Process for the synthesis of a class of polyfunctionalized beta-amino acid esters

Abstract

The application discloses an imine compound and a preparation method thereof and a method for synthesizing various functionalized beta-amino acid esters by taking the imine compound as a substrate, and comprises the following steps: dissolving an imine compound shown in formula (I) and a free radical precursor shown in formula (II), formula (III), formula (IV) or formula (V) in an organic solvent, performing a photocatalytic reaction under the action of a photosensitizer, a base and light in an inert atmosphere, separating and purifying the reaction system after the reaction is completed, and obtaining an intermediate; and acidizing the intermediate to obtain a beta-amino acid ester shown in formula (VI), formula (VII), formula (VIII) or formula (IX). The synthesis method has the advantages of novel reaction mechanism, simple and easily obtained starting material, mild reaction condition, wide substrate applicability and the like, and meets the requirements of developing green and environment-friendly chemistry.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of chemical synthesis, and particularly relates to a synthesis method of a plurality of functionalized beta-amino acid esters. BACKGROUND

[0002] Beta-amino acids are widely present in many bioactive molecules, drugs and natural products as an important structural skeleton. In addition, due to the metabolic stability of such a skeleton, beta-amino acids are also widely used to construct bioactive polypeptides and mimic peptides. Therefore, exploring the efficient synthesis of beta-amino acids and their derivatives has important significance in organic chemistry and medicinal chemistry.

[0003] In view of the important application of beta-amino acids in chemistry, chemists have developed a series of synthesis methods of beta-amino acids, including Mannich reaction, conjugate addition of nitrogen-based nucleophiles, Micheal addition reaction of beta-amino alpha, beta-unsaturated systems, intermolecular aminocarbonylation of olefins or (hetero)arenes, and organocatalytic Ugi reaction. Although the above methods can achieve the preparation of beta-amino acids, these methods generally require pre-functionalization of the starting material through multi-step operation, thereby reducing the practicability of the reaction. In addition, the groups of Liu Guosheng (J. Am. Chem. Soc. 2015, 137, 2480) and Ruben Martin (J. Am. Chem. Soc. 2021, 143, 4949) respectively used CO and CO2 as the carbonyl source to achieve the preparation of beta-amino acids, but also had the disadvantages of limited substrate range, multi-step preparation of raw materials, long reaction time, and metal catalyst residues.

[0004] The existing catalytic synthesis method generally introduces amino groups or ester groups into the substrate skeleton, or introduces both two groups. In comparison, the remodeling of the existing alpha-amino acid skeleton is a more direct method, which, once achieved, will constitute a conceptually simple and applicationally attractive strategy, and can conveniently prepare structurally different beta-amino acids. So far, such a strategy has not been widely studied.

[0005] Radical intermediates exist in many biochemical processes, including the biosynthesis of beta-amino acids. In the biosynthesis of phenylalanine, researchers believe that it undergoes a three-membered ring intermediate to realize 1,2-amino migration, thereby remodeling alpha-amino acids to construct beta-amino acids. Unfortunately, due to the specificity of enzyme catalysis in biosynthesis, this reaction is only limited to the synthesis of a few beta-amino acids.

[0006] Therefore, developing a new organic catalytic mode combined with the strategy of 1,2-amino migration is expected to broaden the substrate range and increase the reaction type, which has important significance in the synthesis of beta-amino acids. SUMMARY

[0007] The present application provides a new type of imine compound, which can be synthesized into β-amino acid ester compound through 1,2-amino migration under the action of a photocatalyst.

[0008] The technical scheme of the present application is as follows:

[0009] An imine compound, the structural formula of which is shown in formula (I):

[0010]

[0011] wherein R is selected from halogen and optionally substituted alkyl, alkoxy, aryl.

[0012] The halogen can be fluorine, chlorine, etc.; the alkyl can be methyl, ethyl, propyl, isopropyl, isobutyl and various types of alkyl and the like; the aryl can be phenyl, 4-F phenyl, 4-Cl phenyl, benzyl, thienyl and various types of aryl.

[0013] Preferably, the imine compound is selected from the following compounds:

[0014] (E)-2-((3,5-bis(trifluoromethyl)benzylidene)amino)-2-methylbut-3-enate (S1), (E)-2-((3,5-bis(trifluoromethyl)benzylidene)amino)-2-ethylbut-3-enate (S2), (E)-2-((3,5-bis(trifluoromethyl)benzylidene)amino)-2-isopropylbut-3-enate (S3), (E)-2-((3,5-bis(trifluoromethyl)benzylidene)amino)-2-vinylpentanoic acid methyl ester (S4), (E)-2-((3,5-bis(trifluoromethyl)benzylidene)amino)-4-methyl-2-vinylpentanoic acid methyl ester (S5), (E)-2-((3,5-bis(trifluoromethyl)benzylidene)amino)-2-cyclohexylbut-3-enate (S6), (E)-2-((3,5-bis(trifluoromethyl)benzylidene)amino)-2-phenethylbut-3-enate (S7), (E)-2-((3,5-bis(trifluoromethyl)benzylidene)amino)-2-(thiophen-2-ylmethyl)but-3-enate (S8), (E)-2-benzyl-2-((3,5-bis(trifluoromethyl)benzylidene)amino)but-3-enate (S9), (E)-2-((3,5-bis(trifluoromethyl)benzylidene)amino)-2-(4-methylbenzyl)but-3-enate (S 10 ), (E)-2-((3,5-bis(trifluoromethyl)benzylidene)amino)-2-(4-methoxybenzyl)but-3-enate (S 11 ), (E)-2-((3,5-bis(trifluoromethyl)benzylidene)amino)-2-phenylbut-3-enate (S12 ), (E)-2-((3,5-bis(trifluoromethyl)benzylidene)amino)-2-(4- chlorophenyl)but-3-enoic acid methyl ester (S 13 ), (E)-2-((3,5-bis(trifluoromethyl)benzylidene)amino)-2-(4- chlorophenyl)but-3-enoic acid methyl ester (S 14 ), (E)-2-((3,5-bis(trifluoromethyl)benzylidene)amino)-2- ethylidenepentanedioic acid dimethyl ester (S 15 ), (E)-2-((3,5-bis(trifluoromethyl)benzylidene)amino)-2- ethylidenepentanedioic acid dimethyl ester (S 16 ), (E)-2-((3,5-bis(trifluoromethyl)benzylidene)amino)-2- ethylidenepentanedioic acid dimethyl ester (S 17 ).

[0015]

[0016] The present application also provides a preparation method of the imine compound, comprising: starting from a benzoyl-protected a-amino acid, synthesizing the imine compound shown in formula (I) through DCC condensation, alkyne group, ring opening, Lindlar reduction hydrogenation multi-step reactions.

[0017] Further, the preparation method of the imine compound comprises:

[0018] (a): DCC condensation of the benzoyl-protected a-amino acid SM-1a with carbodiimide to obtain a five-membered ring lactone compound SM-1b;

[0019] (b): adding the five-membered ring lactone compound SM-1b, N,N- diisopropylethylamine into an organic solvent, and then adding iodine salt I-Salt for reaction, and after treatment, the five-membered ring lactone compound SM-1c is obtained;

[0020] The preparation method of the iodine salt I-Salt: dissolving iodosylbenzene and bis(trimethylsilyl)acetylene in an organic solvent, and then adding a boron trifluoride ether solution for reaction, and after treatment, the iodine salt I-Salt is obtained;

[0021] (c): dissolving the five-membered ring lactone compound SM-1c and potassium fluoride in an organic solvent, and reacting at 50-70°C, and after the reaction is completed, treatment is performed to obtain an alkyne group-substituted a-amino acid ester derivative SM-1d;

[0022] (d): dissolving the alkyne group-substituted a-amino acid ester derivative SM-1d, Lindlar catalyst and N,N-dimethylformamide in an organic solvent, and performing reaction in a hydrogen atmosphere, and after treatment, the vinyl group-substituted a-amino acid ester derivative SM-1e is obtained;

[0023] (e) the vinyl-substituted α-amino acid ester derivative SM-1e is dissolved in hydrochloric acid solution, and the reaction is carried out at 100-150°C, after which the reaction is treated to obtain the vinyl-substituted α-amino acid hydrochloride SM-1f;

[0024] (f) the vinyl-substituted α-amino acid hydrochloride SM-1f is dissolved in an organic solvent, and dichlorosulfoxide is added dropwise, after which the reaction is carried out at 50-70°C, after which the reaction is treated to obtain the vinyl-substituted α-amino acid ester SM-1g;

[0025] (g) the vinyl-substituted α-amino acid ester SM-1g, 3,5-bis(trifluoromethyl)benzaldehyde, and a drying agent are added to a dry organic solvent, and triethylamine is added dropwise, after which the reaction is carried out, after which the reaction is treated to obtain the imine product SM;

[0026] The reaction formula is as follows:

[0027]

[0028] The present application also provides another preparation method of the imine compound, which comprises: starting from α-amino acid hydrochloride, first condensing with aldehyde, then undergoing nucleophilic substitution with 1,2-dibromoethane, and finally eliminating to obtain the imine shown in formula (I).

[0029] Further, another preparation method of the imine compound comprises:

[0030] (A) α-amino acid hydrochloride, 3,5-bis(trifluoromethyl)benzaldehyde, benzyltriethylammonium chloride, and a drying agent are added to a dry organic solvent, and triethylamine is added dropwise, after which the reaction is carried out, after which the reaction is treated to obtain the intermediate SM-1j;

[0031] (B) the intermediate SM-1j and 1,2-dibromoethane undergo nucleophilic substitution reaction under alkaline conditions, after which the reaction is treated to obtain the imine product SM;

[0032] The reaction formula is as follows:

[0033]

[0034] The present application provides a synthesis method of a plurality of functionalized β-amino acid esters, which comprises the following steps:

[0035] The imine compound shown in formula (I) and the free radical precursor shown in formula (II), formula (III), formula (IV), or formula (V) are dissolved in an organic solvent, and the photocatalytic reaction is carried out under the action of a photosensitizer, a base, and light in an inert atmosphere, after which the reaction system is separated and purified to obtain the intermediate.

[0036] acidifying the intermediate to obtain a β-amino acid ester of formula (VI), (VII), (VIII) or (IX);

[0037]

[0038] wherein R is selected from halogen and optionally substituted alkyl, alkoxy, aryl;

[0039] when X is 0, Y is 1 and Z is 3, or Y is 4 and Z is 9; when X is 1, Y is 1 and Z is 2;

[0040] R1is selected from alkyl, optionally substituted aryl;

[0041] R2is selected from optionally substituted aryl;

[0042] R3is selected from optionally substituted aryl.

[0043] Preferably, the radical precursor of formula (II) is selected from sodium trifluoromethylsulfinates (CF3SO2Na, S 18 ), sodium difluoromethylsulfinates (HCF2SO2Na, S 19 ), and sodium perfluorobutylsulfinates (C4F9SO2Na, S 20 ).

[0044] Preferably, the radical precursor of formula (III) is selected from:

[0045]

[0046] Preferably, the radical precursor of formula (IV) is selected from:

[0047]

[0048] Preferably, the radical precursor of formula (V) is selected from:

[0049]

[0050] Preferably, the photosensitizer is selected from fac-tris(2-phenylpyridine)iridium (fac-Ir(ppy)3), (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate (Ir(ppy)2(dtbbpy)PF6), bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium hexafluorophosphate (Ir[dF(CF3)ppy]2(dtbbpy)PF6), Eosin Y disodium salt, 3,6-di-tert-butyl-9-mesityl-10-phenylacridin-10-ium tetrafluoroborate ((Mes-Acr-Ph)BF4), 2,4,5,6-tetracarbazoyl-1,3-dicyanobenzene (4CzIPN), tris(2,2'-bipyridine)ruthenium dichloride (Ru(bpy)3(PF6)2).

[0051] The organic solvent is selected from dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), tetrahydrofuran (THF), 1,6-dioxane (Dioxane), acetonitrile (CH3CN), acetone (Acetone), ethanol (EtOH), dichloromethane (DCM), 1,2-dichloroethane (DCE), ethyl acetate (EA).

[0052] Preferably, the base is selected from potassium phosphate (K3PO4), potassium carbonate (K2CO3), sodium carbonate (Na2CO3), cesium carbonate (CsCO3), lithium carbonate (Li2CO3), 4-dimethylaminopyridine (DMAP), 1,8-diazabicycloundec-7-ene (DBU).

[0053] Preferably, a method for synthesizing a plurality of functionalized β-amino acid esters comprises the following steps:

[0054] The imine compound shown in formula (I), the radical precursor shown in formula (II), and the photosensitizer are dissolved in an organic solvent, and the reaction is irradiated with light under an inert atmosphere for 10-24 h. After the reaction is completed, the reaction system is separated and purified to obtain an intermediate. The intermediate is acidified to obtain the β-amino acid ester shown in formula (VI).

[0055]

[0056] Preferably, a method for synthesizing a plurality of functionalized β-amino acid esters comprises the following steps:

[0057] The imine compound shown in formula (I), the radical precursor shown in formula (III), a photosensitizer are dissolved in an organic solvent, and the reaction is irradiated with light under an inert atmosphere for 10-24 h. After the reaction is completed, the reaction system is separated and purified to obtain an intermediate. The intermediate is acidified to obtain the β-amino acid ester shown in formula (VII);

[0058]

[0059] Preferably, a synthesis method of a plurality of functionalized β-amino acid esters comprises the following steps:

[0060] The imine compound shown in formula (I), the radical precursor shown in formula (IV), a photosensitizer, and a base are dissolved in an organic solvent, and the reaction is irradiated with light under an inert atmosphere for 1-5 h. After the reaction is completed, the reaction system is separated and purified to obtain an intermediate. The intermediate is acidified to obtain the β-amino acid ester shown in formula (VIII);

[0061]

[0062] Preferably, a synthesis method of a plurality of functionalized β-amino acid esters comprises the following steps:

[0063] The imine compound shown in formula (I), the radical precursor shown in formula (V), a photosensitizer, and a base are dissolved in an organic solvent, and the reaction is irradiated with light under an inert atmosphere for 1-5 h. After the reaction is completed, the reaction system is separated and purified to obtain an intermediate. The intermediate is acidified to obtain the β-amino acid ester shown in formula (IX);

[0064]

[0065] Preferably, the molar amount of the photosensitizer is 1-30% of the molar amount of the imine substrate; and the molar amount of the base is 0-200% of the molar amount of the reaction substrate.

