Synthesis method of high propargyl tertiary alcohol containing two adjacent chiral centers

Abstract

The invention discloses a synthesis method of high propargyl tertiary alcohol containing two adjacent chiral centers. The synthesis method comprises the following steps: by taking allene boronic acid pinacol ester and aromatic ketone as raw materials and tetrahydrofuran as a reaction solvent, sequentially adding n-butyllithium and trifluoroacetic anhydride at-60 to-80 DEG C, carrying out in-situ conversion on the allene boronic acid pinacol ester into allene boronic acid-trifluoroacetic acid mixed anhydride, and carrying out addition reaction on the allene boronic acid-trifluoroacetic acid mixed anhydride and ketone to obtain the allene boronic acid-trifluoroacetic acid compound. The high propargyl tertiary alcohol containing two adjacent chiral centers is prepared. The reaction conditions are relatively mild, the chemical selectivity and stereoselectivity of the product are excellent, the yield is excellent, and the synthesized homopropargyl tertiary alcohol has a wide application prospect in the synthesis of medical intermediates.

Description

Technical Field

[0001] The invention relates to a method for synthesizing a homopropargyl tertiary alcohol containing two adjacent chiral centers, and belongs to the technical field of organic synthetic chemistry. Background Art

[0002] Homopropargyl alcohols are a very important class of organic intermediates. They contain convertible carbon-carbon triple bonds and hydroxyl functional groups in their structures. They have very strong conversion capabilities and expansibility and are important intermediate structures in the synthesis of bioactive molecules, pharmaceutical preparations and natural products. Therefore, the synthesis of homopropargyl alcohols, especially the stereoselective synthesis of homopropargyl tertiary alcohols containing two adjacent chiral centers, is a research frontier and hotspot in the field of organic synthesis.

[0003] In 2011, Schaus's group first used unstable ethylene glycol boronic acid esters to achieve propargyl borylation reaction with ketones under the catalysis of binaphthol (BINOL) to synthesize high propargyl tertiary alcohols containing two adjacent chiral centers (David S.Barnett and Scott E.Schaus.Organic Letters 2011 13(15),4020-4023). Professor Szabó achieved propargyl borylation reaction of tetrasubstituted boronic acid with ketones and synthesized high propargyl tertiary alcohols containing two adjacent quaternary carbon chiral centers by using equivalent chiral binaphthol (BINOL) (J.Zhao, SJTJonker, DNMeyer, et al.Chem.Sci.,2018,9,3305-3312). The Buchwald and Yin groups used 1,3-conjugated ene ynes to achieve stereoselective synthesis of high-propargyl tertiary alcohols containing two adjacent chiral centers through copper-hydrogenation and copper-boration reactions (Yang Yang et al., Copper-catalyzed asymmetric addition of olefin-derived nucleophiles to ketones. Science, 353, 144-150 (2016); Xu-Cheng Gan and Liang Yin. Organic Letters 2019 21 (4), 931-936). Recently, Wang's group used propargyl halides and ketones to develop a chromium-catalyzed reaction to achieve the construction of such high-propargyl tertiary alcohols (Xiaochong Guo, Zhaoxin Shi, Feng-Hua Zhang, and Zhaobin Wang. ACS Catalysis 2023 13 (5), 3170-3178). However, the transformations that have been developed so far all use relatively expensive catalysts / chiral ligands, which poses a challenge to the large-scale industrial application of these methods. Summary of the invention

[0004] The purpose of the present invention is to provide a catalyst-free, inexpensive and effective method for synthesizing a high-propargyl tertiary alcohol containing two adjacent chiral centers. The method utilizes a propargyl borylation reaction of allene boronic acid pinacol ester and aromatic ketone to synthesize a high-propargyl tertiary alcohol containing two adjacent chiral centers.

[0005] The technical solution for achieving the purpose of the present invention is as follows:

[0006] The synthesis method of a homopropargyl tertiary alcohol containing two adjacent chiral centers is as follows:

[0007] Under an argon atmosphere, allene boronic acid pinacol ester represented by formula (I), a hexane solution of n-butyl lithium (nBuLi), trifluoroacetic anhydride (TFAA), and an aromatic ketone represented by formula (II) are mixed in tetrahydrofuran (THF) and reacted at -60 to -80°C for more than 24 hours to generate a homopropargyl tertiary alcohol represented by formula (III) containing two adjacent chiral centers. The general reaction formula is as follows:

[0008]

[0009] In the formula, R 1 is n-hexyl, cyclohexyl, chloropropyl, phenethyl, butenyl, tert-butyldimethylsilylethoxy, R 2 is methyl or ethyl, R 3 It is hydrogen, chlorine, bromine, nitro, 4-methyl, 3-methyl, 2-methyl, methoxy, benzyloxy, cyano, methylthio, 3,4-methylenedioxy or other aromatic heterocyclic structures such as furan ring, benzothiophene ring, etc.

[0010] Furthermore, the specific steps are as follows: under an argon atmosphere, the pinacol ester of allene boronate represented by formula (I) is added to an anhydrous Schlenk reaction bottle containing a polytetrafluoroethylene magnet and tetrahydrofuran is added and stirred, then the temperature of the reaction system is lowered to -78°C, a hexane solution of n-butyl lithium is added dropwise and stirred for 25 minutes, and then trifluoroacetic anhydride is added dropwise, and the reaction mixture is stirred at -78°C for 45 minutes. Finally, the aromatic ketone represented by formula (II) is added at -78°C, and the reactor is rinsed with tetrahydrofuran. The reaction mixture finally formed is stirred at -78°C for 30 minutes and then naturally warmed to room temperature for reaction for 24 hours. After the reaction is completed, the reaction is quenched with a saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phase is washed with saturated brine, dried over anhydrous magnesium sulfate, filtered to remove the solid, and finally concentrated under reduced pressure. The crude product is purified by column chromatography using ethyl acetate / petroleum ether in a volume ratio of 1:500-1:100 as eluent to obtain a homopropargyl tertiary alcohol containing two adjacent chiral centers represented by formula (III).

[0011] Furthermore, the molar ratio of allene boronic acid pinacol ester to aromatic ketone is 1.0:1.2 to 1.0:2.0, preferably 1.0:1.5.

[0012] Furthermore, the molar ratio of allene boronic acid pinacol ester to n-butyl lithium is 1.0:1.25 to 1.0:1.5, preferably 1.0:1.25.

[0013] Furthermore, the molar ratio of allene boronic acid pinacol ester to trifluoroacetic anhydride is 1.0:2.0 to 1.0:3.0, preferably 1.0:2.0.

[0014] Furthermore, in the tetrahydrofuran solution of allene boronic acid pinacol ester, the concentration of allene boronic acid pinacol ester is 0.05M to 0.1M.

[0015] Compared with the prior art, the present invention has the following advantages:

[0016] (1) The trisubstituted allene boronic acid pinacol esters of the present invention are both abundant in source and easy to store. By changing the structure of the allene substituent, a variety of high-propargyl tertiary alcohols containing two adjacent chiral centers can be synthesized.

[0017] (2) The synthesis method of the present invention has relatively mild reaction conditions, wide substrate adaptability, and excellent chemical selectivity and stereoselectivity.

[0018] (3) The present invention avoids the use of catalysts and active organometallic reagents that are difficult to prepare.

