Method for synthesizing dialkyl substituted chiral alpha-hydroxy ketone from propargyl alcohol ester

Abstract

The invention discloses a method for synthesizing dialkyl substituted chiral alpha-hydroxy ketone from propargyl alcohol ester, which specifically comprises the following steps of: reacting propargyl alcohol ester and acid serving as substrates and metal palladium serving as a catalyst in an organic solvent under the regulation and control of a specific chiral ligand, and adding alkali for treatment after the reaction is finished to obtain optically pure (88-97% ee) alpha-hydroxy ketone. The product provided by the invention is carbonyl alpha-position chiral secondary alcohol with a chain structure, and has a dialkyl substituted structure with high regioselectivity; the catalyst and the ligand are wide in source, and the substrate is cheap and easily available; and the method has excellent enantioselectivity and good functional group compatibility, can be suitable for structural modification of bioactive molecules and intermediates, and is a simple and efficient asymmetric catalysis strategy for synthesizing the dialkyl substituted chiral alpha-hydroxy ketone.

Description

Technical Field

[0001] The invention belongs to the fields of catalytic synthesis technology and fine chemical synthesis, and relates to a method for synthesizing dialkyl-substituted chiral α-hydroxy ketone from propargyl alcohol ester. Background Art

[0002] α-Hydroxyketones are important molecular scaffolds in chemistry, widely found in natural products and pharmaceutical molecules. According to data released by the University of Arizona and DrugTopics & Pharmacompass, small molecules containing α-hydroxyketone scaffolds will account for over 10% of the top 200 global small molecule drug sales in 2023, making them a significant commodity category in the small molecule pharmaceutical sector. Furthermore, these compounds are important synthons, capable of participating in a range of classic reactions. Chemists have long been interested in the efficient and selective construction of α-hydroxyketones, particularly chiral α-hydroxyketone scaffolds. However, unlike the well-established catalytic synthesis systems for diaryl-substituted or arylalkyl-substituted chiral α-hydroxyketones, few methods have been reported for the synthesis of dialkyl-substituted chiral α-hydroxyketones, and effective asymmetric catalytic methods remain lacking. Therefore, developing novel synthetic strategies for the construction of dialkyl-substituted chiral α-hydroxyketones is of great practical significance and scientific research value. Summary of the Invention

[0003] To address the challenges of the prior art, the present invention provides a method for synthesizing dialkyl-substituted chiral α-hydroxyketones from propargyl alcohol esters. This method utilizes a specific palladium catalyst and a chiral ligand to achieve the high-value-added conversion of propargyl alcohol esters to chiral ketone alcohols.

[0004] In order to solve the problems of the prior art, the technical solution adopted by the present invention is:

[0005] A method for synthesizing a dialkyl-substituted chiral α-hydroxy ketone from a propargyl alcohol ester, wherein the propargyl alcohol ester and an acid are used as reaction substrates in an organic solvent, and a catalytic system of transition metal palladium and a chiral ligand is used to react. After the reaction is completed, a base is added to treat the reaction to obtain a chiral α-hydroxy ketone.

[0006] As an improvement, the following steps are included:

[0007] Step 1: Add propargyl alcohol ester, transition metal palladium, chiral ligand and acid into a sealed tube, replace the atmosphere with nitrogen, add organic solvent, and stir at 30-80° C. for 6-36 hours;

[0008] Step 2: After the temperature returns to room temperature, add a base and stir the reaction at -20 to 20°C for 1 to 30 minutes;

[0009] Step 3: After adding 1N dilute hydrochloric acid to quench the reaction, ethyl acetate and saturated ammonium chloride aqueous solution were added, the layers were allowed to stand, and the aqueous phase was extracted three times with ethyl acetate. The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The dialkyl-substituted chiral α-hydroxy ketone was obtained by column chromatography.

[0010] As an improvement, the molar ratio of the acid, propargyl alcohol ester, transition metal palladium and base is 1: (1-2): (0.01-0.2): (1-5).

[0011] As an improvement, R 1 With R 2 is an unsubstituted or substituted C1-C10 alkyl group, or an aryl group, wherein the aryl group includes but is not limited to phenyl, naphthyl, pyridine, furan, thiophene, thiazole, a substituted benzene ring or a substituted heterocycle; the substituted group is a halogen, an ester group, a cyano group, a nitro group, an aldehyde group, an alkoxy group, a phenol group, a thioether, a silyl ether, an amino group, an allyl group, an alkenyl group or a borate ester; the R 3 is an aryl carboxylate, an alkyl carboxylate, an aryloxycarbonate, an alkyloxycarbonate, a phosphate or a sulfonate.

[0012] As an improvement, the transition metal palladium is selected from palladium chloride, palladium acetate, palladium pivalate, bis(triphenylphosphine) palladium acetate, 1,2-bis(diphenylphosphine) ethane palladium chloride, acetylacetonate palladium, bis(hexafluoroacetylacetonate) palladium, bis(triphenylphosphine) palladium dichloride, tetrakis(triphenylphosphine) palladium, bis(tri-tert-butylphosphine) palladium, bis(dibenzylideneacetone) palladium, chloro(crotyl)(tricyclohexylphosphine) palladium, tris(dibenzylideneacetone)dipalladium, tris(dibenzylideneacetone) )dipalladium-chloroform adduct, (1,5-cyclooctadiene)palladium dibromide, palladium trifluoroacetate, tetrakis(triphenylphosphite)palladium, tetrakis(tri-o-tolylphosphine)palladium, allylpalladium chloride dimer, (1-methylallyl)palladium chloride dimer, allyl(cyclopentadienyl)palladium, bis(tricyclohexylphosphine)palladium, bis(tri-o-tolylphosphine)palladium, tetrakis(acetonitrile)palladium tetrafluoroborate, palladium benzoate or 1,2-bis(phenylsulfinyl)ethyldiacetate palladium.

[0013] A further improvement is that the transition metal palladium is palladium acetate, bis(tricyclohexylphosphine)palladium, tetrakis(acetonitrile)palladium tetrafluoroborate or palladium acetylacetonate.

[0014] A further improvement is that the transition metal palladium is tetrakis(acetonitrile)palladium tetrafluoroborate.

[0015] As an improvement, the chiral ligand is a chiral oxazoline ligand, a chiral diamine ligand, a chiral monodentate phosphine ligand, a chiral phosphoramidite ligand, a chiral biphenyl bidentate phosphine ligand, a chiral spirocyclic bidentate phosphine ligand, a chiral binaphthyl bidentate phosphine ligand or a chiral sulfenamide substituted phosphine ligand.

[0016] It is further preferred that the chiral ligand is a chiral phosphoramidite ligand, a chiral biphenyl bidentate phosphine ligand, a chiral spirocyclic bidentate phosphine ligand or a chiral binaphthyl bidentate phosphine ligand.

[0017] It is further preferred that the chiral ligand is a chiral binaphthyl bidentate phosphine ligand, such as (R)-BINAP.

[0018] As an improvement, the acid is selected from one or more of alkyl carboxylic acids, aryl carboxylic acids, alkyl sulfonic acids and aryl sulfonic acids, alkyl phosphoric acids, and aryl phosphonic acids.

[0019] More preferably, the acid is pivalic acid.

[0020] As an improvement, the base used is selected from one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, sodium tert-amylate, potassium tert-amylate, sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, triethylamine, DBU (1,8-diazobispiro[5.4.0]undec-7-ene), triethylenediamine, TBD (1,5,7-triazidobicyclo(4.4.0)dec-5-ene), and tetramethylguanidine.

[0021] A further improvement is that the base is sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and sodium tert-amylate.

[0022] A further improvement is that the base is potassium methoxide.

