A process for the asymmetric catalytic preparation of alpha-aryl amino acid esters

Abstract

The application discloses a method for preparing alpha-arylamino acid ester through asymmetric catalysis, and the preparation process is as follows: alpha-amino acid ester and aromatic hydrocarbon derivative are fully reacted in a solvent in the presence of a chiral aldehyde catalyst and a base, and an arylamino acid ester is obtained through post-treatment; wherein the aromatic hydrocarbon derivative is an aromatic hydrocarbon derivative with adjacent halogen atoms and an electron-withdrawing group on a benzene ring; the base is selected from any one of Cs2CO3, K2CO3 and K3PO4; and the reaction temperature T is 10-100 DEG C. The synthesis method has the advantages of mild reaction condition, short route, wide selection range of reaction raw materials, no protection of amino groups in the reaction process, direct obtaining of optically active arylamino acid ester compounds and high yield.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of compound preparation, and particularly relates to a method for preparing alpha-aryl amino acid ester through asymmetric catalysis. BACKGROUND

[0002] Optically active alpha-aryl amino acid compounds exist in some important natural products, and are widely used as bioactive molecules in drugs, agricultural chemicals and functional materials. There are many methods for asymmetric synthesis of alpha-amino acids, mainly including enzyme synthesis method, alpha, beta-dehydrogenated amino acid hydrogenation or cycloaddition method, Strecker type reaction, electrophilic or nucleophilic amination method and electrophilic or nucleophilic alkylation method, which all involve chiral control of alpha-carbon, and the chiral auxiliary method accounts for the majority, and the chiral reagent method is less. Due to the presence of aromatic groups, the synthesis of alpha-aryl amino acids has some particularity. At present, the chiral synthesis of such structural compounds is mainly completed through chiral phase transfer catalysts, and N-protected aldimine esters must be used. Patent document CN108569978A discloses a method for preparing alpha-aryl substituted amino acid derivatives, the process is: the oxazolidinone compound is dissolved in a solvent, a base is added, an arylating agent is added, and the reaction is carried out at-78℃ for 2 hours and at room temperature for 12 hours to obtain an aryl-substituted oxazolidinone compound; the obtained aryl-substituted oxazolidinone compound is hydrolyzed by trifluoroacetic acid to obtain an alpha-aryl-substituted amino acid derivative. However, this method prepares amino acid derivatives with substituents connected to the amino group. At present, there is no method for directly preparing aryl amino acid esters using amino acid without protection as raw materials. SUMMARY

[0003] Therefore, one of the purposes of the application is to provide a method for preparing alpha-aryl amino acid ester through asymmetric catalysis, which has the characteristics of mild reaction conditions, low cost and high yield of products.

[0004] The technical scheme is as follows:

[0005] A method for preparing alpha-aryl amino acid ester through asymmetric catalysis, the key of which is that the preparation process is: under the condition of the presence of chiral aldehyde catalyst and base, alpha-amino acid ester and aromatic hydrocarbon derivative are fully reacted in a solvent, and aryl amino acid ester is obtained through post-treatment;

[0006] The base is selected from any one of Cs2CO3, K2CO3, Na3PO4 and K3PO4;

[0007] The reaction temperature T is 10℃-100℃;

[0008] The structure of the alpha-amino acid ester is as formula (I),

[0009]

[0010] wherein R 1 is selected from H, C1-C7 alkyl, C1-C5 alkyl substituted with aryl or alkenyl or ether linkage or sulfinyl group;

[0011] wherein R 2 is selected from t Bu, i Pr, Bn, Et or Me group;

[0012] said aromatic hydrocarbon derivative is or a compound having a structure as shown in formula (II),

[0013]

[0014] wherein X is a halogen atom,

[0015] wherein R 3 is H or a substituent at ortho-, meta- or para-position of the benzene ring, R 3 is 1-2 substituents selected from methyl, methoxy, substituted or unsubstituted phenyl, halogen atom, nitro group, cyano group, trifluoromethyl group, ester group;

[0016] the obtained aryl amino acid ester is

[0017]

[0018] or a compound having a structure as shown in formula (III),

[0019]

[0020] said chiral aldehyde catalyst has a structure as shown in formula (IV),

[0021]

[0022] In one embodiment, in the structure of said α-amino acid ester, R 1 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl substituted methyl or ethyl, phenyl or indolyl substituted methyl or ethyl, formate or acetate group, ether linkage or thioether linkage substituted methyl or ethyl, sulfinyl substituted methyl or ethyl, allyl group.

[0023] In one embodiment, in said aromatic hydrocarbon derivative, when X is a fluorine atom, R 3 is H or a substituent at ortho-, meta- or para-position of the benzene ring, R 3 is 1-2 substituents selected from methyl, methoxy, substituted or unsubstituted phenyl, halogen atom, nitro group, cyano group, trifluoromethyl group, ester group; 3when a substituent, is selected from the group consisting of methyl, methoxy, substituted or unsubstituted phenyl, fluorine, chlorine, bromine, iodine;

[0024] when X is a chlorine atom, R 3 is a substituent on the meta or para position of the benzene ring, selected from the group consisting of nitro, cyano, trifluoromethyl, ester group.

[0025] In one embodiment, the aromatic hydrocarbon derivative is any one of the following compounds:

[0026]

[0027] In one embodiment, the reaction temperature T is 20℃≤T≤90℃.

[0028] In one embodiment, the reaction temperature T is 30℃≤T≤60℃.

[0029] In one embodiment, the reaction temperature T is 30℃≤T≤60℃.

[0030] In one embodiment, the concentration of the aromatic hydrocarbon derivative in the reaction system is 0.025-0.2 mol / L, and the molar ratio of the aromatic hydrocarbon derivative to the base is 1:(1-15).

[0031] In one embodiment, the solvent is one of mesitylene, hexafluorobenzene, dichloromethane, trichloromethane, carbon tetrachloride, fluorobenzene, chlorobenzene, methanol, diethyl ether, tetrahydrofuran, butyl ether, or a mixture of two or more capable of mutual solubility.

[0032] The second object of the present application is to provide an α-aryl amino acid ester. The technical solution is:

[0033] An α-aryl amino acid ester, the key is that the structure is as formula (III):

[0034]

[0035] wherein R 1 is selected from H, C1-C7 alkyl, methyl or ethyl substituted with aryl or alkenyl or ether bond or sulfinyl group, formate or acetate group,

[0036] wherein R 2 is selected from t Bu, i Pr, Bn, Et or Me group;

[0037] wherein R 3H or a substituent at the meta- or para-position of the nitro group on the benzene ring, R 3 when a substituent, the number is 1-2, selected from methyl, methoxy, substituted or unsubstituted phenyl, halogen atom, nitro, cyano, trifluoromethyl, ester group.

[0038] Compared with the prior art, the present application has the following advantages:

[0039] (1) mild reaction conditions, short synthesis route;

[0040] (2) wide selection range of reaction raw materials, capable of preparing aryl amino acid esters with different functional groups;

[0041] (3) no protection of amino group during the reaction process, directly obtaining optically active aryl amino acid ester compounds with high yield. BRIEF DESCRIPTION OF DRAWINGS

[0042] Figure 1 is the reaction schematic diagram of the method of the present application, and the reaction conditions, product molecular structure, yield and enantiomeric excess percentage of some typical examples. DETAILED DESCRIPTION

[0043] The present application will be further described below in combination with examples.

[0044] A method for asymmetric catalytic preparation of α-aryl amino acid ester, the preparation process is: under the condition of chiral aldehyde catalyst and base, α-amino acid ester (compound 1) and aromatic hydrocarbon derivative (compound 2) are fully reacted in a solvent to obtain a mixture containing aryl amino acid ester (compound 3), and then compound 3 is obtained after treatment. The base is selected from any one of Cs2CO3, K2CO3, Na3PO4 and K3PO4. The reaction temperature T is 10-100℃; preferably 20℃≤T≤90℃; further preferably 30℃≤T≤60℃. The solvent is one of mesitylene, hexafluorotoluene, dichloromethane, trichloromethane, carbon tetrachloride, fluorobenzene, chlorobenzene, methanol, diethyl ether, tetrahydrofuran, butyl ether, or a mixed solvent composed of two or more solvents mixed in a mutually soluble proportion. In the reaction system, the concentration of the aromatic hydrocarbon derivative is 0.025-0.2 mol / L, and the amount-of-substance ratio of the aromatic hydrocarbon derivative to the base is 1:(1-15).

