A method for synthesizing chiral β-amino alcohols

Abstract

This invention relates to the field of organic synthesis technology, specifically to a method for synthesizing chiral β-amino alcohols. This method uses a chiral chromium complex as a catalyst to catalyze the reaction of aldehydes with imines to prepare chiral β-amino alcohols. The synthetic method provided by this invention uses simple and readily available reactants, is easy to operate, operates under mild conditions, and has good universality for the reaction substrates. It is applicable not only to alkyl aldehydes but also to aromatic aldehydes, exhibiting broad adaptability and practicality. Furthermore, the reaction products demonstrate excellent stereoselectivity, making it highly suitable for industrial production and application.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and more specifically to a method for synthesizing chiral β-amino alcohols. Background Technology

[0002] Molecules containing chiral β-amino alcohol structures are widely found in natural products and drugs, and often possess unique biological and pharmacological activities. For example, dipeptides and bestain exhibit good immunomodulatory activity and are used clinically as adjuvant drugs in cancer chemotherapy; Sulfobacin B has been shown to exhibit good antithrombotic activity, etc. Simultaneously, these structures are also very important organic synthetic intermediates, used to synthesize chiral ligands with various skeletons, such as bisoxazolines, pyridineoxazolines, and Kishi ligands, and are widely used in the field of asymmetric catalysis.

[0003]

[0004] Among existing synthetic methods, the most efficient is the direct carbon-carbon coupling reaction to construct chiral β-amino alcohols. Starting from readily available aldehydes and imine substrates, amino alcohols can be rapidly obtained under reducing conditions in the presence of metals such as Li, Mg, Zn, Ti, and SmI2. However, controlling the stereoselectivity of the reaction remains a major challenge. To address this, Lin Guoqiang's research group utilized the stereoselectivity induced by the chiral sulfinyl group on the imine to achieve a SmI2-promoted reductive coupling reaction between aldehydes and imines, enabling the rapid synthesis of chiral amino alcohols. However, this reaction requires the prior preparation of an equivalent amount of chiral cofactor, resulting in high raw material costs. Furthermore, the addition of an equivalent amount of SmI2 is necessary, as its strong reducing properties lead to poor compatibility with many functional groups, and it also results in the formation of a significant amount of pinacol in the reaction system, affecting the reaction conversion rate. Additionally, to suppress the dimerization of the aldehyde itself, this reaction is only applicable to alkyl aldehyde substrates. Furthermore, Knowles' group utilized chiral phosphoric acid and photo-redox synergistic catalysis to achieve intramolecular reductive coupling of ketones and imines, preparing cyclic chiral β-amino alcohols; Huang Peiqiang's group, on the other hand, utilized the stereoselectivity of chiral Lewis acid-induced reactions to achieve the reductive coupling reaction of nitrones and aldehydes under photocatalytic conditions.

[0005] In recent years, some progress has been made in direct hydrocarbon functionalization reactions, selectively activating the nitrogen α-carbon-hydrogen bond to achieve the addition reaction of aldehydes, and by selecting a suitable chiral source, chiral β-amino alcohols can also be obtained. However, there is still considerable room for improvement in the chemoselectivity and stereoselectivity of this type of reaction, as well as its practicality.

[0006] In summary, current methods for synthesizing chiral β-amino alcohols suffer from drawbacks such as poor substrate universality, low selectivity, and limited practicality. Therefore, achieving efficient construction of chiral β-amino alcohols from simple starting materials under mild conditions is a pressing technical challenge in this field. Summary of the Invention

[0007] In view of this, the present invention provides a method for synthesizing chiral β-amino alcohols to solve the problems of poor substrate universality and limited reaction applicability of existing methods.

[0008] In a first aspect, the present invention provides the application of a chiral chromium complex in the catalytic reaction of aldehydes with imines to prepare chiral β-amino alcohols, wherein the chiral ligand in the chiral chromium complex is selected from the following compounds:

[0009]

[0010] The chiral chromium complex provided by this invention utilizes a chiral source for catalysis, requiring only a small amount of catalyst to efficiently catalyze the reaction of aldehydes with imines to prepare chiral β-amino alcohols. Furthermore, the chiral chromium complex catalyst of this invention has good substrate versatility, capable of catalyzing not only the reaction of alkyl aldehydes with imines but also aromatic aldehyde substrates.

[0011] In one optional embodiment, the molar ratio of the chiral chromium complex to the imine is 0.01-0.15:1. Too little chiral chromium complex will severely affect the reaction yield, while too much will result in catalyst waste.

[0012] Secondly, the present invention also provides a method for synthesizing chiral β-amino alcohols, comprising the following steps: reacting an aldehyde with an imine under the catalysis of a chiral chromium complex to prepare a chiral β-amino alcohol; the reaction formula is as follows:

[0013]

[0014] Among them, R 1 Selected from any one of substituted or unsubstituted alkyl or phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl;

[0015] R 2 Selected from substituted or unsubstituted phenyl or heteroaryl groups;

[0016] R 3 Selected from substituted or unsubstituted phenylsulfonyl or alkylsulfonyl groups;

[0017] The chiral ligands in the chiral chromium complex are selected from the following compounds:

[0018]

[0019] The method for synthesizing chiral β-amino alcohols provided by this invention uses the above-mentioned chiral chromium complex as a catalyst. By utilizing the chiral source for catalysis, only a small amount of catalyst is needed to efficiently catalyze the reaction of aldehydes with imines to prepare chiral β-amino alcohols. Furthermore, the synthesis method of this invention has good substrate versatility, and can be used not only for the reaction of alkyl aldehydes with imines, but also for the reaction of aromatic aldehyde substrates with imines to prepare chiral β-amino alcohols.

[0020] Compared to alkylimines, arylimines have lower reduction potentials and are more easily reduced in the reaction system, making the synthesis method of this invention more suitable for aromatic imines. In this invention, the protecting group R... 3 The imine compound was prepared in advance, and its preparation process was very simple, requiring only the addition of aldehyde R. 2 CHO and amine R 3 NH2 can be condensed under the catalysis of a base (such as tetrahydropyrrole), and the raw materials are all very inexpensive.

[0021] In one alternative embodiment, the molar ratio of the chiral chromium complex to the imine is 0.01-0.15:1.

[0022] In one optional embodiment, the molar ratio of the aldehyde to the imine is 1-2:1. Since the aldehyde is cheaper than the imine, it can be used in slight excess from an economic point of view to ensure the reaction conversion rate.

[0023] In one optional embodiment, the reaction is carried out in an anhydrous and oxygen-free organic solvent, wherein the organic solvent is at least one selected from ethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, acetonitrile, toluene, xylene, methyl tert-butyl ether, diethyl ether, dioxane, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, and 1,2-dichloroethane.

[0024] In an optional embodiment, the synthesis method further includes adding a reducing agent, which can reduce high-valent chromium in the catalyst to low-valent chromium to ensure the smooth progress of the reaction. In this invention, the molar ratio of the reducing agent to the imine is 2-3:1. If the amount of reducing agent is too small, the reaction yield will decrease, while if the amount of reducing agent is too large, the reduction rate will not match the other reaction rates, which may also affect the reaction yield.

[0025] In one optional embodiment, the reducing agent is at least one selected from sodium, magnesium, lithium, manganese, zinc, sodium borohydride, and lithium aluminum hydride.