[0023] As an improvement, the organic solvent is selected from one or more of methanol, ethanol, ethylene glycol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, sec-butanol, tert-amyl alcohol, 4-methyl-2-pentanol, isopentanol, 2-pentanol, ethyl ether, tert-butyl methyl ether, n-butyl ether, isopropyl ether, diphenyl ether, dimethyl sulfide, cyclopentyl methyl ether, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, acetonitrile, benzonitrile, toluene, trifluorotoluene, acetone, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, ethyl acetate, ethyl formate, propyl formate, 1,4-dioxane, 1,3-dioxolane, tetrahydrofuran, 2-methyltetrahydrofuran or 1,3-dimethyl-2-imidazolidinone.

[0024] A further improvement is that the organic solvent is selected from methanol, tetrahydrofuran, sec-butanol, N,N-diformamide, trifluorotoluene, acetonitrile or N-methylpyrrolidone.

[0025] A further improvement is that the organic solvent is acetonitrile.

[0026] As an improvement, when the transition metal palladium catalyst is tetrakis(acetonitrile)palladium tetrafluoroborate, the chiral ligand is (R)-BINAP, the acid is pivalic acid, the solvent is acetonitrile, the base is potassium methoxide, the temperature is 50°C, the reaction time is 24 hours, and the enantiomeric selectivity is 88%ee to 97%ee.

[0027] Reaction formula of the present invention is as follows:

[0028]

[0029] The present invention combines palladium with a chiral ligand to form a chiral metal complex, achieving enantioselective control during the reaction, yielding the target product with 88-97% ee. The palladium catalyst employed in this invention is widely available, diverse, and inexpensive. Furthermore, the preparation method is mild, exhibits good functional group compatibility, and can be directly used for structural modification of bioactive molecular intermediates.

[0030] Beneficial effects:

[0031] Compared to existing technologies, this invention achieves an efficient and concise synthesis of dialkyl-substituted chiral α-hydroxyketones from propargyl alcohol esters via a "one-pot, two-step" strategy. First, the chiral ketone alcohol precursor is generated from the propargyl alcohol ester using palladium catalysis, and then the chiral ketone alcohol is released by base treatment. This has the following advantages:

[0032] (1) The present invention synthesizes dialkyl-substituted chiral α-hydroxy ketones. Traditional strategies are highly limited to the construction of diaryl-substituted and arylalkyl-substituted chiral α-hydroxy ketones.

[0033] (2) The present invention synthesizes a chain-like chiral α-hydroxy ketone. Traditional strategies rely on the use of cyclic substrates to achieve the construction of cyclic chiral α-hydroxy ketones.

[0034] (3) The present invention provides a highly regioselective reaction mode for the synthesis of dialkyl-substituted chiral α-hydroxy ketone compounds, thereby avoiding the problem of difficult-to-control regioselectivity in the traditional method for synthesizing dialkyl-substituted chiral α-hydroxy ketones.

[0035] (4) The present invention synthesizes chiral secondary alcohols at the α-position of the carbonyl group with an enantioselectivity of 88-97% ee. This substance is easily racemized under alkaline conditions. Traditional strategies are difficult to achieve highly enantioselective synthesis of such secondary alcohols.

[0036] (5) The present invention adopts a "one-pot, two-step" synthesis strategy, first constructing the chiral ketone alcohol precursor through palladium catalysis of propargyl alcohol ester, and then obtaining the chiral ketone alcohol through base treatment. This step-by-step reaction mode avoids the occurrence of side reactions of the ketone alcohol structure during the catalytic reaction and has better functional group compatibility. DETAILED DESCRIPTION

[0037] The present invention can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the contents described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0038] The experimental methods described in the examples are conventional methods unless otherwise specified; the reagents and materials can be obtained from commercial sources or simply prepared by the following methods unless otherwise specified.

[0039] Among them, some initial substrates were synthesized by the following method. Substrates 1a-11a and substrate 13a are all known compounds reported in the literature. Substrates 12a, substrate 14a and substrate 15a were synthesized with reference to the following method.

[0040]

[0041] A stirred solution of the alkyne reagent (1.0 equiv) in anhydrous THF (0.25 M) was placed in a 0°C cold reactor. nBuLi (0.25 M in Hexane, 1.0 equiv) was slowly added dropwise. The reaction was maintained at 0°C and stirred for 15 minutes. Next, a solution of the aldehyde reagent (1.0 equiv) in anhydrous THF (1.0 M) was added dropwise to the solution, and the mixture was transferred to room temperature and stirred for 1 hour. Pivaloyl chloride (PivCl, 1.5 equiv) was then added and stirred at room temperature for 3 hours. Finally, the reaction was quenched with saturated ammonium chloride solution, and the aqueous phase was extracted three times with EtOAC (1 M). The resulting organic phase was dried over anhydrous NaSO, filtered to remove the NaSO, and the solvent was removed using a rotary evaporator. The crude propargyl alcohol ester was then concentrated in vacuo to yield the product. Purification was performed by flash column chromatography and confirmed by NMR before use in the reaction.

[0042]

[0043] Substrate 12a was prepared from 12a1 and 12a2 according to the above method. The data are characterized as follows: 1 H NMR (400MHz, CDCl3) δ7.50–7.45(m,2H),7.38–7.32(m,3H),6.82(s,4H),6.42(s,1H),4.00(t ,J=6.1Hz,2H),3.77(s,3H),2.48(td,J=7.0,2.0Hz,2H),1.98(p,J=6.6Hz,2H),1.20(s,9H). 13C NMR (100MHz, CDCl3) δ177.39,153.95,153.16,137.99,128.63,127.37,115.64,114.77,86.90,77.83,67.03,65.81,55.88 ,38.88,28.38,27.12,15.76.IR(neat):2957,2936,1730,1507,1228,1131,1031,937,823,696.HRMS(ESI):Calcd403.1880 for C 24 H 28 O4Na[M+Na] + Found:403.1874.

[0044]

[0045] Substrate 14a was prepared from 14a1 and 14a2 according to the above method. The data are characterized as follows: 1 H NMR (400MHz, CDCl3) δ8.24(d,J=2.3Hz,1H),7.93(dd,J=8.6,2.3Hz,1H),6.88(d,J=8.7Hz,1 H),6.74(t,J=2.0Hz,1H),4.32(q,J=7.1Hz,2H),3.77(ddd,J=28.6,8.7,6.6Hz,2H),2.74(s ,3H),2.26(td,J=6.9,2.0Hz,2H),2.07(dp,J=13.1,6.5Hz,1H),1.56–1.48(m,2H),1.47–1. 40(m,2H),1.35(t,J=7.1Hz,3H),1.19(s,9H),1.01(t,J=6.6Hz,6H),0.90(t,J=7.2Hz,3H). 13 C NMR (100MHz, CDCl3) δ177.05,169.88,162.58,161.16,158.75,128.60,127. 75,127.04,125.49,121.02,111.68,87.88,76.53,74.96,61.27,60.67,38.8 2,30.66,28.43,27.19,22.07,19.38,19.30,18.72,17.71,14.48,13.77.IR( neat):2958,2933,2873,1712,1371,1255,1136,1090,731.HRMS(ESI):Calcd 514.2622 for C 29H 40 NO5S[M+H] + Found:514.2613.