[0045] The structure of the chiral aldehyde catalyst is as formula (IV):

[0046]

[0047] The structure of the α-amino acid ester is as formula (I),

[0048]

[0049] wherein R 1 selected from H, C1-C7 alkyl, C1-C5 alkyl substituted with aryl or alkenyl or ether bond or sulfinyl group;

[0050] wherein R 2 selected from t Bu, i Pr, Bn, Et or Me group;

[0051] The aromatic hydrocarbon derivative is or a compound having a structure as shown in formula (II),

[0052]

[0053] wherein X is a halogen atom,

[0054] wherein R 3 is H or a substituent at ortho-, meta- or para-position of the benzene ring, R 3 is 1-2 substituents selected from methyl, methoxy, substituted or unsubstituted phenyl, halogen atom, nitro group, cyano group, trifluoromethyl, ester group;

[0055] The obtained aryl amino acid ester is

[0056]

[0057] or a compound having a structure as shown in formula (III),

[0058]

[0059] The benzene ring of the aromatic hydrocarbon derivative has adjacent halogen atom and electron-withdrawing group, so that the halogen atom is used as the active site of the reaction.

[0060] The preparation process and effects of the method are described below with specific examples, and the effects of different reaction conditions on the reaction results are studied. The reagents used in each example and control example are commercially available analytical pure reagents, and the products are analyzed by nuclear magnetic resonance spectroscopy (NMR) after separation and purification. The product purity is determined by chiral high performance liquid chromatography analysis, and the enantiomeric excess percentage ee% is used to represent the product purity.

[0061] (I) The effect of adding different bases on the reaction

[0062] In a sealed tube, 0.01 mmol of chiral aldehyde catalyst and 0.20 mmol of compound 1a were added, 1 mL of toluene was added as solvent, 1 mmol of base reagent was added, stirred at room temperature for 10 min, then 0.10 mmol of compound 2a was added, and the reaction was carried out at 50°C for 48 h. That is, the molar ratio of compound 2a to base reagent in the reaction system was 1:10, or the amount of base reagent was 10 equivalents of compound 2a. During the reaction, the reaction progress was monitored by thin layer chromatography (TLC), and the reaction mixture was concentrated under reduced pressure, and then column chromatography was used to obtain the optically active aryl amino acid ester compound 3a. Among them, compound 1a is Compound 2a is The reaction formula of the reaction is:

[0063]

[0064] The difference between each example and the control example is that different bases are added to the reaction system, as shown in Table 1; the yield of the target substance and the enantiomeric excess percentage ee value of each reaction are shown in Table 1. By comparing control examples 1-9 and examples 1-3, it can be seen that among the commonly used base reagents, only Cs2CO3, K2CO3 and K3PO4 can promote the reaction to proceed, and among them, Cs2CO3 and K3PO4 have better effects. K3PO4 is selected as the base reagent in subsequent experiments.

[0065] Table 1 Effect of adding different bases in the reaction system on the reaction

[0066]

[0067] Note: b Purification yield; c Determined by chiral HPLC analysis; d 1,1,3,3-tetramethylguanidine; e N.R. = no reaction; f N.D. = not determined; g 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0068] (B) Effect of different reaction temperatures on the reaction

[0069] The experimental process is the same as part (I), except that the base reagent used is K3PO4, and the reaction temperature is different at 30-120°C. The reaction formula of the reaction is:

[0070]

[0071] From Table 2, it can be seen that, keeping other reaction conditions unchanged, the yield first increases and then decreases with the increase of reaction temperature; when the reaction temperature reaches 100°C, the yield is very low. When the reaction temperature is 50°C, the yield is the highest.

[0072] Table 2 Influence of different reaction temperatures on the reaction

[0073]

[0074] Note: b Purification yield; c Determined by chiral HPLC analysis.

[0075] (III) Influence of different solvents on the reaction

[0076] The experimental process is the same as that in the first part, except that the base reagent used is K3PO4, and the solvents used in Examples 9-21 are mesitylene, hexafluorobenzene (C6F6), chloroform (CHCl3), fluorobenzene (PhF), chlorobenzene (PhCl), methanol (CH3OH), N,N-dimethylformamide (DMF), dichloromethane (CH2Cl2), carbon tetrachloride (CCl4), a mixed solvent of dichloromethane and toluene (CH2Cl2:PhMe = 1:4 by volume), diethyl ether (Et2O), tetrahydrofuran (THF), dibutyl ether (Bu2O), respectively; and the solvents used in Comparative Examples 10-13 are acetonitrile (CH3CN), ethyl acetate (EA), 1,2-dimethoxyethane and 1,4-dioxane, respectively. The reaction formula of this reaction is as follows: n Bu2O); and the solvents used in Comparative Examples 10-13 are acetonitrile (CH3CN), ethyl acetate (EA), 1,2-dimethoxyethane and 1,4-dioxane, respectively. The reaction formula of this reaction is as follows:

[0077]

[0078] The reaction results are shown in Table 3. It can be seen that when diethyl ether is used as the reaction solvent, the yield is significantly higher than that when other solvents are used. Under the given experimental conditions, the reactions of several groups of comparative examples cannot be carried out at all.

[0079] Table 3 Influence of different solvents on the reaction

[0080]

[0081] (IV) Influence of base equivalent on the reaction

[0082] The experimental process is the same as that in the first part, except that the base reagent used is K3PO4, and the amount of the base reagent used is 1-15 equivalents of compound 2a; and the reaction solvent is diethyl ether. The reaction formula of this reaction is as follows:

[0083]

[0084] As can be seen from Table 2, the yield first increases and then decreases with the increase of the equivalent of K3PO4; the yield is the highest when the equivalent of K3PO4 is 5-10.

[0085] Table 4 Influence of different base equivalents on the reaction

[0086]

[0087] (V) Influence of the concentration of reactants on the reaction

[0088] The experimental process is the same as that in the fourth part, except that the base reagent used is K3PO4, and the amount of K3PO4 used is 5 equivalents of compound 2a; the amount of solvent ethyl ether used is 0.5-4 mL, and the corresponding concentration of compound 2a is 0.025-0.2 mol / L. The reaction formula of the reaction is as follows:

[0089]

[0090] As can be seen from Table 5, although the reaction can proceed in a wide concentration range, appropriate reaction concentration helps to improve the yield of the product.

[0091] Table 5 Influence of the concentration (amount of solvent) of reactants on the reaction

[0092]

[0093]

[0094] (VI) Preparation of aryl amino acid esters using different α-amino acid esters as raw materials

[0095] According to the optimal reaction conditions determined in the above experiments, the experiments were carried out according to the operation of the first part. The difference is that 0.02 mmol of aldehyde catalyst and 0.4 mmol of compound 1 are added to the sealed tube, 2 mL of ethyl ether, 1 mmol of K3PO4, and the mixture is stirred at room temperature for 10 min, then 0.2 mmol of compound 2 is added, and the reaction is carried out at 50°C. According to the TLC detection result, the reaction is carried out for 24 h, 48 h or 72 h. In Examples 32-50, different compounds 1 are used as raw materials α-amino acid esters, and compound 2a is used as raw material aryl derivative, and the obtained products are compounds 3a-3r, respectively, as shown in Figure 1 (a). The difference between Example 50 and Example 32 is that the reaction time of Example 50 is 72 h, which is longer than that of Example 32, but the yield of the product is reduced.

[0096] It is found in the experiment that the R 1 group on the α-amino acid ester molecule affects the conversion rate of the target reaction. Although the R 1The group can be an alkyl group or an alkyl group containing a substituent group such as an ester or ether bond, but when R 1 The reaction conversion rate is higher when the C chain length directly connected to the α carbon in the group is 1 and 2, and the reaction conversion rate is lower when the C chain length directly connected to the α carbon is 3-7.