[0019] (4) The synthesis method of the present invention can prepare chiral high propargyl tertiary alcohols with high enantiomeric excess (ee value) by using optically active allene borate esters, which is of great significance for the synthesis of bioactive molecules and pharmaceutical intermediates. DETAILED DESCRIPTION

[0020] The present invention is further described in detail below in conjunction with specific embodiments.

[0021] The synthesis of the pinacol ester of allene boronic acid of the present invention is prepared by reference to the existing method (1, De-Wei Gao, Yiyang Xiao, Mingyu Liu, Zhen Liu, Malkanthi K. Karunananda, Jason S. Chen, and Keary M. Engle. ACS Catal. 2018 8 (4), 3650-3654; 2, Youming Huang, Juan del Pozo, Sebastian Torker, and Amir H. Hoveyda. J. Am. Chem. Soc. 2018 140 (7), 2643-2655; 3, Hajime Ito, Yusuke Sasaki, and Masaya Sawamura. J. Am. Chem. Soc. 2008 130 (47), 15774-15775).

[0022] Taking 2-(deca-2,3-dien-4-yl)-4,4,5,5-tetramethyl-1,3-2-dioxaborane as an example, the specific synthesis steps are as follows:

[0023] Cuprous chloride (CuCl), potassium tert-butoxide (tBuOK), bis(boronic acid pinacol) (B2Pin2), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (Xantphos) and tetrahydrofuran (THF) are stirred and mixed uniformly, and non-terminal propargyl alcohol methyl carbonate represented by formula (IV) is added, and the mixture is reacted at 60° C. for 12 hours. After the reaction is completed, the reaction mixture is diluted with petroleum ether and the solid precipitated in the reaction solution is removed. The obtained clear solution of the mixture is subjected to vacuum rotary evaporation to remove the solvent, and the residue is purified by column chromatography to obtain 2-(deca-2,3-dien-4-yl)-4,4,5,5-tetramethyl-1,3-2-dioxaborane represented by formula (I).

[0024]

[0025] In the present invention, cuprous chloride, potassium tert-butoxide, bis(pinacol) borate, 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene, aromatic ketone, n-butyl lithium, trifluoroacetic anhydride and tetrahydrofuran are commercial raw materials and reagents, and can be purchased through market channels.

[0026] Example 1

[0027] 2-(4-Bromophenyl)-3-methylundec-4-yn-2-ol (R 1 is n-hexyl, R 2 is methyl, R 3 is 4-bromo):

[0028]

[0029] Under argon atmosphere, 2-(decane-2,3-dien-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (80 mg, 0.30 mmol, 1.0 equiv.) was added to an anhydrous Schlenk reaction bottle containing a polytetrafluoroethylene magnet, tetrahydrofuran (2 mL) was added and stirred, the temperature of the reaction system was lowered to -78 ° C, and then n-butyl lithium (0.24 mL, 1.6 M hexane solution, 0.375 mmol, 1.25 equiv.) was added dropwise and stirred for 25 minutes, followed by trifluoroacetic anhydride (84 μL, 0.60 mmol, 2.0 equiv.), and the reaction mixture was stirred at -78 ° C for 45 minutes. Then, p-bromoacetophenone (90 mg, 0.45 mmol) was added at -78 ° C, and the reactor was rinsed with tetrahydrofuran (2 mL). The final reaction mixture was stirred at -78 ° C for 30 minutes and naturally warmed to room temperature for 24 hours. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography using ethyl acetate / petroleum ether (1:500-1:100) as eluent to obtain a pure product, 82 mg, with a yield of 81%.

[0030] NMR data: 1 H NMR (500MHz, CDCl3) δ7.44(d,J=8.6Hz,2H),7.29(d,J=8.6Hz,2H),2.78(qt,J=7.0Hz,J=2.2Hz,1H),2.20(td,J=7.0Hz,J=2. 1Hz,2H),1.62(s,3H),1.53-1.47(m,2H),1.41-1.35(m,2H),1.34-1.25(m,4H),0.89(t,J=7.8Hz,3H),0.88(d,J=7.0Hz,3H); 13 C NMR (126MHz, CDCl3) δ144.2,130.9,127.0,120.4,84.3,80.7,74.9,38.8,31.3,29.5,28.9,28.5,22.5,18.7,16.0,14.0; HRMS(ESI):m / z calcd.for[C 18 H 25 OBrNa] + 359.0.986, found 359.0984.

[0031] Example 2

[0032] 2-(4-Chlorophenyl)-3-methylundec-4-yn-2-ol (R 1is n-hexyl, R 2 is methyl, R 3 is 4-chloro):

[0033]

[0034] Under argon atmosphere, 2-(decane-2,3-dien-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (80 mg, 0.30 mmol, 1.0 equiv.) was added to an anhydrous Schlenk reaction bottle containing a polytetrafluoroethylene magnet, tetrahydrofuran (2 mL) was added and stirred, the temperature of the reaction system was lowered to -78 ° C, and then n-butyl lithium (0.24 mL, 1.6 M hexane solution, 0.375 mmol, 1.25 equiv.) was added dropwise and stirred for 25 minutes, followed by trifluoroacetic anhydride (84 μL, 0.60 mmol, 2.0 equiv.), and the reaction mixture was stirred at -78 ° C for 45 minutes. Then, p-chloroacetophenone (70 mg, 0.45 mmol) was added at -78 ° C, and the reactor was rinsed with tetrahydrofuran (2 mL). The final reaction mixture was stirred at -78 ° C for 30 minutes and naturally warmed to room temperature for 24 hours. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography using ethyl acetate / petroleum ether (1:500-1:100) as eluent to obtain a pure product, 62 mg, with a yield of 71%.

[0035] NMR data: 1 H NMR (500MHz, CDCl3) δ7.34(d,J=8.6Hz,2H),7.28(d,J=8.6Hz,2H),2.78(qt,J=7.0Hz,J=2.2Hz,1H),2.20(td,J=7.0Hz,J=2. 0Hz,2H),1.63(s,3H),1.53-1.47(m,2H),1.41-1.35(m,2H),1.34-1.25(m,4H),0.89(t,J=7.1Hz,3H),0.88(d,J=7.1Hz,3H); 13 C NMR (126MHz, CDCl3) δ143.7,132.3,128.0,126.6,84.3,80.7,74.9,38.8,31.3,29.5,28.9,28.5,22.5,18.7,16.0,14.0; HRMS(ESI):m / z calcd.for[C 18 H 25 OClNa] +315.1492, found 315.1491.

[0036] Example 3

[0037] 3-Methyl-2-(4-nitrophenyl)undec-4-yn-2-ol (R 1 is n-hexyl, R 2 is methyl, R 3 is 4-nitro):

[0038]

[0039] Under argon atmosphere, 2-(decane-2,3-dien-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (80 mg, 0.30 mmol, 1.0 equiv.) was added to an anhydrous Schlenk reaction bottle containing a polytetrafluoroethylene magnet, tetrahydrofuran (2 mL) was added and stirred, the temperature of the reaction system was lowered to -78 ° C, and then n-butyl lithium (0.24 mL, 1.6 M hexane solution, 0.375 mmol, 1.25 equiv.) was added dropwise and stirred for 25 minutes, followed by trifluoroacetic anhydride (84 μL, 0.60 mmol, 2.0 equiv.), and the reaction mixture was stirred at -78 ° C for 45 minutes. Then, p-nitroacetophenone (75 mg, 0.45 mmol) was added at -78 ° C, and the reactor was rinsed with tetrahydrofuran (2 mL). The final reaction mixture was stirred at -78 ° C for 30 minutes and naturally warmed to room temperature for 24 hours. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography using ethyl acetate / petroleum ether (1:500-1:100) as eluent to obtain a pure product, 68 mg, with a yield of 75%.