[0026] In an optional embodiment, the synthesis method further includes adding a dissociating agent, wherein the molar ratio of the dissociating agent to the imine is 2-3:1. The dissociating agent is used to dissociate the chromium catalyst from the reaction substrate. If the amount of dissociating agent is too small, the dissociation will be slower, affecting the reaction yield. However, if the amount of dissociating agent is too large, it will not only waste raw materials, but more importantly, other side reactions will occur, leading to a decrease in the reaction yield.

[0027] In one optional embodiment, the dissociating agent is at least one of zirconium dichlorocerocenium (Cp2ZrCl2), trimethylchlorosilane (TMSCl), and triethylchlorosilane (TESCl).

[0028] In one optional embodiment, the synthesis method includes the following steps:

[0029] Under anhydrous and oxygen-free conditions, the chromium halide, the chiral ligand, and the organic solvent are mixed and stirred. Then, the reducing agent, the aldehyde, the imine, and the dissociating agent are added, and the reaction is continued with stirring to obtain a chiral β-amino alcohol compound with the structure shown in formula (I).

[0030] When the aldehyde is an alkyl aldehyde, the synthesis method further includes the step of adding an additive simultaneously with the alkyl aldehyde, wherein the molar ratio of the additive to the imine is 0.2-2:1. Using the additive can improve the yield of the alkyl aldehyde.

[0031] In one alternative embodiment, the additive is LiBF4.

[0032] In one optional embodiment, when the reaction substrate is an aromatic aldehyde, the reaction temperature is 20–35°C and the reaction time is 24–48 h; when the reaction substrate is an alkyl aldehyde, the reaction temperature is 40–60°C and the reaction time is 18–24 h.

[0033] The synthesis method provided by this invention uses simple and readily available raw materials, is easy to operate, and has mild reaction conditions, making it suitable for industrial production and application.

[0034] In one optional embodiment, the substituent in the substituted alkyl group is a C1-C5 alkylthio, alkoxy, alkynyl, or alkenyl, phenyl, mercapto, or halogen; the alkyl group contains 1-5 carbon atoms. In a preferred embodiment, the alkylthio group is methylthio, the alkoxy group is methoxy, the alkyl group is methyl, ethyl, isopropyl, or tert-butyl, and the halogen is fluorine or chlorine.

[0035] In one optional embodiment, the substituent in the substituted phenyl group is a C1-C5 alkyl, alkoxy, haloalkoxy, haloalkyl, alkynyl, alkenyl, or heterocyclic alkyl, borate, mercapto, cyano, ester, sulfonyl, hydroxyl, halogen, or phenyl. In a preferred embodiment, the alkyl group is methyl, ethyl, isopropyl, or tert-butyl; the haloalkoxy group is trifluoromethoxy; the heterocyclic alkyl group forms a benzodioxane group with the substituted phenyl group; and the halogen is fluorine or chlorine.

[0036] In one optional embodiment, the cycloalkyl group or the heterocycloalkyl group contains 1-10 carbon atoms. In a preferred embodiment, the cycloalkyl group is cyclopropyl, cyclobutyl, or cyclohexyl, and the heterocycloalkyl group is tetrahydropyranyl or N-tert-butoxycarbonylpiperidinyl.

[0037] In one optional embodiment, the heteroaryl group is any one of furanyl, benzofuranyl, thiophenyl, benzothiophenyl, indolyl, and pyridyl.

[0038] In one alternative embodiment, the substituent in the substituted phenylsulfonyl group is a C1-C5 alkyl, haloalkyl, or alkoxy group.

[0039] In one alternative embodiment, the substituent in the substituted alkyl sulfonyl group is a C1-C5 alkyl or haloalkyl.

[0040] As a preferred embodiment, the R 3 Selected from any one of the following groups:

[0041]

[0042] As a preferred embodiment, the chiral β-amino alcohol compound with the structure shown in formula (I) is selected from any one of the following compounds:

[0043]

[0044]

[0045] Among them, Ts F =p-CF3-PhSO2-, Bpin = pinacol boronic acid ester group.

[0046] In an optional embodiment, the synthesis method further includes a deprotection step: under the action of a deprotection reagent, the chiral β-amino alcohol compound with the structure shown in formula (I) undergoes a deprotection reaction to obtain the chiral β-amino alcohol compound with the structure shown in formula (II);

[0047] The deprotecting agent is at least one of sodium, magnesium, lithium, manganese, zinc, sodium borohydride, and lithium aluminum hydride.

[0048] The reaction formula is as follows:

[0049]

[0050] The deprotecting reagent selected in this invention does not racemize the chiral center, thus not affecting the stereoconfiguration of the reaction substrate, and has the advantage of high deprotection efficiency.

[0051] In summary, the synthesis method provided by this invention uses simple and readily available reaction raw materials, has simple reaction operation, mild reaction conditions, and good universality for reaction substrates. It is applicable not only to alkyl aldehydes but also to aromatic aldehydes, has wide reaction adaptability, good practicality, and excellent stereoselectivity of reaction products, making it very suitable for industrial production and application. Detailed Implementation

[0052] The following embodiments are provided to better understand the present invention and are not limited to the preferred embodiments described. They do not constitute a limitation on the content and scope of protection of the present invention. Any product that is the same as or similar to the present invention, derived by any person under the guidance of the present invention or by combining the features of the present invention with other prior art, falls within the protection scope of the present invention.

[0053] For experiments not specifically described in the examples, the procedures or conditions should be followed according to the conventional experimental procedures described in the literature in this field. Reagents or instruments whose manufacturers are not specified are all commercially available conventional reagent products.

[0054] Example 1

[0055]

[0056] In a glove box, CrCl2, (S)-L, and ethyl acetate were added to the reaction flask and pre-stirred at room temperature for 2 hours. Then, manganese powder, benzaldehyde 1, imine 2 (0.2 mmol), and Cp2ZrCl2 were added. The flask was capped, removed from the glove box, and stirred at room temperature for 48 hours. The cap was then opened, and 200 μL of H2O was added to quench the reaction. The solvent was removed using a rotary evaporator to obtain the crude product. After removing the catalyst and manganese powder using a short silica gel column, the conversion, yield, and dr value of the reaction were analyzed by thin-layer chromatography or nuclear magnetic resonance. The optical purity of the product was analyzed by high-performance liquid chromatography. The experimental results showed a yield of 73%, a dr value >20:1, and an ee value of 78%.

[0057] Example 2

[0058] The solvent ethyl acetate in Example 1 was replaced with an equimolar amount of acetonitrile, and the reaction and detection were carried out in the same manner as in Example 1. The experimental results obtained were: yield 66%, dr value > 20:1, and ee value 43%.

[0059] Example 3

[0060] The solvent ethyl acetate in Example 1 was replaced with an equimolar amount of tetrahydrofuran, and the reaction and detection were carried out in the same manner as in Example 1. The experimental results obtained were: yield 78%, dr value >20:1, and ee value 90%.

[0061] Example 4

[0062] The solvent ethyl acetate in Example 1 was replaced with an equimolar amount of ethylene glycol dimethyl ether, and the reaction and detection were carried out in the same manner as in Example 1. The experimental results obtained were: yield 84%, dr value >20:1, and ee value 91%.

[0063] The resolution conditions and data of the chiral β-amino alcohol I1 prepared in Examples 1-4 are as follows:

[0064] SFC analysis: The ee value was determined using CHIRALPAK AD-3 (15% i-PrOH in CO2, 2.0 mL / min), and the retention time of the product was obtained using (S)-L: 2.5 min (major) and 3.4 min (minor).