[0097] (VII) Preparation of aryl amino acid esters using different aromatic hydrocarbon derivatives as raw materials

[0098] The experiment was performed according to the procedure of (VI), except that compound 1a was used as the raw material α-amino acid ester, and different compounds 2 were used as the raw material aromatic hydrocarbon derivative, as shown in Examples 51-68, to obtain products 3s-3z and 3aa-3aj, respectively, as shown in Figure 1 (b) and 1(c). For the reaction shown in Figure 1 (b), X in compound 2 is a fluorine atom, and the third substituent R on the benzene ring is a halogen atom or a methyl group, a methoxy group, a substituted or unsubstituted phenyl group. It was found that when R is a chlorine atom among the halogen atoms, the conversion rate of the target reaction is not as good as that of the reaction system in which R is other halogen atoms.

[0099] (VIII) Preparation of aryl amino acid esters using special aromatic hydrocarbon derivatives as raw materials

[0100] The experiment was performed according to the procedure of (VII), except that the raw material α-amino acid ester was selected to be compound 1a or compound respectively, to obtain products 3ak-3am, respectively, as shown in Figure 1 (d).

[0101] The amount, yield, enantiomeric excess percentage ee%, and nuclear magnetic resonance analysis data of the aryl amino acid esters prepared in Examples 32-71 above are as follows.

[0102] tert-Butyl (S)-2-amino-2-(2-nitrophenyl) propanoate (3a):

[0103]

[0104] HPLC analysis was performed (70 / 30, flow rate 1.0 mL / min, T = 30°C) to determine that the enantiomeric excess percentage was greater than 99%, UV 254 nm, t R (minor) 7.186 min; [α] D 25 = -58.93 (c = 0.67, CHCl3); 1H NMR (600 MHz, CDC13) δ 7.91 (d, J = 6.0 Hz, 1H), 7.87 (d, J = 6.0 Hz, 1H), 7.60 (t, J = 6.0 Hz, 1H), 7.42 (t, J = 6 Hz, 1H), 2.02 (s, 2H), 1.77 (s, 3H), 1.41 (s, 9H); 13 C NMR (151 MHz, CDC13) δ 173.81, 148.84, 138.88, 132.82, 128.45, 128.03, 124.95, 82.10, 60.27, 27.87, 27.59. HRMS (ESI) m / z: [M + H] + Calculated for C 14 H 21 N2O4 + 267.1334; found 267.1349.

[0105] Isopropyl (S)-2-amino-2-(2-nitrophenyl) propanoate (3b):

[0106]

[0107] HPLC analysis (Chiralpak® AD-H, 70 / 30, flow rate 1.0 mL / min, T = 30 °C) determined a percent enantiomeric excess greater than 98%, UV 254 nm, t R (major) 8.362 min, t R (minor) 14.792 min; [a] D 25 = -65.85 (c = 0.33, CHCl3); 1 H NMR (600 MHz, CDC13) δ 7.93 (d, J = 6.0 Hz, 1H), 7.89 (d, J = 6.0 Hz, 1H), 7.62 (t, J = 9.0 Hz, 1H), 7.43 (t, J = 9.0 Hz, 1H), 4.99 - 5.05 (m, 1H), 2.09 (s, 2H), 1.79 (s, 3H), 1.18 - 1.21 (m, 6H). 13 C NMR (151 MHz, CDC13) δ 174.26, 148.66, 138.69, 132.97, 128.40, 128.21, 125.12, 69.33, 59.85, 27.80, 21.43, 21.39. HRMS (ESI) m / z: [M + H] + Calculated for C11 H 17 N2O4 + 253.1183; found 283.1189.

[0108] Benzyl (S)-2-amino-2-(2-nitrophenyl)propanoate (3c):

[0109]

[0110] HPLC analysis (Chiralpak® AD-H, 70 / 30, flow rate 1.0 mL / min, T = 30 °C) determined a percent enantiomeric excess greater than 97%, UV 254 nm, t R (major) 19.592 min, t R (minor) 12.693 min; [a] D 25 = -77.13 (c = 0.36, CHCl3); 1 H NMR (600 MHz, CDC13) δ 7.92 (d, J = 12.0 Hz, 1H), 7.88 (d, J = 6.0 Hz, 1H), 7.60 (t, J = 9.0 Hz, 1H), 7.43 (t, J = 9.0 Hz, 1H), 7.34 - 7.24 (m, 5H), 5.12 (s, 2H), 1.99 (s, 2H), 1.80 (s, 3H); 13 C NMR (151 MHz, CDC13) δ 174.64, 148.69, 138.50, 135.49, 133.04, 128.53, 128.40, 128.36, 128.32, 125.15, 67.28, 59.94, 27.79; HRMS (ESI) m / z: [M + H] + Calculated for C 16 H 17 N2O4 + 301.1183; found 301.1189.

[0111] Ethyl (S)-2-amino-2-(2-nitrophenyl)propanoate (3d):

[0112]

[0113] HPLC analysis (Chiralpak® AD-H, 70 / 30, flow rate 1.0 mL / min, T = 30 °C) determined a percent enantiomeric excess greater than 98%, UV 254 nm, t R(major) 11.767 min, t R (minor) 25.945 min; [a] D 25 = -105.0 (c = 0.30, CHCI3); 1 H NMR (600 MHz, CDCI3) δ 7.94 (d, J = 6.0 Hz, 1 H), 7.89 (d, J = 6.0 Hz, 1 H), 7.62 (t, J = 6.0 Hz, 1 H), 7.44 (t, J = 6.0 Hz, 1 H), 4.18 - 4.14 (m, 2 H), 2.13 (s, 2 H), 1.81 (s, 3 H), 1.22 (t, J = 6.0 Hz, 3 H); 13 C NMR (151 MHz, CDCI3) 174.70, 148.70, 138.45, 133.00, 128.40, 128.32, 125.09, 61.64, 59.79, 27.77, 13.89; HRMS (ESI) m / z: [M + H] + Calculated for C 11 H 15 N2O4 + 239.1026; found 239.1038.

[0114] Methyl (S)-2-amino-2-(2-nitrophenyl)propanoate (3e):

[0115]

[0116] HPLC analysis (Chiralpak® AD-H, 4.6 x 150 mm, 5 μm, 70 / 30, flow rate 1.0 mL / min, T = 30 °C) determined a percent enantiomeric excess greater than 96%, UV 254 nm, t R (major) 11.973 min, t R (minor) 28.145 min; [a] D 25 = -85.43 (c = 0.30, CHCI3); 1 H NMR (600 MHz, CDCI3) δ 7.93 (d, J = 6.0 Hz, 1 H), 7.88 (d, J = 6.0 Hz, 1 H), 7.62 (t, J = 9.0 Hz, 1 H), 7.45 (t, J = 9.0 Hz, 1 H), 3.70 (s, 3 H), 1.97 (s, 2 H), 1.80 (s, 3 H); 13C NMR (151 MHz, CDCI3) δ 175.31, 148.71, 138.49, 132.99, 128.35, 128.27, 125.09, 59.75, 52.42, 27.86; HRMS (ESI) m / z: [M+H] + Calculated for C 10 H 13 N2O4 + 225.0870; found 225.0878.

[0117] tert-Butyl (S)-2-amino-2-(2-nitrophenyl)butanoate (3f):

[0118]

[0119] HPLC analysis (Chiralpak® AD-H, 70 / 30, flow rate 1.0 mL / min, T = 30 °C) determined a percent enantiomeric excess greater than 99%, UV 254 nm, t R (major) 7.077 min; [a] D 25 = -38.53 (c = 0.78, CHCI3); 1 H NMR (600 MHz, CDCI3) δ 7.83 - 7.77 (m, 2H), 7.57 (t, J = 6.0 Hz, 1H), 7.40 (t, J = 6.0 Hz, 1H), 2.23 - 2.29 (m, 1H), 2.13 - 2.60 (m, 1H), 2.08 (s, 2H), 1.42 (s, 9H), 0.90 (t, J = 6.0 Hz, 3H); 13 C NMR (151 MHz, CDCI3) δ 172.92, 149.79, 136.97, 132.09, 129.25, 127.96, 124.95, 82.28, 63.29, 32.00, 27.69, 8.23; HRMS (ESI) m / z: [M+H] + Calculated for C 14 H 21 N2O4 + 281.1496; found 281.1501. Ethyl (S)-2-amino-2-(2-nitrophenyl)butanoate (3g):

[0120]

[0121] percent enantiomeric excess greater than 95%, UV 254 nm, t R (major) 11.379 min, t R (minor) 20.724 min; [a] D 25 = -6.18 (c = 0.36, CHCl3); 1 H NMR (600 MHz, CDC13) δ 7.83 - 7.80 (m, 2H), 7.59 (t, J = 6.0 Hz, 1H), 7.42 (t, J = 6.0 Hz, 1H), 4.21 - 4.12 (m, 2H), 2.22 - 2.11 (m, 2H), 1.97 (s, 2H), 1.36 - 1.26 (m, 2H), 1.22 (t, J = 6.0 Hz, 3H), 1.17 - 1.10 (m, 1H), 0.89 (t, J = 6.0 Hz, 3H); 13 CNMR (151 MHz, CDC13) δ 174.17, 149.53, 137.01, 132.29, 129.07, 128.17, 125.01, 62.60, 61.50, 38.88, 25.94, 22.89, 13.94, 13.85. HRMS (ESI) m / z: [M + H] + Calculated for C 14 H 21 N2O4 + 281.1496; found 281.1502.

