment, the racemic 1-phenyl-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol from Example 1 was replaced with racemic 1-(2-methylphenyl)-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol. The chiral catalyst C1 was 0.1 equivalents of the tertiary alcohol, the reaction time was 24 hours, and the other steps were the same as in Example 1. 13.1 mg of (S)-1-(2-methylphenyl)-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol and 12.8 mg of (S)-1-(2-methylphenyl)-1-benzyl-3-(pyridin-2-yl)propadiene were obtained.

[0042] (S)-1-(2-methylphenyl)-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol is a yellow solid with a yield of 42% and an optical purity of 86% ee. Its melting point is 89.2-90.8℃, and its NMR data are as follows: 1 H NMR (400MHz, CDCl3) δ8.47(dd,J=4.9,0.7Hz,1H),7.62(d,J=7.5Hz,1H),7.56(td,J=7.7,1.8Hz,1H),7.26(d,J=7.8Hz ,1H),7.22–7.16(m,5H),7.14(m,3H),7.11–7.05(m,1H),3.38(d,J=13.4Hz,1H),3.24(d,J=13.4Hz,1H),2.65(s,4H). 13 C NMR (101MHz, CDCl3) δ 149.8, 142.7, 140.6, 136.6, 135.8, 135.5, 132.4, 131.3, 128.1, 127.9, 127.3, 127.2, 126.4, 125.9, 123.2, 92.3, 86.3, 73.3, 48.5, 21.8. High-resolution data: HRMS (ESI) m / z 314.1533 (M+H + ),calc.for C 22 H 20 NO + 314.1539.

[0043] (S)-1-(2-methylphenyl)-1-benzyl-3-(pyridin-2-yl)propadiene is a yellow oil in yield of 43% and has an optical purity of 85% ee. NMR data are as follows: 1H NMR (600MHz, CDCl3) δ8.42(s,1H),7.50(td,J=7.8,1.6Hz,1H),7.28(d,J=7.9Hz,1H),7.20–7.10(m ,5H),7.12–7.06(m,4H),7.01–6.96(m,1H),6.34(t,J=2.5Hz,1H),3.77–3.68(m,2H),2.23(s,3H). 13 C NMR (151MHz, CDCl3) δ 206.9, 154.8, 149.2, 138.7, 136.3, 136.2, 135.9, 130.6, 129.1, 128.3, 128.2, 127.4, 126.5, 125.9, 121.5, 121.4, 109.0, 96.8, 41.0, 20.6. High-resolution data: HRMS (ESI) m / z 298.1587 (M+H + ),calc.for C 22 H 20 N + 298.1590.

[0044] Example 5

[0045] The reaction formulas for the synthesis of (S)-1-(3-methoxyphenyl)-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol and (S)-1-(3-methoxyphenyl)-1-benzyl-3-(pyridin-2-yl)propadiene are as follows:

[0046]

[0047] In this embodiment, the racemic 1-phenyl-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol from Example 1 was replaced with racemic 1-(3-methoxyphenyl)-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol, and the other steps were the same as in Example 1, yielding 14.8 mg of (S)-1-(3-methoxyphenyl)-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol and 13.1 mg of (S)-1-(3-methoxyphenyl)-1-benzyl-3-(pyridin-2-yl)propadiene.

[0048] (S)-1-(3-methoxyphenyl)-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol is a yellow solid with a yield of 45% and an optical purity of 91% ee. Its melting point is 103.1–104.2 °C. NMR data are as follows: 1H NMR(400MHz, CDCl3) δ8.46(dd,J=4.9,0.7Hz,1H),7.56(td,J=7.7,1.8Hz,1H),7.28(d,J=7.8Hz,1H),7.22–7.13(m, 8H),7.11–7.08(m,1H),6.81–6.63(m,1H),3.70(s,3H),3.24(d,J=13.2Hz,1H),3.20(d,J=13.2Hz,1H),2.88(s,1H). 13 C NMR (151MHz, CDCl3) δ 159.6, 149.9, 145.4, 142.7, 136.4, 135.8, 131.2, 129.3, 128.0, 127.4, 127.1, 123.2, 118.3, 113.6, 111.4, 91.8, 86.1, 73.4, 55.4, 51.7. High-resolution data: HRMS (ESI) m / z 330.1484 (M+H + ),calc.for C 22 H 20 NO2 + 330.1489.

[0049] (S)-1-(3-methoxyphenyl)-1-benzyl-3-(pyridin-2-yl)propadiene is a yellow oil with a yield of 42% and an optical purity of 92% ee. NMR data are as follows: 1 H NMR(600MHz, CDCl3)δ8.45(d,J=4.5Hz,1H),7.51(td,J=7.7,1.7Hz,1H),7.29(d,J=7.9Hz,1H),7.25(d,J=7.3Hz,2H),7.20–7.11(m,3H),7.0 9(t,J=7.4Hz,1H),7.05–6.96(m,2H),6.95–6.92(m,1H),6.70(dd,J=8.1,2.4Hz,1H),6.60(t,J=2.4Hz,1H),3.91–3.81(m,2H),3.67(s,3H). 13 C NMR (151MHz, CDCl3) δ 210.0, 159.9, 154.4, 149.5, 138.9, 136.6, 136.5, 129.7, 128.9, 128.5, 126.6, 121.8, 121.6, 119.1, 112.9, 112.5, 109.8, 99.4, 55.3, 37.2. High-resolution data: HRMS (ESI) m / z 314.1535 (M+H + ),calc.for C22 H 20 NO + 314.1539.