[0066] Preferably, the molar amount of the radical precursor shown in formula (II), formula (III), formula (IV), or formula (V) is 20-200% of the molar amount of the imine compound shown in formula (I).

[0067] Preferably, the molar amount of the organic solvent is 10,000-200,000% of the molar amount of the imine substrate.

[0068] Preferably, the light wavelength is 370-467 nm.

[0069] The light wavelength can be selected as 370, 390, 427, 440, 356, 467 nm, etc.

[0070] Preferably, the reaction time is 2-50 h, and the reaction temperature is room temperature.

[0071] In the present application, in the presence of photosensitizer, base and organic solvent, the free radical precursor can produce free radicals, which are added to and migrated from the imine substrate, respectively, and the corresponding functionalized β-amino acid ester product is obtained by treating under hydrochloric acid conditions.

[0072] Compared with the prior art, the present application has the following beneficial effects:

[0073] (1) The synthesis method of the visible light-induced β-amino acid ester compound of the present application has the advantages of novel reaction mechanism, simple and readily available starting materials, mild reaction conditions, wide substrate applicability, etc., and meets the requirements of developing green and environmentally friendly chemistry.

[0074] (2) The synthesis method of the visible light-induced β-amino acid ester compound of the present application utilizes various inexpensive and readily available substrates to generate four types of free radicals, respectively, and then undergoes olefin addition and migration reactions on imines, efficiently introducing aryl, sulfur, phosphine, fluoralkyl and other functional groups into the β-amino acid ester compound. This method is expected to be widely used in the modification of β-amino acid drug molecules. BRIEF DESCRIPTION OF DRAWINGS

[0075] Figure 1 is the flow chart of the reaction for constructing various functionalized β-amino acid esters in the embodiments of the present application;

[0076] Figure 2 is the reaction mechanism diagram for constructing various functionalized β-amino acid esters in the embodiments of the present application;

[0077] Figure 3 is the nuclear magnetic hydrogen spectrum of compound S1 in Example 1 of the present application;

[0078] Figure 4 is the nuclear magnetic carbon spectrum of compound S1 in Example 1 of the present application;

[0079] Figure 5 is the nuclear magnetic fluorine spectrum of compound S1 in Example 1 of the present application;

[0080] Figure 6 is the nuclear magnetic hydrogen spectrum of compound S2 in Example 2 of the present application;

[0081] Figure 7 is the nuclear magnetic carbon spectrum of compound S2 in Example 2 of the present application;

[0082] Figure 8 is the nuclear magnetic fluorine spectrum of compound S2 in Example 2 of the present application;

[0083] Figure 9 is the nuclear magnetic hydrogen spectrum of compound S3 in Example 3 of the present application;

[0084] Figure 10 This is the carbon NMR spectrum of compound S3 in Example 3 of this invention;

[0085] Figure 11 This is the NMR fluorine spectrum of compound S3 in Example 3 of this invention;

[0086] Figure 12 This is the 1H NMR spectrum of compound S4 in Example 4 of this invention;

[0087] Figure 13 This is the carbon NMR spectrum of compound S4 in Example 4 of this invention;

[0088] Figure 14 This is the NMR fluorine spectrum of compound S4 in Example 4 of this invention;

[0089] Figure 15 This is the 1H NMR spectrum of compound S8 in Example 8 of this invention;

[0090] Figure 16 This is the carbon NMR spectrum of compound S8 in Example 8 of this invention;

[0091] Figure 17 This is the NMR fluorine spectrum of compound S8 in Example 8 of this invention;

[0092] Figure 18 This is the hydrogen NMR spectrum of the product in Example 18 of the present invention;

[0093] Figure 19 This is the carbon NMR spectrum of the product in Example 18 of the present invention;

[0094] Figure 20 This is the NMR fluorine spectrum of the product in Example 18 of this invention;

[0095] Figure 21 This is the 1H NMR spectrum of the product in Example 53 of this invention;

[0096] Figure 22 This is the phosphorus NMR spectrum of the product in Example 53 of this invention;

[0097] Figure 23 This is the carbon NMR spectrum of the product in Example 53 of the present invention;

[0098] Figure 24 This is the 1H NMR spectrum of the product in Example 67 of this invention;

[0099] Figure 25 This is the carbon NMR spectrum of the product in Example 67 of this invention. Detailed Implementation

[0100] In order to make the object, technical scheme and technical advantages of the present application more clear, the present application provides a kind of β-amino acid ester compound synthesis method with specific examples and referring to the drawings further described as follows.

[0101] The present application provides a kind of β-amino acid ester compound synthesis method, comprising: imine substrate is reacted with four kinds of radical precursors respectively in the presence of photosensitizer, base and organic solvent, four kinds of radical precursors can produce radical addition, migration to olefin in imine substrate respectively, and the corresponding β-amino acid ester compound is obtained by treating under hydrochloric acid condition.

[0102] The general formula of imine substrate is shown as formula (I):

[0103]

[0104] Among them, R group includes but is not limited to alkyl, benzyl, aryl and other chemical groups, such as methyl, ethyl, propyl, isopropyl, isobutyl and their analogues and other types of alkyl, phenyl, 4-F phenyl, 4-Cl phenyl and other types of aryl.

[0105] Radical precursor includes sodium fluoroalkyl sulfinate, diaryl phosphine oxide, aryl bromide and the like.

[0106] The flow chart of the β-amino acid ester compound synthesis method is shown as Figure 1 When X is 0, Y is 1 and Z is 3, or Y is 4 and Z is 9. When X is 1, Y is 1 and Z is 2; R1 group includes phenyl, 4-methoxyphenyl, 4-methylphenyl, 4-chlorophenyl and 3-pyridyl and the like, R2 group includes phenyl, 4-methoxyphenyl, 4-methylphenyl, 4-chlorophenyl, 4-phenylphenyl, 3-methylphenyl, 3,5-dimethylphenyl and the like, and R3 group includes 4-cyanophenyl, 4-acetylphenyl, 3,5-dicyanophenyl, 4-pyridyl, 2-pyrimidyl and 4-quinolinyl and the like.

[0107] The mechanism of the reaction of various radical precursors with imine substrate in the embodiment of the present application is shown as Figure 2 The four kinds of radical precursors 1 are oxidized to produce radicals by photocatalyst, which add to imine substrate 2 to produce intermediate 4, the newly produced radicals add to imine again to produce intermediate 5, which is rearranged to produce intermediate 6, and finally reduced by photocatalyst. On the one hand, the photocatalyst returns to the oxidation state to complete the catalytic cycle, and on the other hand, the substrate is protonated, and finally acidified to obtain the final product 3.

[0108] The imine substrate shown in formula (I) can be prepared by the following two preparation methods:

[0109] Route A: The imines of formula (I) can be synthesized from the benzoyl protected α-amino acids by DCC condensation, alkynyl substitution, ring opening, Lindlar reduction hydrogenation and other multi-step reactions, as shown in the following reaction scheme:

[0110]

[0111] General procedure A includes:

[0112] (A-1) In a round bottom flask equipped with magnetic stirring, add carboxylic acid (600 mmol), anhydrous dichloromethane (700 mL). Weigh DCC (dicyclohexyl carbodiimide) (660 mmol) and add it to the above reaction solution in batches at 0°C, and then raise the temperature to room temperature and react overnight. After the reaction is completed, filter with diatomite and wash the filter cake with dichloromethane twice. Concentrate the filtrate under reduced pressure to obtain the five-membered ring lactone compound SM-1b, which is directly used in the next step without purification.

[0113] (A-2) In a round bottom flask equipped with magnetic stirring, add the above five-membered ring lactone compound SM-1b (600 mmol), N,N-diisopropyl ethylamine (780 mmol), dichloromethane (750 mL) in sequence. Weigh iodine salt I-Salt (720 mmol) and add it to the above reaction solution in batches at 0°C, and then raise the temperature to room temperature and react overnight. After the reaction is completed, slowly add acetic acid (90 mL) to the system to quench the reaction. Wash with water and saturated brine in sequence, take the lower organic solvent, dry with anhydrous sodium sulfate, spin dry, and separate and purify by column chromatography to obtain the alkynyl-substituted five-membered ring lactone compound SM-1c.

[0114] Preparation of iodine salt I-Salt: In a round bottom flask equipped with magnetic stirring, add the above hypervalent iodine compound (1.0 mol), bis(trimethylsilyl)acetylene (1.6 mol), and chloroform (2.5 L) in sequence. Take boron trifluoride ether solution (1 mol) and add it to the above reaction solution in batches at 0°C, and then raise the temperature to room temperature and react for 3 h. After the reaction is completed, slowly add water (400 mL) and sodium p-toluenesulfonate (3.0 mmol) to the system at 0°C to quench the reaction. Extract the reaction system with chloroform three times, and then wash the organic phase with water three times. Dry the organic phase with anhydrous sodium sulfate, spin dry, and recrystallize with ethyl acetate. The obtained iodine salt I-Salt is a white solid.

[0115] (A-3) Into a round bottom flask equipped with a magnetic stirrer, was added the above-described alkynyl-substituted five-membered ring lactone compound SM-1c (290 mmol), potassium fluoride (870 mmol), and methanol (600 mL). The mixture was stirred at 60°C for 5 hours. After cooling to room temperature, the methanol was removed by concentration under reduced pressure. To the mixture was added ethyl acetate, which was washed sequentially with water and saturated brine, and the organic layer was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was recrystallized from ethyl acetate and diethyl ether to obtain an alkynyl-substituted α-amino acid ester derivative SM-1d.

[0116] (A-4) Into a round bottom flask equipped with a magnetic stirrer, was added the above-described alkynyl-substituted α-amino acid ester derivative SM-1d (210 mmol), Lindlar catalyst (41 mmol), diethyl ether (320 mL), and N,N-dimethylformamide (80 mL). The mixture was stirred at room temperature under a hydrogen atmosphere. After the reaction was completed, as determined by TLC, the mixture was filtered through celite, and the filter cake was washed twice with ethyl acetate. The filtrate was washed sequentially with water and saturated brine, and the organic layer was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain a vinyl-substituted α-amino acid ester derivative SM-1e.

[0117] (A-5) Into a round bottom flask equipped with a magnetic stirrer, was added the above-described vinyl-substituted α-amino acid ester derivative SM-1e (190 mmol), 6N HCl (360 mL), and 1,4-dioxane (45 mL). The mixture was stirred at 120°C overnight. After the reaction was completed, water (400 mL) was added, and the mixture was extracted three times with diethyl ether. The aqueous layer was concentrated under reduced pressure to obtain a vinyl-substituted α-amino acid hydrochloride SM-1f, which was used as is in the next step.

[0118] (A-6) Into a round bottom flask equipped with a magnetic stirrer, was added the above-described vinyl-substituted α-amino acid hydrochloride SM-1f (100 mmol) and anhydrous methanol (100 mL). To the mixture was added dropwise dichlorosulfoxide (150 mmol) at room temperature. After the addition was completed, the mixture was stirred at 60°C overnight. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a vinyl-substituted α-amino acid ester SM-1g, which was used as is in the next step.

[0119] (A-7) Take the above vinyl-substituted α-amino acid hydrochloride SM-1g (30 mmol), 3,5-bis(trifluoromethyl)benzaldehyde (30 mmol), anhydrous magnesium sulfate (33 mmol), and dry dichloromethane (50 mL) in turn and add them to a round bottom flask equipped with a magnetic stirrer. At 0°C, add triethylamine (33 mmol) dropwise. Raise the temperature to room temperature and allow the reaction to proceed overnight. After the reaction is complete, filter, and wash the filter cake twice with dichloromethane. Wash the resulting filtrate with water and saturated brine in turn, take the lower organic layer, dry over anhydrous sodium sulfate, and distill off the solvent. Purify the resulting product by column chromatography to obtain the vinyl-substituted imine product SM.

[0120] Route B: Starting from α-amino acid hydrochloride, condensation with aldehyde, nucleophilic substitution with 1,2-dibromoethane, and elimination to obtain the imine represented by formula (I), as shown in the following reaction scheme:

[0121]

[0122] General procedure B includes:

[0123] (B-1) Take 3,5-bis(trifluoromethyl)benzaldehyde (100 mmol), amino acid ester hydrochloride SM-1i (100 mmol), anhydrous magnesium sulfate (110 mmol), and dry dichloromethane (250 mL) in turn and add them to a round bottom flask equipped with a magnetic stirrer. At 0°C, add triethylamine (110 mmol) dropwise. Raise the temperature to room temperature and allow the reaction to proceed overnight. After the reaction is complete, filter, and wash the filter cake twice with dichloromethane. Wash the resulting filtrate with water and saturated brine in turn, take the lower organic layer, dry over anhydrous sodium sulfate, and distill off the solvent. Purify the resulting product by column chromatography to obtain the imine product SM-1j, which is directly used in the next step without purification.