[0122] Ethyl (S)-2-amino-2-(2-nitrophenyl)butanoate (3h):

[0123]

[0124] percent enantiomeric excess greater than 99%, UV 254 nm, t R (major) 13.929 min, t R (minor) 25.271 min; [a] D 25 = -13.13 (c = 0.72, CHCl3); 1H NMR (600 MHz, CDC13) δ 7.83 - 7.79 (m, 2H), 7.59 (t, J = 6.0 Hz, 1H), 7.42 (t, J = 6.0 Hz, 1H), 4.16 (m, 2H), 2.22 - 2.09 (m, 2H), 2.06 (s, 2H), 1.30 (m, 5H), 1.21 (t, J = 9.0 Hz, 3H), 1.16 (m, 1H), 0.89 - 0.83 (m, 3H); 13 C NMR (151 MHz, CDC13) δ 174.18, 149.55, 137.09, 132.24, 129.05, 128.13, 124.98, 62.64, 61.46, 39.13, 31.96, 23.42, 22.37, 13.92, 13.86. HRMS (ESI) m / z: [M + H] + Calculated for C 15 H 23 N2O4 + 295.1652; found 295.1674. Ethyl (S)-2-amino-2-(2-nitrophenyl)butanoate (3i):

[0125]

[0126] percent of body excess greater than 97%, UV 254 nm, t R (major) 10.527 min, t R (minor) 17.661 min; [a] D 25 = -6.56 (c = 0.43, CHCl3); 1 H NMR (600 MHz, CDC13) δ 7.81 (m, 2H), 7.59 (t, J = 6.0 Hz, 1H), 7.42 (t, J = 6.0 Hz, 1H), 4.22 - 4.10 (m, 2H), 2.16 (m, 2H), 1.99 (s, 2H), 1.34 - 1.19 (m, 11H), 0.86 (t, J = 6.8 Hz, 3H). 13 C NMR (151 MHz, CDC13) δ 13C NMR (151 MHz, Chloroform-d) δ 174.19, 149.55, 137.08, 132.25, 129.05, 128.14, 125.01, 62.65, 61.49, 39.19, 31.56, 29.46, 23.74, 22.50, 13.94, 13.93; HRMS (ESI) m / z: [M+H]+Calcd for C16H25N2O4+ 309.1809; found 309.1824. + Calculated for C 16 H 25 N2O4 + 309.1809; found 309.1824.

[0127] tert-Butyl (S)-2-amino-4-methyl-2-(2-nitrophenyl)pentanoate (3j):

[0128]

[0129] HPLC analysis, enantiomeric excess percentage greater than 99%, UV 254 nm, tR(major) 7.437 min, tR(minor) 18.990 min; [a]D25= -39.58 (c = 0.32, CHCl3); 1H NMR (600 MHz, CDC13) δ 7.97 (d, J = 6.0 Hz, 1H), 7.80 (d, J = 6.0 Hz, 1H), 7.56 (t, J = 6.0 Hz, 1H), 7.40 (t, J = 6.0 Hz, 1H), 2.17 (dd, J = 18.0, 6.0 Hz, 1H), 2.04 (dd, J = 18.0, 6.0 Hz, 1H), 1.86 (s, 2H), 1.72 - 1.65 (m, 1H), 1.41 (s, 9H), 0.95 (d, J = 6.0 Hz, 3H), 0.70 (d, J = 6.0 Hz, 3H);13C NMR (151 MHz, CDC13) δ 173.24, 149.42, 137.82, 131.98, 129.29, 127.90, 124.87, 82.08, 63.50, 46.92, 27.68, 24.81, 24.38, 23.91; HRMS (ESI) m / z: [M+H]+Calcd for C16H25N2O4+ 309.1809; found 309.1812.

[0130] Methyl (S)-2-amino-3-cyclohexyl-2-(2-nitrophenyl)propanoate (3k):

[0131]

[0132] HPLC analysis (hexane / isopropanol = 70 / 30, flow rate 1.0 mL / min, T = 30 °C) confirmed a percentage of enantiomeric excess greater than 92%, UV 254 nm, t R (major) 9.234 min, t R (minor) 7.983 min; [a] D 25 = 8.05 (c = 0.29, CHCl3); 1 H NMR (600 MHz, CDC13) δ 7.91 (d, J = 6.0 Hz, 1H), 7.80 (d, J = 6.0 Hz, 1H), 7.59 (t, J = 6.0 Hz, 1H), 7.48 (t, J = 6.0 Hz, 1H), 3.68 (s, 3H), 2.12 - 2.05 (m, 2H), 1.70 - 1.62 (m, 2H), 1.56 - 1.52 (m, 2H), 1.37 - 1.27 (m, 2H), 1.21 - 0.97 (m, 4H), 0.91 - 0.85 (m, 1H); 13 C NMR (151 MHz, CDC13) δ 174.86, 149.43, 137.40, 132.33, 128.93, 128.30, 125.09, 62.67, 52.28, 46.15, 35.22, 35.01, 33.11, 26.37, 26.21, 26.10; HRMS (ESI) m / z: [M + H] + Calculated for C 16 H 23 N2O4 + 307.1652; found 307.1666.

[0133] tert-Butyl (S)-2-amino-2-(2-nitrophenyl)pent-4-enoate (3l):

[0134]

[0135] HPLC analysis (hexane / isopropanol = 70 / 30, flow rate 1.0 mL / min, T = 30 °C) confirmed a percentage of enantiomeric excess greater than 99%, UV 254 nm, t R (major) 6.515 min, t R (minor) 13.024 min; [a] D25 = -78.53 (c = 0.29, CHCI3); 1 H NMR (600 MHz, CDCI3) δ 7.81 - 7.78 (m, 2H), 7.56 (t, J = 6.0 Hz, 1H), 7.40 (t, J = 6.0 Hz, 1H), 5.69 - 5.70 (m, 1H), 5.16 - 5.12 (m, 2H), 2.98 - 2.89 (m, 2H), 1.96 (s, 2H), 1.42 (s, 9H); 13 C NMR (151 MHz, CDCI3) δ 172.54, 149.58, 137.32, 132.27, 132.04, 129.16, 128.05, 124.91, 119.86, 82.48, 62.47, 43.70, 27.71; HRMS (ESI) m / z: [M + H] + Calculated for C 15 H 21 N2O4 + 293.1496; found 293.1510.

[0136] tert-Butyl (S)-2-amino-2-(2-nitrophenyl)-4-phenylbutanoate (3m):

[0137]

[0138] HPLC analysis (hexane / isopropanol = 70 / 30, flow rate 1.0 mL / min, T = 30°C) confirmed a percentage of enantiomeric excess greater than 99%, UV 254 nm, t R (major) 7.404 min, t R (minor) 16.385 min; [a] D 25 = -78.53 (c = 0.29, CHCI3); 1 H NMR (600 MHz, CDCI3) δ 7.81 - 7.78 (m, 2H), 7.56 (t, J = 6.0 Hz, 1H), 7.40 (t, J = 6.0 Hz, 1H), 5.69 - 5.70 (m, 1H), 5.16 - 5.12 (m, 2H), 2.98 - 2.89 (m, 2H), 1.96 (s, 2H), 1.42 (s, 9H); 13C NMR (151 MHz, CDCI3) δ 172.86, 149.62, 141.41, 136.96, 132.27, 129.16, 128.52, 128.29, 128.17, 126.07, 125.07, 82.53, 63.09, 40.89, 30.38, 27.74; HRMS (ESI) m / z: [M + H] + Calculated for C 20 H 25 N2O4 + 357.1809; found 357.1822.