[0050] Example 6

[0051] The reaction formulas for the synthesis of (S)-1-(3-trifluoromethylphenyl)-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol and (S)-1-(3-trifluoromethylphenyl)-1-benzyl-3-(pyridin-2-yl)propadiene are as follows:

[0052]

[0053] In this embodiment, the racemic 1-phenyl-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol from Example 1 was replaced with racemic 1-(3-trifluoromethylphenyl)-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol, the chiral catalyst C1 was 0.1 equivalents of the tertiary alcohol, and the other steps were the same as in Example 1, yielding 16.1 mg of (S)-1-(3-trifluoromethylphenyl)-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol and 15.4 mg of (S)-1-(3-trifluoromethylphenyl)-1-benzyl-3-(pyridin-2-yl)propadiene.

[0054] (S)-1-(3-trifluoromethylphenyl)-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol is a yellow solid with a yield of 44% and an optical purity of 90% ee. Its melting point is 113.4-115.0 °C, and its NMR data are as follows: 1 H NMR(600MHz, CDCl3)δ8.45(d,J=4.0Hz,1H),7.58(td,J=7.7,1.5Hz,1H),7.56–7.51(m,2H),7.40(d,J=6.8Hz,1H) ,7.35(s,1H),7.31–7.20(m,6H),7.20–7.12(m,1H),3.29(d,J=13.3Hz,1H),3.23(d,J=13.3Hz,1H),2.37(s,1H). 13 C NMR(151MHz, CDCl3)δ149.7,143.3,142.3,136.9,136.4,134.4,129.9(q,J=32.1Hz),128.2,128.0,128.0, 127.8(q,J=3.8Hz),127.2,125.7,124.2(q,J=272.1Hz),123.6(q,J=3.8Hz),123.3,91.3,86.5,73.4,51.3. 19F NMR (565MHz, CDCl3) δ -62.5. High-resolution data are: HRMS (ESI) m / z 368.1253 (M+H + ), calc.forC 22 H 17 F3NO + 368.1257.

[0055] (S)-1-(3-trifluoromethylphenyl)-1-benzyl-3-(pyridin-2-yl)propadiene is a yellow oil with a yield of 44% and an optical purity of 90% ee. NMR data are as follows: 1 H NMR (600MHz, CDCl3) δ8.46(dt,J=5.0,1.5Hz,1H),7.54(s,1H),7.51(td,J=7.7,1.8Hz,1H),7.43(d,J=7.6Hz,1H),7.40–7.37(m,2H),7.35 (d,J=7.8Hz,1H),7.29(d,J=7.7Hz,1H),7.27–7.23(m,3H),7.20–7.14(m,1H),7.06–6.99(m,1H),6.58(t,J=2.7Hz,1H),3.97–3.86(m,2H). 13 C NMR (151MHz, CDCl3) δ209.6, 153.9, 149.6, 139.7, 136.4, 134.6, 132.3, 130.6 (q, J = 32.1Hz), 128.8, 128.7, 127. 7,126.4,126.3,125.7(q,J=3.7Hz),124.1(q,J=272.1Hz),123.4(q,J=3.8Hz),121.8,121.4,109.4,99.9,36.8. 19 F NMR (565MHz, CDCl3) δ -62.6. High-resolution data are: HRMS (ESI) m / z 352.1304 (M+H + ),calc.for C 22 H 17 F3N + 352.1308. Example 7

[0056] The reaction formulas for the synthesis of (S)-1-phenyl-1-(3-methylbenzyl)-3-(pyridin-2-yl)propyl-2-yn-1-ol and (S)-1-phenyl-1-(3-methylbenzyl)-3-(pyridin-2-yl)propadiene are as follows:

[0057]

[0058] In this embodiment, the racemic 1-phenyl-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol from Example 1 was replaced with racemic 1-phenyl-1-(3-methylbenzyl)-3-(pyridin-2-yl)propyl-2-yn-1-ol, and the other steps were the same as in Example 1, yielding 14.1 mg of (S)-1-phenyl-1-(3-methylbenzyl)-3-(pyridin-2-yl)propyl-2-yn-1-ol and 12.8 mg of (S)-1-phenyl-1-(3-methylbenzyl)-3-(pyridin-2-yl)propadiene.

[0059] (S)-1-Phenylon-1-(3-methylbenzyl)-3-(pyridin-2-yl)propyl-2-yn-1-ol is a yellow solid with a yield of 45% and an optical purity of 89% ee. Its melting point is 110.4–112.2 °C, and its NMR data are as follows: 1 H NMR (600MHz, CDCl3) δ8.59–8.52(m,1H),7.71–7.65(m,2H),7.63(td,J=7.7,1.8Hz,1H),7.36(t,J=7.5Hz,3H),7.30(m ,1H),7.23(m,1H),7.15(t,J=7.7Hz,1H),7.09–7.01(m,3H),3.3(d,J=13.3Hz,1H),3.2(d,J=13.3Hz,1H),2.28(s,3H). 13 C NMR (151MHz, CDCl3) δ 149.8, 143.7, 142.7, 137.4, 136.3, 135.5, 132.0, 128.1, 128.1, 127.8, 127.8, 127.3, 125.7, 123.1, 91.9, 86.1, 73.4, 51.7, 21.4. High-resolution data: HRMS (ESI) m / z 314.1536 (M+H + ),calc.for C 22 H 20 NO + 314.1539.

[0060] (S)-1-Phenylon-1-(3-methylbenzyl)-3-(pyridin-2-yl)propadiene is a yellow oil with a yield of 43% and an optical purity of 90% ee. NMR data are as follows: 1H NMR (600MHz, CDCl3) δ8.56–8.51(m,1H),7.59(td,J=7.7,1.8Hz,1H),7.53–7.44(m,2H),7.39(d,J=8.0Hz,1H),7.34–7.2 8(m,2H),7.24–7.20(m,1H),7.17–7.06(m,4H),7.02–6.93(m,1H),6.68(t,J=2.6Hz,1H),4.06–3.80(m,2H),2.26(s,3H). 13 C NMR (151MHz, CDCl3) δ 209.9, 154.4, 149.4, 138.7, 137.9, 136.4, 134.9, 129.6, 128.6, 128.2, 127.4, 127.2, 126.5, 125.8, 121.6, 121.5, 109.8, 99.3, 36.9, 21.4. High-resolution data: HRMS (ESI) m / z 298.1587 (M+H + ),calc.for C 22 H 20 N + 298.1590.