[0124] (B-2) Take the above imine SM-1j (100 mmol), 1,2-dibromoethane (300 mmol), dry DMF (400 mL), benzyltriethylammonium chloride (10 mmol), potassium carbonate (200 mmol), and potassium hydroxide (200 mmol) in turn and add them to a round bottom flask equipped with a magnetic stirrer. Allow the reaction to proceed at room temperature for 6 hours. After the reaction is complete, filter through neutral alumina, and wash the filter cake twice with ethyl acetate. Wash the resulting filtrate with water and saturated brine in turn, take the upper organic layer, dry over anhydrous sodium sulfate, and distill off the solvent. Take the above alkyl-substituted imine substrate (100 mmol) and DBU (200 mmol) and add them to a round bottom flask equipped with a magnetic stirrer. Allow the reaction to proceed at 90°C for 2 hours. After the reaction is complete, filter through neutral alumina, and wash the filter cake twice with ethyl acetate. Wash the resulting filtrate with water and saturated brine in turn, take the upper organic layer, dry over anhydrous sodium sulfate, and distill off the solvent. Purify the resulting product by column chromatography to obtain the alkynyl-substituted imine compound SM.

[0125] Example 1: Synthesis of (E)-methyl 2-((3,5-bis(trifluoromethyl)benzylidene)amino)- 2-methylbut-3-enoate (S1)

[0126]

[0127] A yellow liquid was obtained as compound S1 according to general procedure A using benzoylalanine as starting material or general procedure B using alanine methyl ester hydrochloride as starting material.

[0128] 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.52 - 8.43 (m, 2H), 8.19 (dd, J = 2.3, 1.2 Hz, 1H), 6.13 (dd, J = 17.4, 10.7 Hz, 1H), 5.41 - 5.25 (m, 2H), 3.69 (s, 3H), 1.56 (s, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -61.69. 13 C NMR (100 MHz, DMSO-d6) δ 172.28, 158.64, 138.96, 138.26, 130.80 (q, J = 33.2 Hz), 128.33 (d, J = 4.2 Hz), 124.18 (m), 123.13 (q, J = 273.1 Hz), 116.61, 69.80, 52.45, 22.98. HRMS (ESI-TOF) m / z calcd for C 15 H 14 F6NO2 ([M+H] + ) 354.0923, found: 354.0918.

[0129] Figures 3-5 Respectively, the nuclear magnetic hydrogen spectrum, carbon spectrum, fluorine spectrum of compound S1.

[0130] Example 2: Synthesis of (E)-methyl 2-((3,5-bis(trifluoromethyl)benzylidene)amino)- 2-ethylbut-3-enoate (S2)

[0131]

[0132] A yellow liquid was obtained as compound S2 according to general procedure B using methyl 2-aminobutyrate hydrochloride as starting material.

[0133] 1H NMR (400 MHz, CD2CI2) δ 8.49 (s, 1H), 8.34 (d, J = 1.8 Hz, 2H), 8.10 - 7.94 (m, 1H), 6.11 (dd, J = 17.5, 10.8 Hz, 1H), 5.53 - 5.27 (m, 2H), 3.81 (s, 3H), 2.22 (dq, J = 13.7, 7.4 Hz, 1H), 2.11 - 1.96 (m, 1H), 1.02 (t, J = 7.4 Hz, 3H). 19 F NMR (376 MHz, CD2CI2) δ -63.39. 13 C NMR (100 MHz, CD2CI2) δ 172.86, 159.74, 139.17, 138.50, 132.57 (q, J = 33.5 Hz), 128.92 (q, J = 3.8 Hz), 124.81 (m), 123.99 (q, J = 272.7 Hz), 117.77, 74.66, 52.90, 32.26, 8.86. HRMS (ESI-TOF) m / z calcd for C 16 H 16 F6NO2([M+H] + ) 368.1080, found: 368.1075.

[0134] Figures 6-8 H NMR,13C NMR,19F NMR of compound S2, respectively.

[0135] Example 3: Synthesis of (E)-2-((3,5-bis(trifluoromethyl)benzylidene)amino)-2- isopropylbut-3-enoic acid methyl ester (S3)

[0136]

[0137] Yellow liquid was obtained as compound S3 following general procedure A using benzoyl valine as starting material.

[0138] 1 H NMR (400 MHz, CD2CI2) δ 8.46 (s, 1H), 8.30 (d, J = 1.8 Hz, 2H), 7.98 (dt, J = 2.1, 1.0 Hz, 1H), 6.10 (dd, J = 17.4, 10.9 Hz, 1H), 5.38 (dd, J = 10.9, 1.1 Hz, 1H), 5.18 (dd, J = 17.5, 1.1 Hz, 1H), 3.75 (s, 3H), 2.44 (p, J = 6.8 Hz, 1H), 1.00 (dd, J = 13.1, 6.8 Hz, 6H). 19F NMR (376 MHz, CD2Cl2) δ -63.36. 13 C NMR (100 MHz, CD2Cl2) δ 172.80, 160.82, 139.23, 137.45, 132.50 (q, J = 33.6 Hz), 128.83 (q, J = 3.9 Hz), 124.76 (m), 123.96 (q, J = 272.6 Hz), 117.91, 77.55, 52.70, 37.05, 18.06, 17.60. HRMS (ESI-TOF) m / z calcd for C 17 H 18 F6NO2([M+H] + ) 382.1236, found: 382.1231.

[0139] Figures 9-11 HNMR,13CNMRand19FNMRof compound S3, respectively.

[0140] Example 4: Synthesis of (E)-2-((3,5-bis(trifluoromethyl)benzylidene)amino)-2- vinylpentanoic acid methyl ester (S4)

[0141]

[0142] A pale yellow liquid was obtained as compound S4 following general procedure A using 2-benzoylamino pentanoic acid as starting material.

[0143] 1 H NMR (400 MHz, CD2Cl2) δ 8.43 (s, 1H), 8.29 (d, J = 1.8 Hz, 2H), 7.97 (s, 1H), 6.07 (dd, J = 17.5, 10.8 Hz, 1H), 5.39 (dd, J = 10.9, 1.0 Hz, 1H), 5.29 (dd, J = 17.5, 1.0 Hz, 1H), 3.75 (s, 3H), 2.10 (ddd, J = 13.4, 11.8, 4.8 Hz, 1H), 1.92 (ddd, J = 13.4, 11.9, 4.6 Hz, 1H), 1.58 - 1.20 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). 19 F NMR (376 MHz, CD2Cl2) δ -63.35. 13C NMR (100 MHz, CD2CI2) δ 172.91, 159.54, 139.12, 138.73, 132.51 (q, J = 33.5 Hz), 128.89 (d, J = 3.8 Hz), 124.78 (m), 123.95 (q, J = 272.7 Hz), 117.53, 74.28, 52.90, 41.52, 17.99, 14.76. HRMS (ESI-TOF) m / z calcd for C 17 H 18 F6NO2([M+H] + ) 382.1236, found: 382.1231.

[0144] Figures 12-14 NMR,13C NMR,19F NMR of compound S4, respectively.

[0145] Example 5: Synthesis of (E)-2-((3,5-bis(trifluoromethyl)benzylidene)amino)-4- methyl-2-vinylpentanoic acid methyl ester (S5)

[0146]

[0147] White solid was obtained as compound S5 following General Procedure A using 2-benzoylamino-4-methylpentanoic acid as starting material or Procedure B using leucine methyl ester hydrochloride as starting material.

[0148] 1 H NMR (400 MHz, CD3Cl) δ 8.44 (s, 1H), 8.26 (d, J = 1.7 Hz, 2H), 7.93 (s, 1H), 6.04 (dd, J = 17.4, 10.8 Hz, 1H), 5.45 - 5.23 (m, 2H), 3.77 (s, 3H), 2.30 - 2.03 (m, 1H), 2.00 - 1.71 (m, 2H), 0.93 (dd, J = 11.7, 6.5 Hz, 6H). 19 F NMR (376 MHz, CD2CI2) δ -63.02. 13 C NMR (100 MHz, CD3Cl) δ 172.86, 159.13, 138.56, 138.45, 132.26 (q, J = 33.5 Hz), 128.37 (q, J = 3.8 Hz), 124.32 (p, J = 3.9 Hz), 123.30 (q, J = 273.0 Hz), 117.16, 73.52, 52.55, 47.79, 24.84, 24.37, 23.88. HRMS (ESI-TOF) m / z calcd for C 18 H20 F6NO2([M+H] + )396.1393, found:396.1388.

[0149] Example 6: Synthesis of (E)-methyl 2-((3,5-bis(trifluoromethyl)benzylidene)amino)- 2-cyclohexylbut-3-enoate (S6)

[0150]

[0151] White solid was obtained as compound S6 following general procedure A using 2-benzylamino-2-cyclohexylacetic acid as starting material.

[0152] 1 H NMR (400 MHz, CD2Cl2) δ 8.44 (s, 1H), 8.29 (d, J = 1.8 Hz, 2H), 8.08 - 7.92 (m, 1H), 6.12 (dd, J = 17.4, 10.9 Hz, 1H), 5.35 (dd, J = 10.9, 1.2 Hz, 1H), 5.16 (dd, J = 17.4, 1.2 Hz, 1H), 3.74 (s, 3H), 2.09 (ddd, J = 11.5, 8.5, 3.1 Hz, 1H), 1.84 - 1.57 (m, 5H), 1.42 - 1.05 (m, 5H). 19 F NMR (376 MHz, CD2Cl2) δ -63.35. 13 C NMR (100 MHz, CD2Cl2) δ 172.78, 160.58, 139.30, 137.73, 132.53 (q, J = 33.5 Hz), 128.84 (d, J = 3.8 Hz), 124.74 (m), 123.99 (q, J = 272.5 Hz), 117.62, 77.57, 52.69, 47.34, 28.46, 28.04, 27.26, 27.16, 27.12. HRMS (ESI-TOF) m / z calcd for C 20 H 22 F6NO2([M+H] + )422.1549, found:422.1544.

[0153] Example 7: Synthesis of (E)-methyl 2-((3,5-bis(trifluoromethyl)benzylidene)amino)- 2-phenethylbut-3-enoate (S7)

[0154]

[0155] A general procedure A was used to obtain compound S7 as a pale yellow liquid.

[0156] 1 H NMR (400 MHz, CD2CI2) δ 8.55 - 8.45 (m, 1H), 8.34 (s, 2H), 8.03 (s, 1H), 7.34 - 7.16 (m, 5H), 6.15 (ddd, J = 19.5, 10.8, 1.6 Hz, 1H), 5.53 - 5.35 (m, 2H), 3.81 (s, 3H), 2.92 - 2.69 (m, 2H), 2.57 - 2.45 (m, 1H), 2.38 - 2.22 (m, 1H). 19 F NMR (376 MHz, CD2CI2) δ -63.27. 13 C NMR (100 MHz, CD2CI2) δ 172.64, 160.16, 142.75, 139.08, 138.52, 132.59 (q, J = 33.6 Hz), 129.06, 129.03, 128.98, 126.52, 124.92 (m), 124.00 (q, J = 272.7 Hz), 118.12, 74.24, 53.25 (d, J = 41.4 Hz), 41.29, 31.14. HRMS (ESI-TOF) m / z calcd for C 22 H 20 F6NO2([M+H] + ) 444.1393, found: 444.1388.

[0157] Example 8: Synthesis of (E)-2-((3,5-bis(trifluoromethyl)benzylidene)amino)-2- (thiophen-2-ylmethyl)but-3-enoic acid methyl ester (S8)

[0158]

[0159] A general procedure B was used to obtain compound S8 as a yellow liquid from 2-amino-3-(thiophen-2-yl)propanoic acid methyl ester hydrochloride.

[0160] 1 H NMR (400 MHz, CD3CI) δ 8.27 (s, 3H), 7.95 (s, 1H), 7.15 (d, J = 5.1 Hz, 1H), 6.97 - 6.88 (m, 1H), 6.84 (s, 1H), 6.00 (dd, J = 17.5, 10.8 Hz, 1H), 5.55 - 5.12 (m, 2H), 3.77 (d, J = 19.9 Hz, 4H), 3.51 (d, J = 14.4 Hz, 1H).19 F NMR (376 MHz, CD3Cl) δ -62.95. 13 C NMR (100 MHz, CD3Cl) δ 171.40, 160.80, 138.20, 137.79, 137.30, 132.26 (q, J = 33.7 Hz), 128.55 (d, J = 2.8 Hz), 128.22, 126.40, 125.38, 124.49 (p, J = 3.6 Hz), 123.29 (q, J = 272.8 Hz), 118.41, 74.25, 52.80, 39.69. HRMS (ESI-TOF) m / z calcd for C 19 H 16 F6NO2S ([M+H] + ) 436.0800, found: 436.0795.

[0161] Figures 15-17 NMR,13C NMR,19F NMR of compound S8, respectively.

[0162] Example 9: Synthesis of (E)-2-benzyl-2-((3,5-bis(trifluoromethyl)benzylidene)amino)but-3-enoic acid methyl ester (S9)

[0163]

[0164] was obtained as a light yellow liquid following general procedure B using phenylalanine methyl ester hydrochloride as starting material.

[0165] 1 H NMR (400 MHz, CD3Cl) δ 8.19 (d, J = 6.5 Hz, 3H), 7.93 (s, 1H), 7.36 - 7.04 (m, 5H), 6.01 (ddd, J = 17.5, 10.7, 1.2 Hz, 1H), 5.62 - 5.14 (m, 2H), 3.77 (d, J = 1.2 Hz, 3H), 3.53 (d, J = 13.3 Hz, 1H), 3.29 (d, J = 13.3 Hz, 1H). 19 F NMR (376 MHz, CD2Cl2) δ -62.97. 13C NMR (100 MHz, CD3Cl) δ 171.82, 159.98, 138.31, 137.84, 135.94, 132.25 (q, J = 33.8 Hz), 131.24, 128.36 (d, J = 3.7 Hz), 128.04, 127.04, 124.37 (p, J = 3.7 Hz), 123.30 (q, J = 273.0 Hz), 117.78, 74.42, 52.64, 45.25. HRMS (ESI-TOF) m / z calcd for C 21 H 18 F6NO2([M+H] + ) 430.1236, found: 430.1231.