[0139] di-tert-Butyl (S)-2-amino-2-(2-nitrophenyl)pentanedioate (3n):

[0140]

[0141] HPLC analysis (hexane / isopropanol = 70 / 30, flow rate 1.0 mL / min, T = 30 °C) determined a percent enantiomeric excess greater than 97%, UV 254 nm, t R (major) 10.283 min, t R (minor) 8.419 min; [a] D 25 = -75.11 (c = 0.29, CHCI3); 1 H NMR (600 MHz, CDCI3) δ 7.93 (d, J = 6.0 Hz, 1 H), 7.86 (d, J = 6.0 Hz, 1 H), 7.59 (t, J = 6.0 Hz, 1 H), 7.42 (t, J = 6.0 Hz, 1 H), 2.51 (t, J = 6.0 Hz, 2 H), 2.26 - 2.33 (m, 1 H), 2.1 1 - 2.15 (m, 1 H), 1.80 (s, 2 H), 1.42 (s, 9 H), 1.41 (s, 9 H); 13 C NMR (151 MHz, CDCI3) δ 172.64, 172.46, 149.37, 136.74, 132.42, 129.20, 128.19, 125.16, 82.44, 80.46, 62.68, 33.35, 30.41, 28.06, 27.65; HRMS (ESI) m / z: [M + H] + Calculated for C 19 H 29 N2O6+ 381.2020; found 381.2031.

[0142] Diethyl (R)-2-amino-2-(2-nitrophenyl)succinate (3o):

[0143]

[0144] HPLC analysis (hexane / isopropanol = 70 / 30, flow rate 1.0 mL / min, T = 30 °C) determined a percent enantiomeric excess greater than 96%, UV 254 nm, t R (major) 16.689 min, t R (minor) 12.347 min; [a] D 25 = -57.86 (c = 0.58, CHCl3); 1 H NMR (600 MHz, CDC13) δ 7.91 (d, J = 6.0 Hz, 1H), 7.77 (d, J = 6.0 Hz, 1H), 7.58 (t, J = 9.0 Hz, 1H), 7.45 (t, J = 9.0 Hz, 1H), 4.19 (q, J = 6.0 Hz, 2H), 4.11 (q, J = 6.0 Hz, 1H), 3.25 (d, J = 18.0 Hz, 1H), 3.12 (d, J = 18.0 Hz, 1H), 2.61 (s, 2H), 1.25 - 1.20 (m, 6H); 13 C NMR (151 MHz, CDC13) δ 172.73, 170.80, 149.24, 136.29, 132.22, 128.80, 128.77, 124.94, 62.20, 61.95, 60.75, 42.76, 14.03, 13.84; HRMS (ESI) m / z: [M + H] + Calculated for C 14 H 19 N2O6 + 311.1238; found 311.1248.

[0145] Ethyl (2S)-2-amino-4-(methylsulfinyl)-2-(2-nitrophenyl)butanoate (3p):

[0146] HPLC analysis (hexane / isopropanol = 70 / 30, flow rate 1.0 mL / min, T = 30 °C) to determine the enantiomeric excess percentage greater than 96%, UV 254 nm, t R (major) 16.443 min, t R (minor) 22.888 min; [a] D 25 = -54.76 (c = 0.45, CHCl3). 1 H NMR (600 MHz, CDC13) δ 7.92 (d, J = 6.0, 1H), 7.87 (d, J = 6.0 Hz, 1H), 7.62 (t, J = 6.0 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 4.17 (q, J = 6.0 Hz, 2H), 2.55 - 2.48 (m, 3H), 2.30 - 2.26 (m, 1H), 2.08 (s, 3H), 1.61 (s, 2H), 1.22 (t, J = 7.1 Hz, 3H); 13 C NMR (151 MHz, CDC13) δ 173.59, 149.21, 136.29, 132.59, 128.99, 128.51, 125.28, 62.59, 61.71, 38.49, 28.68, 15.55, 13.92; HRMS (ESI) m / z: [M + Na] + Calculated for C 13 H 19 N2O5SNa + 315.1009; found 315.1010.

[0147] tert-Butyl (S)-2-amino-3-(tert-butoxy)-2-(2-nitrophenyl)propanoate (3q):

[0148] HPLC analysis (hexane / isopropanol = 70 / 30, flow rate 1.0 mL / min, T = 30 °C) to determine the enantiomeric excess percentage greater than 96%, UV 254 nm, t R (major) 8.820 min, t R (minor) 27.267 min; [a] D 25 = -58.86 (c = 0.25, CHCl3). 1H NMR (600 MHz, CDC13) δ 7.67 - 7.69 (m, 2H), 7.51 (t, J = 6.0 Hz, 1H), 7.38 (t, J = 6.0 Hz, 1H), 3.92 (d, J = 6.0 Hz, 1H), 3.83 (d, J = 6.0 Hz, 1H), 2.01 (s, 2H), 1.44 (s, 9H), 1.18 (s, 9H); 13 C NMR (151 MHz, CDC13) δ 171.79, 150.11, 135.95, 131.55, 129.47, 128.06, 124.69, 82.39, 73.66, 67.09, 63.85, 27.81, 27.45; HRMS (ESI) m / z: [M + H] + Calculated for C 17 H 27 N2O5 + 339.1914; found 339.1914.

[0149] Ethyl (S)-2-amino-3-(1H-indol-3-yl)-2-(2-nitrophenyl)propanoate (3r):

[0150]

[0151] HPLC analysis was performed to determine the percentage of enantiomeric excess to be greater than 95%, UV 254 nm, t R (major) 14.276 min, t R (minor) 15.798 min; [a] D 25 = -24.15 (c = 0.43, CHCl3); 1 H NMR (600 MHz, CDC13) δ 7.67 - 7.69 (m, 2H), 7.51 (t, J = 6.0 Hz, 1H), 7.38 (t, J = 6.0 Hz, 1H), 3.92 (d, J = 6.0 Hz, 1H), 3.83 (d, J = 6.0 Hz, 1H), 2.01 (s, 2H), 1.44 (s, 9H), 1.18 (s, 9H); 13C NMR (151 MHz, CDC13) δ 173.78, 149.54, 137.46, 135.85, 131.90, 129.32, 128.52, 128.20, 124.75, 124.09, 122.02, 119.62, 118.90, 110.98, 109.61, 63.72, 61.63, 34.77, 13.79; HRMS (ESI) m / z: [M + H] + Calculated for C 19 H 20 N3O4 + 354.1448; found 354.1469.

[0152] tert-Butyl (S)-2-amino-2-(4-fluoro-2-nitrophenyl) propanoate (3s):

[0153]

[0154] HPLC analysis was performed to determine the enantiomeric excess percentage to be greater than 99%, UV 254 nm, t R (major) 8.586 min; [a] D 25 = -77.35 (c = 0.75, CHCI3); 1 H NMR (600 MHz, CDC13) δ 7.94 (dd, J = 12.0, 6.0 Hz, 1H), 7.59 (dd, J = 8.3, 2.8 Hz, 1H), 7.34 - 7.26 (m, 1H), 2.06 (s, 2H), 1.75 (s, 3H), 1.41 (s, 9H); 13 CNMR (151 MHz, CDC13) δ 173.44, 161.81, 160.15, 149.24, 134.88, 130.42, 130.37, 119.75, 119.61, 112.59, 112.41, 82.34, 60.03, 27.86, 27.56; HRMS (ESI) m / z: [M + H] + Calculated for C 13 H 18 FN2O4 + 285.1245; found 285.1259.

[0155] tert-Butyl (S)-2-amino-2-(4-bromo-2-nitrophenyl) propanoate (3t):

[0156]

[0157] HPLC analysis (hexane / isopropanol = 70 / 30, flow rate 1.0 mL / min, T = 30 °C) to determine the enantiomeric excess percentage greater than 94%, UV 254 nm, t R (major) 10.941 min, t R (minor) 8.513 min; [a] D 25 = -81.92 (c = 0.78, CHCl3); 1 H NMR (600 MHz, CDC13) δ 7.98 (s, 1H), 7.82 (d, J = 12.0 Hz, 1H), 7.70 (d, J = 12.0 Hz, 1H), 1.98 (s, 2H), 1.74 (s, 3H), 1.41 (s, 9H); 13 CNMR (151 MHz, CDC13) δ 173.23, 149.29, 138.13, 135.66, 130.15, 127.75, 121.11, 82.42, 60.16, 27.76, 27.58; HRMS (ESI) m / z: [M + H] + Calculated for C 13 H 18 BrN2O4 + 345.0444; found 345.0458.