[0040] NMR data: 1 H NMR (500MHz, CDCl3) δ8.18(d,J=8.9Hz,2H),7.59(d,J=8.9Hz,2H),2.85(qt,J=6.9Hz,J=1.9Hz,1H),2.33(br s,1H),2.21(td,J=7.0Hz,J=1.9Hz,2H),1.67(s,3H),1.54-1.48(m,2H),1.41 -1.35(m,2H),1.34-1.27(m,4H),0.89(t,J=6.8Hz,3H),0.88(d,J=7.0Hz,3H); 13C NMR (126MHz, CDCl3) δ152.7,146.6,126.2,123.1,84.9,80.1,75.2,38.8,31.2,29.5,28.8,28.5,22.5,18.6,16.0,13.9; HRMS(ESI):m / zcalcd.for[C 18 H 25 NO3Na] + 326.1732, found 326.1729.

[0041] Example 4

[0042] 3-methyl-2-p-tolylundec-4-yn-2-ol (R 1 is n-hexyl, R 2 is methyl, R 3 is 4-methyl):

[0043]

[0044] Under argon atmosphere, 2-(decane-2,3-dien-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (80 mg, 0.30 mmol, 1.0 equiv.) was added to an anhydrous Schlenk reaction bottle containing a polytetrafluoroethylene magnet, tetrahydrofuran (2 mL) was added and stirred, the temperature of the reaction system was lowered to -78 ° C, and then n-butyl lithium (0.24 mL, 1.6 M hexane solution, 0.375 mmol, 1.25 equiv.) was added dropwise and stirred for 25 minutes, followed by trifluoroacetic anhydride (84 μL, 0.60 mmol, 2.0 equiv.), and the reaction mixture was stirred at -78 ° C for 45 minutes. Then, p-methylacetophenone (61 mg, 0.45 mmol) was added at -78 ° C, and the reactor was rinsed with tetrahydrofuran (2 mL). The final reaction mixture was stirred at -78 ° C for 30 minutes and naturally warmed to room temperature for 24 hours. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography using ethyl acetate / petroleum ether (1:500-1:100) as eluent to obtain a pure product, 76 mg, with a yield of 94%.

[0045] NMR data: 1H NMR (500MHz, CDCl3) δ7.29(d,J=8.0Hz,2H),7.13(d,J=7.8Hz,2H),2.81(qt,J=6.9Hz,J=1.7Hz,1H),2.33(s,3H),2.20(td,J=7.0Hz ,J=1.6Hz,2H),1.64(s,3H),1.54-1.47(m,2H),1.42-1.35(m,2H),1.34-1.26(m,4H),0.90(d,J=6.7Hz,3H),0.89(t,J=5.8Hz,3H); 13 C NMR(126MHz, CDCl3)δ142.2,135.9,128.5,124.9,83.9,81.2,75.0,38.8,31.3,29.7,28.9,28.5,22.5,20.9,18.7,16.1,14.0; HRMS(ESI):m / zcalcd.for[C 19 H 28 ONa] + 295.2038, found 295.2038.

[0046] Example 5

[0047] 3-Methyl-2-m-tolylundec-4-yn-2-ol (R 1 is n-hexyl, R 2 is methyl, R 3 is 3-methyl):

[0048]

[0049] Under argon atmosphere, 2-(decane-2,3-dien-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (80 mg, 0.30 mmol, 1.0 equiv.) was added to an anhydrous Schlenk reaction bottle containing a polytetrafluoroethylene magnet, tetrahydrofuran (2 mL) was added and stirred, the temperature of the reaction system was lowered to -78 °C, and then n-butyl lithium (0.24 mL, 1.6 M hexane solution, 0.375 mmol, 1.25 equiv.) was added dropwise and stirred for 25 minutes, followed by trifluoroacetic anhydride (84 μL, 0.60 mmol, 2.0 equiv.), and the reaction mixture was stirred at -78 °C for 45 minutes. Then, m-methylacetophenone (61 mg, 0.45 mmol) was added at -78 °C, and the reactor was rinsed with tetrahydrofuran (2 mL). The final reaction mixture was stirred at -78 ° C for 30 minutes and naturally warmed to room temperature for 24 hours. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography using ethyl acetate / petroleum ether (1:500-1:100) as eluent to obtain a pure product, 67 mg, with a yield of 82%.

[0050] NMR data: 1 H NMR (500MHz, CDCl3) δ7.25-7.15(m,3H),7.04(d,J=6.9Hz,1H),2.82(qt,J=6.9Hz,J=2.1Hz,1H),2.35(s,3H),2.21(td,J=7.0Hz,J=1.8Hz,2H),1.98(br s,1H),1.64(s,3H),1.54-1.47(m,2H),1.42-1.35(m,2H),1.34-1.25(m,4H),0.897(t,J=7.1Hz,3H),0.896(d,J=6.9Hz,3H); 13 C NMR (126MHz, CDCl3) δ145.1,137.4,127.8,127.2,125.7,122.1,84.0,81.2,75 .1,38.8,31.3,29.8,28.9,28.5,22.5,21.6,18.7,16.1,14.0; HRMS(ESI):m / z calcd.for[C 19 H 28 ONa] + 295.2038, found 295.2040.

[0051] Example 6

[0052] 3-Methyl-2-o-tolylundec-4-yn-2-ol (R 1 is n-hexyl, R 2 is methyl, R 3 is 2-methyl):

[0053]

[0054] Under argon atmosphere, 2-(decane-2,3-dien-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (80 mg, 0.30 mmol, 1.0 equiv.) was added to an anhydrous Schlenk reaction bottle containing a polytetrafluoroethylene magnet, tetrahydrofuran (2 mL) was added and stirred, the temperature of the reaction system was lowered to -78 ° C, and then n-butyl lithium (0.24 mL, 1.6 M hexane solution, 0.375 mmol, 1.25 equiv.) was added dropwise and stirred for 25 minutes, followed by trifluoroacetic anhydride (84 μL, 0.60 mmol, 2.0 equiv.), and the reaction mixture was stirred at -78 ° C for 45 minutes. Then, o-methylacetophenone (61 mg, 0.45 mmol) was added at -78 ° C, and the reactor was rinsed with tetrahydrofuran (2 mL). The final reaction mixture was stirred at -78 ° C for 30 minutes and naturally warmed to room temperature for 24 hours. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography using ethyl acetate / petroleum ether (1:500-1:100) as eluent to obtain a pure product, 62 mg, with a yield of 76%.

[0055] NMR data: 1 H NMR (500MHz, CDCl3) δ7.60 (d, J=7.7Hz, 1H), 7.19-7.07 (m, 3H), 3.18 (qt, J=6.8Hz, J=1.8Hz, 1H), 2.47 (s, 3H), 2.20 (td, J=7.1Hz, J=1.6Hz,2H),1.72(s,3H),1.54-1.47(m,2H),1.42-1.35(m,2H),1.35-1.24(m,4H),0.93(d,J=6.9Hz,3H),0.89(t,J=7.0Hz,3H); 13C NMR (126MHz, CDCl3) δ142.6,134.1,132.2,126.9,126.7,125.6,83.9,81.2,76.2,36. 6,31.3,28.9(7),28.9(0),28.5,22.5(7),22.5(5),18.7,16.1,14.0; HRMS(ESI):m / z calcd.for[C 19 H 28 ONa] + 295.2038, found 295.2038.