[0046]

[0047] Substrate 15a was prepared from 15a1 and 15a2 according to the above method. The data are characterized as follows: 1 H NMR (400MHz, CDCl3) δ8.76 (dd, J=4.8, 1.4Hz, 1H), 8.58 (d, J=2.1Hz, 1H), 7.69 (ddd, J=8.1 ,2.2,1.7Hz,1H),7.57(dd,J=1.7,0.9Hz,1H),7.42–7.37(m,1H),7.36–7.31(m,1H),7.20– 7.11(m,2H),7.01(t,J=8.9Hz,1H),6.38–6.35(m,1H),6.30(d,J=1.8Hz,1H),2.27(td,J= 7.0, 2.0Hz, 2H), 1.56–1.48 (m, 2H), 1.46–1.39 (m, 2H), 1.19 (s, 9H), 0.91 (t, J = 7.3Hz, 3H). 13 C NMR (100MHz, CDCl3) δ177.43, 160.83 (d, J = 249.5Hz), 154.36, 148.09, 135. 11,134.89,133.49(d,J=1.5Hz),131.49(d,J=8.2Hz),128.85,126.07,123. 60,123.50(d,J=3.7Hz),122.43,118.70(d,J=15.3Hz),116.68,115.48(d, J=21.9Hz),87.38,76.03,59.74,38.86,30.54,27.08,22.01,18.55,13.68. 19 F NMR(376MHz, CDCl3): δ-111.08.IR(neat):2960,2933,2873,1728,1572,1477,1417,1397,1104,1182,1138,1068,744,698.HRMS(ESI):Calcd 519.1724for C 27 H 29 FN2O4SNa[M+Na] + Found:519.1730.

[0048] The chiral ligands L used in the examples are all (R)-BINAP, CAS No. 76189-55-4, which are commercially available products with the following specific structural formulas:

[0049]

[0050] The specific structures of all substrates and products in the examples are shown in Table 1.

[0051] Example 1

[0052] Under nitrogen, a 10 mL reaction vial equipped with a magnetic separator was charged with propargyl alcohol ester 1a (0.2 mmol), pivalic acid (0.2 mmol), palladium tetra(acetonitrile)tetrafluoroborate (0.006 mmol), (R)-BINAP (0.012 mmol), and acetonitrile (4.0 mL). The vial was sealed and incubated at 50°C for 24 h. The reaction was then slowly allowed to return to room temperature and placed in a low-temperature reactor at 0°C. Potassium methoxide (0.4 mmol) was then added and allowed to react for 20 minutes. Finally, quenching was performed with 1N hydrochloric acid (4.0 mL). The organic phases were extracted with ethyl acetate (4.0 mL x 3), and the combined organic phases were subjected to rotary evaporation to remove the solvent. The product ((S)-3-hydroxy-1-phenylheptan-2-one) was isolated using flash column chromatography (eluent: petroleum ether:ethyl acetate, v / v = 20:1) and designated as compound 1 (67% yield, 93% ee). 1 H NMR (400MHz, CDCl3) δ7.37–7.28(m,3H),7.23–7.18(m,2H),4.29(dd,J=7.3,3.7Hz,1H),3.85–3.74(m,2H),3.41– 3.32(br,OH,1H),1.92–1.84(m,1H),1.59(ddd,J=9.1,3.6,1.6Hz,1H),1.47–1.32(m,4H),0.90(t,J=7.1Hz,3H). 13 CNMR(100MHz, CDCl3)δ209.99,133.17,129.55,128.93,127.45,76.11,45.03,33.40,26.99,22. 61,14.03.IR(neat):3464,2956,2924,2855,1713,1496,1455,1079,1050,698.HRMS(ESI):Calcd 207.1380forC 13 H 19 O2[M+H] +; Found: 207.1374.HPLC analysis: The enantiomeric excess was determined on aCHIRALPAK IC column (10% iPrOH in hexane, 0.5mL / min, 35℃, λ = 220nm), t R (major)=20.69min,t R (minor)=19.19min.[α] D 25 =14.7°(c=1.0,CHCl3).

[0053] Example 2

[0054] Under nitrogen, a 10 mL reaction vial equipped with a magnetic field was charged with propargyl alcohol ester 2a (0.2 mmol), pivalic acid (0.2 mmol), palladium tetra(acetonitrile)tetrafluoroborate (0.006 mmol), (R)-BINAP (0.012 mmol), and acetonitrile (4.0 mL). The vial was sealed and incubated at 50°C for 24 h. The reaction was then slowly allowed to return to room temperature and placed in a low-temperature reactor at 0°C. Potassium methoxide (0.4 mmol) was then added and allowed to react for 20 minutes. Finally, the reaction was quenched with 1N hydrochloric acid (4.0 mL). The organic phases were extracted with ethyl acetate (4.0 mL x 3) and combined. The solvent was removed by rotary evaporation and isolated by flash column chromatography (eluent: petroleum ether:ethyl acetate, v / v = 15:1) to afford the product ((S)-3-hydroxy-1-(2-methoxyphenyl)heptan-2-one), designated as compound 2 (62% yield, 97% ee). 1 H NMR (400MHz, CDCl3) δ7.27(td,J=8.0,1.7Hz,1H),7.14(dd,J=7.4,1.6Hz,1H),6.93(td,J=7.4,1.0Hz,1H),6.87(d,J=8.2Hz,1H),4.29(dd,J=7.5, 3.6Hz,1H),3.79(s,3H),3.77–3.70(m,2H),3.59–3.27(br,OH,1H),1.93– 1.86(m,1H),1.63–1.55(m,1H),1.47–1.32(m,4H),0.92(t,J=7.1Hz,3H). 13CNMR(100MHz, CDCl3)δ210.44,157.22,131.42,128.95,122.58,120.89,110.59,76.08,55.44,40.07, 33.48,27.07,22.67,14.07.IR(neat):2928,2858,1713,1494,1245,1048,1027,751.HRMS(ESI):Calcd 259.1304for C 14 H 20 O3Na[M+Na] + ; Found: 259.1305.HPLC analysis: Theenantiomeric excess was determined on aCHIRALPAK AD-H column (10% iPrOH inhexane, 0.5mL / min, 35℃, λ = 220nm), t R (major)=19.34min,t R (minor)=18.39min.[α] D 25 =1.2°(c=0.2,CHCl3).

[0055] Example 3

[0056] Under nitrogen, a 10 mL reaction vial equipped with a magnetic field was charged with propargyl alcohol ester 3a (0.2 mmol), pivalic acid (0.2 mmol), palladium tetra(acetonitrile)tetrafluoroborate (0.006 mmol), (R)-BINAP (0.012 mmol), and acetonitrile (4.0 mL). The vial was sealed and incubated at 50°C for 24 h. The reaction was then slowly allowed to return to room temperature and placed in a low-temperature reactor at 0°C. Potassium methoxide (0.4 mmol) was then added and allowed to react for 20 minutes. Finally, quenching was performed with 1N hydrochloric acid (4.0 mL). The organic phases were extracted with ethyl acetate (4.0 mL x 3) and combined. The solvent was removed by rotary evaporation and isolated by flash column chromatography (eluent: petroleum ether:ethyl acetate, v / v = 20:1) to afford the product ((S)-1-(2-fluorophenyl)-3-hydroxyheptan-2-one), designated as compound 3 (70% yield, 90% ee). 11H NMR (400 MHz, CDCl3) δ 7.31–7.26 (m, 1H), 7.20 (td, J = 7.5, 1.7 Hz, 1H), 7.12 (td, J = 7.5, 1.1 Hz, 1H), 7.07 (t, J = 9.1 Hz, 1H), 4.33 (dd, J = 7.5, 3.7 Hz, 1H), 3.89–3.75 (m, 2H), 3.46–3.21 (m, 1H), 1.96–1.85 (m, 1H), 1.68–1.62 (m, 1H), 1.49–1.32 (m, 4H), 0.92 (t, J = 7.1 Hz, 3H). 13 13C NMR (100 MHz, CDCl3) δ 208.89, δ 161.01 (d, J = 245.9 Hz), 131.82 (d, J = 4.0 Hz), 129.46 (d, J = 8.1 Hz), 124.46 (d, J = 3.6 Hz), 120.71 (d, J = 16.0 Hz), 115.61 (d, J = 21.8 Hz), 76.34, 38.31, 33.50, 26.99, 22.63, 14.03. 19 19F NMR (376 MHz, CDCl3): δ -117.00. IR (neat): 2959, 2927, 2864, 1727, 1274, 1228, 1144, 1094, 855, 757. HRMS (ESI): Calcd 225.1286 for C 13 1<00> 18 19FO2 [M + H] + ; Found: 225.1286. HPLC analysis: The enantiomeric excess was determined on a CHIRALPAK IC column (10% iPrOH in hexane, 0.5 mL / min, 35 °C, λ = 250 nm), t R (major) = 18.40 min, t R (minor) = 17.42 min. [α] D 25 = 14.7° (c = 1.0, CHCl3).