[0158] tert-Butyl (S)-2-amino-2-(4-iodo-2-nitrophenyl)propanoate (3u):

[0159]

[0160] HPLC analysis (hexane / isopropanol = 70 / 30, flow rate 1.0 mL / min, T = 30 °C) to determine the enantiomeric excess percentage greater than 91%, UV 254 nm, t R (major) 9.297 min, t R (minor) 8.154 min; [a] D 25 = -51.67 (c = 0.33, CHCl3); 1H NMR (600 MHz, CDC13) δ 8.14 (s, 1H), 7.89 (d, J = 6.0 Hz, 1H), 7.66 (d, J = 6.0 Hz, 1H), 2.02 (s, 2H), 1.73 (s, 3H), 1.40 (s, 9H); 13 C NMR (151 MHz, CDC13) δ 173.22, 149.17, 141.66, 138.77, 133.34, 130.25, 91.62, 82.44, 60.20, 27.71, 27.59; HRMS (ESI) m / z: [M + Na] + Calculated for C 13 H 17 IN2NaO4 + 415.0125; found 415.0123.

[0161] tert-Butyl (S)-2-amino-2-(4-methyl-2-nitrophenyl)propanoate (3v):

[0162]

[0163] HPLC analysis was performed to determine the percent enantiomeric excess to be greater than 97%, UV 254 nm, t R (major) 8.375 min, t R (minor) 13.806 min; [a] D 25 = -27.6 (c = 0.51, CHCl3); 1 H NMR (600 MHz, CDC13) δ 8.14 (s, 1H), 7.89 (d, J = 6.0 Hz, 1H), 7.66 (d, J = 6.0 Hz, 1H), 2.02 (s, 2H), 1.73 (s, 3H), 1.40 (s, 9H); 13 C NMR (151 MHz, CDC13) δ 173.22, 149.17, 141.66, 138.77, 133.34, 130.25, 91.62, 82.44, 60.20, 27.71, 27.59; HRMS (ESI) m / z: [M + Na] + Calculated for C 14 H 21 N2O4 + 281.1496; found 281.1495.

[0164] tert-Butyl (S)-2-amino-2-(4-methoxy-2-nitrophenyl)propanoate (3w):

[0165]

[0166] HPLC analysis was performed to determine the enantiomeric excess percentage to be greater than 99%, UV 254 nm, t R (major) 16.487 min; [a] D 25 = -30.6 (c = 0.25, CHCI3); 1 H NMR (600 MHz, CDCI3) δ 7.77 (d, J = 12.0 Hz, 1 H), 7.38 (s, 1 H), 7.10 (d, J = 6.0 Hz, 1 H), 3.86 (s, 3 H), 2.19 (s, 2 H), 1.74 (s, 3 H), 1.40 (s, 9 H); 13 C NMR (151 MHz, CDCI3) δ 174.09, 158.80, 149.32, 130.63, 129.51, 118.70, 110.10, 82.00, 59.87, 55.79, 27.90, 27.60; HRMS (ESI) m / z: [M + H] + Calculated for C 14 H 21 N2O5 + 297.1445; found 297.1447. tert-Butyl (S)-2-amino-2-(3-nitro-[1,1 '-biphenyl]-4-yl)propanoate (3x):

[0167]

[0168] HPLC analysis was performed to determine the enantiomeric excess percentage to be greater than 99%, UV 254 nm, t R (major) 10.551 min, t R (minor) 8.497 min; [a] D 25 = -31.17 (c = 0.80, CHCI3); 1H NMR (600 MHz, CDC13) δ 8.09 (s, 1H), 7.96 (d, J = 12.0 Hz, 1H), 7.81 (d, J = 6.0 Hz, 1H), 7.61 (d, J = 6.0 Hz, 2H), 7.49 - 7.40 (m, 3H), 2.04 (s, 2H), 1.80 (s, 3H), 1.43 (s, 9H); 13 CNMR (151 MHz, CDC13) δ 173.85, 149.20, 141.38, 138.22, 137.49, 130.97, 129.10, 129.01, 128.45, 126.99, 123.35, 82.19, 60.20, 27.90, 27.64; HRMS (ESI) m / z: [M + H] + Calculated for C 19 H 23 N2O4 + 343.1652; found 343.1652.

[0169] tert-Butyl (S)-2-amino-2-(4'-fluoro-3-nitro-[l,l'-biphenyl]-4-yl)propanoate (3y):

[0170]

[0171] 30 °C) was analyzed by HPLC to determine the percent enantiomeric excess to be greater than 98%, UV 254 nm, t R (major) 8.648 min, t R (minor) 12.074 min; [a] D 25 = -40.20 (c = 0.60, CHCI3); 1 H NMR (600 MHz, CDC13) δ 8.09 (s, 1H), 7.96 (d, J = 12.0 Hz, 1H), 7.81 (d, J = 6.0 Hz, 1H), 7.61 (d, J = 6.0 Hz, 2H), 7.49 - 7.40 (m, 3H), 2.04 (s, 2H), 1.80 (s, 3H), 1.43 (s, 9H); 13C NMR (151 MHz, CDCI3) δ 173.69, 163.93, 162.29, 149.20, 140.40, 137.36, 134.32, 130.84, 129.17, 128.74, 128.69, 123.18, 116.17, 116.02, 82.31, 60.18, 27.80, 27.62; HRMS (ESI) m / z: [M+H] + Calculated for C 19 H 22 FN2O4 + 361.1558; found 361.1557.

[0172] tert-Butyl (S)-2-amino-2-(5-methyl-2-nitrophenyl)propanoate (3z):

[0173]

[0174] HPLC analysis (hexane / isopropanol = 70 / 30, flow rate 1.0 mL / min, T = 30 °C) determined a percent enantiomeric excess greater than 99%, UV 254 nm, t R (major) 8.396 min; [a] D 25 = -11.95 (c = 0.66, CHCI3); 1 H NMR (600 MHz, CDCI3) δ 7.82 (d, J = 6.0 Hz, 1H), 7.70 (s, 1H), 7.20 (d, J = 12.0 Hz, 1H), 2.45 (s, 3H), 2.06 (s, 2H), 1.75 (s, 3H), 1.40 (s, 9H); 13 C NMR (151 MHz, CDCI3) δ 173.97, 146.50, 144.09, 138.75, 128.95, 128.46, 125.28, 81.99, 60.26, 27.61, 27.59, 21.64; HRMS (ESI) m / z: [M+H] + Calculated for C 14 H 21 N2O4 + 281.1496; found 281.1496.

[0175] tert-Butyl (S)-2-amino-2-(5-methoxy-2-nitrophenyl)propanoate (3aa):

[0176]

[0177] HPLC analysis was performed to determine the enantiomeric excess percentage to be greater than 99%, UV 254 nm, t R (major) 10.975 min; [a] D 25 = -31.47 (c = 0.62, CHCI3); 1 H NMR (600 MHz, CDCI3) δ 8.03 (d, J = 12.0 Hz, 1 H), 7.48 (s, 1 H), 6.85 (d, J = 12.0 Hz, 1 H), 3.91 (s, 3 H), 2.09 (s, 2 H), 1.74 (s, 3 H), 1.40 (s, 9 H); 13 C NMR (151 MHz, CDCI3) δ 173.70, 163.35, 142.04, 141.61, 127.97, 114.38, 111.85, 81.87, 60.53, 55.79, 27.60, 27.21 ; HRMS (ESI) m / z: [M + H] + Calculated for C 14 H 21 N2O5 + 297.1445; found 297.1445. tert-Butyl (S)-2-amino-2-(2-fluoro-6-nitrophenyl)propanoate (3ab):

[0178]

[0179] HPLC analysis was performed to determine the enantiomeric excess percentage to be greater than 96%, UV 254 nm, t R (major) 8.250 min, t R (minor) 6.601 min; [a] D 25 = 85.05 (c = 0.66, CHCI3); 1 H NMR (600 MHz, CDCI3) δ 7.35 (m, 1 H), 7.30 - 7.25 (m, 1 H), 7.23 - 7.17 (m, 1 H), 1.86 (s, 2 H), 1.76 (d, J = 6.0 Hz, 3 H), 1.44 (s, 9 H); 13C NMR (151 MHz, CDCI3) δ 173.00, 161.16, 159.50, 151.06, 128.90, 128.84, 126.14, 126.03, 119.76, 119.74, 118.75, 118.59, 82.09, 59.74, 27.59, 26.03, 25.99; HRMS (ESI) m / z: [M + H] + Calculated for C 13 H 18 N2O4 + 285.1245; found 285.1247.