[0061] Example 8

[0062] The reaction formulas for the synthesis of (S)-1-phenyl-1-(4-methoxybenzyl)-3-(pyridin-2-yl)propyl-2-yn-1-ol and (S)-1-phenyl-1-(4-methoxybenzyl)-3-(pyridin-2-yl)propadiene are as follows:

[0063]

[0064] In this embodiment, the racemic 1-phenyl-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol from Example 1 was replaced with racemic 1-phenyl-1-(4-methoxybenzyl)-3-(pyridin-2-yl)propyl-2-yn-1-ol, and the other steps were the same as in Example 1, yielding 14.8 mg of (S)-1-phenyl-1-(4-methoxybenzyl)-3-(pyridin-2-yl)propyl-2-yn-1-ol and 13.1 mg of (S)-1-phenyl-1-(4-methoxybenzyl)-3-(pyridin-2-yl)propadiene.

[0065] (S)-1-Phenylon-1-(4-methoxybenzyl)-3-(pyridin-2-yl)propyl-2-yn-1-ol is a yellow solid with a yield of 45% and an optical purity of 88% ee. Its melting point is 111.4–113.0 °C. NMR data are as follows: 1H NMR (600MHz, CDCl3) δ8.47(d,J=4.8Hz,1H),7.57(d,J=7.5Hz,3H),7.30(d,J=7.8Hz,1H),7.27(t,J=7.5Hz,1H),7.21(t,J=7.3Hz,1H), 7.16(dt,J=17.9,8.5Hz,1H),7.06(d,J=8.5Hz,1H),6.71(d,J=8.5Hz,1H),3.68(s,1H),3.19(d,J=13.5Hz,1H),3.15(d,J=13.5Hz,1H). 13 C NMR (151MHz, CDCl3) δ 158.7, 149.8, 143.7, 142.7, 136.3, 132.0, 128.1, 127.7, 127.7, 127.3, 125.7, 123.1, 113.4, 91.9, 86.0, 73.5, 55.2, 50.9. High-resolution data: HRMS (ESI) m / z 330.1484 (M+H + ),calc.for C 22 H 20 NO2 + 330.1489.

[0066] (S)-1-Phenylon-1-(4-methoxybenzyl)-3-(pyridin-2-yl)propadiene is a yellow oil in yield of 42% and has an optical purity of 91% ee. NMR data are as follows: 1 H NMR(600MHz, CDCl3)δ8.57–8.50(m,1H),7.60(td,J=7.7,1.8Hz,1H),7.48–7.44(m,2H),7.39(dt,J=8.0,1.1Hz,1H),7.33–7 .28(m,2H),7.25–7.20(m,3H),7.13–7.09(m,1H),6.81–6.76(m,2H),6.70(t,J=2.6Hz,1H),3.96–3.84(m,2H),3.75(s,3H). 13 C NMR (151MHz, CDCl3) δ 209.8, 158.2, 154.4, 149.4, 136.5, 134.9, 130.8, 129.8, 128.6, 127.4, 126.5, 121.6, 121.4, 113.8, 110.1, 99.3, 55.2, 36.2. High-resolution data: HRMS (ESI) m / z 314.1535 (M+H + ),calc.for C 22 H20 NO + 314.1539.

[0067] Example 9

[0068] The reaction formulas for the synthesis of (S)-1-phenyl-1-benzyl-3-(3-bromopyridin-2-yl)propyl-2-yn-1-ol and (S)-1-phenyl-1-benzyl-3-(3-bromopyridin-2-yl)propadiene are as follows:

[0069]

[0070] In this embodiment, the racemic 1-phenyl-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol from Example 1 was replaced with racemic 1-phenyl-1-benzyl-3-(3-bromopyridin-2-yl)propyl-2-yn-1-ol, and the other steps were the same as in Example 1, yielding 17.7 mg of (S)-1-phenyl-1-benzyl-3-(3-bromopyridin-2-yl)propyl-2-yn-1-ol and 17.0 mg of (S)-1-phenyl-1-benzyl-3-(3-bromopyridin-2-yl)propadiene.

[0071] (S)-1-Phenylacetyl-1-benzyl-3-(3-bromopyridin-2-yl)propyl-2-yn-1-ol is a yellow solid with a yield of 47% and an optical purity of 90% ee. Its melting point is 114.4-116.4 °C. NMR data are as follows: 1 H NMR (400MHz, CDCl3) δ8.47(dd,J=4.7,1.4Hz,1H),7.89(dd,J=8.2,1.5Hz,1H),7.75–7.61(m,2H),7.34(m, 3H),7.23(s,5H),7.11(dd,J=8.2,4.7Hz,1H),3.35(d,J=13.3Hz,1H),3.31(d,J=13.3Hz,1H),2.7(s,1H). 13 C NMR (151MHz, CDCl3) δ 148.2, 143.4, 143.0, 140.1, 135.5, 131.2, 128.2, 128.0, 127.9, 127.1, 125.9, 124.0, 123.9, 96.5, 84.9, 73.8, 51.7. High-resolution data are: HRMS (ESI) m / z 378.0483 (M+H + ),calc.for C 21 H 17 BrNO + 378.0488.