[0057] Example 4

[0058] Under nitrogen, a 10 mL reaction vial equipped with a magnetic field was charged with propargyl alcohol ester 4a (0.2 mmol), pivalic acid (0.2 mmol), palladium tetra(acetonitrile)tetrafluoroborate (0.006 mmol), (R)-BINAP (0.012 mmol), and acetonitrile (4.0 mL). The vial was sealed and incubated at 50°C for 24 h. The reaction was then slowly allowed to return to room temperature and placed in a low-temperature reactor at 0°C. Potassium methoxide (0.4 mmol) was then added and allowed to react for 20 minutes. Finally, quenching was performed with 1N hydrochloric acid (4.0 mL). The organic phases were extracted with ethyl acetate (4.0 mL x 3) and combined. The solvent was removed by rotary evaporation and isolated by flash column chromatography (eluent: petroleum ether:ethyl acetate, v / v = 20:1) to afford the product ((S)-3-hydroxy-1-(p-tolyl)heptan-2-one), designated as compound 4 (64% yield, 88% ee). 1 H NMR (400MHz, CDCl3) δ7.19–7.13(m,2H),7.12–7.07(m,2H),4.28(dd,J=7.4,3.7Hz,1H),3.81–3.67(m,2H),3.55 –3.21(br,OH,1H),2.33(s,3H),1.95–1.82(m,1H),1.64–1.56(m,1H),1.47–1.30(m,4H),0.90(t,J=7.1Hz,3H). 13 C NMR (100MHz, CDCl3) δ210.21,137.11,130.08,129.61,129.39,76.02,44.65,33.41,27.00,22.62,2 1.19,14.01.IR(neat):2955,2925,2858,1709,1515,1049,806,719.HRMS(ESI):Calcd221.1536for C 14 H 21 O2[M+H] + ; Found: 221.1534.HPLC analysis: The enantiomeric excess was determined on aCHIRALPAKAD-H column (10% iPrOH in hexane, 0.5mL / min, 35℃, λ = 220nm), t R (major)=14.31min,t R (minor)=13.63min.[α] D 25 =0.5°(c=0.2,CHCl3).

[0059] Example 5

[0060] Under nitrogen, a 10 mL reaction vial equipped with a magnetic field was charged with propargyl alcohol ester 5a (0.2 mmol), pivalic acid (0.2 mmol), palladium tetra(acetonitrile)tetrafluoroborate (0.006 mmol), (R)-BINAP (0.012 mmol), and acetonitrile (4.0 mL). The vial was sealed and incubated at 50°C for 24 h. The reaction was then slowly allowed to return to room temperature and placed in a low-temperature reactor at 0°C. Potassium methoxide (0.4 mmol) was then added and allowed to react for 20 minutes. Finally, quenching was performed with 1N hydrochloric acid (4.0 mL). The organic phases were extracted with ethyl acetate (4.0 mL x 3), and the combined organic phases were freed from the solvent by rotary evaporation. The product ((S)-3-hydroxy-1-(naphthalen-2-yl)heptan-2-one) was isolated by flash column chromatography (eluent: petroleum ether:ethyl acetate, v / v = 20:1) to yield compound 5 (61% yield, 90% ee). 1 H NMR (400MHz, CDCl3) δ7.85–7.78(m,3H),7.67(s,1H),7.52–7.43(m,2H),7.32(dd,J=8.4,1.7Hz,1H),4.39–4.27(m,1H),4 .02–3.89(m,2H),3.39–3.33(br,OH,1H),1.97–1.86(m,1H),1.67–1.63(m,1H),1.48–1.31(m,4H),0.90(t,J=7.1Hz,3H). 13 CNMR(100MHz, CDCl3)δ210.01,133.60,132.63,130.69,128.63,128.36,127.83,127.73,127.44,126.47,126.13,76. 22,45.18,33.47,27.04,22.63,14.02.IR(neat):3418,2955,2926,2872,1708,1455,1047,801,736.HRMS(ESI):Calcd 257.1536for C 17 H 21 O2[M+H] + ; Found: 257.1536.HPLC analysis: The enantiomeric excess was determined on aCHIRALPAKAD-H column (10% iPrOH in hexane, 0.5mL / min, 35℃, λ = 220nm), tR (major)=22.10min,t R (minor)=22.61min.[α] D 25 =0.6°(c=0.2,CHCl3).

[0061] Example 6

[0062] Under nitrogen, a 10 mL reaction vial equipped with a magnetic field was charged with propargyl alcohol ester 6a (0.2 mmol), pivalic acid (0.2 mmol), palladium tetra(acetonitrile)tetrafluoroborate (0.006 mmol), (R)-BINAP (0.012 mmol), and acetonitrile (4.0 mL). The vial was sealed and incubated at 50°C for 24 h. The reaction was then slowly allowed to return to room temperature and placed in a low-temperature reactor at 0°C. Potassium methoxide (0.4 mmol) was then added and allowed to react for 20 minutes. Finally, quenching was performed with 1N hydrochloric acid (4.0 mL). The organic phases were extracted with ethyl acetate (4.0 mL x 3), and the combined organic phases were freed from the solvent by rotary evaporation. The product ((S)-3-hydroxy-1-(p-cyanophenyl)octan-2-one) was isolated by flash column chromatography (eluent: petroleum ether:ethyl acetate, v / v = 10:1) to yield compound 6 (61% yield, 89% ee). 1 H NMR(400MHz, CDCl3)δ7.63(d,J=8.3Hz,2H),7.32(d,J=8.3Hz,2H),4.34–4.23(m,1H),3.93–3.79(m,2H) ,3.28–3.16(br,OH,1H),1.94–1.81(m,1H),1.61–1.53(m,1H),1.52–1.29(m,6H),0.89(t,J=6.7Hz,3H). 13 CNMR (100MHz, CDCl3) δ208.60,138.60,132.53,130.51,118.71,111.47,76.75,44.61,33.72,31.68, 24.60,22.60,14.10.IR(neat):2960,2920,2850,2360,1715,1258,1080,1011,789.HRMS(ESI):Calcd 228.1383for C 15 H 18 NO[M-OH] +; Found: 228.1386.HPLC analysis: The enantiomeric excess was determined on aCHIRALPAKAD-H column (15% iPrOH in hexane, 0.5mL / min, 35℃, λ = 254nm), t R (major)=20.14min,t R (minor)=23.23min.[α] D 25 =1.5°(c=0.3,CHCl3).