[0166] Example 10: Synthesis of (E)-methyl 2-((3,5-bis(trifluoromethyl)benzylidene)amino)-2- (4-methylbenzyl)but-3-enoate (S 10 )

[0167]

[0168] A yellow liquid was obtained as compound S 10 .

[0169] 1 H NMR (500 MHz, CD2Cl2) δ 8.50 - 8.15 (m, 3H), 8.00 (s, 1H), 7.30 - 6.76 (m, 4H), 6.07 (dd, J = 17.5, 10.7 Hz, 1H), 5.45 - 5.28 (m, 2H), 3.77 (s, 3H), 3.50 (d, J = 13.3 Hz, 1H), 3.26 (d, J = 13.3 Hz, 1H), 2.31 (s, 3H). 19 F NMR (471 MHz, CD2Cl2) δ -63.32. 13 C NMR (126 MHz, CD2Cl2) δ 172.25, 160.38, 139.08, 138.67, 137.13, 133.53, 132.56 (q, J = 33.9 Hz), 131.58, 129.19, 128.91 (d, J = 3.9 Hz), 128.84 (m), 123.99 (q, J = 272.2 Hz), 117.81, 75.01, 52.90, 45.42, 21.33. HRMS (ESI-TOF) m / z calcd for C 22 H 20 F6NO2([M+H]+ )444.1393, found: 444.1388.

[0170] Example 11: Synthesis of (E)-methyl 2-((3,5-bis(trifluoromethyl)benzylidene)amino)- 2-(4-methoxybenzyl)but-3-enoate (S 11 ) from 2-benzylamino-3-(4-methoxyphenyl)propanoic acid as a yellow liquid.

[0171]

[0172] from 2-benzylamino-3-(4-methoxyphenyl)propanoic acid as a yellow liquid. 11 .

[0173] 1 H NMR (400 MHz, CD2Cl2) δ 8.34 (d, J = 7.0 Hz, 3H), 8.07 (s, 1H), 7.21 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.3 Hz, 2H), 6.14 (dd, J = 17.5, 10.8 Hz, 1H), 5.54 - 5.31 (m, 2H), 3.83 (dd, J = 6.6, 1.1 Hz, 6H), 3.55 (d, J = 13.5 Hz, 1H), 3.30 (d, J = 13.5 Hz, 1H). 19 F NMR (376 MHz, CD2Cl2) δ -63.31. 13 C NMR (100 MHz, CD2Cl2) δ 172.30, 160.43, 159.39, 139.16, 138.74, 132.76, 132.62 (q, J = 33.6 Hz), 128.93 (q, J = 3.8 Hz), 128.60, 124.85 (m), 124.04 (q, J = 272.6 Hz), 117.83, 113.88, 75.16, 55.64, 52.90, 45.03. HRMS (ESI-TOF) m / z calcd. for C 22 H 20 F6NO3 ([M+H] + )460.1342, found: 460.1337.

[0174] Example 11: Synthesis of (E)-methyl 2-((3,5-bis(trifluoromethyl)benzylidene)amino)- 2-(4-methoxybenzyl)but-3-enoate (S 12 ) from 2-benzylamino-3-(4-methoxyphenyl)propanoic acid as a yellow liquid.

[0175]

[0176] White solid as compound S was obtained following general procedure A starting from 2-benzylamino-2-phenylacetic acid or following procedure B starting from 2-amino-2-phenylacetic acid methyl ester hydrochloride 12 .

[0177] 1 H NMR (400 MHz, CD2Cl2) δ 8.32 (s, 2H), 8.19 (dd, J = 4.3, 1.9 Hz, 1H), 8.00 (s, 1H), 7.50 - 7.31 (m, 5H), 6.46 (ddt, J = 17.9, 10.7, 2.4 Hz, 1H), 5.68 - 5.47 (m, 1H), 5.33 (ddt, J = 17.4, 2.9, 1.5 Hz, 1H), 3.79 (dd, J = 3.5, 1.5 Hz, 3H). 19 F NMR (376 MHz, CD2Cl2) δ -63.31. 13 CNMR (100 MHz, CD2Cl2) δ 172.24, 160.99, 140.34, 139.09, 138.88, 132.62 (q, J = 33.6 Hz), 129.20, 129.13 (d, J = 4.0 Hz), 128.77, 128.64, 125.03 (q, J = 3.8 Hz), 123.93 (q, J = 272.7 Hz), 118.59, 77.90, 53.42. HRMS (ESI-TOF) m / z calcd for C 20 H 16 F6NO2([M+H] + ) 416.1080, found: 416.1075.

[0178] Example 13: Synthesis of (E)-methyl 2-((3,5-bis(trifluoromethyl)benzylidene)amino)-2- (4-fluorophenyl)but-3-enoate (S 13 ) 416.1080, found: 416.1075.

[0179]

[0180] White solid as compound S was obtained following general procedure A starting from 2-benzylamino-2-(4-fluorophenyl)acetic acid 13 .

[0181] 1H NMR (400 MHz, CD2CI2) δ 8.38 (s, 2H), 8.28 (s, 1H), 8.06 (s, 1H), 7.61 - 7.43 (m, 2H), 7.17 (t, J = 8.7 Hz, 2H), 6.45 (dd, J = 17.4, 10.6 Hz, 1H), 5.60 (dd, J = 10.6, 1.0 Hz, 1H), 5.35 (dd, J = 17.4, 1.0 Hz, 1H), 3.83 (s, 3H). 19 F NMR (376 MHz, CD2CI2) δ -63.32, -114.82. 13 CNMR (100 MHz, CD2CI2) δ 172.04, 163.10 (d, J = 246.5 Hz), 161.09, 138.92, 138.76, 136.38 (d, J = 3.1 Hz), 132.65 (q, J = 33.7 Hz), 130.57 (d, J = 8.0 Hz), 129.17 (q, J = 3.7 Hz), 125.16 (m), 123.92 (q, J = 272.7 Hz), 119.01, 115.91 (d, J = 21.3 Hz), 77.34, 53.51. HRMS (ESI-TOF) m / z calcd for C 20 H 15 F7NO2([M+H] + ) 434.0986, found: 434.0981.

[0182] Example 14: Synthesis of (E)-methyl 2-((3,5-bis(trifluoromethyl)benzylidene)amino)-2- (4-chlorophenyl)but-3-enoate (S 14 ) according to general procedure A from 2-benzylamino-2-(4-chlorophenyl)acetic acid as a white solid.

[0183]

[0184] according to general procedure A from 2-benzylamino-2-(4-chlorophenyl)acetic acid as a white solid. 14 .

[0185] 1 H NMR (500 MHz, CD2CI2) δ 8.33 (d, J = 1.7 Hz, 2H), 8.25 (s, 1H), 8.01 (s, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.7 Hz, 2H), 6.38 (dd, J = 17.3, 10.7 Hz, 1H), 5.56 (d, J = 10.6 Hz, 1H), 5.29 (d, J = 17.3 Hz, 1H), 3.78 (s, 3H). 19F NMR (471MHz, CD2Cl2) δ -63.31. 13 CNMR(126MHz,CD2Cl2)δ171.80,161.20,139.19,138.68,138.64,134.56,132.63(q,J=33.3Hz),13 0.17,129.20,129.15,125.18(m),123.88(q,J=272.6Hz),119.22,77.34,53.55.HRMS(ESI-TOF)m / z calcd.for C 20 H 15 ClF6NO2([M+H) + )450.0690,found:450.0685.

[0186] Example 15: (E)-2-((3,5-bis(trifluoromethyl)benzyl)amino)-2-vinylpentanoic acid dimethyl ester (S 15 Synthesis of

[0187]

[0188] Using dimethyl glutamic acid hydrochloride as a raw material, a yellow liquid was obtained by following the general procedure B, which is compound S. 15 .

[0189] 1 H NMR (400MHz, CD3Cl) δ8.40(d,J=1.1Hz,1H),8.19(d,J=1.9Hz,2H),7.88(s,1H),5.93(ddd,J=17.5,10.7,1.1H z,1H),5.59–4.97(m,2H),3.73(d,J=1.2Hz,3H),3.58(d,J=1.2Hz,3H),2.61–2.37(m,3H),2.31–2.20(m,1H). 19 F NMR (376MHz, CD2Cl2) δ -63.10. 13 C NMR(100MHz,CD3Cl)δ173.71,171.64,160.11,138.10,137.28,132.97–131.17(m),128.40(p,J=3.7Hz), 127.39–118.86(m),124.34(p,J=3.9Hz),118.28,73.06,52.60,51.49,33.42,29.17.HRMS(ESI-TOF)m / z calcd.for C 18 H 18F6NO4([M+H] + ) 426.1135, found: 426.1130.

[0190] Example 16: Synthesis of (E)-2-((3,5-bis(trifluoromethyl)benzylidene)amino)-2- ethylvinylsuccinic acid dimethyl ester (S 16 ) 426.1135, found: 426.1130.

[0191]

[0192] General procedure B using aspartic acid dimethyl ester hydrochloride as starting material gave a yellow liquid as compound S 16 .

[0193] 1 H NMR (400 MHz, CD3Cl) δ 8.49 (s, 1H), 8.22 (s, 2H), 7.93 (s, 1H), 6.11 (dd, J = 17.5, 10.8 Hz, 1H), 5.52 - 5.20 (m, 2H), 3.81 (s, 3H), 3.69 (s, 3H), 3.25 (d, J = 16.2 Hz, 1H), 3.07 (d, J = 16.2 Hz, 1H). 19 F NMR (376 MHz, CD2Cl2) δ -63.00. 13 C NMR (100 MHz, CD3Cl) δ 171.19, 170.68, 160.51, 138.01, 136.89, 132.24 (q, J = 33.7 Hz), 128.55 (d, J = 2.9 Hz), 124.37 (p, J = 3.7 Hz), 123.30 (q, J = 273.0 Hz), 118.32, 71.30, 52.99, 51.93, 42.89. HRMS (ESI-TOF) m / z calcd for C 17 H 16 F6NO4([M+H] + ) 412.0978, found: 412.0973.

[0194] Example 17: Synthesis of (E)-2-((3,5-bis(trifluoromethyl)benzylidene)amino)-2- (tert-butoxymethyl)but-3-enoic acid methyl ester (S 17 ) 412.0978, found: 412.0973.

[0195]

[0196] General procedure B using O-(tert-butyl)serine methyl ester hydrochloride as starting material gave a yellow liquid as compound S 17 .

[0197] 1 H NMR (400 MHz, CD3Cl) δ 8.52 (d, J = 1.1 Hz, 1H), 8.26 (s, 2H), 7.93 (s, 1H), 6.17 (ddd, J = 17.4, 10.7, 1.1 Hz, 1H), 5.80 - 5.18 (m, 2H), 3.88 (dd, J = 8.8, 1.1 Hz, 1H), 3.79 (d, J = 1.1 Hz, 3H), 3.69 (dd, J = 8.8, 1.1 Hz, 1H), 1.14 (s, 9H). 19 F NMR (376 MHz, CD3Cl) δ -62.99. 13 C NMR (100 MHz, CD3Cl) δ 171.54, 160.77, 138.64, 136.20, 132.22 (q, J = 33.7 Hz), 128.38 (q, J = 3.8 Hz), 124.29 (p, J = 4.0 Hz), 123.33 (q, J = 272.7 Hz), 118.37, 73.72, 73.68, 65.82, 52.55, 27.51. HRMS (ESI-TOF) m / z calcd for C 19 H 22 F6NO3([M+H] + ) 426.1498, found: 426.1493.

[0198] According to the reaction mechanism of the addition of various radicals to the olefin in the imine substrate again migration, the present application provides the following route to prepare β-amino acid ester.

[0199] Route C:

[0200]

[0201] General procedure C:

[0202] In a 40 mL reaction vial with magnetic stirring bar, Ir[ppy]2(dtbbpy)PF6(8 mg, 0.003 mmol), imine substrate (0.3 mmol), sodium sulfinic acid substrate (0.45 mmol), acetonitrile (18 mL) were added successively, the vial was tightly capped, bubbled with nitrogen for 10 minutes, and irradiated with a Kessil lamp (power 40 W, wavelength 440 nm) at room temperature for 15 hours with stirring. After the reaction was completed, ethyl acetate was added to the system, washed with water and saturated brine respectively, and the organic phase was combined and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the intermediate product was separated by column chromatography. The intermediate product was placed in a reaction vial containing 1N HC1 (1.5 mL) and tetrahydrofuran (3 mL), and stirred for 6 hours. After the reaction was completed, 10 mL of water was added, washed twice with n-hexane (3 mL), and the water phase was combined and concentrated under reduced pressure to obtain the amino acid product.

[0203] Scheme D:

[0204]

[0205] General procedure D:

[0206] In a 20 mL reaction vial with magnetic stirring bar, Eosin Y Na (62 mg, 0.003 mmol), imine substrate (0.3 mmol), sodium sulfinic acid substrate (0.6 mmol), water (0.135 mL), dimethyl sulfoxide (9 mL) were added successively, the vial was tightly capped, bubbled with nitrogen for 10 minutes, and irradiated with a Kessil lamp (power 40 W, wavelength 440 nm) at room temperature for 15 hours with stirring. After the reaction was completed, ethyl acetate was added to the system, washed with water and saturated brine respectively, and the organic phase was combined and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the intermediate product was separated by column chromatography. The intermediate product was placed in a reaction vial containing 2N HC1 (2 mL) and tetrahydrofuran (2 mL), and stirred for 6 hours. After the reaction was completed, 10 mL of water was added, washed twice with n-hexane (3 mL), and the water phase was combined and concentrated under reduced pressure to obtain the amino acid product.