[0072] (S)-1-Phenylacetyl-1-benzyl-3-(3-bromopyridin-2-yl)propadiene is a yellow oil with a yield of 47% and an optical purity of 91% ee. NMR data are as follows: 1 H NMR (600MHz, CDCl3) δ8.45(dd,J=4.6,1.5Hz,1H),7.74(dd,J=8.0,1.5Hz,1H),7.40(dd,J=8.2,0.9Hz,2H),7.37–7.3 2(m,2H),7.23–7.14(m,4H),7.14–7.06(m,2H),6.97(t,J=2.2Hz,1H),6.91(dd,J=8.0,4.6Hz,1H),3.96–3.83(m,2H). 13 CNMR (151MHz, CDCl3) δ 212.0, 152.3, 148.5, 140.8, 138.9, 135.1, 129.0, 128.6, 128.4, 127.4, 126.8, 126.4, 122.8, 119.8, 108.9, 96.9, 37.3. High-resolution data is: HRMS (ESI) m / z 362.0535 (M+H + ),calc.for C 21 H 17 BrN + 362.0539.

[0073] Example 10

[0074] The reaction formulas for synthesizing (S)-1-phenyl-1-benzyl-3-(3-methylpyridin-2-yl)propyl-2-yn-1-ol and (S)-1-phenyl-1-benzyl-3-(3-methylpyridin-2-yl)propadiene are as follows:

[0075]

[0076] In this embodiment, the racemic 1-phenyl-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol from Example 1 was replaced with racemic 1-phenyl-1-benzyl-3-(3-methylpyridin-2-yl)propyl-2-yn-1-ol, and the other steps were the same as in Example 1, yielding 14.7 mg of (S)-1-phenyl-1-benzyl-3-(3-bromopyridin-2-yl)propyl-2-yn-1-ol and 12.8 mg of (S)-1-phenyl-1-benzyl-3-(3-methylpyridin-2-yl)propadiene.

[0077] (S)-1-Phenylacetyl-1-benzyl-3-(3-methylpyridin-2-yl)propyl-2-yn-1-ol is a yellow solid with a yield of 47% and an optical purity of 90% ee. Its melting point is 121.4–122.9 °C, and its NMR data are as follows: 1 H NMR (600MHz, CDCl3) δ8.37(d,J=4.2Hz,1H),7.68–7.62(m,2H),7.50(d,J=7.7Hz,1H),7.35(t,J=7.5Hz,2H) ,7.32–7.27(m,2H),7.26–7.17(m,5H),7.14(dd,J=7.7,4.8Hz,1H),3.33(s,2H),3.00(s,1H),2.29(s,3H). 13 CNMR (151MHz, CDCl3) δ 147.2, 143.9, 142.3, 137.4, 136.3, 135.8, 131.2, 128.2, 128.0, 127.9, 127.1, 125.8, 123.1, 95.7, 85.0, 73.8, 51.8, 19.5. High-resolution data is: HRMS (ESI) m / z 314.1533 (M+H + ),calc.for C 22 H 20 NO + 314.1539.

[0078] (S)-1-Phenylon-1-benzyl-3-(3-methylpyridin-2-yl)propadiene is a yellow oil with a yield of 43% and an optical purity of 90% ee. NMR data are as follows: 1 H NMR (600MHz, CDCl3) δ8.46–8.41(m,1H),7.49(d,J=7.4Hz,2H),7.45(d,J=7.4Hz,1H),7.35(d,J=7.5Hz,2H),7.30(t,J=7.8Hz,2H),7.2 7–7.22(m,2H),7.20(t,J=7.4Hz,1H),7.16(t,J=7.4Hz,1H),7.08(dd,J=7.0,4.7Hz,1H),6.89(s,1H),4.01–3.92(m,2H),2.31(s,3H). 13C NMR (151MHz, CDCl3) δ 210.7, 152.4, 147.2, 139.0, 138.4, 135.7, 131.8, 129.0, 128.6, 128.4, 127.2, 126.7, 126.4, 121.7, 107.4, 97.5, 37.3, 19.9. High-resolution data is: HRMS (ESI) m / z 298.1588 (M+H + ),calc.for C 22 H 20 N + 298.1590.

[0079] Example 11

[0080] The reaction formulas for synthesizing (S)-1-phenyl-1-benzyl-3-(3-trifluoromethanesulfonyloxypyridin-2-yl)propyl-2-yn-1-ol and (S)-1-phenyl-1-benzyl-3-(3-trifluoromethanesulfonyloxypyridin-2-yl)propadiene are as follows:

[0081]

[0082] In this embodiment, the racemic 1-phenyl-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol from Example 1 was replaced with racemic 1-phenyl-1-benzyl-3-(3-trifluoromethanesulfonyloxypyridin-2-yl)propyl-2-yn-1-ol. The chiral catalyst C1 was 0.1 equivalents of the tertiary alcohol, the reaction time was 17 hours, and the other steps were the same as in Example 1, yielding 18.8 mg of (S)-1-phenyl-1-benzyl-3-(3-trifluoromethanesulfonyloxypyridin-2-yl)propyl-2-yn-1-ol and 18.1 mg of (S)-1-phenyl-1-benzyl-3-(3-trifluoromethanesulfonyloxypyridin-2-yl)propadiene.