[0056] Example 7

[0057] 2-(4-methoxyphenyl)-3-methylundec-4-yn-2-ol (R 1 is n-hexyl, R 2 is methyl, R 3 is 4-methoxy):

[0058]

[0059] Under argon atmosphere, 2-(decane-2,3-dien-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (80 mg, 0.30 mmol, 1.0 equiv.) was added to an anhydrous Schlenk reaction bottle containing a polytetrafluoroethylene magnet, tetrahydrofuran (2 mL) was added and stirred, the temperature of the reaction system was lowered to -78 ° C, and then n-butyl lithium (0.24 mL, 1.6 M hexane solution, 0.375 mmol, 1.25 equiv.) was added dropwise and stirred for 25 minutes, followed by trifluoroacetic anhydride (84 μL, 0.60 mmol, 2.0 equiv.), and the reaction mixture was stirred at -78 ° C for 45 minutes. Then, p-methoxyacetophenone (68 mg, 0.45 mmol) was added at -78 ° C, and the reactor was rinsed with tetrahydrofuran (2 mL). The final reaction mixture was stirred at -78 ° C for 30 minutes and naturally warmed to room temperature for 24 hours. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography using ethyl acetate / petroleum ether (1:500-1:100) as eluent to obtain a pure product, 77 mg, with a yield of 90%.

[0060] Colorless oil(77mg,90%).NMR data: 1H NMR (500MHz, CDCl3) δ7.32(d,J=8.7Hz,2H),6.85(d,J=8.7Hz,2H),3.80(s,3H),2.78(qt,J=6.9Hz,J=2.0Hz,1H),2.20(td,J=7.0Hz ,J=1.9Hz,2H),1.63(s,3H),1.53-1.47(m,2H),1.41-1.35(m,2H),1.34-1.25(m,4H),0.90(d,J=7.1Hz,3H),0.89(t,J=7.9Hz,3H); 13 C NMR (126MHz, CDCl3) δ158.1,137.4,126.2,113.2,84.0,81.2,74.9,55.1,39.0,31.3,29.6,28.9,28.5,22.5,18.7,16.1,14.0; HRMS (ESI): m / z calcd.for[C 19 H 28 O2Na] + 311.1987, found 311.1988.

[0061] Example 8

[0062] 2-(4-Benzyloxy)phenyl-3-methylundec-4-yn-2-ol (R 1 is n-hexyl, R 2 is methyl, R 3 is 4-benzyloxy):

[0063]

[0064] Under argon atmosphere, 2-(decane-2,3-dien-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (80 mg, 0.30 mmol, 1.0 equiv.) was added to an anhydrous Schlenk reaction bottle containing a polytetrafluoroethylene magnet, tetrahydrofuran (2 mL) was added and stirred, the temperature of the reaction system was lowered to -78 ° C, and then n-butyl lithium (0.24 mL, 1.6 M hexane solution, 0.375 mmol, 1.25 equiv.) was added dropwise and stirred for 25 minutes, followed by trifluoroacetic anhydride (84 μL, 0.60 mmol, 2.0 equiv.), and the reaction mixture was stirred at -78 ° C for 45 minutes. Then, p-benzyloxyacetophenone (102 mg, 0.45 mmol) was added at -78 ° C, and the reactor was rinsed with tetrahydrofuran (2 mL). The final reaction mixture was stirred at -78 ° C for 30 minutes and naturally warmed to room temperature for 24 hours. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography using ethyl acetate / petroleum ether (1:500-1:100) as eluent to obtain a pure product, 78 mg, with a yield of 72%.

[0065] NMR data: 1 H NMR (500MHz, CDCl3) δ7.44 (d, J = 7.4Hz, 2H), 7.39 (t, J = 7.6Hz, 2H), 7.36-7. 30(m,3H),6.94(d,J=8.8Hz,2H),5.05(s,2H),2.79(qt,J=6.9Hz,J=2.0Hz,1 H),2.20(td,J=7.0Hz,J=2.0Hz,2H),1.64(s,3H),1.55-1.48(m,2H),1.43-1 .36(m,2H),1.35-1.27(m,4H),0.92(d,J=7.0Hz,3H),0.90(t,J=7.1Hz,3H); 13 C NMR (126MHz, CDCl3) δ157.4,137.6,137.0,128.5,127.8,127.4,126.2,114.1,83.9,8 1.2,74.9,69.9,39.0,31.3,29.6,28.9,28.5,22.5,18.7,16.1,14.0; HRMS(ESI):m / z calcd.for[C 25 H 32 O2Na] + 387.2300, found 387.22950.

[0066] Example 9

[0067] 4-(2-Hydroxy-3-methylundec-4-yn-2-yl)benzonitrile (R 1 is n-hexyl, R 2 is methyl, R 3 is 4-nitrile):

[0068]

[0069] Under argon atmosphere, 2-(decane-2,3-dien-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (80 mg, 0.30 mmol, 1.0 equiv.) was added to an anhydrous Schlenk reaction bottle containing a polytetrafluoroethylene magnet, tetrahydrofuran (2 mL) was added and stirred, the temperature of the reaction system was lowered to -78 ° C, and then n-butyl lithium (0.24 mL, 1.6 M hexane solution, 0.375 mmol, 1.25 equiv.) was added dropwise and stirred for 25 minutes, followed by trifluoroacetic anhydride (84 μL, 0.60 mmol, 2.0 equiv.), and the reaction mixture was stirred at -78 ° C for 45 minutes. Then, p-nitriloacetophenone (66 mg, 0.45 mmol) was added at -78 ° C, and the reactor was rinsed with tetrahydrofuran (2 mL). The final reaction mixture was stirred at -78 ° C for 30 minutes and naturally warmed to room temperature for 24 hours. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography using ethyl acetate / petroleum ether (1:500-1:100) as eluent to obtain a pure product, 60 mg, with a yield of 71%.

[0070] NMR data: 1 H NMR (500MHz, CDCl3) δ7.62 (d, J = 8.4Hz, 2H), 7.53 (d, J = 8.4Hz, 2H), 2.81 (qt, J = 6.9Hz, J = 2.1Hz, 1H), 2.20 (td, J = 7.0Hz, J = 2. 0Hz,2H),1.65(s,3H),1.53-1.48(m,2H),1.41-1.35(m,2H),1.34-1.26(m,4H),0.89(t,J=6.7Hz,3H),0.87(d,J=6.9Hz,3H); 13C NMR (126MHz, CDCl3) δ150.7,131.8,126.0,118.9,110.4,84.8,80.2,75.1,38.7,31.2,29.4,28.8,28.5,22.5,18.6,16.0,14.0; HRMS (ESI): m / z calcd.for[C 19 H 25 NONa] + 306.1834, found 306.1838.