[0180] tert-Butyl (S)-2-amino-2-(2-fluoro-3-methoxy-6-nitrophenyl)propanoate (3ac):

[0181]

[0182] HPLC analysis was performed to determine the percent enantiomeric excess to be greater than 96%, UV 254 nm, t R (major) 10.031 min, t R (minor) 8.852 min; [a] D 25 = 116.16 (c = 0.30, CHCI3); 1 H NMR (600 MHz, CDCI3) δ 7.44 (d, J = 6.0 Hz, 1 H), 6.90 (t, J = 9.0 Hz, 1 H), 3.94 (s, 3 H), 1.89 (s, 2 H), 1.82 (d, J = 6.0 Hz, 3 H), 1.44 (s, 9 H); 13 C NMR (151 MHz, CDCI3) δ 173.96, 168.25, 154.38, 135.47, 131.26, 125.17, 124.24, 123.42, 119.20, 117.46, 116.46, 79.63, 61.78, 59.82, 30.96, 28.44, 24.11, 23.97, 14.05; HRMS (ESI) m / z: [M + H] + Calculated for C 14 H 20 FN2O5 + 315.1351 ; found 315.1352.

[0183] tert-Butyl (S)-2-amino-2-(4-fluoro-5-methyl-2-nitrophenyl)propanoate (3ad):

[0184]

[0185] HPLC analysis was performed to determine the enantiomeric excess percentage to be greater than 99%, UV 254 nm, t R (major) 6.792 min; [a] D 25 = -39.38 (c = 0.77, CHCI3); 1 H NMR (600 MHz, CDCI3) δ 7.77 (d, J = 6.0 Hz, 1 H), 7.60 (d, J = 12.0 Hz, 1 H), 2.36 (s, 3 H), 2.12 (s, 2 H), 1.74 (s, 3 H), 1.40 (s, 9 H); 13 C NMR (151 MHz, CDCI3) δ 173.68, 160.02, 158.37, 146.90, 146.85, 134.66, 134.63, 131.45, 131.42, 130.83, 130.72, 112.38, 112.20, 82.15, 60.03, 27.65, 27.56, 14.81, 14.79.; HRMS (ESI) m / z: [M + H] + Calculated for C 14 H 20 FN2O4 + 299.1402; found 299.1405.

[0186] tert-Butyl (S)-2-amino-2-(5-chloro-4-methyl-2-nitrophenyl)propanoate (3ae):

[0187]

[0188] HPLC analysis was performed to determine the enantiomeric excess percentage to be greater than 94%, UV 254 nm, t R (major) 7.353 min, t R (minor) 9.440 min; [a] D 25 = -44.03 (c = 0.54, CHCI3); 1H NMR (600 MHz, CDC13) δ 7.91 (s, 1H), 7.79 (s, 1H), 2.42 (s, 3H), 2.19 (s, 2H), 1.74 (s, 3H), 1.40 (s, 9H); 13 C NMR (151 MHz, CDC13) δ 173.32, 146.63, 139.48, 138.04, 136.50, 129.21, 127.20, 82.33, 60.03, 27.58, 27.48, 19.43; HRMS (ESI) m / z: [M + H] + Calculated for C 14 H 20 ClN2O4 + 315.1106; found 315.1109.

[0189] tert-Butyl (S)-2-amino-2-(2,4-dinitrophenyl)propanoate (3af):

[0190]

[0191] HPLC analysis was performed to determine the percent enantiomeric excess to be greater than 91%, UV 254 nm, t R (major) 14.257 min, t R (minor) 11.888 min; [a] D 25 = -130.02 (c = 0.37, CHCl3); 1 H NMR (600 MHz, CDC13) δ 8.67 (d, J = 2.4 Hz, 1H), 8.41 (dd, J = 6.0, 2.4 Hz, 1H), 8.22 (d, J = 12.0 Hz, 1H), 1.97 (s, 2H), 1.81 (s, 3H), 1.42 (s, 9H); 13 C NMR (151 MHz, CDC13) δ 172.45, 149.05, 146.93, 145.99, 130.36, 126.67, 120.30, 83.08, 60.64, 27.85, 27.62; HRMS (ESI) m / z: [M + Na] + Calculated for C 13 H 17 N3NaO6 + 334.1010; found 334.1011.

[0192] tert-Butyl (S)-2-amino-2-(4-cyano-2-nitrophenyl)propanoate (3ag):

[0193]

[0194] HPLC analysis was performed to determine the enantiomeric excess percentage to be greater than 96%, UV 254 nm, t R (major) 9.585 min, t R (minor) 7.666 min; [a] D 25 = -178.52 (c = 0.72, CHCI3); 1 H NMR (600 MHz, CDCI3) δ 8.15 - 8.12 (m, 2H), 7.86 (d, J = 12.0 Hz, 1H), 2.02 (s, 2H), 1.78 (s, 3H), 1.41 (s, 9H); 13 C NMR (151 MHz, CDCI3) δ 172.52, 149.08, 144.36, 135.54, 130.03, 128.31, 116.39, 112.52, 82.90, 60.52, 27.71, 27.56; HRMS (ESI) m / z: [M + H] + Calculated for C 14 H 18 N3O4 + 292.1292; found 292.1294.

[0195] tert-Butyl (S)-2-amino-2-(2-nitro-4-(trifluoromethyl)phenyl)propanoate (3ah):

[0196]

[0197] HPLC analysis was performed to determine the enantiomeric excess percentage to be greater than 99%, UV 254 nm, t R (major) 4.819 min; [a] D 25 = -113.01 (c = 0.50, CHCI3); 1H NMR (600 MHz, CDC13) δ 8.13 (d, J = 12.0 Hz, 1H), 8.11 (s, 1H), 7.84 (d, J = 12.0 Hz, 1H), 2.07 (s, 2H), 1.79 (s, 3H), 1.42 (s, 9H); 13 C NMR (151 MHz, CDC13) δ 172.91, 148.91, 143.04, 131.10, 130.87, 130.64, 129.68, 129.16, 129.14, 129.12, 129.09, 125.51, 123.71, 122.18, 122.15, 122.12, 122.10, 121.90, 82.67, 60.41, 27.78, 27.57; HRMS (ESI) m / z: [M + H] + Calculated for C 14 H 18 F3N2O4 + 335.1213; found 335.1215.

[0198] Methyl (S)-4-(2-amino-1-(tert-butoxy)-1-oxopropan-2-yl)-3-nitrobenzoate (3ai):

[0199]

[0200] HPLC analysis (hexane / isopropanol = 70 / 30, flow rate 1.0 mL / min, T = 30 °C) to determine the percentage of enantiomeric excess greater than 96%, UV 254 nm, t R (major) 32.480 min, t R (minor) 17.663 min; [a] D 25 = -82.76 (c = 0.71, CHCl3); 1 H NMR (600 MHz, CDC13) δ 8.13 (d, J = 12.0 Hz, 1H), 8.11 (s, 1H), 7.84 (d, J = 12.0 Hz, 1H), 2.07 (s, 2H), 1.79 (s, 3H), 1.42 (s, 9H); 13C NMR (151 MHz, CDCI3) δ 173.16, 164.87, 148.93, 143.58, 133.30, 130.43, 129.02, 126.03, 82.54, 60.47, 52.64, 27.86, 27.62; HRMS (ESI) m / z: [M+H] + Calculated for C 15 H 21 N2O6 + 325.1394; found 325.1395.