[0065] 1 H NMR(500MHz,d6-DMSO)δ8.43(d,J=6.0Hz,1H),7.60-7.56(m,4H),7.20-7.19(m,2H),7.15-7.06 (m,5H),7.02-7.00(m,3H),5.57(d,J=4.5Hz,1H),4.67(t,J=4.5Hz,1H),4.47(t,J=4.5Hz,1H).

[0066] 13 C NMR (126MHz, d6-DMSO) δ145.8, 142.8, 139.9, 131.6 (q, J = 32.0Hz), 128.1, 128.0, 127. 9,127.5,127.4,127.3,127.1,125.9(q,J=3,7Hz),124.0(q,J=273.0Hz),76.2,64.6.

[0067] 19 F NMR(471MHz,d6-DMSO)δ-61.70.

[0068] HRMS(ESI)m / z[M-H2O+H] + calcd for C 21 H 17F3NO2S:404.0932,found:404.0940.

[0069] [α] 24 D=-2.00 (c=0.5, CHCl3); 96%ee, from (S)-L.

[0070] Example 5

[0071] For aromatic aldehyde substrates, the following reactions and detections were performed using the same method as in Example 4, and the experimental results are as follows:

[0072]

[0073]

[0074] For alkyl aldehyde substrates, the procedure is as follows: In a glove box, add CrCl2 (0.015 mmol), (S)-L (0.016 mmol), and ethyl acetate (0.2 mmol) to the reaction flask, and pre-stir at room temperature for 2 h. Then add manganese powder (0.2 mmol), additive LiBF4 (0.1 mmol), alkyl aldehyde 1 (0.2 mmol), imine 2 (0.1 mmol), and Cp2ZrCl2 (0.2 mmol). Cap the flask, remove it from the glove box, and stir at 50 °C for 24 h. After capping, add 200 μL of H2O to quench the reaction. Remove the solvent using a rotary evaporator to obtain the crude product. After removing the catalyst and manganese powder using a short silica gel column, analyze the conversion, yield, and dr value of the reaction by thin-layer chromatography or nuclear magnetic resonance, and analyze the optical purity of the product by high-performance liquid chromatography. The experimental results are as follows:

[0075]

[0076] The resolution conditions and data for chiral β-amino alcohol I2 are as follows:

[0077] SFC analysis: The ee value was determined using CHIRALPAK AD-3 (15% i-PrOH in CO2, 2.0 mL / min), and the retention time of the product was obtained using (S)-L: 2.4 min (major) and 3.5 min (minor).

[0078] 1H NMR(500MHz, CDCl3)δ7.52(d,J=8.5Hz,2H),7.41(d,J=8.0Hz,2H),7.16-7.12(m,3H),7.07-7.06(m,2H), 7.00-6.95(m,4H),5.86(br,1H),4.79(d,J=4.5Hz,1H),4.50(t,J=5.0Hz,1H),2.46(br,1H),2.28(s,3H).

[0079] 13 C NMR (126MHz, CDCl3) δ143.6, 137.8, 137.6, 133.5 (q, J = 33.1Hz), 129.0, 128.4, 127. 8,127.4,127.3,125.9,125.5(q,J=3.7Hz),123.2(q,J=273.3Hz),76.7,64.0,21.0.

[0080] 19 F NMR (471MHz, CDCl3) δ -63.14.

[0081] HRMS(ESI)m / z[M-H2O+H] + calcd for C 22 H 19 F3NO2S:418.1089,found:418.1093.

[0082] [α] 24 D=5.36 (c=0.5, CHCl3); 90%ee, from (S)-L.

[0083] The resolution conditions and data for chiral β-amino alcohol I3 are as follows:

[0084] SFC analysis: The ee value was determined using CHIRALPAK AD-3 (15% i-PrOH in CO2, 2.0 mL / min), and the retention time of the product was obtained using (S)-L at 1.7 min (major) and 2.3 min (minor).

[0085] 1H NMR(500MHz,d6-DMSO)δ8.44(d,J=9.0Hz,1H),7.59(s,4H),7.23(t,J=8.0Hz,2H),7.14-7.12(m,2H),7.0 6-7.05(m,2H),6.91(t,J=9.0Hz,2H),5,61(d,J=4.5Hz,1H),4.70(t,J=4.5Hz,1H),4.46(q,J=5.0Hz,1H).

[0086] 13 C NMR(126MHz,d6-DMSO)δ162.6,160.6,145.8,140.1 139.0(d,J=2.8Hz),131.7(q,J=32.3Hz),128.9(d,J=8.1Hz),128.0(d,J=11.1Hz),127 .5,127.0,126.0(q,J=3.7Hz),124.0(q,J=272.7Hz),114.6(d,J=21.2Hz),75.4,64.5.

[0087] 19 F NMR(471MHz,d6-DMSO)δ-61.69,-116.06--116.15(m).

[0088] HRMS(ESI)m / z[M-H2O+H] + calcd for C 21 H 16 F4NO2S:422.0838,found:422.0836.

[0089] [α] 24 D=-25.20 (c=0.5, CHCl3); 94%ee, from (S)-L1.

[0090] The resolution conditions and data for chiral β-amino alcohol I4 are as follows:

[0091] SFC analysis: ee value was determined using CHIRALPAK AD-3 (10% i-PrOH in CO2, 2.0 mL / min); retention time of the product was obtained using (S)-L: 5.8 min (major) and 10.9 min (minor).

[0092] 1H NMR (600MHz, CDCl3) δ7.55-7.54(m,2H),7.47-7.46(m,2H),7.19-7.12(m,5H),7.06-7.05(m,. 2H),7.02-7.01(m,2H),5.73(d,J=6.6Hz),4.82(d,J=5.4Hz),4.47(t,J=5.4Hz),2.45(br,1H).

[0093] 13 C NMR (151MHz, CDCl3) δ143.5, 137.9, 137.0, 134.0, 133.9 (q, J = 33.7Hz), 128.6, 128.5 ,128.2,127.5,127.4,127.3,125.7(q,J=4.4Hz),123.2(q,J=272.6Hz),76.3,64.0.

[0094] 19 F NMR (565MHz, CDCl3) δ -63.17.

[0095] HRMS(ESI)m / z[M-H2O+H] + calcd for C 21 H 16 ClF3NO2S:438.0542,found:438.0536.

[0096] [α] 24 D=-22.40 (c=0.5, CHCl3); 90%ee, from (S)-L1.

[0097] The resolution conditions and data for chiral β-amino alcohol I5 are as follows:

[0098] SFC analysis: ee value was determined using CHIRALPAK AD-3 (15% i-PrOH in CO2, 2.0 mL / min); retention time of the product was obtained using (S)-L: 1.7 min (major) and 2.3 min (minor).

[0099] 1H NMR (500MHz, CDCl3) δ7.63(d,J=7.5Hz,2H),7.49(d,J=8.0Hz,2H),7.40(d,J=8.5Hz,2H),7.16-7.12(m,5H),7.05 (d,J=7.0Hz,2H),5.74(d,J=6.0Hz,1H),4.83(d,J=3.5Hz,1H),4.52(t,J=6.0Hz,1H),2.43(s,1H),1.34(s,12H).