[0083] (S)-1-Phenylacetyl-1-benzyl-3-(3-trifluoromethanesulfonyloxypyridin-2-yl)propyl-2-yn-1-ol is a yellow solid with a yield of 42% and an optical purity of 90% ee. Its melting point is 88.7-90.5℃, and its NMR data are as follows: 1 H NMR(600MHz, CDCl3)δ8.57(dd,J=4.7,1.3Hz,1H),7.72–7.56(m,3H),7.39–7.33(m,3H),7.34 –7.28(m,1H),7.26–7.15(m,5H),3.38(d,J=13.4Hz,1H),3.29(d,J=13.4Hz,1H),2.64(s,1H). 13C NMR (151MHz, CDCl3) δ149.4,147.6,142.9,137.3,135.2,131.1,129.3,128.3,12 8.1,128.1,127.2,125.7,124.3,118.63(q,J=321.0Hz),99.6,80.3,73.6,51.4. 19 F NMR (565MHz, CDCl3) δ-73.4. High-resolution data are: HRMS (ESI) m / z 448.0818 (M+H + ),calc.for C 22 H 17 F3NO4S + 448.0825.

[0084] (S)-1-Phenylon-1-benzyl-3-(3-trifluoromethanesulfonyloxypyridin-2-yl)propadiene is a yellow oil with a yield of 42% and an optical purity of 92% ee. NMR data are as follows: 1 H NMR (600MHz, CDCl3) δ8.51(dd,J=4.6,1.3Hz,1H),7.52(dd,J=8.4,1.3Hz,1H),7.38(d,J=7.4Hz,2H),7.33(d,J=7. 4Hz,2H),7.21(t,J=7.7Hz,2H),7.19–7.10(m,4H),7.09(t,J=7.4Hz,1H),6.72(t,J=2.3Hz,1H),3.96–3.83(m,2H). 13 C NMR (151MHz, CDCl3) δ212.4,149.5,147.3,143.9,138.6,134.6,129.4,129.1,12 8.7,128.4,127.7,126.8,126.5,122.8,118.7(q,J=320.8Hz),110.1,92.0,37.1. 19 FNMR (565MHz, CDCl3) δ-73.2. High-resolution data are: HRMS (ESI) m / z 432.0870 (M+H + ), calc.forC 22 H 17 F3NO3S + 432.0876.

[0085] Example 12

[0086] The reaction formulas for the synthesis of (S)-1-phenyl-1-benzyl-3-(4-chloropyridin-2-yl)propyl-2-yn-1-ol and (S)-1-phenyl-1-benzyl-3-(4-chloropyridin-2-yl)propadiene are as follows:

[0087]

[0088] In this embodiment, the racemic 1-phenyl-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol from Example 1 was replaced with racemic 1-phenyl-1-benzyl-3-(4-chloropyridin-2-yl)propyl-2-yn-1-ol. The chiral catalyst C1 was 0.1 equivalents of the tertiary alcohol, the reaction time was 24 hours, and the other steps were the same as in Example 1. 16.1 mg of (S)-1-phenyl-1-benzyl-3-(3-bromopyridin-2-yl)propyl-2-yn-1-ol and 15.0 mg of (S)-1-phenyl-1-benzyl-3-(4-chloropyridin-2-yl)propadiene were obtained.

[0089] (S)-1-Phenylacetyl-1-benzyl-3-(4-chloropyridin-2-yl)propyl-2-yn-1-ol is a yellow solid with a yield of 46% and an optical purity of 97% ee. Its melting point is 137.9-138.5 °C, and its NMR data are as follows: 1 H NMR(600MHz, CDCl3)δ8.45(d,J=5.4Hz,1H),7.66–7.58(m,2H),7.41(d,J=2.0Hz,1H),7.38–7.3 3(m,2H),7.07–7.03(m,2H),6.77–6.68(m,2H),3.21(d,J=13.5Hz,1H),3.15(d,J=13.5Hz,1H). 13 C NMR (151MHz, CDCl3) δ 155.5, 150.3, 144.7, 143.7, 143.3, 132.1, 128.2, 127.9, 127.5, 126.9, 125.5, 123.8, 115.1, 93.7, 84.7, 73.5, 50.8. High-resolution data: HRMS (ESI) m / z 350.0937 (M+H + ),calc.for C 21 H 17 ClNO2 + 350.0942.

[0090] (S)-1-Phenylacetyl-1-benzyl-3-(4-chloropyridin-2-yl)propadiene is a yellow oil in yield of 45% and has an optical purity of 89% ee. NMR data are as follows: 1H NMR (400MHz, CDCl3) δ8.29 (d, J = 5.2Hz, 1H), 7.41–7.34 (m, 2H), 7.29–7.21 (m, 3H), 7.21–7. 13(m,1H),7.09–7.00(m,3H),6.68–6.61(m,2H),6.57(t,J=2.4Hz,1H),3.87–3.68(m,2H). 13 C NMR (151MHz, CDCl3) δ 210.3, 156.0, 154.8, 149.8, 144.9, 134.4, 130.1, 129.9, 128.7, 127.7, 126.5, 122.2, 121.6, 115.4, 111.4, 98.3, 36.0. High-resolution data is: HRMS (ESI) m / z 334.0990 (M+H + ),calc.for C 21 H 17 ClNO + 334.0993.

[0091] Example 13

[0092] The reaction formulas for the synthesis of (S)-1-phenyl-1-benzyl-3-(quinolin-2-yl)propyl-2-yn-1-ol and (S)-1-phenyl-1-benzyl-3-(quinolin-2-yl)propadiene are as follows:

[0093]

[0094] In this embodiment, the racemic 1-phenyl-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol from Example 1 was replaced with racemic 1-phenyl-1-benzyl-3-(quinolin-2-yl)propyl-2-yn-1-ol, the chiral catalyst C1 was replaced with C2, which was 0.1 equivalents of the tertiary alcohol, the reaction time was 16 hours, and the other steps were the same as in Example 1, yielding 16.1 mg of (S)-1-phenyl-1-benzyl-3-(quinolin-2-yl)propyl-2-yn-1-ol and 15.0 mg of (S)-1-phenyl-1-benzyl-3-(quinolin-2-yl)propadiene.