[0071] Example 10

[0072] 3-Methyl-2-(4-methylthio)phenylundec-4-yn-2-ol (R 1 is n-hexyl, R 2 is methyl, R 3 is 4-methylthio):

[0073]

[0074] Under argon atmosphere, 2-(decane-2,3-dien-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (80 mg, 0.30 mmol, 1.0 equiv.) was added to an anhydrous Schlenk reaction bottle containing a polytetrafluoroethylene magnet, tetrahydrofuran (2 mL) was added and stirred, the temperature of the reaction system was lowered to -78 ° C, and then n-butyl lithium (0.24 mL, 1.6 M hexane solution, 0.375 mmol, 1.25 equiv.) was added dropwise and stirred for 25 minutes, followed by trifluoroacetic anhydride (84 μL, 0.60 mmol, 2.0 equiv.), and the reaction mixture was stirred at -78 ° C for 45 minutes. Then, p-methylthioacetophenone (75 mg, 0.45 mmol) was added at -78 ° C, and the reactor was rinsed with tetrahydrofuran (2 mL). The final reaction mixture was stirred at -78 ° C for 30 minutes and naturally warmed to room temperature for 24 hours. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography using ethyl acetate / petroleum ether (1:500-1:100) as eluent to obtain a pure product, 72 mg, with a yield of 79%.

[0075] NMR data: 1H NMR (500MHz, CDCl3) δ7.33(d,J=8.5Hz,2H),7.21(d,J=8.5Hz,2H),2.79(qt,J=7.0Hz,J=2.2Hz,1H),2.47(s,3H),2.20(td,J=7.0Hz ,J=2.2Hz,2H),1.63(s,3H),1.53-1.47(m,2H),1.41-1.35(m,2H),1.34-1.27(m,4H),0.89(d,J=7.0Hz,3H),0.89(t,J=7.1Hz,3H); 13 C NMR(126MHz, CDCl3)δ142.2,136.2,126.1,125.6,84.1,80.9,74.9,38.8,31.2,29.5,28.9,28.5,22.5,18.7,16.1,15.8,14.0; HRMS(ESI):m / zcalcd.for[C 19 H 28 ONaS] + 327.1759, found 327.1762.

[0076] Embodiment 11

[0077] 2-Furan-2-yl-3-methylundec-4-yn-2-ol (R 1 is n-hexyl, R 2 is methyl, R 3 is a furan ring):

[0078]

[0079] Under argon atmosphere, 2-(decane-2,3-dien-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (80 mg, 0.30 mmol, 1.0 equiv.) was added to an anhydrous Schlenk reaction bottle containing a polytetrafluoroethylene magnet, tetrahydrofuran (2 mL) was added and stirred, the temperature of the reaction system was lowered to -78 ° C, and then n-butyl lithium (0.24 mL, 1.6 M hexane solution, 0.375 mmol, 1.25 equiv.) was added dropwise and stirred for 25 minutes, followed by trifluoroacetic anhydride (84 μL, 0.60 mmol, 2.0 equiv.), and the reaction mixture was stirred at -78 ° C for 45 minutes. Then, 2-acetylfuran (50 mg, 0.45 mmol) was added at -78 ° C, and the reactor was rinsed with tetrahydrofuran (2 mL). The final reaction mixture was stirred at -78 ° C for 30 minutes and naturally warmed to room temperature for 24 hours. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography using ethyl acetate / petroleum ether (1:500-1:100) as eluent to obtain a pure product, 63 mg, with a yield of 85%.

[0080] NMR data: 1 H NMR (500MHz, CDCl3) δ7.36-7.33(m,1H),6.31(dd,J=3.2Hz,J=1.8Hz,1H),6.26(dd,J=3.2Hz,J=0.8Hz,1H),2.91(qt,J=7.0Hz,J=2.2Hz,1H),2.1 5(td,J=7.1Hz,J=2.3Hz,2H),1.60(s,3H),1.49-1.43(m,2H),1.37-1.31 (m,2H),1.30-1.24(m,4H),1.05(d,J=7.0Hz,3H),0.88(t,J=7.2Hz,3H); 13 C NMR (126MHz, CDCl3) δ157.8,141.2,109.9,105.4,83.7,80.5,73.2,37.4,31.3,28.8,28.4,25.1,22.5,18.6,16.0,14.0; HRMS(ESI):m / z calcd.for[C 16 H 24 O2Na] + 271.1674, found 271.1675.

[0081] Example 12

[0082] 2-(Benzothiophene-2-yl)-3-methylundec-4-yn-2-ol (R 1 is n-hexyl, R 2 is methyl, R 3 is a benzothiophene ring):

[0083]

[0084] Under argon atmosphere, 2-(decane-2,3-dien-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (80 mg, 0.30 mmol, 1.0 equiv.) was added to an anhydrous Schlenk reaction bottle containing a polytetrafluoroethylene magnet, tetrahydrofuran (2 mL) was added and stirred, the temperature of the reaction system was lowered to -78 ° C, and then n-butyl lithium (0.24 mL, 1.6 M hexane solution, 0.375 mmol, 1.25 equiv.) was added dropwise and stirred for 25 minutes, followed by trifluoroacetic anhydride (84 μL, 0.60 mmol, 2.0 equiv.), and the reaction mixture was stirred at -78 ° C for 45 minutes. Then, 2-acetylbenzothiophene (80 mg, 0.45 mmol) was added at -78 ° C, and the reactor was rinsed with tetrahydrofuran (2 mL). The final reaction mixture was stirred at -78 ° C for 30 minutes and naturally warmed to room temperature for 24 hours. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography using ethyl acetate / petroleum ether (1:500-1:100) as eluent to obtain a pure product, 61 mg, with a yield of 65%.

[0085] NMR data: 1 H NMR (500MHz, CDCl3) δ7.79(d,J=7.9Hz,2H),7.70(d,J=7.8Hz,2H),7.34-7.27(m,2H),7.17(s,1H),2.90(qt,J=6.9Hz,J=2.1Hz,1H),2.20(td ,J=7.1Hz,J=2.1Hz,2H),1.77(s,3H),1.53-1.47(m,2H),1.40-1.34(m,2H),1.33-1.25(m,4H),1.11(d,J=7.0Hz,3H),0.88(t,J=7.0Hz,3H); 13C NMR (126MHz, CDCl3) δ151.0,139.7,139.2,124.0,123.7,123.2,122.1,119.5,84. 6,80.4,75.2,39.5,31.3,29.5,28.8,28.5,22.5,18.7,16.3,14.0; HRMS(ESI):m / z calcd.for[C 20 H 26 ONaS] + 281.1881, found 281.1879.

[0086] Embodiment 13

[0087] 2-(4-Bromophenyl)-3-ethylundec-4-yn-2-ol (R 1 is n-hexyl, R 2 Ethyl, R 3 is 4-bromo):

[0088]

[0089] Under argon atmosphere, 4,4,5,5-tetramethyl-2-undec-3,4-dien-5-yl)-1,3,2-dioxaborane (83 mg, 0.30 mmol, 1.0 equiv.) was added to an anhydrous Schlenk reaction bottle containing a polytetrafluoroethylene magnet, tetrahydrofuran (2 mL) was added and stirred, the temperature of the reaction system was lowered to -78 ° C, and then n-butyl lithium (0.24 mL, 1.6 M hexane solution, 0.375 mmol, 1.25 equiv.) was added dropwise and stirred for 25 minutes, followed by trifluoroacetic anhydride (84 μL, 0.60 mmol, 2.0 equiv.), and the reaction mixture was stirred at -78 ° C for 45 minutes. Then, p-bromoacetophenone (90 mg, 0.45 mmol) was added at -78 ° C, and the reactor was rinsed with tetrahydrofuran (2 mL). The final reaction mixture was stirred at -78 ° C for 30 minutes and naturally warmed to room temperature for 24 hours. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography using ethyl acetate / petroleum ether (1:500-1:100) as eluent to obtain a pure product, 67 mg, with a yield of 64%.