[0207] In general procedures C and D, the sodium sulfinic acid substrate can be:

[0208]

[0209] Scheme E:

[0210]

[0211] General procedure E:

[0212] In an 8 mL reaction vial with magnetic stirring bar, 4CzIPN (2.4 mg, 0.003 mmol), imine substrate (0.3 mmol), potassium carbonate (0.6 mmol), diaryl phosphine oxide (0.6 mmol), acetonitrile (7.5 mL) were added successively, the vial was tightly capped, bubbled with nitrogen for 10 min, and then sealed with parafilm. The reaction was irradiated with a Kessil lamp (power 40 W, wavelength 440 nm) at room temperature for 24 h with stirring. After the reaction was completed, ethyl acetate was added to the system, washed with water and saturated brine respectively, and the organic phase was combined and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the intermediate product was separated by column chromatography. The intermediate product was placed in a reaction vial containing 1 N HC1 (1.5 mL) and tetrahydrofuran (3 mL), and stirred for 6 h. After the reaction was completed, 10 mL of water was added, washed twice with n-hexane (3 mL), and the water phase was combined and concentrated under reduced pressure to obtain the amino acid product.

[0213] In general procedure E, the diaryl phosphine oxide substrate can be:

[0214]

[0215] Scheme F:

[0216]

[0217] General procedure F:

[0218] In an 8 mL reaction vial with magnetic stirring bar, Ir[dF(CF3)ppy]2(dtbbpy)PF6 (3.4 mg, 0.003 mmol), imine substrate (1.5 mmol), potassium carbonate (0.6 mmol), (TMS)3SiNH-Ad (0.3 mmol), aryl bromide substrate (0.3 mmol), acetonitrile (1.5 mL) were added successively, the vial was tightly capped, bubbled with nitrogen for 10 min, and then sealed with parafilm. The reaction was irradiated with a Kessil lamp (power 40 W, wavelength 440 nm) at room temperature for 2 h with stirring. After the reaction was completed, ethyl acetate was added to the system, washed with water and saturated brine respectively, and the organic phase was combined and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the intermediate product was separated by column chromatography. The intermediate product was placed in a reaction vial containing 1 N HC1 (1.5 mL) and tetrahydrofuran (3 mL), and stirred for 6 h. After the reaction was completed, 10 mL of water was added, washed twice with n-hexane (3 mL), and the water phase was combined and concentrated under reduced pressure to obtain the amino acid product.

[0219] In general procedure F, the aryl bromide substrate can be:

[0220]

[0221] Example 18: Methyl 3-amino-5,5,5-trifluoro-2-methylpentanoate hydrochloride

[0222]

[0223] With compounds S1 and S 18 Following general procedure C, a white solid (52 mg, 74% yield, 2.9:1 dr) was obtained as methyl 3-amino-5,5,5-trifluoro-2-methylvalerate hydrochloride.

[0224] 1 H NMR (400MHz, D2O) δ4.12–4.00(m,1H),3.80(s,3H),3.21–3.08(m,1H),2.87–2.66(m,2H),1.34(dd,J=12.1,7.4Hz,3H). 19 F NMR(376MHz,D2O)δ-64.01,-64.23. 13 C NMR(100MHz,D2O)δ174.57,174.39,125.55(q,J=276.5Hz),52.99,52.97,47.41(d,J=2.8Hz),47.03(d ,J=2.7Hz),41.17,40.89,33.83(q,J=29.3Hz),33.45(q,J=29.4Hz),11.98,11.08.HRMS(ESI-TOF)m / z calcd.for C7H 13 F3NO2([M+H) + )200.0893,found:200.0888.

[0225] Figures 18-19 The NMR spectra are 1H NMR, 1C NMR, and fluorine NMR for methyl 3-amino-5,5,5-trifluoro-2-methylvalerate hydrochloride.

[0226] Example 19: Methyl 3-amino-2-ethyl-5,5,5-trifluorovalerate hydrochloride

[0227]

[0228] With compounds S2 and S 18 Following standard procedure C, a white solid (57 mg, 76% yield, 3.0:1 dr) was obtained as methyl 3-amino-2-ethyl-5,5,5-trifluorovalerate hydrochloride.

[0229] 1H NMR (400 MHz, D20) δ 4.01 (td, J = 7.8, 3.7 Hz, 1H), 3.82 (d, J = 2.2 Hz, 3H), 2.94 (td, J = 9.8, 5.0 Hz, 1H), 2.89 - 2.65 (m, 2H), 1.93 - 1.60 (m, 2H), 1.09 - 0.91 (m, 3H). 19 F NMR (376 MHz, D20) δ -63.83, -64.09. 13 C NMR (100 MHz, D20) δ 174.23, 174.11, 125.62 (q, J = 276.7 Hz), 52.92, 52.89, 46.44 (dd, J = 5.6, 2.7 Hz), 34.45 (q, J = 29.2 Hz), 33.25 (q, J = 29.5 Hz), 21.46, 20.68, 10.90, 10.63. HRMS (ESI-TOF) m / z calcd for C8H 15 F3NO2([M+H] + ) 214.1049, found: 214.1047.

[0230] Example 20: 3-Amino-5,5,5-trifluoro-2-isopropylpentanoic acid methyl ester hydrochloride

[0231]

[0232] Following General Procedure C, compound S3 and S 18 were used as substrates to give yellow solid (62 mg, 78% yield, 2.9:1 dr) of 3-amino-5,5,5-trifluoro-2-isopropylpentanoic acid methyl ester hydrochloride.

[0233] 1 H NMR (400 MHz, D20) δ 4.05 (ddd, J = 14.9, 10.5, 5.7 Hz, 1H), 3.83 (d, J = 5.8 Hz, 3H), 2.99 - 2.61 (m, 3H), 2.20 - 1.98 (m, 1H), 1.06 (dd, J = 15.3, 6.7 Hz, 3H), 0.98 (d, J = 6.6 Hz, 3H). 19 F NMR (376 MHz, D20) δ -63.80, -64.00. 13C NMR (100 MHz, D20) δ 174.10, 173.28, 125.76 (q, J = 276.7 Hz), 125.35 (q, J = 276.4 Hz), 53.94, 53.89, 52.78, 52.76, 45.51 (q, J = 2.9 Hz), 45.13 (d, J = 3.0 Hz), 35.16 (q, J = 29.6 Hz), 32.63 (q, J = 29.4 Hz), 27.14, 26.89, 19.45, 19.42, 19.35, 19.20. HRMS (ESI-TOF) m / z calcd for C9H 17 F3NO2([M+H] + ) 228.1206, found: 228.1202.

[0234] Example 21: 3-Amino-5,5,5-trifluoro-2-pentanoic acid propyl ester hydrochloride

[0235]

[0236] Following General Procedure C, compound S4 and S 18 were used as substrates to give white solid (65 mg, 82% yield, 3.4: 1 dr) of 3-amino-5,5,5-trifluoro-2-pentanoic acid propyl ester hydrochloride.

[0237] 1 H NMR (400 MHz, D20) δ 4.10 - 3.94 (m, 1H), 3.82 (s, 3H), 3.03 (d, J = 4.3 Hz, 1H), 2.79 (dd, J = 20.5, 10.1 Hz, 2H), 1.88 - 1.53 (m, 2H), 1.53 - 1.28 (m, 2H), 0.95 (t, J = 7.0 Hz, 3H). 19 F NMR (376 MHz, D20) δ -63.81, -64.07. 13 C NMR (100 MHz, D20) δ 174.37, 174.28, 125.63 (q, J = 276.7 Hz), 52.94, 46.67 (q, J = 4.5, 2.8 Hz), 46.56, 46.32, 34.50 (q, J = 29.5 Hz), 33.27 (q, J = 29.3 Hz), 30.02, 29.23, 19.87, 19.69, 12.96, 12.92. HRMS (ESI-TOF) m / z calcd for C9H 17 F3NO2([M+H] + ) 228.1206, found: 228.1205.

[0238] Example 22: Methyl 3-amino-5,5,5-trifluoro-2-isobutylvalerate hydrochloride

[0239]

[0240] With compounds S5 and S 18 Following standard procedure C, a white solid (73 mg, 88% yield, 6.1:1 dr) was obtained as methyl 3-amino-5,5,5-trifluoro-2-isobutylvalerate hydrochloride.

[0241] 1 H NMR(400MHz,D2O)δ3.99(dt,J=9.3,3.6Hz,1H),3.82(s,3H),3.09(ddt,J=13.0,9.4,4.5Hz,1H),2.94–2.65(m,2H),1.7 6(ddd,J=13.5,9.7,5.8Hz,1H), 1.65(dq,J=8.4,6.2Hz,1H), 1.41(ddd,J=13.3,8.3,4.9Hz,1H), 0.95(d,J=6.6Hz,6H). 19 F NMR(376MHz,D2O)δ-64.03,-64.24. 13 C NMR(100MHz,D2O)δ174.40,125.61(q,J=276.6Hz),52.95,46.92(d,J=2.8Hz) ,44.71,36.03,33.21(q,J=29.4Hz),25.37,21.95,20.91.HRMS(ESI-TOF)m / z calcd.for C 10 H 19 F3NO2([M+H) + )242.1362,found:342.1358.

[0242] Example 23: Methyl 3-amino-2-cyclohexyl-5,5,5-trifluorovalerate hydrochloride

[0243]

[0244] With compounds S6 and S 18 Following standard procedure C, a white solid (65 mg, 72% yield, 1.5:1 dr) was obtained as methyl 3-amino-2-cyclohexyl-5,5,5-trifluorovalerate hydrochloride.

[0245] 1H NMR (400MHz, D2O) δ4.19–4.02(m,1H),3.83(d,J=5.1Hz,3H),3.02–2.62(m,3H),1.94–1.53(m,6H),1.40–0.99(m,5H). 19 F NMR(376MHz,D2O)δ-63.79,-63.97. 13 C NMR(100MHz,D2O)δ174.16,173.41,125.77(q,J=276.3Hz),125.53(q,J=276.4Hz),53.11,53.08,52.72,44.87(d,J=2.9Hz),44.25(q,J=3.1Hz ),35.95,35.89,35.18(q,J=29.2Hz),32.54(q,J=29.3Hz),30.34,30.29,29.77,29.65,25.46,25.40,25.33,25.28,25.19.HRMS(ESI-TOF)m / z calcd.for C 12 H 21 F3NO2([M+H) + )268.1519,found:268.1516.

[0246] Example 24: Methyl 3-amino-5,5,5-trifluoro-2-phenylethylpentanoate hydrochloride

[0247]

[0248] With compounds S7 and S 18 Following general procedure C, a white solid (60 mg, 61% yield, 5.4:1 dr) was obtained as methyl 3-amino-5,5,5-trifluoro-2-phenylethylpentanoate hydrochloride.

[0249] 1 H NMR(400MHz,D2O)δ7.40(t,J=7.4Hz,2H),7.31(t,J=6.1Hz,3H),4.02–3.89(m,1H),3.77(d ,J=6.9Hz,3H),3.06–2.91(m,1H),2.86–2.63(m,4H),2.25–2.06(m,1H),2.02–1.83(m,1H). 19 F NMR(376MHz,D2O)δ-63.94,-64.22. 13C NMR (100 MHz, D20) δ 173.88, 173.81, 140.60, 140.44, 128.81, 128.69, 126.91, 126.58, 52.95, 52.26, 46.75 (d, J = 3.2 Hz), 46.22, 45.89, 33.13 (q, J = 29.5 Hz), 32.56, 32.32, 29.49, 28.71. HRMS (ESI-TOF) m / z calcd for C 14 H 19 F3NO2([M+H] + ) 290.1362, found: 290.1357.

[0250] Example 25: 3-Amino-5,5,5-trifluoro-2-(thiophen-2-ylmethyl)pentanoic acid methyl ester hydrochloride

[0251]

[0252] Following General Procedure C with compound S8 and S 18 as substrates gave brown solid (43 mg, 45% yield, 2.8: 1 dr) of 3-amino-5,5,5-trifluoro-2-(thiophen-2-ylmethyl)pentanoic acid methyl ester hydrochloride.

[0253] 1 H NMR (400 MHz, D20) δ 7.36 (d, J = 6.4 Hz, 1H), 7.12 - 6.90 (m, 2H), 4.00 - 3.88 (m, 1H), 3.76 (d, J = 5.5 Hz, 3H), 3.46 - 3.30 (m, 2.21H), 3.25 - 3.17 (m, 0.79H), 3.00 - 2.62 (m, 2H). 19 F NMR (376 MHz, D20) δ -63.88, -64.14. 13 C NMR (101 MHz, D20) δ 172.94, 172.58, 138.94, 138.46, 127.52, 127.49, 126.93, 125.51, 125.43, 125.42 (q, J = 255.5 Hz), 53.13, 53.11, 49.19, 49.08, 46.13 (d, J = 3.1 Hz), 45.97 (d, J = 3.0 Hz), 34.61 (q, J = 29.8 Hz), 32.71 (q, J = 29.6 Hz), 28.16, 27.50. HRMS (ESI-TOF) m / z calcd for C 11 H 15 F3NO2S([M+H]+ ) 282.0770, found: 282.0767.

[0254] Example 26: 3-Amino-2-benzyl-5,5,5-trifluoropentanoic acid methyl ester hydrochloride

[0255]

[0256] Following General Procedure C with compound S9 and S 18 as substrates gave white solid (52 mg, 56%, 1.8:1 dr) of 3-amino-2-benzyl-5,5,5- trifluoropentanoic acid methyl ester hydrochloride.

[0257] 1 H NMR (400 MHz, D20) δ 7.38 (t, J = 7.4 Hz, 2H), 7.29 (dt, J = 16.5, 7.6 Hz, 3H), 3.97 - 3.83 (m, 1H), 3.65 (d, J = 11.9 Hz, 3H), 3.30 (dddd, J = 26.1, 8.5, 6.7, 4.0 Hz, 1H), 3.16 - 3.03 (m, 1.34H), 2.97 - 2.68 (m, 2.66H). 19 F NMR (376 MHz, D20) δ -63.88, -64.11. 13 C NMR (100 MHz, D20) δ 173.21, 173.07, 136.94, 136.75, 129.02, 128.90, 128.86, 127.40, 127.33, 125.56 (q, J = 276.6 Hz), 52.92, 52.89, 49.09, 48.71, 46.51 (d, J = 3.1 Hz), 46.16 (d, J = 3.1 Hz), 34.70 (q, J = 29.3 Hz), 34.08, 32.93 (q, J = 29.5 Hz), 33.13. HRMS Calcd for C 13 H 17 F3NO2[M+H + ]: 276.1206, Found: 276.1201.