[0100] 13 C NMR (126MHz, CDCl3) δ143.4, 142.4, 137.3, 134.8, 133.6 (q, J = 32.9Hz), 128.4, 128.0 ,127.37,127.35,125.6(q,J=3.7Hz),123.2(q,J=273.3Hz),83.9,76.9,63.8,24.8.

[0101] 19 F NMR (471MHz, CDCl3) δ -63.10

[0102] HRMS(ESI)m / z[M-H2O+H] + calcd for C 27 H 28 BF3NO4S:530.1789,found:530.1796.

[0103] [α] 24 D=-20.24 (c=0.5, CHCl3); 94%ee, from (S)-L1.

[0104] The resolution conditions and data for chiral β-amino alcohol I6 are as follows:

[0105] (S)-L: 45 mg, 45% yield, 87% ee, > 20: 1dr; (R)-L1: 39 mg, 40% yield, 87% ee, > 20: 1dr.

[0106] SFC analysis: ee value was determined using CHIRALPAK AD-3 (15% i-PrOH in CO2, 2.0 mL / min); retention time of the product was obtained using (S)-L: 1.2 min (major) and 2.4 min (minor).

[0107] 1H NMR (600MHz, CDCl3) δ7.57-7.56(m,2H),7.47-7.46(m,2H),7.18-7.16(m,3H),7.14-7.11(m,2H),7.04-7.03(m,2 H),7.00-6.98(m,2H),5.68(d,J=6.6Hz,1H),4.85(q,J=1.6Hz,1H),4.50(t,J=6.0Hz,1H),2.43(d,J=3.0Hz,1H).

[0108] 13 C NMR (151MHz, CDCl3) δ149.0,143.5,138.0,136.9,134.0(q,J=32.8Hz),128.6,128.2,127.7,12 7.4, 127.3, 125.7 (q, J = 3.2Hz), 123.1 (q, J = 272.6Hz), 120.7, 120.4 (q, J = 257.3Hz), 76.3, 64.0.

[0109] 19 F NMR (565MHz, CDCl3) δ-57.91,-63.30.

[0110] HRMS(ESI)m / z[M-H2O+H] + calcd for C 22 H 16 F3NO3S:488.0755,found:488.0766.

[0111] [α] 24 D=22.64 (c=0.5, CHCl3); 87%ee, from (S)-L.

[0112] The resolution conditions and data for chiral β-amino alcohol I7 are as follows:

[0113] SFC analysis: ee value was determined using CHIRALPAK AD-3 (15% i-PrOH in CO2, 2.0 mL / min); retention time of the product was obtained using (S)-L: 2.8 min (major) and 3.5 min (minor).

[0114] 1H NMR (600MHz, CDCl3) δ7.54(d,J=7.8Hz,2H),7.43(d,J=8.4Hz,2H),7.19-7.14(m,3H),7.09-7.06(m,3H),6.70( t,J=7.2Hz,2H),6.66(s,1H),5.82(d,J=6.6Hz,1H),4.81(br,1H),4.52(6.0Hz,1H),3.68(s,3H),2.43(br,1H).

[0115] 13 C NMR (151MHz, CDCl3) δ159.5,143.6,141.1,137.7,133.6(q,J=32.6Hz),129.5,128.5,128.0,12 7.35,127.31,125.6(q,J=3.3Hz),123.3(q,J=272.5Hz),118.3,113.6,111.7,76.7,64.0,55.1.

[0116] 19 F NMR (565MHz, CDCl3) δ -63.21

[0117] HRMS(ESI)m / z[M-H2O+H] + calcd for C 22 H 19 F3NO3S:434.1038,found:434.1039.

[0118] [α] 24 D=9.12 (c=0.5, CHCl3); 90%ee, from (S)-L.

[0119] The resolution conditions and data for chiral β-amino alcohol I8 are as follows:

[0120] SFC analysis: ee value was determined using CHIRALPAK AD-3 (15% i-PrOH in CO2, 2.0 mL / min); retention time of the product was obtained using (S)-L: 2.1 min (major) and 3.2 min (minor).

[0121] 1H NMR(500MHz,d6-DMSO)δ8.47(d,J=8.5Hz,1H),7.60(q,J=8.0Hz,4H),7.41(d,J=7.5Hz,1H),7.06-6.99(m,6H),6 .90(d,J=7.5Hz,1H),5.45(d,J=4.5Hz,1H),4.84(t,J=5.0Hz,1H),4.44-4.42(m,1H),3.30(s,1H),2.05(s,3H).

[0122] 13 C NMR(126MHz,d6-DMSO)δ145.7,140.9,140.1,134.4,131.7(q,J=32.0Hz),130.0,127.9,127.8, 127.6,127.5,127.3,127.1,126.0(q,J=3.7Hz),125.9,124.0(q,J=273.3Hz),72.3,63.2,19.2.

[0123] 19 F NMR(471MHz,d6-DMSO)δ-61.67.

[0124] HRMS(ESI)m / z[M-H2O+H] + calcd for C 22 H 19 F3NO2S:418.1089,found:418.1093.

[0125] [α] 24 D=47.52 (c=0.5, CHCl3); 99%ee, from (S)-L.

[0126] The resolution conditions and data for chiral β-amino alcohol I9 are as follows:

[0127] SFC analysis: ee value was determined using CHIRALPAK AD-3 (15% i-PrOH in CO2, 2.0 mL / min); retention time of the product was obtained using (S)-L: 4.3 min (major) and 5.5 min (minor).

[0128] 1H NMR(500MHz,d6-DMSO)δ8.36(d,J=9.0Hz,1H),7.60(s,4H),7.10-7.08(m,2H),7.03-7.02(m,3H),6.74(d,J=1.5Hz,1H),6.63(dd,J= 8.5Hz,1.5Hz,1H),6,58-6.56(m,1H),5.45(d,J=4.5Hz,1H),4.56(t,J=5.0Hz,1H),4.43(dd,J=9.0Hz,5.0Hz,1H),4.19-4.13(m,4H).

[0129] 13 C NMR(126MHz,d6-DMSO)δ145.9,143.0,142.6,140.1,136.0,131.6(d,J=32.1Hz),128.1,127.8, 127.6, 127.0, 125.9 (q, J = 3.9Hz), 124.0 (q, J = 273.3Hz), 119.9, 116.5, 115.9, 75.6, 64.5, 64.4.

[0130] 19 F NMR(471MHz,d6-DMSO)δ-61.62.

[0131] HRMS(ESI)m / z[M-H2O+H] + calcd for C 23 H 19 F3NO4S:462.0987,found:462.0998.

[0132] [α] 24 D=-29.28 (c=0.5, CHCl3); 82%ee, from (S)-L.

[0133] The resolution conditions and data for chiral β-amino alcohol I10 are as follows:

[0134] SFC analysis: ee value was determined using CHIRALPAK AD-3 (15% i-PrOH in CO2, 2.0 mL / min); retention time of the product was obtained using (S)-L: 3.2 min (major) and 4.5 min (minor).

[0135] 1H NMR(500MHz, CDCl3)δ7.61(d,J=2.5Hz,1H),7.46(d,J=8.0Hz,2H),7.41(s, 1H),7.30(d,J=8.5Hz,2H),7.26-7.25(m,1H),7.18-7.14(m,3H),7.12-7.10 (m,2H),7.01(dd,J=8.5Hz,1.5Hz,1H),6.65(d,J=1.0Hz,1H),5.80(d,J=6.5 Hz, 1H), 4.96 (q, J = 2.5Hz, 1H), 4.56 (t, J = 5.5Hz, 1H), 2.44 (d, J = 3.0Hz, 1H).