[0090] NMR data: 1H NMR (500MHz, CDCl3) δ7.44(d,J=8.2Hz,2H),7.28(d,J=8.2Hz,2H),2.59-2.53(m,1H),2.27(br s,1H),2.22(td,J=7.2Hz,J=1.4Hz,2H),1.62(s,3H),1.55-1.48(m,2H),1.4 3-1.36(m,2H),1.35-1.27(m,4H),1.26-1.07(m,2H),0.89(t,J=7.2Hz,6H); 13 C NMR (126MHz, CDCl3) δ144.6,130.9,127.0,120.4,85.5,79.2,75.1,47.1,31.2,29.8,28.9,28.5,22.9,22.5,18.7,14.0,12.5; HRMS (ESI): m / z calcd.for[C 19 H 27 ONaBr] + 373.1143, found 373.1149.

[0091] Embodiment 14

[0092] 2-(4-Bromophenyl)-3-methylnon-8-en-4-yn-2-ol (R 1 is 1-butenyl, R 2 is methyl, R 3 is 4-bromo):

[0093]

[0094] Under argon atmosphere, 4,4,5,5-tetramethyl-2-(octa-2,3,7-trien-4-yl)-1,3,2-dioxaborane (70 mg, 0.30 mmol, 1.0 equiv.) was added to an anhydrous Schlenk reaction bottle containing a polytetrafluoroethylene magnet, tetrahydrofuran (2 mL) was added and stirred, the temperature of the reaction system was lowered to -78 ° C, and then n-butyl lithium (0.24 mL, 1.6 M hexane solution, 0.375 mmol, 1.25 equiv.) was added dropwise and stirred for 25 minutes, followed by trifluoroacetic anhydride (84 μL, 0.60 mmol, 2.0 equiv.), and the reaction mixture was stirred at -78 ° C for 45 minutes. Then, p-bromoacetophenone (90 mg, 0.45 mmol) was added at -78 ° C, and the reactor was rinsed with tetrahydrofuran (2 mL). The final reaction mixture was stirred at -78 ° C for 30 minutes and naturally warmed to room temperature for 24 hours. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography using ethyl acetate / petroleum ether (1:500-1:100) as eluent to obtain a pure product, 67 mg, with a yield of 64%.

[0095] NMR data: 1 H NMR (500MHz, CDCl3) δ7.44(d,J=8.2Hz,2H),7.28(d,J=8.4Hz,2H),5.90-5.80(m,1H),5.14-5.03 (m,2H),2.77(qt,J=7.0Hz,J=2.1Hz,1H),2.34-2.25(m,4H),1.62(s,3H),0.87(d,J=7.0Hz,3H); 13 C NMR(126MHz, CDCl3)δ144.2,137.1,130.9,127.0,120.4,115.8,83.4,81.5,74.9,38.7,33.1,29.6,18.4,,16.0; HRMS(ESI):m / zcalcd.for[C 16 H 19 ONaBr] + 329.0517, found 329.0520.

[0096] Embodiment 15

[0097] 2-(4-Bromophenyl)-5-cyclohexyl-3-methyl-4-yn-2-ol (R 1 is cyclohexyl, R 2 is methyl, R 3 is 4-bromo):

[0098]

[0099] Under argon atmosphere, 2-(1-cyclohexylbuta-1,2-dienyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (79 mg, 0.30 mmol, 1.0 equiv.) was added to an anhydrous Schlenk reaction bottle containing a polytetrafluoroethylene magnet, tetrahydrofuran (2 mL) was added and stirred, the temperature of the reaction system was lowered to -78 ° C, and then n-butyl lithium (0.24 mL, 1.6 M hexane solution, 0.375 mmol, 1.25 equiv.) was added dropwise and stirred for 25 minutes, followed by trifluoroacetic anhydride (84 μL, 0.60 mmol, 2.0 equiv.), and the reaction mixture was stirred at -78 ° C for 45 minutes. Then, p-bromoacetophenone (90 mg, 0.45 mmol) was added at -78 ° C, and the reactor was rinsed with tetrahydrofuran (2 mL). The final reaction mixture was stirred at -78 ° C for 30 minutes and naturally warmed to room temperature for 24 hours. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography using ethyl acetate / petroleum ether (1:500-1:100) as eluent to obtain a pure product, 70 mg, with a yield of 70%.

[0100] NMR data: 1 H NMR (500MHz, CDCl3) δ7.44(d,J=8.3Hz,2H),7.29(d,J=8.4Hz,2H),2.81-2.75(m,1H),2.44-2.35(m,1H),2.24(br s,1H),1.83-1.74(m,2H),1.72-1.64(m,2H),1.62(s,3H),1.55-1.48(m,1H),1.47-1.38(m,2H),1.37-1.27(m,3H),0.88(d,J=6.9Hz,3H); 13 C NMR(126MHz, CDCl3)δ144.2,130.9,127.0,120.4,88.5,80.6,74.8,38.7,32.8,29.4,28.9,25.8,24.7,16.1; HRMS(ESI):m / z calcd.for[C 18 H 23 ONaBr] + 357.0830, found 357.0823.

[0101] Example 16

[0102] 2-(4-Bromophenyl)-8-chloro-3-methyloct-4-yn-2-ol (R 1 is chloropropyl, R 2 is methyl, R 3 is 4-bromo):

[0103]

[0104] Under argon atmosphere, 2-(7-chloroheptyl-2,3-dien-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (77 mg, 0.30 mmol, 1.0 equiv.) was added to an anhydrous Schlenk reaction bottle containing a polytetrafluoroethylene magnet, tetrahydrofuran (2 mL) was added and stirred, the temperature of the reaction system was lowered to -78°C, and then n-butyl lithium (0.24 mL, 1.6 M hexane solution, 0.375 mmol, 1.25 equiv.) was added dropwise and stirred for 25 minutes, followed by the addition of trifluoroacetic anhydride (84 μL, 0.60 mmol, 2.0 equiv.), and the reaction mixture was stirred at -78°C for 45 minutes. Then, p-bromoacetophenone (90 mg 0.45 mmol) was added at -78°C, and the reactor was rinsed with tetrahydrofuran (2 mL). The final reaction mixture was stirred at -78 ° C for 30 minutes and naturally warmed to room temperature for 24 hours. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography using ethyl acetate / petroleum ether (1:500-1:100) as eluent to obtain a pure product, 74 mg, with a yield of 75%.

[0105] NMR data: 1 H NMR (500MHz, CDCl3) δ7.45(d,J=8.5Hz,2H),7.29(d,J=8.5Hz,2H),3.63(t,J=6.3H z,2H),2.78(qt,J=7.0Hz,J=1.8Hz,1H),2.41(td,J=6.7Hz,J=1.7Hz,2H),2.12(br s,1H),1.98-1.92(m,2H),1.63(s,3H),0.91(d,J=6.9Hz,3H); 13 C NMR (126MHz, CDCl3) δ144.2,131.0,127.0,120.6,82.0(7),82.0(2),75.0,43.6,38.8,31.4,29.3,16.1,16.0; HRMS(ESI):m / z calcd.for[C 15 H18 ONaClBr] + 351.0127, found 351.0114.