[0258] Example 27: 3-Amino-5,5,5-trifluoro-2-(4-methylbenzyl)pentanoic acid methyl ester hydrochloride

[0259]

[0260] Following General Procedure C with compound S 10 and S 18Following general procedure C, a white solid (68 mg, 70%, 2.4:1 dr) was obtained as methyl 3-amino-5,5,5-trifluoro-2-(4-methylbenzyl)valerate hydrochloride.

[0261] 1 H NMR(500MHz,D2O)δ7.15(d,J=9.1Hz,4H),4.01–3.82(m,1H),3.67(d,J=17.2Hz,3H),3.29(dddd, J=49.8,8.6,6.9,4.3Hz,1H),3.13–3.00(m,1.28H),2.96–2.71(m,2.72H),2.25(d,J=3.0Hz,3H). 19 F NMR(471MHz,D2O)δ-63.71,-64.00. 13 C NMR(126MHz,D2O)δ173.11,172.96,137.27,137.21,133.71,133.58,129.49,128.80,128.75,125.58(q,J=276.6Hz),52.86,52.81,49 .09,48.68,46.49(d,J=2.5Hz),46.13(d,J=2.3Hz),34.64(q,J=29.4Hz),33.72,32.90(q,J=29.4Hz),32.76,20.12.HRMS(ESI-TOF)m / z calcd.forC 14 H 19 F3NO2([M+H) + )290.1362,found:290.1357.

[0262] Example 28: Methyl 3-amino-5,5,5-trifluoro-2-(4-methoxybenzyl)valerate hydrochloride

[0263]

[0264] With compound S 11 and S 18 Following general procedure C, a grayish-white solid (74 mg, 72% yield, 1.8:1 dr) was obtained as methyl 3-amino-5,5,5-trifluoro-2-(4-methoxybenzyl)valerate hydrochloride.

[0265] 1H NMR (400 MHz, D20) δ 7.22 (t, J = 8.0 Hz, 2H), 7.04 - 6.84 (m, 2H), 3.97 - 3.87 (m, 1H), 3.80 (s, 3H), 3.69 (dd, J = 12.3, 1.3 Hz, 3H), 3.41 - 3.19 (m, 1H), 3.14 - 2.71 (m, 4H). 19 F NMR (376 MHz, D20) δ -63.80, -64.07. 13 C NMR (100 MHz, D20) δ 173.24, 173.08, 157.97, 157.92, 130.11, 130.08, 129.32, 129.17, 125.56 (q, J = 276.6 Hz), 125.33 (q, J = 276.6 Hz), 55.36, 52.89, 52.85, 49.26, 48.86, 46.46 (d, J = 2.8 Hz), 46.12 (d, J = 2.7 Hz), 34.68 (q, J = 29.3 Hz), 33.30, 32.92 (q, J = 29.3 Hz), 32.33. HRMS (ESI-TOF) m / z calcd for C 14 H 19 F3NO3([M+H] + ) 306.1312, found: 306.1307.

[0266] Example 29: 3-amino-5,5,5-trifluoro-2-(4-fluorophenyl)pentanoic acid methyl ester hydrochloride

[0267]

[0268] with compounds S 13 and S 18 as substrates according to general procedure C to give diastereoisomers separable as white solids (65 mg, 72%, 1.5:1 dr).

[0269] wherein one fraction 12a (26 mg, 29%). 1 H NMR (400 MHz, D20) δ 7.39 (dd, J = 8.6, 5.3 Hz, 2H), 7.22 (t, J = 8.8 Hz, 2H), 4.44 - 4.36 (m, 1H), 4.28 (d, J = 9.0 Hz, 1H), 3.77 (s, 3H), 2.73 - 2.47 (m, 2H). 19 F NMR (376 MHz, D20) δ -63.59, -112.85. 13C NMR (100 MHz, D20) δ 172.38, 162.82 (d, J = 246.3 Hz), 130.72 (d, J = 8.7 Hz), 128.45 (d, J = 3.3 Hz), 125.46 (dd, J = 553.2, 276.7 Hz), 116.57 (d, J = 21.9 Hz), 53.44, 51.79, 47.46 (d, J = 1.8 Hz), 33.64 (q, J = 29.6 Hz). HRMS (ESI-TOF) m / z calcd for C 12 H 21 F3NO2([M+H] + ) 280.0955, found: 280.0950.

[0270] Another fraction 12b (39 mg, 43%). 1 H NMR (400 MHz, D20) δ 7.43 (dd, J = 8.7, 5.2 Hz, 2H), 7.25 (t, J = 8.8 Hz, 2H), 4.39 (td, J = 8.4, 3.3 Hz, 1H), 4.30 (d, J = 7.2 Hz, 1H), 3.77 (s, 3H), 2.95 - 2.63 (m, 2H). 19 F NMR (376 MHz, D20) δ -63.54, -112.44. 13 C NMR (100 MHz, D20) δ 172.35, 163.05 (d, J = 246.7 Hz), 131.09 (d, J = 8.7 Hz), 127.29 (d, J = 3.2 Hz), 125.39 (q, J = 276.5 Hz), 116.73 (d, J = 22.0 Hz), 53.36, 51.60, 47.26, 34.35 (q, J = 29.5 Hz). HRMS (ESI-TOF) m / z calcd for C 12 H 21 F3NO2([M+H] + ) 280.0955, found: 280.0950.

[0271] Example 30: (E)-2-(l-((3,5-bis(trifluoromethyl)benzylidene)amino)-3,3,3- trifluoropropyl)dimethyl pentanedioate

[0272]

[0273] with compounds S 15 and S 18The substrate was reacted according to standard procedure C (note: no acidification required) to yield a pale yellow liquid (98 mg, 66%, 3.6:1 dr).

[0274] 1 H NMR (400MHz, CD3Cl) δ8.33(d,J=10.0Hz,1H),8.17(dd,J=10.2,1.5Hz,2H),7.93(s,1H),3.92–3.78(m,1H),3.73(s,2.4H),3.65(d ,J=8.6Hz,3.6H),2.75(q,J=7.3Hz,1H),2.70–2.58(m,1.2H),2.53–2.25(m,2.8H),2.09–1.94(m,0.5H),1.88(q,J=7.5Hz,1.5H). 19 F NMR (376MHz, CDCl3) δ-63.05,-63.07,-63.09,-63.18. 13 C NMR (100MHz, CDCl3) δ173.32,173.11,173.09,172.80,160.09,159.88,137.52,137.4 6,132.40(q,J=33.5Hz),128.44(d,J=4.0Hz),126.22(q,J=277.5Hz),124.78–124.52( m),121.85,119.14,66.56(d,J=2.9Hz),66.23(d,J=2.4Hz),52.16,52.00,51.86,51. 82,50.03,49.84,37.85(q,J=27.1Hz),31.62,31.55,23.83,23.64.HRMS(ESI-TOF)m / z calcd.forC 19 H 19 F9NO4([M+H) + )496.1165,found:496.1157.

[0275] Example 31: (E)-2-(1-((3,5-bis(trifluoromethyl)benzyl)amino)-3,3,3-trifluoropropyl)dimethyl succinate

[0276]

[0277] With compound S 16 and S 18 The substrate was reacted according to standard procedure C (note: no acidification required) to yield a pale yellow oil (121 mg, 84%, 2.1:1 dr).

[0278] 1 H NMR (400 MHz, CD3Cl) δ 8.35 (d, J = 16.2 Hz, 1H), 8.16 (d, J = 2.0 Hz, 2H), 7.94 (s, 1H), 4.07 - 3.88 (m, 1H), 3.74 (d, J = 10.6 Hz, 3H), 3.66 (d, J = 14.0 Hz, 3H), 3.21 (ddt, J = 13.5, 11.7, 4.7 Hz, 1H), 2.80 (dd, J = 16.9, 9.0 Hz, 1H), 2.72 - 2.46 (m, 3H). 19 F NMR (376 MHz, CDCl3) δ -63.10, -63.11, -63.12, -63.43. 13 C NMR (100 MHz, CDCl3) δ 172.51, 172.03, 171.88, 137.33, 132.43 (q, J = 33.8 Hz), 128.48, 128.44, 128.40, 127.66, 127.47, 125.0 - 124.7 (m), 123.18 (q, J = 272.9 Hz), 65.36 (d, J = 2.3 Hz), 65.06 (q, J = 2.7 Hz), 52.46, 52.42, 52.11, 52.06, 46.73, 46.56, 38.12 (q, J = 27.4 Hz), 37.21 (q, J = 27.4 Hz), 32.29, 32.03. HRMS (ESI-TOF) m / z calcd for C 18 H 17 F9NO4 ([M+H] + ) 482.1008, found: 482.1000.

[0279] Example 32: (E)-3-((3,5-bis(trifluoromethyl)benzylidene)amino)-2-tert- butoxymethyl-5,5,5-trifluoropentanoic acid methyl ester

[0280]

[0281] Compound S 17 and S 18 was obtained as yellow oil (110 mg, 74%, 2.3:1 dr) following the general procedure C (note: no acidification).

[0282] 1H NMR (400 MHz, CD3Cl) δ 8.36 (d, J = 8.8 Hz, 1H), 8.17 (d, J = 11.7 Hz, 2H), 7.93 (d, J = 4.2 Hz, 1H), 4.07 (dddd, J = 12.4, 8.9, 7.2, 2.9 Hz, 1H), 3.73 (d, J = 1.4 Hz, 2H), 3.71 - 3.58 (m, 2H), 3.49 (ddd, J = 14.5, 9.0, 6.3 Hz, 1H), 2.89 (qd, J = 5.3, 2.8 Hz, 1H), 2.81 - 2.52 (m, 2H), 1.14 (d, J = 29.9 Hz, 9H). 19 F NMR (376 MHz, CDCl3) δ -63.03, -63.06, -63.12. 13 C NMR (100 MHz, CDCl3) δ 172.43, 171.84, 159.98, 159.87, 137.75, 137.72, 132.42 (q, J = 33.8 Hz), 128.30, 128.26, 127.91, 127.31, 125.15, 125.06, 124.60 - 124.47 (m), 121.89, 119.18, 73.65, 73.33, 63.82 (d, J = 2.7 Hz), 63.43 (d, J = 2.2 Hz), 59.64, 59.32, 52.01, 51.85, 51.04, 50.77, 38.12 (q, J = 26.8 Hz), 27.49, 27.42. HRMS (ESI-TOF) m / z calcd for C 20 H 23 F9NO3([M+H] + ) 496.1529, found: 496.1526.

[0283] Example 33: 3-amino-5,5-difluoro-2-isobutylpentanoic acid methyl ester hydrochloride

[0284]

[0285] Following General Procedure C, compound S5 and S 19 were used as substrates to give a white solid (28 mg, 36%, 7.1:1 dr).

[0286] 1H NMR (500 MHz, D20) δ 6.24 (t, J = 55.2 Hz, 1H), 3.93 (td, J = 8.0, 4.0 Hz, 1H), 3.82 (s, 3H), 3.16 - 2.98 (m, 1H), 2.51 - 2.25 (m, 2H), 1.84 - 1.70 (m, 1H), 1.67 - 1.58 (m, 1H), 1.50 - 1.35 (m, 1H), 0.95 (d, J = 6.6 Hz, 6H). 19 F NMR (471 MHz, D20) δ -82.22, -113.65, -124.96, -126.71. 13 C NMR (126 MHz, D20) δ 174.74, 115.60 (t, J = 238.1 Hz), 52.91, 47.04 (t, J = 5.1 Hz), 44.98, 36.08, 33.26 (t, J = 21.5 Hz), 25.43, 22.07, 20.91. HRMS (ESI-TOF) m / z calcd for C 10 H 20 ClF2NO2 ([M+H] + ) 224.1457, found: 224.1454.

[0287] Example 34: 3-amino-5,5,6,7,7,8,8-heptafluoro-2-isooctanoic acid methyl ester hydrochloride

[0288]

[0289] Following general procedure C, compound S5 and S 20 were used as substrates to give a white solid (58 mg, 45%, 3.6:1).

[0290] 1 H NMR (500 MHz, D20) δ 4.20 - 3.91 (m, 1H), 3.78 (d, J = 7.9 Hz, 3H), 3.18 - 2.99 (m, 1H), 2.95 - 2.47 (m, 2H), 1.83 - 1.46 (m, 2.2H), 1.37 - 1.26 (m, 0.8H), 0.91 (dd, J = 13.7, 6.5 Hz, 6H). 19 F NMR (471 MHz, D20) δ -82.22, -113.65, -124.96, -126.71. 13C NMR (126 MHz, D20) δ 173.83, 173.72, 119.99 - 114.81 (m), 52.74, 52.51, 46.13, 45.75, 44.44, 37.20, 35.82, 30.07 (t, J = 21.2 Hz), 25.31, 25.28, 21.74, 21.35, 20.75, 20.64. HRMS (ESI-TOF) m / z calcd for C 13 H 19 F9 NO2([M+H] + ): 392.1267, found: 392.1262.

[0291] Example 35: 3-amino-2-phenyl-4-(phenylsulfonyl)butanoic acid methyl ester hydrochloride

[0292]

[0293] According to general procedure D, compound S 12 and S 21 as substrates gave a white solid (56 mg, 50% yield, 1.0:1 dr).