[0201] tert-Butyl (S)-2-amino-2-(2-nitro-5-(trifluoromethyl)phenyl)propanoate (3aj):

[0202]

[0203] HPLC analysis was performed to determine the percent enantiomeric excess to be greater than 99%, UV 254 nm, t R (major) 6.259 min, t R (minor) 9.549 min; [a] D 25 = -92.15 (c = 0.45, CHCI3); 1 H NMR (600 MHz, CDCI3) δ 8.26 (s, 1 H), 7.93 (d, J = 6.0 Hz, 1 H), 7.69 (d, J = 12.0 Hz, 1 H), 2.06 (s, 2 H), 1.80 (s, 3 H), 1.42 (s, 9 H); 13 C NMR (151 MHz, CDCI3) δ 172.88, 150.82, 140.35, 134.58, 134.36, 134.14, 133.92, 126.19, 126.17, 126.14, 126.12, 125.36, 125.26, 125.24, 125.21, 125.19, 123.97, 122.17, 82.68, 60.37, 27.77, 27.55; HRMS (ESI) m / z: [M+H] + Calculated for C 14 H 18 F3N2O4 + 335.1213; found 335.1215.

[0204] tert-Butyl (S)-2-amino-2-(5-nitroquinolin-8-yl)propanoate (3ak):

[0205]

[0206] HPLC analysis was performed to determine the enantiomeric excess percentage to be greater than 70%, UV 254 nm, t R (major) 17.301 min, t R (minor) 12.002 min; [a] D 25 = -8.99 (c = 0.46, CHCI3); 1 H NMR (600 MHz, CDCI3) δ 9.04 (d, J = 6.0 Hz, 1 H), 8.95 (d, J = 6.0 Hz, 1 H), 8.38 (d, J = 6.0 Hz, 1 H), 7.98 (d, J = 12.0 Hz, 1 H), 7.62 (dd, J = 12.0, 6.0 Hz 1 H), 2.40 (s, 2 H), 1.83 (s, 3 H), 1.25 (s, 9 H); 13 C NMR (151 MHz, CDCI3) δ 176.21, 150.34, 149.54, 145.59, 144.76, 132.39, 124.55, 124.05, 123.43, 121.24, 80.71, 60.10, 27.63, 25.63; HRMS (ESI) m / z: [M + H] + Calculated for C 16 H 20 N3O4 + 318.1448; found 318.1449. tert-Butyl (S)-1 -methyl-5-nitro-3-oxoisoindoline-1 - carboxylate (3al):

[0207]

[0208] HPLC analysis was performed to determine the enantiomeric excess percentage to be greater than 75%, UV 254 nm, t R (major) 22.616 min, t R (minor) 10.133 min; [a] D 25 = -9.97 (c = 0.49, CHCI3); 1H NMR (600 MHz, CDC13) δ 8.65 (d, J = 6.0 Hz, 1H), 8.48 (m, 1H), 7.85 (d, J = 12.0 Hz, 1H), 7.38 (s, 1H), 1.84 (s, 3H), 1.47 (s, 9H); 13 CNMR (101 MHz, CDC13) δ 168.63, 167.22, 152.01, 149.08, 132.58, 127.25, 124.51, 119.49, 84.21, 65.45, 27.78, 25.53; HRMS (ESI) m / z: [M + H] + Calculated for C 14 H 17 N2O5 + 293.1132; found 293.1131. tert-Butyl (S)-1-(2-(methylthio)ethyl)-5-nitro-3-oxoisoindoline-1-carboxylate (3am):

[0209]

[0210] 30 °C) was analyzed by HPLC to determine the percent enantiomeric excess to be greater than 67%, UV 254 nm, t R (major) 23.316 min, t R (minor) 20.853 min; [a] D 25 = 2.64 (c = 0.32, CHCl3); 1 H NMR (600 MHz, CDC13) δ 8.65 (d, J = 6.0 Hz, 1H), 8.48 (m, 1H), 7.85 (d, J = 12.0 Hz, 1H), 7.38 (s, 1H), 1.84 (s, 3H), 1.47 (s, 9H); 13 CNMR (101 MHz, CDC13) δ 168.63, 167.22, 152.01, 149.08, 132.58, 127.25, 124.51, 119.49, 84.21, 65.45, 27.78, 25.53; HRMS (ESI) m / z: [M + H] + Calculated for C 16 H 20N2NaO5S + 375.0985; found 375.0986.

[0211] Finally, it should be noted that the above description is merely preferred embodiments of the present application, and those of ordinary skill in the art can make various similar modifications under the inspiration of the present application without departing from the purpose of the present application and the claims, and such modifications shall fall within the protection scope of the present application.

Claims

1. A process for the asymmetric catalytic preparation of α-aryl amino acid esters, characterized in that The preparation process is: under the condition of the presence of a chiral aldehyde catalyst and a base, an α-amino acid ester is fully reacted with an aromatic hydrocarbon derivative in a solvent, and an aryl amino acid ester is obtained through post-treatment; The base is selected from any one of Cs2CO3, K2CO3, Na3PO4 and K3PO4; The reaction temperature T is 10-100 ℃; The alpha-amino acid ester structure is of the formula (I) ), （ ）， wherein R 1 selected from H, C1-C7 alkyl, C1-C5 alkyl substituted with aryl or alkenyl or ether linkage or sulfinyl group, C1-C5 fatty acid ester group; wherein R 2 selected from t Bu, i any one of a Pr, Bn, Et or Me group; The aromatic hydrocarbon derivative is or , or a compound having a structure as formula ( ) （ ）， X is a halogen atom, wherein R 3 is H or a substituent in the ortho-, meta- or para-position of the phenyl ring, R 3 is 1-2 substituents selected from the group consisting of methyl, methoxy, phenyl, halogen, nitro, cyano, trifluoromethyl; The arylamino acid ester obtained is , or , or , or a compound of the structure of formula ( ) （ ）； The chiral aldehyde catalyst structure is of formula (I) ), （ ）。 2. The process for the asymmetric catalytic preparation of α-arylglycine esters according to claim 1, characterized in that: In the α-amino acid ester structure, R 1 is selected from H, C1-C6 alkyl, phenyl-substituted methyl or ethyl, formate or acetate, ether-linked methyl or ethyl, sulfinyl-substituted methyl or ethyl, allyl.

3. The process for the asymmetric catalytic preparation of α-arylglycine esters according to claim 1, characterized in that: In the aromatic hydrocarbon derivative, when X is a fluorine atom, R 3 is H or a substituent at the ortho-, meta- or para-position of the benzene ring, R 3 is 1 to 2 in number when R 3 is selected from the group consisting of a methyl group, a methoxy group, a phenyl group, fluorine, chlorine, bromine and iodine; R is a substituent on the phenyl ring in the meta or para position relative to X, selected from one of nitro, cyano, trifluoromethyl, ester group. 3 R is a substituent on the phenyl ring in the meta or para position relative to X, selected from one of nitro, cyano, trifluoromethyl, ester group.

4. The process for the asymmetric catalytic preparation of α-arylglycine esters according to claim 1, characterized in that: The aromatic hydrocarbon derivative is any one of the following compounds: 。 5. The process for the asymmetric catalytic preparation of α-arylglycine esters according to any one of claims 1 to 4, characterized in that: The reaction temperature T is 20 ℃≤T≤90 ℃.

6. The process for the asymmetric catalytic preparation of α-arylglycine esters according to any one of claims 1 to 4, characterized in that: The reaction temperature T is 30 ℃≤T≤60 ℃.

7. The process for the asymmetric catalytic preparation of α-arylglycine esters according to any one of claims 1 to 4, characterized in that: The reaction temperature T is 30 ℃≤T<35 ℃, 35 ℃≤T<40 ℃, 40 ℃≤T<45 ℃, 45 ℃≤T<50 ℃, 50 ℃≤T<55 ℃, or 55 ℃≤T≤60 ℃.

8. The process for the asymmetric catalytic preparation of α-arylglycine esters according to any one of claims 1 to 4, characterized in that: In the reaction system, the concentration of the aromatic hydrocarbon derivative is 0.025-0.2 mol / L, and the molar ratio of the aromatic hydrocarbon derivative to the base is 1:(1-15).

9. The process for the asymmetric catalytic preparation of α-arylglycine esters according to claim 1, characterized in that: The solvent is one of mesitylene, hexafluorobenzene, dichloromethane, chloroform, carbon tetrachloride, fluorobenzene, chlorobenzene, methanol, diethyl ether, tetrahydrofuran, butyl ether, or a mixture of two or more kinds capable of mutual solubility.

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