[0106] Embodiment 17

[0107] 2-(4-Bromophenyl)-3-methyl-7-phenylhept-4-yn-2-ol (R 1 is phenethyl, R 2 is methyl, R 3 is 4-bromo):

[0108]

[0109] Under argon atmosphere, 4,4,5,5-tetramethyl-2-(1-phenylhexa-3,4-dien-3-yl)-1,3,2-dioxaborane (85 mg, 0.30 mmol, 1.0 equiv.) was added to an anhydrous Schlenk reaction bottle containing a polytetrafluoroethylene magnet, tetrahydrofuran (2 mL) was added and stirred, the temperature of the reaction system was lowered to -78 ° C, and then n-butyl lithium (0.24 mL, 1.6 M hexane solution, 0.375 mmol, 1.25 equiv.) was added dropwise and stirred for 25 minutes, followed by the addition of trifluoroacetic anhydride (84 μL, 0.60 mmol, 2.0 equiv.), and the reaction mixture was stirred at -78 ° C for 45 minutes. Then, p-bromoacetophenone (90 mg, 0.45 mmol) was added at -78 ° C, and the reactor was rinsed with tetrahydrofuran (2 mL). The final reaction mixture was stirred at -78 ° C for 30 minutes and naturally warmed to room temperature for 24 hours. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography using ethyl acetate / petroleum ether (1:500-1:100) as eluent to obtain a pure product, 82 mg, with a yield of 77%.

[0110] NMR data: 1 H NMR (500MHz, CDCl3) δ7.41(d,J=8.5Hz,2H),7.32(t,J=7.1Hz,2H),7.25-7.20(m,5H),2.83( t,J=7.2Hz,2H),2.73(qt,J=6.9Hz,J=2.1Hz,1H),2.53(td,J=7.2Hz,J=1.9Hz,2H),1.99(br s,1H),1.50(s,3H),0.85(d,J=7.0Hz,3H); 13C NMR (126MHz, CDCl3) δ144.1,140.5,130.9,128.4,128.3,127.0,126.3,120.4,83.2,81.8,74.8,38.7,35.0,29.3,20.7,15.9; HRMS (ESI): m / z calcd.for[C 20 H 21 ONaBr] + 379.0673, found 379.0674.

[0111] Embodiment 18

[0112] (2R,3S)-7-(tert-butyldimethylsilyloxy)-3-methyl-2-phenylhept-4-yn-2-ol (R 1 is tert-butyldimethylsilylethoxy, R 2 is methyl, R 3 is 4-hydrogen):

[0113]

[0114] Under argon atmosphere, (R)-tert-butyldimethyl(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexa-3,4-dien-1-yl)oxy)silane (101 mg, 0.30 mmol, 1.0 equiv.) was added to an anhydrous Schlenk reaction bottle containing a polytetrafluoroethylene magnet, tetrahydrofuran (2 mL) was added and stirred, the temperature of the reaction system was lowered to -78°C, and then n-butyllithium (0.24 mL, 1.6 M hexane solution, 0.375 mmol, 1.25 equiv.) was added dropwise and stirred for 25 minutes, followed by the addition of trifluoroacetic anhydride (84 μL, 0.60 mmol, 2.0 equiv.), and the reaction mixture was stirred at -78°C for 45 minutes. Then, acetophenone (54 mg, 0.45 mmol) was added at -78°C, and the reactor was rinsed with tetrahydrofuran (2 mL). The final reaction mixture was stirred at -78 ° C for 30 minutes and naturally warmed to room temperature for 24 hours. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography using ethyl acetate / petroleum ether (1:500-1:100) as eluent to obtain a pure product, 77 mg, with a yield of 78%.

[0115] NMR data: 1H NMR (500MHz, CDCl3) δ7.41(d,J=8.5Hz,2H),7.32(t,J=7.8Hz,2H),7.22(t,J=7.2Hz,1H),3.7 2(t,J=6.9Hz,2H),2.81(qt,J=7.0Hz,J=1.9Hz,1H),2.42(td,J=6.9Hz,J=2.0Hz,2H),1.97(br s,1H),1.66(s,3H),0.91(s,9H),0.89(d,J=7.0Hz,3H),0.08(s,9H); 13 C NMR (126MHz, CDCl3) δ145.0,127.9,126.4,125.0,82.4,80.8,75.1,62.1,38.8,29.8,25.8,23.2,18.3,16.0,-5.2; HRMS(ESI):m / z calcd.for[C 20 H 32 O2NaSi] + 355.2069, found 355.2067.HPLC analysis (AD-H column, 1% i-PrOH / hexanes, 1.00mL / min, 220nm) indicated 99%ee:t R (major)=6.2min,t R (minor) = 6.7min.

[0116] Embodiment 19

[0117] (2R,3S)-2-(Benzo[d][1,3]dioxol-5-yl)-3-methylundec-4-yn-2-ol (R 1 is n-hexyl, R 2 is methyl, R 3 is 3,4-methylenedioxy):

[0118]

[0119] Under argon atmosphere, 2-(decane-2,3-dien-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (80 mg, 0.30 mmol, 1.0 equiv.) was added to an anhydrous Schlenk reaction bottle containing a polytetrafluoroethylene magnet, tetrahydrofuran (2 mL) was added and stirred, the temperature of the reaction system was lowered to -78 ° C, and then n-butyl lithium (0.24 mL, 1.6 M hexane solution, 0.375 mmol, 1.25 equiv.) was added dropwise and stirred for 25 minutes, followed by trifluoroacetic anhydride (84 μL, 0.60 mmol, 2.0 equiv.), and the reaction mixture was stirred at -78 ° C for 45 minutes. Then, 3,4-methylenedioxyacetophenone (73 mg, 0.45 mmol) was added at -78 ° C, and the reactor was rinsed with tetrahydrofuran (2 mL). The final reaction mixture was stirred at -78 ° C for 30 minutes and naturally warmed to room temperature for 24 hours. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography using ethyl acetate / petroleum ether (1:500-1:100) as eluent to obtain a pure product, 76 mg, with a yield of 84%.

[0120] NMR data: 1 H NMR (500MHz, CDCl3) δ6.93 (d, J=1.6Hz 1H),6.86(dd,J=8.1Hz,J=1.7Hz,1H),6.76(d,J=8.1Hz,1H),5.93(s,2H),2.75(qt,J=7.0Hz,J=2.2Hz,1H),2.20(td,J=7.1Hz,J =2.1Hz,2H),1.62(s,3H),1.54-1.47(m,2H),1.41-1.35(m,2H),1.34-1.25(m,4H),0.91(d,J=6.9Hz,3H),0.89(t,J=7.1Hz,3H); 13 C NMR (126MHz, CDCl3) δ147.3,145.9,139.4,118.1,107.5,106.1,100.8,84.0,8 1.1,75.0,39.0,31.2,29.7,28.9,28.5,22.5,18.6,16.1,13.9; HRMS(ESI):m / z calcd.for[C 19 H 26 O3Na] +325.1780, found325.1783.HPLC analysis (AD-H column, 1% i-PrOH / hexanes, 1.00mL / min, 220nm) indicated 99%ee:t R (major)=15.5min,t R (minor) = 14.5min.