[0136] 13 C NMR (126MHz, CDCl3) δ154.5,145.7,143.5,137.8,134.1,133.6(q,J=32.9Hz),128.5,128.0,127.5, 127.29, 127.28, 125.4 (q, J = 3.7Hz), 123.2 (q, J = 273.4Hz), 122.2, 118.7, 111.2, 106.5, 76.9, 64.3.

[0137] 19 F NMR (471MHz, CDCl3) δ -63.19.

[0138] HRMS(ESI)m / z[M-H2O+H] + calcd for C 23 H 17 F3NO3S:444.0881,found:444.0889.

[0139] [α] 24 D=-11.28 (c=0.5, CHCl3); 91%ee, from (S)-L.

[0140] The resolution conditions and data for chiral β-amino alcohol I11 are as follows:

[0141] SFC analysis: ee value was determined using CHIRALCEL OD-3 (15% i-PrOH in CO2, 2.0 mL / min); retention time of the product was obtained using (S)-L: 2.4 min (major) and 4.4 min (minor).

[0142] 1H NMR (500MHz, CDCl3) δ7.67-7.65(m,2H),7.46-7.43(m,2H),7.26-7.21(m,2H),7.18-7.06(m,6H),6.92-6.90(m,2H),5.93(d ,J=7.5Hz,1H),4.38-4.36(m,1H),3.73-3.71(m,1H),2.79-2.75(m,1H),2.68-2.62(m,1H),2.28(br,1H),1.83-1.71(m,2H).

[0143] 13 C NMR (126MHz, CDCl3) δ144.0, 141.0, 137.6, 133.8 (q, J = 32.9), 128.53, 128.46, 128.3, 127. 9,127.4,127.0,126.1,125.6(q,J=3.8Hz),123.1(q,J=273.3Hz),74.1,62.5,35.1,31.6.

[0144] 19 F NMR (471MHz, CDCl3) δ -63.24.

[0145] HRMS(ESI)m / z[M+Na] + calcd for C 23 H 22 F3NO3SNa:472.1170,found:472.1177.

[0146] [α] 24 D=4.24 (c=0.5, CHCl3); 92%ee, from (S)-L.

[0147] The resolution conditions and data for chiral β-amino alcohol I12 are as follows:

[0148] SFC analysis: ee value was determined using CHIRALCEL OD-3 (15% i-PrOH in CO2, 2.0 mL / min); retention time of the product was obtained using (S)-L: 1.0 min (major) and 1.5 min (minor).

[0149] 1H NMR (500MHz, CDCl3) δ7.67-7.66(m,2H),7.48-7.46(m,2H),7.14-7.07(m,3H),6.98-6.97(m,2H),5.97(br ,1H),4.36(t,J=5.0Hz,1H),3.64(q,J=5.0Hz,1H),2.26(br,1H),1.52-1.46(m,2H),0.94(t,J=7.5Hz,3H).

[0150] 13 C NMR (126MHz, CDCl3) δ144.1, 137.8, 133.7 (q, J = 32.9Hz), 128.5, 127.8, 127 .5,127.1,125.6(q,J=3.8Hz),123.2(q,J=273.5Hz),76.3,62.1,26.6,9.8.

[0151] 19 F NMR (471MHz, CDCl3) δ -63.26.

[0152] HRMS(ESI)m / z[M+H] + calcd for C 17 H 19 F3NO3SNa:374.1038,found:374.1029.

[0153] [α] 24 D=23.40 (c=0.5, CHCl3); 94%ee, from (S)-L.

[0154] The resolution conditions and data for chiral β-amino alcohol I13 are as follows:

[0155] SFC analysis: ee value was determined using CHIRALCEL OD-3 (15% i-PrOH in CO2, 2.0 mL / min); retention time of the product was obtained using (S)-L: 1.6 min (major) and 3.5 min (minor).

[0156] 1H NMR (500MHz, CDCl3) δ7.66-7.64(m,2H),7.49-7.47(m,2H),7.16-7.08(m,3H),6.98-6.96(m,2H),5.71-5.69(d,J=7.0Hz ,1H),4.35(dd,J=6.5Hz,5.0Hz,1H),3.93(br,1H),2.64-2.58(m,3H),2.04(s,3H),1.86-1.81(m,1H),1.75-1.68(m,1H).

[0157] 13 C NMR (126MHz, CDCl3) δ143.0, 136.4, 132.8 (q, J = 32.9Hz), 127.6, 127.0, 126.5, 126.1 124.6(q,J=3.7Hz),122.2(q,J=273.5Hz),73.0,61.4,30.9,29.6,14.2.

[0158] 19 F NMR (471MHz, CDCl3) δ -63.26.

[0159] HRMS(ESI)m / z[M+Na] + calcd for C 18 H 20 F3NO3SNa:442.0734,found:442.0726.

[0160] [α] 24 D=7.36 (c=0.5, CHCl3); 92%ee, from (S)-L.

[0161] The resolution conditions and data for chiral β-amino alcohol I14 are as follows:

[0162] SFC analysis: ee value was determined using CHIRALCEL OD-3 (10% i-PrOH in CO2, 2.0 mL / min); retention time of the product was obtained using (S)-L: 1.3 min (major) and 2.4 min (minor).

[0163] 1H NMR (500MHz, CDCl3) δ7.65-7.63(m,2H),7.46-7.44(m,2H),7.12-7.06(m,3H),6.96-6.94(m,2H),5.78-5.76(d,J=7. 5Hz,1H),4.56(dd,J=7.5Hz,4.5Hz,1H),3.38(br,1H),1.95(br,1H),1.78-1.71(m,1H),0.97(dd,J=7.0Hz,13.5Hz).

[0164] 13 C NMR(126MHz, CDCl3)δ144.2(q,J=1.1Hz),138.0,133.7(q,J=33.1Hz),128.5,127.8,1 27.5, 127.0, 125.6 (q, J = 3.7Hz), 123.2 (q, J = 273.4Hz), 80.3, 59.8, 29.8, 19.3, 17.3.

[0165] 19 F NMR (471MHz, CDCl3) δ -63.27.

[0166] HRMS(ESI)m / z[M+Na] + calcd for C 18 H 20 F3NO3SNa:410.1014,found:410.1005.

[0167] [α] 24 D=14.48 (c=0.5, CHCl3); 97%ee, from (S)-L.

[0168] The resolution conditions and data for chiral β-amino alcohol I15 are as follows:

[0169] SFC analysis: ee value was determined using CHIRALCEL OD-3 (15% i-PrOH in CO2, 2.0 mL / min); retention time of the product was obtained using (S)-L: 1.1 min (major) and 2.4 min (minor).

[0170] 1H NMR (500MHz, CDCl3) δ7.70-7.69(m,2H),7.49-7.47(m,2H),7.14-7.06(m,3H),7.02-7.00(m,2H),6.07-6.05(m,1H),4.51(dd,J=7.0Hz ,5.0Hz,1H),3.03(dd,J=8.5Hz,5.0Hz,1H),2.31(br,1H),1.03-0.96(m,1H),0.53-0.48(m,1H),0.39-0.28(m,2H),0.04-0.01(m,1H).