[0294] 1 H NMR (400 MHz, D20) δ 7.91 - 7.85 (m, 1H), 7.85 - 7.78 (m, 1H), 7.78 - 7.72 (m, 1H), 7.70 - 7.58 (m, 2H), 7.47 - 7.32 (m, 2H), 7.32 - 7.24 (m, 1H), 7.24 - 7.18 (m, 1H), 7.05 - 6.98 (m, 1H), 4.35 - 4.16 (m, 1H), 3.96 - 3.80 (m, 1H), 3.73 - 3.63 (m, 3.4H), 3.56 - 3.44 (m, 0.6H). 13 CNMR (100 MHz, D20) δ 171.91, 171.72, 135.74, 135.46, 131.83, 131.26, 130.06, 130.02, 129.90, 129.84, 129.58, 129.33, 128.60, 128.22, 127.89, 54.47, 54.11, 53.44, 53.31, 52.18, 52.14, 48.24, 48.02. HRMS (ESI) m / z calculated for C 17 H 20 NO4S + ([M+H] + ): 334.1108, found 334.1102.

[0295] Example 36: Methyl 3-amino-4-((4-methoxyphenyl)sulfonyl)-2-phenylbutyrate hydrochloride

[0296]

[0297] With compound S 12 and S 24 The substrate was prepared according to standard procedure D to obtain a white solid (72 mg, 60%, 1.0:1 dr).

[0298] 1 H NMR(400MHz,D2O)δ7.75–7.68(m,1H),7.63–7.57(m,1H),7.43–7.27(m,2H),7.27–7.13(m,2H),7.08–6.94(m,3H),4.36–4 .30(m,0.5H),4.24–4.08(m,1.5H),3.94–3.83(m,3.4H),3.81–3.72(m,0.6H),3.72–3.60(m,3.4H),3.43–3.33(m,0.6H). 13 C NMR(100MHz,D2O)δ171.91,171.65,164.32,164.29,131.97,131.43,130.30,129.79,129.72,129.38,129.23,128.56,128 .17,126.99,126.92,115.21,115.19,55.95,55.91,54.56,54.39,53.44,53.27,52.13,52.10,48.55,48.20.HRMS(ESI)m / z calculated for C 18 H 22 NO5S + ([M+H)) + ):364.1213,found 364.1208.

[0299] Example 37: Methyl 3-amino-2-phenyl-4-toluenesulfonylbutyrate hydrochloride

[0300]

[0301] With compound S 12 and S 22 The substrate was prepared according to standard procedure D to obtain a white solid (65 mg, 46% yield, 1.1:1 dr).

[0302] 1H NMR (400 MHz, D20) δ 7.71 - 7.64 (m, 1H), 7.58 - 7.50 (m, 1H), 7.45 - 7.30 (m, 4H), 7.29 - 7.20 (m, 1H), 7.19 - 7.13 (m, 1H), 7.01 - 6.94 (m, 1H), 4.33 - 4.28 (m, 0.5H), 4.22 - 4.06 (m, 1.5H), 3.92 - 3.73 (m, 1.2H), 3.70 - 3.60 (m, 3.3H), 3.48 - 3.38 (m, 0.5H), 2.47 - 2.39 (m, 3H). 13 C NMR (100 MHz, D20) δ 171.92, 171.68, 147.13, 132.45, 132.29, 131.87, 131.34, 130.57, 130.53, 129.82, 129.75, 129.42, 129.23, 128.55, 128.16, 127.85, 54.45, 54.23, 53.43, 53.27, 52.15, 52.10, 48.44, 48.13, 20.90. HRMS (ESI) m / z calculated for C 18 H 22 NO4S + ([M+H] + ): 348.1264, found 348.1259.

[0303] Example 38: Methyl 3-amino-4-(benzo[D][l,3]dioxol-5-ylsulfonyl)-2- phenylbutanoate hydrochloride

[0304]

[0305] Following general procedure D, compound S 12 and S 26 as substrates afforded a white solid (65 mg, 52% yield, 1.4: 1 dr). 1H NMR (400 MHz, D20) δ 7.45 - 7.33 (m, 3H), 7.33 - 7.26 (m, 1.1H), 7.21 - 7.13 (m, 0.9H), 7.12 - 7.01 (m, 1.5H), 7.00 - 6.93 (m, 1.5H), 6.20 - 6.12 (m, 2H), 4.38 - 4.33 (m, 0.4H), 4.20 - 4.04 (m, 1.6H), 3.95 - 3.82 (m, 0.5H), 3.82 - 3.74 (m, 0.5H), 3.74 - 3.66 (m, 3H), 3.66 - 3.62 (m, 0.4H), 3.47 - 3.38 (m, 0.6H). 13 C NMR (100 MHz, D20) δ 171.97, 171.74, 153.30, 153.25, 148.52, 148.45, 132.00, 131.53, 129.71, 129.64, 129.35, 129.29, 128.60, 124.93, 124.90, 108.97, 107.22, 107.15, 103.18, 103.16, 54.41, 54.32, 53.47, 53.31, 52.17, 52.12, 48.70, 48.31. HRMS (ESI) m / z calculated for C 18 H 20 NO6S + ([M+H] + ): 378.1006, found 378.1001.

[0306] Example 39: methyl 3-amino-4-((3-chloro-4-fluorophenyl)sulfonyl)-2- phenylbutanoate hydrochloride

[0307]

[0308] with compounds S 12 and S 27 as substrates following general procedure D to give a white solid (65 mg, 51% yield, 1.1:1 dr).

[0309] 1H NMR (400 MHz, CD3OD) δ 8.05 - 7.92 (m, 1H), 7.92 - 7.80 (m, 1H), 7.55 - 7.46 (m, 1H), 7.40 - 7.26 (m, 3H), 7.25 - 7.18 (m, 1H), 7.15 - 7.07 (m, 1H), 4.41 - 4.34 (m, 0.5H), 4.24 - 4.15 (m, 1H), 4.13 - 4.03 (m, 0.5H), 3.90 - 3.75 (m, 1H), 3.75 - 3.66 (m, 3H), 3.66 - 3.56 (m, 0.5H), 3.41 - 3.33 (m, 0.5H). 13 C NMR (100 MHz, CD3OD) δ 172.42, 172.33, 164.30, 164.25, 161.74, 161.69, 136.26, 136.22, 136.14, 136.10, 134.09, 133.41, 132.36, 132.30, 130.82, 130.76, 130.73, 130.67, 130.61, 130.59, 130.19, 130.11, 129.83, 129.42, 123.93, 123.82, 123.74, 123.64, 119.40, 119.37, 119.17, 119.14, 55.84, 53.62, 53.44, 49.87. HRMS (ESI) m / z calcd for C 17 H 18 ClFNO4S + ([M+H] + ): 386.0824, found 386.0619.

[0310] Example 40: methyl 4-((2-amino-4-methoxy-4-oxo-3-phenylbutyl)sulfonyl)benzoate hydrochloride

[0311]

[0312] with compounds S 12 and S 28 as substrates according to general procedure D to give a white solid (47 mg, 36% yield, 1.1:1 dr). 1H NMR (400 MHz, D20) δ 8.15 - 8.06 (m, 2H), 7.94 - 7.76 (m, 2H), 7.59 - 7.29 (m, 3H), 7.27 - 7.13 (m, 2H), 7.05 - 6.98 (m, 1H), 4.39 - 4.33 (m, 0.6H), 4.26 - 4.09 (m, 1.4H), 4.05 - 3.86 (m, 4H), 3.80 - 3.64 (m, 3.5H), 3.61 - 3.52 (m, 0.5H). 13 C NMR (100 MHz, D20) δ 171.89, 171.69, 167.28, 139.72, 139.70, 135.31, 135.30, 131.83, 131.37, 130.78, 130.74, 129.83, 129.78, 129.43, 129.32, 128.57, 128.26, 128.21, 54.26, 54.13, 53.47, 53.31, 53.27, 52.21, 52.13, 48.37, 48.04. HRMS (ESI) m / z calculated for C 19 H 22 NO6S + ([M+H] + ): 392.1162, found 392.1157.

[0313] Example 41 : 3-Amino-2-phenyl-4-(pyridin-2-ylsulfonyl)butanoic acid methyl ester hydrochloride

[0314]

[0315] with compounds S 12 and S 29 as substrates following general procedure D to give a white solid (55 mg, 49% yield, 1.1 :1 dr).

[0316] 1 H NMR (400 MHz, D20) δ 9.30 - 9.10 (m, 1H), 9.09 - 9.01 (m, 1H), 8.82 - 8.59 (m, 1H), 8.14 - 8.01 (m, 1H), 7.43 - 7.33 (m, 2H), 7.35 - 7.26 (m, 1H), 7.27 - 7.19 (m, 1H), 7.16 - 7.10 (m, 1H), 4.44 - 4.18 (m, 2H), 4.12 - 4.01 (m, 1H), 3.93 - 3.82 (m, 0.5H), 3.80 - 3.62 (m, 3.5H). 13CNMR (100 MHz, D20) δ 171.82, 171.73, 150.05, 149.73, 144.57, 144.46, 142.83, 142.39, 135.82, 135.68, 131.77, 131.28, 129.90, 129.84, 129.64, 129.56, 128.70, 128.47, 127.62, 127.51, 54.83, 54.55, 53.49, 53.37, 52.18, 52.12, 47.99, 47.75. HRMS (ESI) m / z calcd for C 16 H 19 N2O4S + ([M+H] + ): 335.1060, found 335.1055.

[0317] Example 42: 3-Amino-4-(cyclopropylsulfonyl)-2-phenylbutanoic acid methyl ester hydrochloride

[0318]

[0319] Following general procedure D, compound S 12 and S 30 as substrates gave a white solid (63 mg, 62% yield, 1.2:1 dr).

[0320] 1 H NMR (400 MHz, D20) δ 7.58 - 7.49 (m, 3H), 7.48 - 7.38 (m, 2H), 4.72 - 4.58 (m, 1H), 4.46 - 4.32 (m, 1H), 3.97 - 3.84 (m, 0.5H), 3.78 - 3.68 (m, 0.5H), 3.62 - 3.53 (m, 1H), 2.89 - 2.63 (m, 1H), 1.37 - 1.15 (m, 3H), 1.16 - 1.02 (m, 1H). 13 C NMR (100 MHz, D20) δ 172.13, 172.09, 132.21, 131.33, 130.03, 129.94, 129.78, 129.59, 128.97, 128.80, 53.52, 53.43, 52.67, 52.40, 52.29, 52.04, 47.70, 29.60, 29.42, 5.18, 4.72, 4.63. HRMS (ESI) m / z calcd for C 14 H 20 NO4S + ([M+H] +): 298.1108, found 298.1103.

[0321] Example 43: C4-(cyclopropylsulfonyl)valine methyl ester hydrochloride

[0322]

[0323] General procedure D was followed using compounds S1 and S 30 as substrates to give a white solid (53 mg, 65% yield, 2.2:1 dr).

[0324] 1 H NMR (400 MHz, D20) δ 4.37 - 4.25 (m, 1H), 3.84 - 3.78 (m, 3H), 3.78 - 3.70 (m, 1H), 3.28 - 3.14 (m, 1H), 2.91 - 2.80 (m, 1H), 1.39 - 1.33 (m, 3H), 1.33 - 1.20 (m, 4H). 13 C NMR (101 MHz, D20) δ 174.17, 174.00, 53.12, 52.29, 52.12, 47.35, 47.12, 41.22, 41.10, 29.62, 29.57, 11.74, 11.52, 5.19, 5.15, 4.71. HRMS (ESI) m / z calculated for C9H 18 NO4S + ([M+H] + ): 236.0951, found 236.0946.

[0325] Example 44: 3-amino-4-(cyclopropylsulfonyl)-2-phenethylbutanoic acid methyl ester hydrochloride

[0326]

[0327] General procedure D was followed using compounds S7 and S 30 as substrates to give a white solid (57 mg, 52% yield, 2.2:1 dr).

[0328] 1 H NMR (400 MHz, D20) δ 7.46 - 7.38 (m, 2H), 7.38 - 7.30 (m, 3H), 4.30 - 4.17 (m, 1H), 3.98 - 3.61 (m, 5H), 3.12 - 3.02 (m, 1H), 2.90 - 2.69 (m, 3H), 2.30 - 1.87 (m, 2H), 1.34 - 1.17 (m, 4H). 13C NMR (100 MHz, D20) δ 173.61, 173.45, 140.49, 140.33, 128.86, 128.73, 126.66, 53.07, 52.74, 51.78, 46.83, 46.51, 45.92, 45.86, 32.45, 32.24, 29.72, 29.52, 29.38, 28.81, 5.17, 5.10, 4.76, 4.69. HRMS (ESI) m / z calcd for C 16 H 24 NO4S + ([M+H] + ): 326.1412, found 326.1416.

[0329] Example 45: Methyl 2-(l-amino-2-(cyclopropylsulfonyl)ethyl)pentanoate hydrochloride

[0330]

[0331] Following general procedure D, compound S4 and S 30 were used as substrates to give a white solid (68 mg, 71% yield, 2.5: 1 dr). 1 H NMR (400 MHz, D20) δ 4.30 - 4.22 (m, 1H), 3.92 - 3.70 (m, 5H), 3.16 - 3.07 (m, 1H), 2.91 - 2.81 (m, 1H), 1.89 - 1.56 (m, 2H), 1.52 - 1.20 (m, 6H), 1.01 - 0.91 (m, 3H). 13 C NMR (100 MHz, D20) δ 174.07, 173.87, 52.98, 52.72, 51.87, 46.64, 46.46, 46.37, 29.88, 29.73, 29.49, 29.38, 19.73, 19.63, 12.88, 12.86, 5.16, 5.10, 4.71, 4.63. HRMS (ESI) m / z calcd for C 11 H 22 NO4 + ([M+H] + ): 264.1264, found 264.1259.

[0332] Example 46: Methyl 3-amino-4-(diphenylphosphoryl)-2-methylbutanoate hydrochloride

[0333]

[0334] As substrates for the general procedure E afforded white solid (62 mg, 56% yield, 2.1 : 1 dr). 31 As substrates for the general procedure E afforded white solid (62 mg, 56% yield, 2.1 : 1 dr).