[0095] (S)-1-Phenylacetyl-1-benzyl-3-(quinolin-2-yl)propyl-2-yn-1-ol is a yellow solid with a yield of 46% and an optical purity of 94% ee. Its melting point is 148.8-150.0 °C. NMR data are as follows: 1H NMR(600MHz, CDCl3)δ8.03(d,J=8.3Hz,2H),7.71(dd,J=8.1,1.1Hz,1H),7.67–7.60(m,1H),7.63–7.58(m,2H),7.50–7.43(m,1H),7.35 (d,J=8.4Hz,1H),7.31–7.26(m,2H),7.26–7.20(m,1H),7.21–7.14(m,5H),3.29(d,J=13.3Hz,1H),3.25(d,J=13.3Hz,1H),2.96(s,1H). 13 C NMR (151MHz, CDCl3) δ 148.0, 143.5, 142.9, 136.5, 135.7, 131.2, 130.3, 129.2, 128.3, 128.0, 128.0, 127.6, 127.4, 127.4, 127.2, 125.8, 124.4, 92.6, 86.9, 73.7, 51.8. High-resolution data are: HRMS (ESI) m / z 350.1534 (M+H + ),calc.for C 25 H 20 NO + 350.1539.

[0096] (S)-1-Phenylon-1-benzyl-3-(quinolin-2-yl)propadiene is a yellow oil in yield of 45% and has an optical purity of 97% ee. NMR data are as follows: 1 H NMR (600MHz, CDCl3) δ7.98(d,J=8.3Hz,1H),7.94(d,J=8.6Hz,1H),7.68(d,J=8.0Hz,1H),7.64–7.58(m,1H),7 .45–7.38(m,4H),7.29–7.21(m,4H),7.19–7.13(m,3H),7.08(t,J=7.4Hz,1H),6.82(s,1H),3.97–3.86(m,2H). 13 C NMR (151MHz, CDCl3) δ 211.4, 154.8, 138.7, 136.5, 135.6, 134.7, 129.9, 129.0, 128.8, 128.6, 127.7, 127.7, 127.2, 126.6, 126.6, 126.4, 119.5, 110.4, 109.2, 100.4, 37.1. High-resolution data is: HRMS (ESI) m / z 334.1586 (M+H + ),calc.for C 25H 20 N + 334.1590.

[0097] Example 14

[0098] The reaction formulas for the synthesis of (S)-1-phenyl-1-benzyl-3-(quinoxalin-2-yl)propyl-2-yn-1-ol and (S)-1-phenyl-1-benzyl-3-(quinoxalin-2-yl)propadiene are as follows:

[0099]

[0100] In this embodiment, the racemic 1-phenyl-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol from Example 1 was replaced with racemic 1-phenyl-1-benzyl-3-(quinoxalin-2-yl)propyl-2-yn-1-ol, and the chiral catalyst C1 was replaced with C2, which was 0.1 equivalents of the tertiary alcohol. The reaction time was 23 hours, and the other steps were the same as in Example 1, yielding 16.1 mg of (S)-1-phenyl-1-benzyl-3-(quinoxalin-2-yl)propyl-2-yn-1-ol and 15.0 mg of (S)-1-phenyl-1-benzyl-3-(quinoxalin-2-yl)propadiene.

[0101] (S)-1-Phenylacetyl-1-benzyl-3-(quinoxalo-2-yl)propyl-2-yn-1-ol is a yellow solid with a yield of 46% and an optical purity of 87% ee. Its melting point is 108.8-110.0 °C, and its NMR data are as follows: 1 H NMR (600MHz, CDCl3) δ8.78 (s, 1H), 8.14–8.05 (m, 2H), 7.85–7.76 (m, 2H), 7.73 (d, J = 7.4Hz, 2H), 7.42 (t, J=7.6Hz,2H),7.36(t,J=7.3Hz,1H),7.34–7.26(m,5H),3.40(d,J=13.3Hz,1H),3.37(d,J=13.3Hz,1H). 13 CNMR (151MHz, CDCl3) δ 147.2, 143.3, 142.2, 141.1, 139.0, 135.5, 131.1, 130.8, 130.8, 129.4, 129.3, 128.4, 128.2, 128.2, 127.4, 125.7, 95.9, 84.7, 73.8, 51.7. High-resolution data is: HRMS (ESI) m / z 351.1487 (M+H + ),calc.for C 24 H 19 N2O + 351.1492.

[0102] (S)-1-Phenylon-1-benzyl-3-(quinoxalo-2-yl)propadiene is a yellow oil in yield of 45% and has an optical purity of 86% ee. NMR data are as follows: 1 H NMR (600MHz, CDCl3) δ8.88(s,1H),8.03(dd,J=8.1,1.6Hz,1H),7.98(dd,J=8.4,1.4Hz,1H),7.73–7.69(m,1H),7.69–7.65(m ,1H),7.50–7.45(m,2H),7.35–7.29(m,4H),7.26–7.21(m,3H),7.17–7.12(m,1H),6.78(t,J=2.9Hz,1H),4.07–3.89(m,2H). 13 C NMR (151MHz, CDCl3) δ 211.7, 149.7, 144.5, 142.5, 141.1, 138.4, 134.3, 130.3, 129.3, 129.3, 129.1, 129.0, 128.9, 128.6, 128.1, 126.8, 126.7, 111.4, 98.2, 37.1. High-resolution data: HRMS (ESI) m / z 335.1540 (M+H + ),calc.for C 24 H 19 N2 + 335.1543.