[0121] Comparative Example 1

[0122] 3,4-Dimethyl-1-phenyldodecane-5-yn-3-ol (R 1 is n-hexyl, R 2 is methyl, R 3 is 1-phenylethyl):

[0123]

[0124] Under argon atmosphere, 2-(decane-2,3-dien-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (80 mg, 0.30 mmol, 1.0 equiv.) was added to an anhydrous Schlenk reaction bottle containing a polytetrafluoroethylene magnet, and 2 mL of tetrahydrofuran was added and stirred. The temperature of the reaction system was lowered to -78 °C, and then n-butyl lithium (0.24 mL, 1.6 M hexane solution, 0.375 mmol, 1.25 equiv.) was added dropwise and stirred for 25 minutes, followed by the addition of trifluoroacetic anhydride (84 μL, 0.60 mmol, 2.0 equiv.), and the reaction mixture was stirred at -78 °C for 45 minutes. Then, benzyl acetone (67 mg, 0.45 mmol) was added at -78 °C, and the reactor was rinsed with 2 mL of tetrahydrofuran. The final reaction mixture was stirred at -78 °C for 30 minutes and naturally warmed to room temperature for reaction for 24 hours. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The nuclear magnetic resonance hydrogen spectrum of the crude product detected the production of isomers, and the ratio of the main product to the by-product was about 1:1.8, indicating that R 3 When the product does not have a flat benzene ring structure or a heterocyclic aromatic structure, the stereochemical selectivity of the product is poor, and it is not suitable to adopt the method of the present invention to selectively synthesize a high propargyl tertiary alcohol containing two adjacent chiral centers.

[0125] Comparative Example 2

[0126] 2-(4-Bromophenyl)-3-methylundec-4-yn-2-ol (R 1 is n-hexyl, R 2 is methyl, R 3 is 4-bromo):

[0127]

[0128] Under argon atmosphere, 2-(decane-2,3-dien-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (80 mg, 0.30 mmol, 1.0 equiv.) was added to an anhydrous Schlenk reaction bottle containing a polytetrafluoroethylene magnet, tetrahydrofuran (2 mL) was added and stirred, the temperature of the reaction system was lowered to -78 ° C, and then phenyl lithium (0.375 mL, 1.0 M ether solution, 0.375 mmol, 1.25 equiv.) was added dropwise and stirred for 25 minutes, followed by the addition of trifluoroacetic anhydride (84 μL, 0.60 mmol, 2.0 equiv.), and the reaction mixture was stirred at -78 ° C for 45 minutes. Then, p-bromoacetophenone (90 mg, 0.45 mmol) was added at -78 ° C, and the reactor was rinsed with tetrahydrofuran (2 mL). The final reaction mixture was stirred at -78°C for 30 minutes, and naturally warmed to room temperature for 24 hours. After the reaction was completed, the reaction was quenched with a saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The nuclear magnetic resonance hydrogen spectrum of the crude product did not detect the production of the target product, indicating that n-butyl lithium in the present invention cannot be replaced by phenyl lithium.

[0129] Comparative Example 3

[0130] 2-(4-Bromophenyl)-3-methylundec-4-yn-2-ol (R 1 is n-hexyl, R 2 is methyl, R 3 is 4-bromo):

[0131]

[0132] Under argon atmosphere, 2-(decane-2,3-dien-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (80 mg, 0.30 mmol, 1.0 equiv.) was added to an anhydrous Schlenk reaction bottle containing a polytetrafluoroethylene magnet, 2 mL of tetrahydrofuran was added and stirred, the temperature of the reaction system was lowered to -78 °C, and then n-butyl lithium (0.24 mL, 1.6 M hexane solution, 0.375 mmol, 1.25 equiv.) was added dropwise and stirred for 25 minutes, followed by the addition of 4-trifluoromethylbenzoic anhydride (218 mg, 0.60 mmol, 2.0 equiv.), and the reaction mixture was stirred at -78 °C for 45 minutes. Then, p-bromoacetophenone (90 mg, 0.45 mmol) was added at -78 °C, and the reactor was rinsed with 2 mL of tetrahydrofuran. The final reaction mixture was stirred at -78 ° C for 30 minutes, and naturally warmed to room temperature for 24 hours. After the reaction was completed, the reaction was quenched with a saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The nuclear magnetic resonance hydrogen spectrum of the crude product did not detect the production of the target product, indicating that trifluoroacetic anhydride in the present invention cannot be replaced by 4-trifluoromethylbenzoic anhydride.

Claims

1. A method for synthesizing a homopropargyl tertiary alcohol containing two adjacent chiral centers, characterized in that: Here are the steps: Under an argon atmosphere, allene boronic acid pinacol ester represented by formula (I), hexane solution of n-butyl lithium, trifluoroacetic anhydride, and aromatic ketone represented by formula (II) are mixed in tetrahydrofuran and reacted at -60 to -80°C for more than 24 hours to generate a homopropargyl tertiary alcohol containing two adjacent chiral centers represented by formula (III). The general reaction formula is as follows: In the formula, R 1 is n-hexyl, cyclohexyl, chloropropyl, phenethyl, butenyl, tert-butyldimethylsilylethoxy, R 2 is methyl or ethyl, R 3 It is hydrogen, chlorine, bromine, nitro, 4-methyl, 3-methyl, 2-methyl, methoxy, benzyloxy, cyano, methylthio, 3,4-methylenedioxy, furan ring or benzothiophene ring.

2. The synthesis method according to claim 1, characterized in that The specific steps are as follows: under an argon atmosphere, the pinacol ester of allene boronate shown in formula (I) is added to an anhydrous Schlenk reaction bottle containing a polytetrafluoroethylene magnet and tetrahydrofuran is added and stirred, then the temperature of the reaction system is lowered to -78°C, a hexane solution of n-butyl lithium is added dropwise and stirred for 25 minutes, and then trifluoroacetic anhydride is added dropwise, and the reaction mixture is stirred at -78°C for 45 minutes. Finally, the aromatic ketone shown in formula (II) is added at -78°C, and the reactor is rinsed with tetrahydrofuran, and the reaction mixture is stirred at -78°C for 30 minutes and then naturally warmed to room temperature for 24 hours. After the reaction is completed, the reaction is quenched with a saturated sodium bicarbonate solution, and extracted with ethyl acetate. The combined organic phase is washed with saturated brine, dried with anhydrous magnesium sulfate, filtered to remove the solid, and finally concentrated under reduced pressure. The crude product is purified by column chromatography using ethyl acetate / petroleum ether with a volume ratio of 1:500-1:100 as the eluent to obtain a homopropargyl tertiary alcohol containing two adjacent chiral centers shown in formula (III).

3. The synthesis method according to claim 1, characterized in that The molar ratio of allene boronic acid pinacol ester to aromatic ketone is 1.0:1.2 to 1.0:2.

0.

4. The synthesis method according to claim 1, characterized in that The molar ratio of allene boronic acid pinacol ester to aromatic ketone is 1.0:1.

5.

5. The synthesis method according to claim 1, characterized in that The molar ratio of allene boronic acid pinacol ester to n-butyl lithium is 1.0:1.25 to 1.0:1.

5.

6. The synthesis method according to claim 1, characterized in that The molar ratio of allene boronic acid pinacol ester to trifluoroacetic anhydride is 1.0:2.0 to 1.0:3.

0.

7. The synthesis method according to claim 1, characterized in that In the tetrahydrofuran solution of allene boronic acid pinacol ester, the concentration of allene boronic acid pinacol ester is 0.05M-0.1M.

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