[0063] Example 7

[0064] Under nitrogen, a 10 mL reaction vial equipped with a magnetic field was charged with propargyl alcohol ester 7a (0.2 mmol), pivalic acid (0.2 mmol), palladium tetra(acetonitrile)tetrafluoroborate (0.006 mmol), (R)-BINAP (0.012 mmol), and acetonitrile (4.0 mL). The vial was sealed and incubated at 50°C for 24 h. The reaction was then slowly allowed to return to room temperature and placed in a low-temperature reactor at 0°C. Potassium methoxide (0.4 mmol) was then added and allowed to react for 20 minutes. Finally, quenching was performed with 1N hydrochloric acid (4.0 mL). The organic phases were extracted with ethyl acetate (4.0 mL x 3), and the combined organic phases were freed from the solvent by rotary evaporation. The product ((S)-3-hydroxy-1-(m-nitrophenyl)heptan-2-one) was isolated by flash column chromatography (eluent: petroleum ether:ethyl acetate, v / v = 10:1) to yield compound 7 (55% yield, 90% ee). 1 H NMR(400MHz, CDCl3)δ8.16(dt,J=6.7,2.4Hz,1H),8.12–8.06(m,1H),7.59–7.49(m,2H),4.38–4.27(m,1H),4.00–3 .85(m,2H),3.22–3.15(br,OH,1H),1.96–1.86(m,1H),1.72–1.59(m,1H),1.52–1.32(m,4H),0.93(t,J=7.1Hz,3H). 13C NMR (100MHz, CDCl3) δ208.59,135.93,135.11,129.71,124.71,122.58,76.76,44.06,33.53,2 7.08,22.63,14.03.IR(neat):2926,2858,1714,1525,1348,1049,804,727.HRMS(ESI):Calcd 274.1050for C 13 H 17 NO4Na[M+Na] + ; Found: 274.1046. HPLC analysis: Theenantiomeric excess was determined on a CHIRALPAK AD-H column (10% iPrOH inhexane, 0.5mL / min, 35℃, λ = 220nm), t R (major)=31.57min,t R (minor)=29.93min.[α] D 25 =7.5°(c=1.5,CHCl3).

[0065] Example 8

[0066] Under nitrogen, a 10 mL reaction vial equipped with a magnetic field was charged with propargyl alcohol ester 8a (0.2 mmol), pivalic acid (0.2 mmol), palladium tetra(acetonitrile)tetrafluoroborate (0.006 mmol), (R)-BINAP (0.012 mmol), and acetonitrile (4.0 mL). The vial was sealed and incubated at 50°C for 24 h. The reaction was then slowly allowed to return to room temperature and placed in a low-temperature reactor at 0°C. Potassium methoxide (0.4 mmol) was then added and allowed to react for 20 minutes. Finally, quenching was performed with 1N hydrochloric acid (4.0 mL). The organic phases were extracted with ethyl acetate (4.0 mL x 3), and the combined organic phases were freed from the solvent by rotary evaporation. The product ((S)-3-hydroxy-1-(pyridin-3-yl)heptan-2-one) was isolated by flash column chromatography (eluent: petroleum ether:ethyl acetate, v / v = 10:1) to yield compound 8 (58% yield, 93% ee). 11H NMR (400 MHz, CDCl3) δ 8.49 (dd, J = 4.8, 1.5 Hz, 1H), 8.41 (d, J = 1.9 Hz, 1H), 7.56 (dt, J = 7.8, 1.9 Hz, 1H), 7.26 (dd, J = 8.0, 4.7 Hz, 1H), 4.28 (dd, J = 7.7, 3.9 Hz, 1H), 3.88–3.72 (m, 2H), 3.62–3.34 (br, OH, 1H), 1.93–1.82 (m, 1H), 1.68–1.58 (m, 1H), 1.49–1.30 (m, 4H), 0.89 (t, J = 7.1 Hz, 3H). 13 13C NMR (100 MHz, CDCl3) δ 209.19, 150.32, 148.48, 137.44, 129.28, 123.67, 76.67, 41.66, 33.45, 27.07, 22.58, 14.01. IR (neat): 2919, 2849, 1715, 1436, 1118, 720, 694. HRMS (ESI): Calcd 208.1332 for C 12 11H 18 NO2 [M + H] + ; Found: 208.1333. HPLC analysis: The enantiomeric excess was determined on a CHIRALPAK AD-H column (30% iPrOH in hexane, 0.4 mL / min, 35 °C, λ = 220 nm), t R (major) = 12.39 min, t R (minor) = 13.66 min. [α] D 25 = +2.2° (c = 0.7, CHCl3).

[0067] Example 9

[0068] Under nitrogen, a 10 mL reaction vial equipped with a magnetic field was charged with propargyl alcohol ester 9a (0.2 mmol), pivalic acid (0.2 mmol), palladium tetrakis(acetonitrile)tetrafluoroborate (0.006 mmol), (R)-BINAP (0.012 mmol), and acetonitrile (4.0 mL). The vial was sealed and incubated at 50°C for 24 h. The reaction mixture was then slowly allowed to return to room temperature and placed in a low-temperature reactor at 0°C. Potassium methoxide (0.4 mmol) was then added and allowed to react for 20 minutes. Finally, 1N hydrochloric acid (4.0 mL) was added to quench the reaction. The reaction mixture was extracted with ethyl acetate (4.0 mL x 3) and the organic phases were combined. The solvent was removed by rotary evaporation and then separated by flash column chromatography (eluent, petroleum ether:ethyl acetate V / V = 10:1) to obtain the product ((S)-6-(benzylthio)-3-hydroxy-1-(4-((trifluoromethyl)thio)phenyl)-2-hexanone), which was designated as compound 9 (62% yield, 88% ee). 1 H NMR (400MHz, CDCl3) δ7.66–7.58(m,2H),7.33–7.28(m,4H),7.28–7.23(m,3H),4.29–4.20(m,1H),3.85–3.75(m,2H ),3.70(s,2H),3.33–3.22(br,OH,1H),2.53–2.42(m,2H),2.03–1.94(m,1H),1.80–1.71(m,1H),1.68–1.61(m,2H). 13 C NMR (100MHz, CDCl3) δ208.76,138.51,136.75,136.22,130.79,128.96,128.67,127.18,75.93,44.34,36.36,32.33,30.96,24.28. 19 F NMR(376MHz, CDCl3): δ-42.67.IR(neat):3417,2921,2359,1715,1494,1154,1115,812,700.HRMS(ESI):Calcd415.1008for C 20 H 22 F3O2S2[M+H] + ; Found: 415.1004. HPLC analysis: The enantiomeric excess was determined on a CHIRALPAKAD-H column (15% iPrOH in hexane, 0.5mL / min, 35℃, λ = 254nm), t R (major)=23.09min,tR (minor)=26.46min.[α] D 25 =0.32°(c=0.3,CHCl3).