[0103] Example 15

[0104] The reaction formulas for synthesizing (S)-1-phenyl-1-methyl-3-(pyridin-2-yl)propyl-2-yn-1-ol and (S)-1-phenyl-1-1-methyl-3-(pyridin-2-yl)propadiene are as follows:

[0105]

[0106] In this embodiment, the racemic 1-phenyl-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol from Example 1 was replaced with racemic 1-phenyl-1-methyl-3-(pyridin-2-yl)propyl-2-yn-1-ol, and the chiral catalyst C1 was replaced with C3, which was 0.1 equivalents of the tertiary alcohol. The other steps were the same as in Example 1, yielding 10.5 mg of (S)-1-phenyl-1-methyl-3-(pyridin-2-yl)propyl-2-yn-1-ol and 6.8 mg of (S)-1-phenyl-1-methyl-3-(pyridin-2-yl)propadiene.

[0107] (S)-1-Phenylon-1-methyl-3-(pyridin-2-yl)propyl-2-yn-1-ol is a yellow solid with a yield of 47% and an optical purity of 70% ee. Its melting point is 96.3-97.9 °C, and its NMR data are as follows: 1 H NMR (600MHz, CDCl3) δ8.52 (d, J=4.3Hz, 1H), 7.76–7.71 (m, 2H), 7.64 (td, J=7.7, 1.7Hz, 1H), 7.44 (d, J= 7.8Hz,1H),7.36(t,J=7.7Hz,2H),7.29(t,J=7.3Hz,1H),7.25–7.19(m,1H),3.46(s,1H),1.90(s,3H). 13 CNMR (151MHz, CDCl3) δ 149.8, 145.4, 142.8, 136.6, 128.5, 127.8, 127.4, 125.2, 123.2, 93.4, 70.1, 33.2. High-resolution data: HRMS (ESI) m / z 224.1068 (M+H + ),calc.for C 15 H 14 NO + 224.1070.

[0108] (S)-1-Phenylon-1-methyl-3-(pyridin-2-yl)propadiene is a yellow oil in yield of 33% and has an optical purity of 90% ee. NMR data are as follows: 1 H NMR (600MHz, CDCl3) δ8.48(d,J=4.6Hz,1H),7.52(td,J=7.7,1.7Hz,1H),7.39(d,J=7.6Hz,2H),7.34(d,J=8.0Hz ,1H),7.27(t,J=7.8Hz,2H),7.21–7.14(m,1H),7.06–7.00(m,1H),6.61(q,J=2.8Hz,1H),2.19(d,J=3.0Hz,3H). 13 C NMR (151MHz, CDCl3) δ 209.0, 154.8, 149.5, 136.6, 135.7, 128.7, 127.5, 126.1, 121.7, 121.7, 105.3, 98.3, 16.7. High-resolution data: HRMS (ESI) m / z 208.1119 (M+H + ),calc.for C 15 H 14 N + 208.1121.

[0109] Example 16

[0110] The reaction formulas for the synthesis of (S)-1-phenyl-1-allyl-3-(pyridin-2-yl)propyl-2-yn-1-ol and (S)-1-phenyl-1-allyl-3-(pyridin-2-yl)propadiene are as follows:

[0111]

[0112] In this embodiment, the racemic 1-phenyl-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol from Example 1 was replaced with racemic 1-phenyl-1-allyl-3-(pyridin-2-yl)propyl-2-yn-1-ol, and the other steps were the same as in Example 1, yielding 10.9 mg of (S)-1-phenyl-1-allyl-3-(pyridin-2-yl)propyl-2-yn-1-ol and 10.0 mg of (S)-1-phenyl-1-allyl-3-(pyridin-2-yl)propadiene.

[0113] (S)-1-Phenylon-1-allyl-3-(pyridin-2-yl)propyl-2-yn-1-ol is a yellow oil with a yield of 44% and an optical purity of 81% ee. Its NMR data are as follows: 1 H NMR (600MHz, CDCl3) δ8.55–8.48(m,1H),7.76–7.70(m,2H),7.64(td,J=7.7,1.8Hz,1H),7.44(dt,J=7.8,1.1Hz,1H),7.41 –7.36(m,2H),7.34–7.27(m,1H),7.24–7.18(m,1H),6.05–5.95(m,1H),5.23–5.13(m,2H),4.05(s,1H),2.95–2.74(m,2H). 13 C NMR (101MHz, CDCl3) δ 149.8, 143.8, 142.7, 136.3, 133.0, 129.5, 128.2, 127.7, 127.4, 125.6, 123.1, 119.7, 115.8, 92.0, 85.0, 72.3, 50.0. High-resolution data are: HRMS (ESI) m / z 250.1223 (M+H + ),calc.for C 17 H 16 NO + 250.1226.

[0114] (S)-1-Phenylon-1-allyl-3-(pyridin-2-yl)propadiene is a yellow oil with a yield of 43% and an optical purity of 82% ee. NMR data are as follows: 1H NMR (600MHz, CDCl3) δ8.48(d,J=4.9Hz,1H),7.52(td,J=7.8,1.6Hz,1H),7.39(d,J=7.6Hz,2H),7.36(d,J=8.0Hz,1H),7.26(t,J=7.7Hz,2H),7.20–7. 13(m,1H),7.07–7.01(m,1H),6.69(t,J=2.7Hz,1H),5.98–5.86(m,1H),5.1 5(dd,J=17.0,1.5Hz,1H),5.03(dd,J=10.1,1.2Hz,1H),3.39–3.21(m,2H). 13 C NMR (151MHz, CDCl3) δ 208.9, 154.5, 149.4, 136.6, 135.1, 134.8, 128.6, 127.5, 126.3, 121.6, 121.4, 116.9, 109.0, 99.6, 34.7. High-resolution data are: HRMS (ESI) m / z 234.1275 (M+H + ),calc.for C 17 H 16 N + 234.1277.