[0171] 13 C NMR(126MHz, CDCl3)δ144.1(q,J=1.0Hz,),137.8,133.7(q,J=33.0Hz),128.3,127.7, 127.5, 127.2, 125.6 (q, J = 3.7Hz), 123.2 (q, J = 273.2Hz), 79.3, 62.8, 15.0, 3.19, 2.71.

[0172] 19 F NMR (471MHz, CDCl3) δ -63.25.

[0173] HRMS(ESI)m / z[M+Na] + calcd for C 18 H 18 F3NO3SNa:408.0857,found:408.0846.

[0174] [α] 24 D=11.84 (c=0.5, CHCl3); 94%ee, from (S)-L.

[0175] The resolution conditions and data for chiral β-amino alcohol I16 are as follows:

[0176] SFC analysis: ee value was determined using CHIRALCEL OD-3 (15% i-PrOH in CO2, 2.0 mL / min); retention time of the product was obtained using (S)-L: 1.2 min (major) and 2.1 min (minor).

[0177] 1H NMR (500MHz, CDCl3) δ7.60-7.58(m,2H),7.40-7.38(m,2H),7.06-6.99(m,3H),6.91-6.89(m,2H),5.96(d,J=8.0Hz,1H),4.20(dd,J= 7.5Hz,5.0Hz,1H),3.56(t,J=6.0Hz,1H),2.42-2.34(m,1H),2.28(br,1H),1.96-1.89(m,1H),1.84-1.75(m,2H),1.69-1.59(m,3H).

[0178] 13 C NMR(126MHz, CDCl3)δ144.1(q,J=1.1Hz),137.9,133.7(q,J=32.9Hz),128.4,127.7,127 .4,127.0,125.6(q,J=3.8Hz),123.2(q,J=273.2Hz),78.8,60.1,37.7,24.4,23.9,17.8.

[0179] 19 F NMR (471MHz, CDCl3) δ -63.27.

[0180] HRMS(ESI)m / z[M+Na] + calcd for C 19 H 20 F3NO3SNa:422.1014,found:422.1021.

[0181] [α] 24 D=2.64 (c=0.5, CHCl3); 94%ee, from (S)-L.

[0182] The resolution conditions and data for chiral β-amino alcohol I17 are as follows:

[0183] SFC analysis: ee value was determined using CHIRALCEL OD-3 (15% i-PrOH in CO2, 2.0 mL / min); retention time of the product was obtained using (S)-L: 1.1 min (major) and 1.7 min (minor).

[0184] 1H NMR (500MHz, CDCl3) δ7.68-7.66(m,2H),7.48-7.46(m,2H),7.14-7.07(m,3H),6.98-6.97(m,2H),5.86(d,J=7.5Hz,1H),4.60(dd,J= 8.0Hz, 4.0Hz, 1H), 3.38 (q, J = 3.5Hz, 1H), 2.01 (br, 1H), 1.90-1.88 (m, 2H), 1.75-1.66 (m, 6H), 1.43-1.10 (m, 1H), 1.17-1.05 (m, 3H).

[0185] 13 C NMR (126MHz, CDCl3) δ144.3, 138.4, 133.7 (q, J = 33.0Hz), 128.4, 127.6, 127.4, 126.9, 12 5.6(q,J=3.8Hz),123.2(q,J=273.3Hz),79.6,58.9,39.2,29.2,28.1,26.2,25.8,25.7.

[0186] 19 F NMR (471MHz, CDCl3) δ -63.27.

[0187] HRMS(ESI)m / z[M+Na] + calcd for C 21 H 24 F3NO3SNa:450.1327found:450.1328.

[0188] [α] 24 D=16.40 (c=0.5, CHCl3); 94%ee, from (S)-L.

[0189] The resolution conditions and data for chiral β-amino alcohol I18 are as follows:

[0190] SFC analysis: ee value was determined using CHIRALCEL OD-3 (15% i-PrOH in CO2, 2.0 mL / min); retention time of the product was obtained using (S)-L: 1.6 min (major) and 11.8 min (minor).

[0191] 1H NMR (500MHz, CDCl3) δ7.66-7.64(m,2H),7.46-7.44(m,2H),7.14-7.06(m,3H),6.93-6.92(m,2H),5.81(d,J=8.5Hz,1H),4.59(dd,J=8.5Hz,3.0H z,1H),4.14-4.11(m,2H),3.39(br,1H),2.63-2.61(m,2H),2.24(br,1H ),1.89-1.86(m,1H),1.74-1.68(m,2H),1.44(s,9H),1.31-1.18(m,2H).

[0192] 13 C NMR (126MHz, CDCl3) δ154.8, 144.1, 137.8, 133.8 (q, J = 32.9Hz), 128.6, 127.8, 127.4, 126.8 ,125.6(q,J=3.9Hz),123.1(q,J=273.0Hz),79.5,78.9,77.2,58.8,38.0,28.4,28.1,27.8.

[0193] 19 F NMR (471MHz, CDCl3) δ -63.28.

[0194] HRMS(ESI)m / z[M+Na] + calcd for C 25 H 31 F3N2O5SNa:551.1804,found:555.1813.

[0195] [α] 24 D=-15.12 (c=0.5, CHCl3); 94%ee, from (S)-L.

[0196] The resolution conditions and data for chiral β-amino alcohol I19 are as follows:

[0197] SFC analysis: ee value was determined using CHIRALCEL OD-3 (15% i-PrOH in CO2, 2.0 mL / min); retention time of the product was obtained using (S)-L: 1.5 min (major) and 2.3 min (minor).

[0198] 1H NMR (500MHz, CDCl3) δ7.66-7.65(m,2H),7.46-7.45(m,2H),7.14-7.07(m,3H),6.94-6.93(m,2H),5.84(d,J=5.5Hz,1H),4.60( d,J=4.5Hz,1H),3.99-3.96(m,2H),3.39-3.31(m,3H),2.04(br,1H),1.81-1.79(m,2H),1.67-1.65(m,2H),1.43-1.17(m,1H).

[0199] 13 C NMR (126MHz, CDCl3) δ144.1, 137.9, 133.9 (q, J = 32.9Hz), 128.61, 127.83, 127.40, 126.7 9,125.6(q,J=3.7Hz),123.1(q,J=273.2Hz),79.2,67.6,67.4,58.4,36.9,28.78,28.77.

[0200] 19 F NMR (471MHz, CDCl3) δ -63.28.

[0201] HRMS(ESI)m / z[M+Na] + calcd for C 20 H 22 F3NO4SNa:452.1119,found:452.1129.

[0202] [α] 24 D=5.68 (c=0.5, CHCl3); 93%ee, from (S)-L.

[0203] The resolution conditions and data for chiral β-amino alcohol I20 are as follows:

[0204] SFC analysis: ee value was determined using CHIRALCEL OD-3 (15% i-PrOH in CO2, 2.0 mL / min); retention time of the product was obtained using (S)-L: 0.8 min (major) and 1.2 min (minor).

[0205] 1H NMR (500MHz, CDCl3) δ7.52-7.50(m,2H),7.31-7.29(m,2H),7.00-6.93(m,3H),6.86-6.85(m ,2H),5.91(d,J=8.5Hz,1H),4.69(d,J=3.5Hz,1H),3.27(br,1H),2.13(br,1H),0.99(s,9H).

[0206] 13 C NMR (126MHz, CDCl3) δ144.4, 140.1, 133.4 (q, J = 33.0Hz), 128.3, 127.32, 127. 27,126.5,125.4(q,J=3.7Hz),123.2(q,J=273.2Hz),82.6,57.2,35.6,26.3.