[0069] Example 10

[0070] Under nitrogen, a 10 mL reaction vial equipped with a magnetic field was charged with propargyl alcohol ester 10a (0.2 mmol), pivalic acid (0.2 mmol), palladium tetra(acetonitrile)tetrafluoroborate (0.006 mmol), (R)-BINAP (0.012 mmol), and acetonitrile (4.0 mL). The vial was sealed and placed at 50°C for 24 h. The reaction was then slowly allowed to return to room temperature and placed in a low-temperature reactor at 0°C. Potassium methoxide (0.4 mmol) was then added and allowed to react for 20 minutes. Finally, quenching was performed with 1N hydrochloric acid (4.0 mL). The organic phases were extracted with ethyl acetate (4.0 mL x 3), and the combined organic phases were freed from the solvent by rotary evaporation. The product ((S)-6-chloro-1-(3-fluorophenyl)-3-hydroxy-2-hexanone) was isolated using flash column chromatography (eluent: petroleum ether:ethyl acetate, v / v = 10:1) to yield compound 10 (61% yield, 88% ee). 1 H NMR(400MHz, CDCl3)δ7.31(td,J=7.9,6.1Hz,1H),7.04–6.90(m,3H),4.36–4.26(m,1H),3.86–3.74(m, 2H),3.60(t,J=6.4Hz,2H),3.37(br,OH,1H),2.16–2.06(m,1H),2.03–1.93(m,1H),1.88–1.69(m,2H). 13 CNMR(100MHz, CDCl3)δ208.80,163.02(d,J=246.8Hz),135.14(d,J=7.7Hz),130.43(d,J=8.3Hz),12 5.30(d,J=3.0Hz),116.66(d,J=21.8Hz),114.58(d,J=21.0Hz),75.44,44.77,44.48,30.69,27.87. 19 F NMR(376MHz, CDCl3): δ-112.53.IR(neat):2961,2360,1714,1256,1076,1009,784.HRMS(ESI):Calcd 267.0558for C 12 H 14 ClFO2Na[M+Na] +; Found: 267.0557.HPLCanalysis: The enantiomeric excess was determined on a CHIRALPAKAD-H column (10% iPrOH in hexane, 0.5mL / min, 35℃, λ = 220nm), t R (major)=21.13min,t R (minor)=22.07min.[α] D 25 =3.4°(c=1.0,CHCl3).

[0071] Example 11

[0072] Under nitrogen, a 10 mL reaction flask equipped with a magnetic field was charged with propargyl alcohol ester 11a (0.2 mmol), pivalic acid (0.2 mmol), palladium tetra(acetonitrile)tetrafluoroborate (0.006 mmol), (R)-BINAP (0.012 mmol), and acetonitrile (4.0 mL). The flask was sealed and incubated at 50°C for 24 h. The reaction was then slowly allowed to return to room temperature and placed in a low-temperature reactor at 0°C. Potassium methoxide (0.4 mmol) was then added and allowed to react for 20 minutes. Finally, quenching was performed with 1N hydrochloric acid (4.0 mL). The organic phases were extracted with ethyl acetate (4.0 mL x 3) and combined. The solvent was removed by rotary evaporation and isolated by flash column chromatography (eluent: petroleum ether:ethyl acetate, v / v = 20:1) to afford the product ((S)-6-tert-butyldimethylsilyl-1-phenyl-3-hydroxy-2-hexanone), designated as compound 11 (63% yield, 90% ee). 1 H NMR (400MHz, CDCl3) δ7.36–7.27(m,3H),7.25–7.18(m,2H),4.29(s,1H),3.91–3.77(m,2H),3.72(s,1H), 3.67(t,J=6.0Hz,2H),2.10–1.96(m,1H),1.71–1.66(m,1H),1.59–1.55(m,2H),0.90(s,9H),0.07(s,6H). 13C NMR (100MHz, CDCl3) δ210.25,133.40,129.64,128.88,127.35,76.14,62.77,45.00,30.61,28.28,26. 08,18.46,-5.21.IR(neat):3403,2927,2855,2359,1714,1253,1098,832,774,697.HRMS(ESI):Calcd 323.2037for C 18 H 31 O3Si[M+H] + ; Found: 323.2042.HPLC analysis: The enantiomeric excess was determined on a CHIRALPAK IC column (10% iPrOH inhexane, 0.5mL / min, 35℃, λ = 220nm), t R (major)=17.49min,t R (minor)=16.92min.[α] D 25 =6.3°(c=0.7,CHCl3).

[0073] Example 12

[0074] Under nitrogen, a 10 mL reaction vial equipped with a magnetic field was charged with propargyl alcohol ester 12a (0.2 mmol), pivalic acid (0.2 mmol), palladium tetra(acetonitrile)tetrafluoroborate (0.006 mmol), (R)-BINAP (0.012 mmol), and acetonitrile (4.0 mL). The vial was sealed and incubated at 50°C for 24 h. The reaction mixture was then slowly allowed to return to room temperature and placed in a low-temperature reactor at 0°C. Potassium methoxide (0.4 mmol) was then added and allowed to react for 20 minutes. Finally, 1N hydrochloric acid (4.0 mL) was added to quench the reaction. The reaction mixture was extracted with ethyl acetate (4.0 mL x 3) and the organic phases were combined. The solvent was removed by rotary evaporation and then separated by flash column chromatography (eluent, petroleum ether:ethyl acetate V / V=10:1) to obtain the product ((S)-3-hydroxy-6-(4-methoxyphenoxy)-1-phenyl-2-hexanone), which was recorded as compound 12 (55% yield, 88% ee). 11H NMR (400 MHz, CDCl3) δ 7.34–7.26 (m, 3H), 7.23–7.13 (m, 2H), 6.84 (s, 4H), 4.35 (dd, J = 7.4, 3.6 Hz, 1H), 3.94 (t, J = 5.8 Hz, 2H), 3.84–3.80 (m, 2H), 3.77 (s, 3H), 3.46 (br, OH, 1H), 2.19–2.09 (m, 1H), 1.98–1.90 (m, 1H), 1.87–1.74 (m, 2H). 13 13C NMR (100 MHz, CDCl3) δ 209.81, 153.99, 153.03, 133.09, 129.59, 128.93, 127.45, 115.53, 114.80, 75.65, 67.82, 55.87, 45.00, 30.28, 24.90. IR (neat): 3456, 2928, 2857, 1714, 1506, 1227, 1034, 823, 698. HRMS (ESI): Calcd 315.1591 for C 19 H 23 O4 [M + H] + ; Found: 315.1589. HPLC analysis: The enantiomeric excess was determined on a CHIRALPAK AD-H column (20% iPrOH in hexane, 0.5 mL / min, 35 °C, λ = 220 nm), t R (major) = 23.05 min, t R (minor) = 25.04 min. [α] D 25 = 12.5° (c = 1.2, CHCl3).

[0075] Example 13

[0076] Under nitrogen, a 10 mL reaction vial equipped with a magnetic field was charged with propargyl alcohol ester 13a (0.2 mmol), pivalic acid (0.2 mmol), palladium tetra(acetonitrile)tetrafluoroborate (0.006 mmol), (R)-BINAP (0.012 mmol), and acetonitrile (4.0 mL). The vial was sealed and incubated at 50°C for 24 h. The reaction was then slowly allowed to return to room temperature and placed in a low-temperature reactor at 0°C. Potassium methoxide (0.4 mmol) was then added and allowed to react for 20 minutes. Finally, quenching was performed with 1N hydrochloric acid (4.0 mL). The organic phases were extracted with ethyl acetate (4.0 mL x 3), and the combined organic phases were freed from the solvent by rotary evaporation. The product ((S)-7-vinyl-1-phenyl-3-hydroxy-2-heptanone) was isolated by flash column chromatography (eluent: petroleum ether:ethyl acetate, v / v = 20:1) and designated as compound 13 (43% yield, 93% ee). 1 H NMR (400MHz, CDCl3) δ7.37–7.28(m,3H),7.20(d,J=7.0Hz,2H),5.79(ddt,J=16.9,10.2,6.7Hz,1H),5.04–4.91(m,2H),4.31–4.27( m,1H),3.85–3.72(m,2H),3.37(br,OH,1H),2.05(dd,J=13.8,6.9Hz,2H),1.92–1.84(m,1H),1.64–1.58(m,1H),1.50–1.34(m,4H). 13 C NMR (100MHz, CDCl3) δ209.89,138.70,133.12,129.53,128.92,127.45,114.75,76.05,45.02,33.64 ,33.51,28.73,24.35.IR(neat):3390,2927,2856,1712,1640,1453,993,911,697.HRMS(ESI):Calcd 233.1536for C 15 H 21 O2[M+H] + ;Found:233.1531.HPLC analysis:The enantiomeric excess was determined ona 5μm Cellulose-1column (5% iPrOH in hexane, 0.5mL / min, 25℃, λ = 220nm), t R (major)=28.81min,t R(minor)=27.25min.[α] D 25 =23°(c=0.8,CHCl3).