[0115] Synthetic Application 1

[0116]

[0117] 29.9 mg (0.1 mmol) of (S)-1-phenyl-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol from Example 1 and 1.0 mL of DMF solvent were added to a 10 mL dried reaction flask. Then, 34.5 mg (0.3 mmol) of azidotrimethylsilane was added and the mixture was stirred in an oil bath at 100°C for 15 hours. After the reaction was completed, ethyl acetate and water were added, and the organic layer was separated. The organic layer was then extracted three more times with water. The organic layer was dried with anhydrous sodium sulfate, filtered, and separated by column chromatography (n-hexane / ethyl acetate = 5:1) to obtain 30.8 mg of (S)-1,2-diphenyl-1-(5-(pyridin-2-yl)-1H-1,2,3-triazol-4-yl)ethyl-1-ol as a yellow solid with a yield of 90% and an optical purity of 91% ee. Its melting point is 161.5-162.0℃, and its NMR data are as follows: 1H NMR (400MHz, CDCl3) δ8.44–8.32(m,1H),8.06(d,J=8.0Hz,1H),7.70(td,J=7.8,1.7Hz,1H),7.33–7.26(m, 3H),7.20–7.06(m,8H),7.00(dd,J=6.8,2.8Hz,2H),3.75(dd,J=13.5,2.4Hz,1H),3.64(d,J=13.5Hz,1H). 13 C NMR (151MHz, CDCl3) δ 149.5, 147.0, 145.4, 143.5, 137.8, 136.9, 131.2, 127.5, 127.3, 126.6, 126.1, 126.1, 122.9, 122.1, 74.4, 48.2. High-resolution data are: HRMS (ESI) m / z 343.1551 (M+H + ), calc.forC 21 H 19 N4O + 343.1553.

[0118] (S)-1,2-diphenyl-1-(5-(pyridin-2-yl)-1H-1,2,3-triazol-4-yl)ethyl-1-ol is a reported ligand that can be used as a catalyst after coordination with copper (for details of this process, please refer to Bizzarri, Claudia; Arndt, Andreas P.; Kohaut, Stephan; Fink, Karin; Nieger, Martin (2018). Mononuclear and dinuclear heteroleptic Cu(I) complexes based on pyridyl-triazole and DPEPhos with long-lived excited-state lifetimes. Journal of Organometallic Chemistry, 871 (2018), 140–149.).

[0119] Synthesis Application 2

[0120]

[0121] In Example 6, 100 equivalents of deuterium water were added to the tertiary alcohol, and the chiral catalyst was 0.2 equivalents of the tertiary alcohol. The reaction time was 45 hours, and the other steps were the same as in Example 6. This yielded 15.8 mg of (S)-1-(3-trifluoromethylphenyl)-1-benzyl-3-(pyridin-2-yl)propyl-2-yn-1-ol, with a yield of 43% and an optical purity of 89% ee; and 16.2 mg of (S)-1-(3-trifluoromethylphenyl)-1-benzyl-3-(pyridin-2-yl)-3-deuterated propadiene.

[0122] (S)-1-(3-trifluoromethylphenyl)-1-benzyl-3-(pyridin-2-yl)-3-deuterated propadiene is a yellow oil with a yield of 46% and an optical purity of 89% ee. NMR data are as follows: 1 ¹H NMR (600MHz, CDCl₃) δ 8.54 (dt, J = 5.0, 1.4Hz, 1H), 7.64–7.58 (m, 2H), 7.51 (d, J = 7.6Hz, 1H), 7.48–7.44 (m, 2H), 7.42 (d, J = 7.8Hz, 1H), 7.39–7.30 (m, 4H), 7.24 (d, J = 7.4Hz, 1H), 7.13 (m, 1H), 6.69 (s, 0.1H), 4.07–3.87 (m, 2H). High-resolution data: HRMS (ESI) m / z 353.1365 (M+H) + ),calc.for C 22 H 16 DF3N + 353.1370.

Claims

1. An asymmetric catalytic synthesis method for chiral azaethynyl tertiary alcohols and aza-alkenes, characterized in that, In an air atmosphere, racemic azirethynyl tertiary alcohols (±)-I and tris(4-tolyl)phosphine II react in an organic solvent with chiral tartaric acid-derived phosphoric acid C1, spirocyclic chiral phosphoric acid C2, or octahydrobinaphthyl phosphate C3 as chiral catalysts. The reaction proceeds to completion at 20–30 °C. The resulting chiral azirethynyl tertiary alcohols SI and chiral azirethenes III are then separated and purified. ， Ar for or R3 and R4 are each independently selected from one of H, Cl, F, Br, Me, MeO, and OTf. 1 for L1 is H, Cl, F, Br, Me, MeO, or CF3, R 2 for or Or a C1-C6 alkyl group, where L2 is H, Me, or MeO.

2. The asymmetric catalytic synthesis method for chiral azaethynyl tertiary alcohols and aza-alkenes according to claim 1, characterized in that, The molar ratio of racemic azaethynyl tertiary alcohol (±)-I to tris(4-tolyl)phosphine II is 1:1.

2.

3. The asymmetric catalytic synthesis method for chiral azaethynyl tertiary alcohols and aza-alkenes according to claim 1 or 2, characterized in that, The amount of chiral catalyst C1, C2 or C3 added is 10-20% of the molar amount of racemic azirtylenic tertiary alcohol compound (±) - I.

4. The asymmetric catalytic synthesis method for chiral azaethynyl tertiary alcohols and aza-alkenes according to claim 1, characterized in that, The organic solvent is toluene.

5. The asymmetric catalytic synthesis method for chiral azaethynyl tertiary alcohols and aza-alkenes according to claim 1, characterized in that, This also includes adding deuterium water to the reaction system, the amount of which is 100 times the molar amount of the azirynyl tertiary alcohol compound (±) – I, thereby obtaining the deuterated compound D-III. .

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