[0207] 19 F NMR (471MHz, CDCl3) δ -63.29.

[0208] HRMS(ESI)m / z[M+H] + calcd for C 19 H 23 F3NO3S:,402.1351,found:402.1356.

[0209] [α] 24 D=12.24 (c=0.5, CHCl3); 84%ee, from (S)-L.

[0210] The resolution conditions and data for chiral β-amino alcohol I21 are as follows:

[0211] SFC analysis: ee value was determined using CHIRALCEL OD-3 (15% i-PrOH in CO2, 2.0 mL / min); retention time of the product was obtained using (S)-L: 2.4 min (major) and 4.8 min (minor).

[0212] 1H NMR (600MHz, CDCl3) δ7.65-7.64(m,2H),7.44-7.42(m,2H),7.25-7.22(m,2H),7 .17-7.16(m,1H),7.09-7.08(m,2H),6.84(d,J=7.8Hz,2H),6.77(d,J=8.4Hz,2H) ,5.92(d,J=7.8Hz,1H),4.32(dd,J=7.2Hz,5.4Hz,1H),3.71(br,1H),2.80-2.75( m,1H),2.66-2.61(m,1H),2.32(d,J=2.4Hz,1H),2.20(s,3H),1.84-1.74(m,2H).

[0213] 13 C NMR (151MHz, CDCl3) δ144.0,141.2,137.8,134.5,133.7(q,J=32.8Hz),129.2,128.5,128.4, 127.6, 127.0, 126.1, 125.6 (q, J = 3.3Hz), 123.2 (q, J = 272.7Hz), 74.2, 62.5, 35.1, 31.7, 20.8.

[0214] 19 F NMR (565MHz, CDCl3) δ -63.18.

[0215] HRMS(ESI)m / z[M+Na] + calcd for C 24 H 24 F3NO3SNa:486.1327,found:486.1330.

[0216] [α] 24 D=-7.68 (c=0.5, CHCl3); 94%ee, from (S)-L.

[0217] The resolution conditions and data for chiral β-amino alcohol I22 are as follows:

[0218] SFC analysis: ee value was determined using CHIRALCEL OD-3 (15% i-PrOH in CO2, 2.0 mL / min); retention time of the product was obtained using (S)-L: 2.9 min (major) and 4.1 min (minor).

[0219] 1H NMR(600MHz, CDCl3) δ7.66(d,J=7.8Hz,2H),7.48(d,J=7.8Hz,2H),7.26-7.2 3(m,2H),7.18-7.15(m,1H),7.09(d,J=7.8Hz,2H),6.82(d,J=8.4Hz,2H),6. 58(d,J=8.4Hz,2H),5.80-5.77(m,1H),4.30(t,J=6.0Hz,1H),3.70-3.68(m, 4H),2.79-2.75(m,1H),2.66-2.61(m,1H),2.18(br,1H),1.82-1.70(m,2H).

[0220] 13 C NMR (151MHz, CDCl3) δ159.3, 144.1, 141.1, 133.8 (q, J = 32.8Hz), 129.5, 128.5, 128.4, 128.3, 127.6,126.1,125.6(q,J=4.4Hz),123.2(q,J=273.8Hz),113.9,74.2,62.2,55.1,35.1,31.7.

[0221] 19 F NMR (565MHz, CDCl3) δ -63.17.

[0222] HRMS(ESI)m / z[M+Na] + calcd for C 22 H 20 F3NO4SNa:502.1276,found:502.1284.

[0223] [α] 24 D=-4.40 (c=0.5, CHCl3); 93%ee, from (S)-L.

[0224] The resolution conditions and data for chiral β-amino alcohol I23 are as follows:

[0225] SFC analysis: ee value was determined using CHIRALCEL OD-3 (30% i-PrOH in CO2, 2.0 mL / min); retention time of the product was obtained using (S)-L: 2.3 min (major) and 1.8 min (minor).

[0226] 1H NMR(600MHz,d6-DMSO)δ8.40(d,J=9.0Hz,1H),7.75(d,J=9.0Hz,2H),7.64(d,J=7.8Hz,2H), 7.51(d,J=6.0Hz,2H),7.42(t,J=7.2Hz,2H),7.34-7.30(m,3H),7.24(t,J=7.8Hz,2H),7.16 -7.13(m,3H),7.09(d,J=7.8Hz,2H),4.99(dJ=6.0Hz,1H),4.34(dd,J=9.0Hz,4.8Hz,1H),3. 60-3.58(m,1H),2.72-2.67(m,1H),2.53-2.48(m,1H),1.62-1.57(m,1H),1.53-1.47(m,1H).

[0227] 13 C NMR (151MHz, d6-DMSO) δ150.6, 147.3, 145.2, 143.9, 143.7, 136.6 (q, J = 31.6Hz), 134.0, 133.5, 133.42, 133. 35,132.6,132.5,131.7,131.0,130.85,130.81(q,J=3.3Hz),128.7(q,J=273.6Hz),77.7,67.5,40.6,36.6.

[0228] 19 F NMR(565MHz,d6-DMSO)δ-56.86.

[0229] HRMS(ESI)m / z[M+Na] + calcd for C 29 H 26 F3NO3SNa:548.1483,found:548.1474.

[0230] [α] 24 D=-2.00 (c=0.5, CHCl3); 99%ee, from (S)-L.

[0231] The resolution conditions and data for chiral β-amino alcohol I24 are as follows:

[0232] SFC analysis: ee value was determined using CHIRALCEL OD-3 (15% i-PrOH in CO2, 2.0 mL / min); retention time of the product was obtained using (S)-L: 2.2 min (major) and 2.7 min (minor).

[0233] 1 H NMR (600MHz, CDCl3) δ7.68 (d, J = 8.4Hz), 7.51 (d, J = 8.4Hz), 7.24-7.23 (m, 2 H),7.19-7.16(m,1H),7.08(d,J=7.2Hz),6.93-6.91(m,2H),6.78(t,J=8.4H z,2H),5.91(d,J=7.2Hz,1H),4.34(dd,J=6.6Hz,5.4Hz,1H),3.70-3.67(m, 1H),2.78-2.74(m,1H),2.66-2.61(m,1H),2.20(br,1H),1.83-1.69(m,2H).

[0234] 13 C NMR (151MHz, CDCl3) δ162.2 (d, J = 248.5Hz), 144.0, 140.9, 134.1 (q, J = 33.8Hz), 133.6 (d, J = 3.2Hz), 128.8 (d, J = 8.8Hz ),128.6,128.3,127.5,126.2,125.8(q,J=4.4Hz),123.1(q,J=272.5Hz),115.5(d,J=21.7Hz),74.2,61.8,35.2,31.7.

[0235] 19 F NMR(565MHz, CDCl3)δ-63.23,-113.66--113.71(m).

[0236] HRMS(ESI)m / z[M+Na] + calcd for C 23 H 21 F4NO3SNa:490.1076,found:490.1073.

[0237] [α] 24 D=-6.32 (c=0.5, CHCl3); 95%ee, from (S)-L.

[0238] The resolution conditions and data for chiral β-amino alcohol I25 are as follows:

[0239] SFC analysis: ee value was determined using CHIRALCEL OD-3 (15% i-PrOH in CO2, 2.0 mL / min); retention time of the product was obtained using (S)-L: 3.0 min (major) and 4.0 min (minor).