[0077] Example 14

[0078] Under nitrogen, a 10 mL reaction vial equipped with a magnetic field was charged with propargyl alcohol ester 14a (0.2 mmol), pivalic acid (0.2 mmol), palladium tetra(acetonitrile)tetrafluoroborate (0.006 mmol), (R)-BINAP (0.012 mmol), and acetonitrile (4.0 mL). The vial was sealed and incubated at 50°C for 24 h. The reaction mixture was then slowly allowed to return to room temperature and placed in a low-temperature reactor at 0°C. Potassium methoxide (0.4 mmol) was then added and allowed to react for 20 minutes. Finally, 1N hydrochloric acid (4.0 mL) was added to quench the reaction. The reaction mixture was extracted with ethyl acetate (4.0 mL x 3) and the organic phases were combined. The solvent was removed by rotary evaporation and then separated by flash column chromatography (eluent, petroleum ether:ethyl acetate V / V=3:1) to obtain the product ((S)-2-(3-(3-hydroxy-2-oxoheptyl)-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester), recorded as compound 14 (56% yield, 89% ee). 1 H NMR (400MHz, CDCl3) δ7.86–7.82(m,1H),7.79(d,J=2.2Hz,1H),6.89(d,J=8 .6Hz,1H),4.40–4.32(m,2H),4.32–4.29(m,1H),3.88–3.73(m,4H),2.75(s ,3H),2.13–2.00(m,1H),1.97–1.85(m,1H),1.65–1.59(m,1H),1.45–1.32( m,7H),1.01(d,J=2.3Hz,3H),0.99(d,J=2.3Hz,3H),0.92(t,J=7.2Hz,3H). 13C NMR (100MHz, CDCl3) δ209.46,169.69,162.52,161.08,159.22,129.98,12 7.96,125.72,123.46,121.05,111.45,76.23,74.91,61.29,40.13,33.55, 28.36,27.09,22.66,19.39,19.37,17.67,14.48,14.05.IR(neat):3263, 2957,2924,2871,1713,1694,1372,1256,1089,809,760.HRMS(ESI):Calcd 448.2152for C 24 H 34 NO5S[M+H] + ; Found: 448.2145.HPLC analysis: The enantiomeric excess was determined on aCHIRALPAKAD-Hcolumn (20% iPrOH in hexane, 0.5mL / min, 35℃, λ = 250nm), t R (major)=34.50min,t R (minor)=32.78min.[α] D 25 =3.5°(c=1.4,CHCl3).

[0079] Example 15

[0080] Under nitrogen, a 10 mL reaction vial equipped with a magnetic field was charged with propargyl alcohol ester 15a (0.2 mmol), pivalic acid (0.2 mmol), palladium tetra(acetonitrile)tetrafluoroborate (0.006 mmol), (R)-BINAP (0.012 mmol), and acetonitrile (4.0 mL). The vial was sealed and incubated at 50°C for 24 h. The reaction mixture was then slowly allowed to return to room temperature and placed in a low-temperature reactor at 0°C. Potassium methoxide (0.4 mmol) was then added and allowed to react for 20 minutes. Finally, 1N hydrochloric acid (4.0 mL) was added to quench the reaction. The reaction mixture was extracted with ethyl acetate (4.0 mL x 3) and the organic phases were combined. The solvent was removed by rotary evaporation and then separated by flash column chromatography (eluent, petroleum ether:ethyl acetate V / V=3:1) to obtain the product ((S)-1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-3-hydroxyheptan-2-one), which was recorded as compound 15 (46% yield, 88% ee). 1H NMR(400MHz,CDCl3)δ8.76(dd,J=4.8,1.4Hz,1H),8.59(d,J=2.2Hz,1H),7.72–7.67(m,1H),7.44–7.39(m,2H),7.35–7.31(m,1H),7.18–7.11(m,2H),7.03(t,J=8.9Hz,1H),6.20(d,J=1.7Hz,1H),4.28(dd,J=7.4,3.7Hz,1H),3.71–3.58(m,2H),3.37(br,OH,1H),1.89–1.82(m,1H),1.60–1.54(m,1H),1.46–1.30(m,4H),0.90(t,J=7.0Hz,3H). 13 C NMR(100MHz,CDCl3)δ209.08,160.76(d,J=249.3Hz),154.32,147.98,135.15,134.80,133.37(d,J=1.6Hz),131.41(d,J=8.2Hz),128.90,123.62,123.52(d,J=3.6Hz),122.40,119.62,118.90,118.73(d,J=15.3Hz),115.48(d,J=21.9Hz),76.33,35.98,33.49,27.03,22.61,14.04. 19 F NMR(376MHz,CDCl3):δ-111.35.IR(neat):3352,2921,2852,1715,1467,1376,1182,1077,969,818,747,697.HRMS(ESI):Calcd 431.1436for C 22 H 24 FN2O4S[M+H] + ;Found:431.1427.HPLC analysis:The enantiomeric excess was determined on a 5μmi-Amylose-1column(30%iPrOH in hexane,0.3mL / min,25℃,λ=220nm),t R (major)=29.32min,t R (minor)=28.32min.[α] D 25 =1.7°(c=0.7,CHCl3).

[0081] Table 1 Raw materials and product structural formulas of Examples 1 to 15 and corresponding experimental results

[0082]

[0083]

[0084]

[0085] Example 16

[0086] The preparation method of Example 16 is the same as that of Example 1, except that the palladium is palladium acetate and the reaction temperature is 50°C.

[0087] Example 17

[0088] The preparation method of Example 17 is the same as that of Example 15, except that the palladium is palladium chloride, the reaction temperature is 60° C., and the reaction time is 48 hours.

[0089] Example 18

[0090] The preparation method of Example 18 is the same as that of Example 1, except that the organic solvent is selected from tetrahydrofuran.

[0091] Example 19

[0092] The preparation method of Example 19 is the same as that of Example 6, except that the exogenous base is sodium tert-butoxide.

[0093] Comparative Example 1

[0094] The method of Comparative Example 1 is the same as that of Example 1, except that no palladium catalyst is added and the yield of the target product is 0.

[0095] Comparative Example 2

[0096] Comparative Example 2 is the same as Example 1, except that the chiral ligand (R)-BINAP is not added and the ee value of the target product is 0.

[0097] Comparative Example 3

[0098] Comparative Example 3 is the same as Example 1, except that: without adding exogenous base potassium methoxide, the target product cannot be obtained, and the reagent product is allyl ester.

[0099] Comparative Example 4

[0100] Comparative Example 4 was the same as Example 1, except that the reaction time after adding potassium methoxide was 24 hours, and the ee value of the target product was 10.

[0101] Comparative Example 5

[0102] Comparative Example 5 is the same as the method of Example 1, except that the ligand (R)-BINAP is replaced with other chiral ligands, such as (R,R)-DACH-pyridyl Trost ligand, Ph-Chiraphite, (R)-1-{(Sp)-2-[bis[2-(methoxy)phenyl]phosphino]ferrocenyl}ethyl di-tert-butylphosphine, (R)-Me-iPr-INDOLPhos and (R)-[1,1'-binaphthyl]-2-yldiphenylphosphine, and the ee value of the target product is 0.