[0240] 1 H NMR (600MHz, CDCl3) δ7.67(d,J=8.4Hz,2H),7.51(d,J=8.4Hz,2H),7.24-7.23(m,2H),7.19-7.16(m,1H),7.08-7.04(m,4H),6.88(d,J=8.4Hz,2H), 5.98(br,1H),4.33(d,J=5.4Hz,1H),3.70-3.67(m,1H),2.78-2.73(m,1H ),2.66-2.61(m,1H),2.28(br,1H),1.81-1.77(m,1H),1.75-1.70(m,1H).

[0241] 13 C NMR (151MHz, CDCl3) δ143.9, 140.8, 136.4, 134.1 (q, J = 32.7Hz), 134.0, 128.7, 128.6, 128. 5,128.3,127.5,126.2,125.8(q,J=3.3Hz),123.1(q,J=272.6Hz),74.0,61.9,35.2,31.7.

[0242] 19 F NMR (565MHz, CDCl3) δ -63.16.

[0243] HRMS(ESI)m / z[M+Na] + calcd for C 23 H 21 ClF3NO3SNa:506.0780,found:506.0784.

[0244] [α] 24 D=-7.30 (c=0.5, CHCl3); 94%ee, from (S)-L.

[0245] Example 6

[0246]

[0247] Under nitrogen protection, sodium, naphthalene, and DME were added to a reaction flask and stirred at room temperature for 2 hours. Then, a DME solution of compound I8 was added at -78°C, and the reaction was continued at room temperature for 12 hours. The reaction was quenched with water, extracted, and the crude product was obtained after solvent removal using a rotary evaporator. The conversion, yield, and dr value of the reaction were analyzed by thin-layer chromatography or nuclear magnetic resonance, and the optical purity of the product was analyzed by high-performance liquid chromatography. The experimental results showed a yield of 86% and a dr value greater than 20:1.

[0248] The data for chiral β-amino alcohol II8 are as follows:

[0249] 1 H NMR (600MHz, CDCl3) δ7.52 (d, J = 7.8Hz, 2H), 7.23-7.18 (m, 4H), 7.24-7.23 (m, 2H), 7.13-7.10 (m, 3H),6.96-6.95(m,1H),4.88(d,J=6.6Hz,1H),4.03(d,J=6.6Hz,1H),3.23(br,3H),1.89(s,3H).

[0250] 13 C NMR (151MHz, CDCl3) δ141.5,140.1,135.3,130.1,128.3,127.5,127.3,127.0,126.4,126.0,73.8,61.3,19.0.

[0251] HRMS(ESI)m / z[M+Na] + calcd for C 15 H 17 NONa:250.1208, found:250.1210.

[0252] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. Use of a chiral chromium complex for catalyzing the reaction of an aldehyde with an imine to produce a chiral β-amino alcohol compound, characterized in that, The chiral ligand in the chiral chromium complex is selected from the following compounds: 。 2. Use according to claim 1, characterized in that, The molar ratio of the chiral chromium complex to the imine is 0.01-0.15:

1.

3. A method for synthesizing a chiral β-amino alcohol compound, characterized by, The method comprises the following steps: reacting an aldehyde with an imine under the catalysis of a chiral chromium complex to prepare a chiral β-amino alcohol compound; and the reaction formula is as follows: Among them, R 1 Selected from any one of substituted or unsubstituted alkyl or phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl; R 2 any one selected from the group consisting of substituted or unsubstituted phenyl, heteroaryl; R 3 selected from substituted or unsubstituted phenylsulfonyl or alkylsulfonyl; The substituent group in the substituted alkyl group is at least one of C1-C5 alkylthio, alkoxy, alkynyl or alkenyl, phenyl, thiol, halogen; The substituent group in the substituted phenyl group is at least one of C1-C5 alkyl, alkoxy, haloalkoxy, haloalkyl, alkynyl, alkenyl or heterocycloalkyl, boronic acid group, thiol, cyano, ester group, sulfonyl group, hydroxyl, halogen, phenyl, wherein the heterocycloalkyl and the phenyl group substituted thereby form a benzodioxane group; The substituent group in the substituted phenylsulfonyl group is C1-C5 alkyl, haloalkyl or alkoxy; The substituent group in the substituted alkylsulfonyl group is C1-C5 alkyl or haloalkyl; The chiral ligand in the chiral chromium complex is selected from the following compounds: ； The synthesis method further comprises adding a reducing agent, and the reducing agent is manganese; The synthesis method further comprises adding a dissociating agent, and the dissociating agent is Cp2ZrCl2; When the aldehyde is an alkyl aldehyde, the synthesis method further comprises the step of adding an additive at the same time of adding the alkyl aldehyde, and the additive is LiBF4.

4. The method of synthesis of claim 3, wherein, The molar ratio of the chiral chromium complex to the imine is 0.01-0.15:1; and / or, The molar ratio of the aldehyde to the imine is 1-2:1; and / or, The reaction is carried out in an anhydrous and anaerobic organic solvent, and the organic solvent is at least one of ethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, acetonitrile, toluene, xylene, methyl tert-butyl ether, diethyl ether, dioxane, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, 1,2-dichloroethane.

5. The method of synthesis of claim 3, wherein, The molar ratio of the reducing agent to the imine is 2-3:

1.

6. The method of synthesis of claim 3, wherein, The molar ratio of the dissociating agent to the imine is 2-3:

1.

7. The method of synthesis according to any one of claims 3-6, wherein, The method comprises the following steps: The halide of chromium, the chiral ligand and the organic solvent are mixed under anhydrous and anaerobic conditions, and then the reducing agent, the aldehyde, the imine and the dissociating agent are added, and the reaction is continued by stirring, so as to obtain the chiral β-amino alcohol compound shown in formula (I); When the aldehyde is an alkyl aldehyde, the molar ratio of the additive to the imine is 0.2-2:

1.

8. The synthesis method according to any one of claims 3-6, wherein, The alkyl group contains 1-5 carbon atoms; and / or, The cycloalkyl group or the heterocycloalkyl group contains 3-10 carbon atoms; and / or, The heteroaryl group is any one of furanyl, benzofuranyl, thienyl, benzothienyl, indolyl, pyridyl.

9. The synthesis method according to any one of claims 3-6, wherein, The alkylthio group is methylthio; The alkoxy group is methoxy; The alkyl group is methyl, ethyl, isopropyl or tert-butyl; The haloalkoxy group is trifluoromethoxy; The halogen is fluorine or chlorine; The cycloalkyl is cyclopropyl, cyclobutyl, cyclohexyl; The heterocycloalkyl is tetrahydropyranyl, N-tert-butoxycarbonylpiperidinyl; R 3 any one selected from the group consisting of: 。 10. The method of synthesis of claim 7, wherein, The chiral β-amino alcohol compound of formula (I) is selected from any one of the following compounds: Wherein, TsF = p-CF3-PhSO2-, Bpin = pinacol boronate; and / or, The synthesis method further comprises a deprotection step: the chiral β-amino alcohol compound of formula (I) undergoes a deprotection reaction under the action of a deprotection reagent to obtain a chiral β-amino alcohol compound of formula (II); The deprotection reagent is at least one of sodium, magnesium, lithium, manganese, zinc, sodium borohydride, and lithium aluminum hydride; The reaction formula is as follows: or 。

Images