[0103] The present invention realizes for the first time the directional conversion of propargyl alcohol ester to dialkyl-substituted chiral α-hydroxy ketone. By screening and establishing experimental conditions, in a reaction system of chiral palladium catalyst, the asymmetric catalytic conversion of propargyl alcohol ester is used to achieve the efficient and concise construction of dialkyl-substituted chiral α-hydroxy ketone with high added value, providing a new strategy and model for the synthesis of dialkyl-substituted chiral α-hydroxy ketone.

[0104] The above is only a preferred embodiment of the present invention and is not intended to limit the present invention in any form. Although the present invention has been disclosed as above with preferred embodiments, it is not intended to limit the present invention. In theory, the various palladium catalysts in the present invention can react with propargyl alcohol ester to undergo oxidative addition, thereby facilitating the smooth progress of the reaction. The modification of the substituent only affects the reaction to a certain extent and does not play a decisive role in the occurrence of the reaction. It is not difficult for any technician familiar with this profession to understand that, without departing from the scope of the technical solution of the present invention, the corresponding embodiments can be obtained by changing or modifying. For example, the substituent can be replaced, changed or modified within the scope of the present invention to achieve the method of the present invention. However, any modification, modification or equivalent and equivalent changes to the above embodiments made according to the present invention, without departing from the purpose of the technical solution of the present invention, still fall within the scope of the technical solution of the present invention.

Claims

1. A method for synthesizing dialkyl-substituted chiral α-hydroxy ketones from propargyl alcohol esters catalyzed by palladium, characterized in that: In an organic solvent, propargyl alcohol ester and acid are used as reaction substrates, and a catalytic system of transition metal palladium and chiral ligand is used to react. After the reaction is completed, a base is added to treat the reaction to obtain a chiral α-hydroxy ketone.

2. The method for synthesizing dialkyl-substituted chiral α-hydroxy ketones from propargyl alcohol esters catalyzed by palladium according to claim 1, characterized in that: The method comprises the following steps: Step 1: Add propargyl alcohol ester, transition metal palladium, chiral ligand and acid into a sealed tube, replace the atmosphere with nitrogen, add organic solvent, and stir at 30-80° C. for 6-36 hours; Step 2: After the temperature returns to room temperature, add a base and stir the reaction at -20 to 20°C for 1 to 30 minutes; Step 2: After adding 1N dilute hydrochloric acid to quench the reaction, ethyl acetate and saturated ammonium chloride aqueous solution were added, the layers were allowed to stand, and the aqueous phase was extracted three times with ethyl acetate. The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The dialkyl-substituted chiral α-hydroxy ketone was obtained by column chromatography.

3. The method for synthesizing dialkyl-substituted chiral α-hydroxy ketones from propargyl alcohol esters catalyzed by palladium according to claim 1, characterized in that: The molar ratio of the acid, propargyl alcohol ester, transition metal palladium and base is 1:(1-2):(0.01-0.2):(1-5).

4. The method for synthesizing dialkyl-substituted chiral α-hydroxy ketones from propargyl alcohol esters catalyzed by palladium according to claim 1, characterized in that: R 1 With R 2 is an unsubstituted or substituted C1-C10 alkyl group, or an aryl group, wherein the aryl group includes but is not limited to phenyl, naphthyl, pyridine, furan, thiophene, thiazole, a substituted benzene ring or a substituted heterocycle; the substituted group is a halogen, an ester group, a cyano group, a nitro group, an aldehyde group, an alkoxy group, a phenol group, a thioether, a silyl ether, an amino group, an allyl group, an alkenyl group or a borate ester; the R 3 is an aryl carboxylate, an alkyl carboxylate, an aryloxycarbonate, an alkyloxycarbonate, a phosphate or a sulfonate.

5. The method for synthesizing dialkyl-substituted chiral α-hydroxy ketones from propargyl alcohol esters catalyzed by palladium according to claim 1, characterized in that: The transition metal palladium is selected from palladium chloride, palladium acetate, palladium pivalate, bis(triphenylphosphine)palladium acetate, 1,2-bis(diphenylphosphine)ethanepalladium chloride, palladium acetylacetonate, bis(hexafluoroacetylacetonate) palladium, bis(triphenylphosphine)palladium dichloride, tetrakis(triphenylphosphine)palladium, bis(tri-tert-butylphosphine)palladium, bis(dibenzylideneacetone)palladium, chloro(crotyl)(tricyclohexylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, tris(dibenzylideneacetone)dipalladium -chloroform adduct, (1,5-cyclooctadiene) palladium dibromide, palladium trifluoroacetate, tetrakis(triphenylphosphite)palladium, tetrakis(tri-o-tolylphosphine)palladium, allylpalladium chloride dimer, (1-methylallyl)palladium chloride dimer, allyl(cyclopentadienyl)palladium, bis(tricyclohexylphosphine)palladium, bis(tri-o-tolylphosphine)palladium, tetrakis(acetonitrile)palladium tetrafluoroborate, palladium benzoate or 1,2-bis(phenylsulfinyl)ethyldiacetate palladium.

6. The method for synthesizing dialkyl-substituted chiral α-hydroxy ketones from propargyl alcohol esters catalyzed by palladium according to claim 1, characterized in that: The chiral ligand is a chiral oxazoline ligand, a chiral diamine ligand, a chiral monodentate phosphine ligand, a chiral phosphoramidite ligand, a chiral biphenyl bidentate phosphine ligand, a chiral spirocyclic bidentate phosphine ligand, a chiral binaphthyl bidentate phosphine ligand or a chiral sulfenamide substituted phosphine ligand.

7. The method for synthesizing dialkyl-substituted chiral α-hydroxy ketones from propargyl alcohol esters catalyzed by palladium according to claim 1, characterized in that: The acid is selected from one or more of alkyl carboxylic acids, aryl carboxylic acids, alkyl sulfonic acids, aryl sulfonic acids, alkyl phosphoric acids, and aryl phosphonic acids.

8. The method for synthesizing dialkyl-substituted chiral α-hydroxy ketones from propargyl alcohol esters catalyzed by palladium according to claim 1, characterized in that: The base used is selected from one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, sodium tert-amylate, potassium tert-amylate, sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, triethylamine, DBU (1,8-diazobispiro[5.4.0]undec-7-ene), triethylenediamine, TBD (1,5,7-triazidobicyclo(4.4.0)dec-5-ene), and tetramethylguanidine.

9. The method for synthesizing dialkyl-substituted chiral α-hydroxy ketones from propargyl alcohol esters catalyzed by palladium according to claim 1, characterized in that: The organic solvent is selected from one or more of methanol, ethanol, ethylene glycol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, sec-butanol, tert-amyl alcohol, 4-methyl-2-pentanol, isopentanol, 2-pentanol, ethyl ether, tert-butyl methyl ether, n-butyl ether, isopropyl ether, diphenyl ether, dimethyl sulfide, cyclopentyl methyl ether, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, acetonitrile, benzonitrile, toluene, trifluorotoluene, acetone, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, ethyl acetate, ethyl formate, propyl formate, 1,4-dioxane, 1,3-dioxolane, tetrahydrofuran, 2-methyltetrahydrofuran or 1,3-dimethyl-2-imidazolidinone.

10. The method for synthesizing dialkyl-substituted chiral α-hydroxy ketones from propargyl alcohol esters catalyzed by palladium according to claim 2, characterized in that: When the transition metal palladium catalyst is palladium tetra(acetonitrile)tetrafluoroborate, the chiral ligand is (R)-BINAP, the acid is pivalic acid, the solvent is acetonitrile, the base is potassium methoxide, the temperature is 50° C., the reaction time is 24 hours, and the enantiomeric selectivity is 88% ee to 97% ee.

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