[0335] 1 H NMR (400 MHz, D20) δ 7.69 - 7.36 (m, 10 H), 3.81 (ddd, J = 11.7, 9.1, 5.3 Hz, 1 H), 3.54 (d, J = 41.3 Hz, 3 H), 3.00 - 2.72 (m, 3 H), 1.14 (dd, J = 25.6, 7.3 Hz, 3 H). 31 P NMR (162 MHz, D20) δ 37.38. 13 C NMR (101 MHz, D20) δ 174.37, 174.04, 133.37 (d, J = 3.2 Hz), 131.05 - 130.11 (m), 130.13 - 127.40 (m), 129.45 - 129.10 (m), 52.87, 52.79, 48.64, 48.19, 41.61 - 41.15 (m), 28.66 (d, J = 69.5 Hz), 11.79, 10.80. HRMS (ESI-TOF) m / z calcd for C 18 H 23 NO3P ([M+H] + ) 332.1410, found: 332.1405.

[0336] Example 47: Methyl 3-amino-4-(dipara-tolylphosphoryl)-2-methylbutanoate hydrochloride

[0337]

[0338] As substrates for the general procedure E afforded white solid (62 mg, 56% yield, 2.1 : 1 dr). 32 As substrates for the general procedure E afforded white solid (62 mg, 56% yield, 2.1 : 1 dr).

[0339] 1 H NMR (400 MHz, D20) δ 7.42 (ddd, J = 18.9, 11.9, 7.8 Hz, 4 H), 7.23 - 6.84 (m, 4 H), 3.78 (dt, J = 11.9, 5.9 Hz, 1 H), 3.51 (d, J = 39.8 Hz, 3 H), 3.06 - 2.56 (m, 3 H), 2.00 (d, J = 3.5 Hz, 6 H), 1.14 (dd, J = 23.3, 7.3 Hz, 3 H). 31 P NMR (162 MHz, D20) δ 36.41, 36.33. 13C NMR(100MHz,D2O)δ174.30,173.98,144.06,144.03,130.74–129.96(m),129.95–129.52(dd,J=12.7,5.5Hz),127.74–124.50(m),52.85 ,52.73,48.74,48.24,41.26(d,J=7.8Hz),41.09(d,J=7.8Hz),28.98(d,J=69.6Hz),20.69,11.98,10.82.HRMS(ESI-TOF)m / zcalcd.for C 20 H 27 NO3P([M+H)) + )360.1723,found:360.1718.

[0340] Example 48: Methyl 3-amino-4-(bis(4-methoxyphenyl)phospho)-2-methylbutyrate hydrochloride

[0341]

[0342] With compounds S1 and S 33 The substrate was prepared according to standard procedure E to obtain a white solid (78 mg, 61% yield, 2.5:1 dr).

[0343] 1 H NMR(400MHz,D2O)δ7.75–7.27(m,4H),7.10–6.62(m,4H),3.88–3.75(m,1H),3.72–3.4 9(m,9H),2.94(qd,J=7.3,4.0Hz,1H),2.81–2.67(m,2H),1.18(dd,J=24.7,7.3Hz,3H). 31 P NMR(162MHz,D2O)δ36.83,36.73. 13 C NMR(101MHz,D2O)δ174.38,174.06,162.64(dd,J=6.4,2.9Hz),133.40–131.35(m),122.72–118.55(m),114.70(ddd,J=12.9,9.5,3.3Hz),55 .36(d,J=3.1Hz),52.86,52.75,48.75,48.31,41.37(d,J=8.1Hz),41.19(d,J=8.3Hz),29.06(d,J=70.5Hz),11.85,10.88.HRMS(ESI-TOF) m / z calcd.forC 20H 27 NO5P([M+H] + )392.1621, found:392.1617.

[0344] Example 49: Methyl 3-amino-4-(di([l,l'-biphenyl]-4-yl)phosphoryl)-2- methylbutanoate hydrochloride

[0345]

[0346] Following general procedure E with compounds S1 and S 34 as substrates afforded a white solid (87 mg, 56% yield, 1.5:1 dr).

[0347] 1 H NMR (500 MHz, CD3OD) δ 7.96 (d, J = 28.9 Hz, 4H), 7.81 (d, J = 19.6 Hz, 4H), 7.69 - 7.55 (m, 4H), 7.50 - 7.31 (m, 6H), 3.92 (s, 1H), 3.67 (d, J = 29.5 Hz, 3H), 3.25 - 2.80 (m, 3H), 1.57 - 1.25 (m, 3H). 31 P NMR (202 MHz, CD3OD) δ 36.41, 35.33. 13 C NMR (126 MHz, CD3OD) δ 174.41, 174.12, 146.86, 140.49, 132.94 (dd, J = 16.8, 9.3 Hz), 132.44 (d, J = 11.4 Hz), 130.10, 129.51, 128.75 (dd, J = 12.3, 5.9 Hz), 128.19, 53.23 (d, J = 6.2 Hz), 50.54, 50.14, 43.45 - 42.24 (m), 13.08, 12.23. HRMS (ESI-TOF) m / z calcd for C 30 H 31 NO3P([M+H] + )484.2036, found:484.2031.

[0348] Example 50: Methyl 3-amino-4-(bis(3,5-dimethylphenyl)phosphoryl)-2- methylbutanoate hydrochloride

[0349]

[0350] Following general procedure E with compounds S3 and S 37 as substrates afforded a white solid (84 mg, 48% yield, 3.1:1 dr).

[0351] 1 H NMR (400 MHz, D20) δ 7.32 (dd, J = 18.5, 12.5 Hz, 4H), 7.06 - 6.67 (m, 2H), 3.92 - 3.75 (m, 1H), 3.70 (d, J = 4.4 Hz, 3H), 2.95 - 2.60 (m, 2.77H), 2.35 (dd, J = 9.1, 4.0 Hz, 0.23H), 2.07 (d, J = 3.6 Hz, 12H), 1.92 (dp, J = 13.8, 6.6 Hz, 1H), 0.80 (t, J = 6.5 Hz, 3H), 0.64 (dd, J = 40.4, 6.6 Hz, 3H). 31 P NMR (162 MHz, D20) δ 37.65, 34.09. 13 C NMR (101 MHz, D20) δ 173.73, 172.79, 139.89 - 138.75 (m), 134.54 (d, J = 10.1 Hz), 130.82 - 127.72 (m), 128.45 - 127.20 (m), 54.47 (d, J = 9.6 Hz), 53.80 (d, J = 4.7 Hz), 52.63, 52.59, 47.62 - 45.56 (m), 30.43 (d, J = 69.4 Hz), 28.05 (d, J = 68.8 Hz), 27.29, 26.58, 20.34, 19.52 (d, J = 28.5 Hz), 18.98 (d, J = 14.8 Hz). HRMS (ESI-TOF) m / z calcd for C 24 H 35 NO3P ([M+H] + ) 416.2349, found: 416.2343.

[0352] Example 51 : Methyl 3-amino-4-((2-methoxyphenyl)(3-methoxyphenyl)phosphoryl)-2- methylbutanoate hydrochloride

[0353]

[0354] Following general procedure E, compound S1 and S 38 were used as substrates to give a white solid (54 mg, 42% yield, 8.0:1 dr).

[0355] 1H NMR(400MHz,D2O)δ7.66(dt,J=22.9,7.8Hz,3H),7.43(dd,J=14.4,7.6Hz,1H),7.25–6.99 (m,4H),3.86–3.60(d,J=29.2Hz,10H),3.03(td,J=8.1,5.2Hz,3H),1.23(d,J=7.2Hz,3H). 31 P NMR(162MHz,D2O)δ37.58,37.49. 13 C NMR(101MHz,D2O)δ174.64,160.71(dd,J=72.7,3.5Hz),135.79(d,J=14.0Hz), 133.20(dd,J=94.5,7.8Hz), 121.29(dd,J=26.8,12.2Hz), 116.36(dd,J=114.4 ,106.4Hz),112.17(dd,J=18.8,6.7Hz),55.66(d,J=19.1Hz),52.92,49.18(d, J=3.0Hz),41.91(d,J=10.0Hz),28.30(d,J=73.3Hz),11.36.HRMS(ESI-TOF)m / z calcd.for C 20 H 27 NO5P([M+H)) + )392.1621,found:392.1617.

[0356] Example 52: Methyl 3-amino-2-methyl-4-(m-tolyl(p-tolyl)phosphoryl)butyrate hydrochloride

[0357]

[0358] With compounds S1 and S 39 The substrate was prepared according to standard procedure E to obtain a white solid (96 mg, 81% yield, 2.7:1 dr).

[0359] 1 H NMR(400MHz,D2O)δ7.58–7.36(m,4H),7.27–7.01(m,4H),3.93–3.81(m,1H),3.55(d,J=43.8Hz ,3H),2.92(ddd,J=53.7,9.2,5.8Hz,3H),2.06(d,J=6.9Hz,6H),1.21(dd,J=24.3,7.3Hz,3H). 31 P NMR(162MHz,D2O)δ35.90,35.75.13 C NMR (101 MHz, D20) δ 174.27, 173.94, 139.35 (dt, J = 12.3, 3.6 Hz), 133.71 (d, J = 3.4 Hz), 131.23 - 130.17 (m), 129.84 - 128.16 (m), 129.09 (d, J = 13.1 Hz), 127.99 - 126.96 (m), 78.04, 52.90, 52.76, 48.76, 48.29, 41.33 (d, J = 7.5 Hz), 41.19 (d, J = 8.0 Hz), 28.91 (d, J = 69.3 Hz), 28.83 (d, J = 69.3 Hz), 20.59, 20.54, 12.00, 10.90. HRMS (ESI-TOF) m / z calcd for C 20 H 27 NO3P ([M+H] + ) 360.1723, found: 360.1717.

[0360] Example 53: 3-Amino-4-(diphenylphosphoryl)-2-isopropylbutanoic acid methyl ester hydrochloride

[0361]

[0362] Following the general procedure E with compounds S3 and S 31 as substrates afforded a white solid (96 mg, 84% yield, 2.0:1 dr).

[0363] 1 H NMR (400 MHz, D20) δ 7.37 - 7.12 (m, 4H), 7.08 - 6.91 (m, 6H), 3.38 (tt, J = 11.5, 5.5 Hz, 1H), 3.24 (s, 3H), 2.65 - 2.22 (m, 2.71H), 2.05 (dd, J = 9.0, 4.1 Hz, 0.29H), 1.56 - 1.37 (m, 1H), 0.32 (dd, J = 15.8, 6.6 Hz, 3H), 0.16 (dd, J = 49.5, 6.6 Hz, 3H). 31 P NMR (162 MHz, D20) δ 37.70, 34.35. 13C NMR (101 MHz, D20) δ 173.38, 172.34, 133.05 (d, J = 19.6 Hz), 130.91 - 129.78 (m), 129.73 - 126.85 (m), 129.06 (dd, J = 12.4, 5.2), 54.13 (d, J = 10.2 Hz), 53.55 (d, J = 4.3 Hz), 52.45, 46.54, 46.14, 30.24 (d, J = 68.9 Hz), 28.02 (d, J = 69.0 Hz), 26.99, 26.21, 19.50, 19.18, 19.09, 18.60. HRMS (ESI-TOF) m / z calcd for C 20 H 27 NO3P ([M+H] + ) 360.1723, found: 360.1719.

[0364] Figures 21-23 The NMR spectra of the hydrogen, phosphorus and carbon of 3-amino-4- (diphenylphosphoryl)-2-isopropylbutanoic acid methyl ester hydrochloride, respectively.

[0365] Example 54: 3-amino-2-benzyl-4-(diphenylphosphoryl)butanoic acid methyl ester hydrochloride

[0366]

[0367] According to general procedure E, using compound S9 and S 31 as substrates, afforded a white solid (69 mg, 52% yield, 1.9:1 dr).

[0368] 1 H NMR (400 MHz, CD3OD) δ 7.99 - 7.45 (m, 10H), 7.29 - 6.86 (m, 5H), 3.63 (d, J = 3.3 Hz, 4H), 3.48 - 3.32 (m, 1H), 3.19 - 2.79 (m, 4H). 31 P NMR (162 MHz, CD3OD) δ 35.62, 33.99. 13C NMR (101 MHz, CD3OD) δ 173.50, 173.12, 138.18, 138.02, 134.61 - 133.93 (m), 133.19 - 130.83 (m), 130.62 - 130.12 (m), 129.89, 129.82, 129.77, 129.70, 128.09, 127.90, 52.97 (d, J = 3.4 Hz), 50.66 (d, J = 9.8 Hz), 50.20 (d, J = 6.9 Hz), 35.27, 34.33, 31.41 (d, J = 69.1 Hz), 29.31 (d, J = 68.6 Hz). HRMS (ESI-TOF) m / z calcd for C 24 H 27 NO3P ([M+H] + ) 408.1723, found: 408.1718.

[0369] Example 55: 3-Amino-4-(diphenylphosphoryl)-2-ethylbutanoic acid methyl ester hydrochloride

[0370]

[0371] According to general procedure E, compound S2 and S 31 as substrates gave white solid (93 mg, 81% yield, 4.0:1 dr).

[0372] 1 H NMR (400 MHz, D20) δ 7.68 - 7.46 (m, 6H), 7.41 (dtd, J = 14.8, 7.5, 3.0 Hz, 4H), 3.72 (dq, J = 11.7, 6.1 Hz, 1H), 3.57 (d, J = 19.0 Hz, 3H), 2.89 - 2.62 (m, 3H), 1.66 - 1.31 (m, 2H), 0.63 (dt, J = 30.8, 7.4 Hz, 3H). 31 P NMR (162 MHz, D20) δ 37.64, 36.52. 13C NMR (100 MHz, D20) δ 174.02, 173.91, 133.42, 133.39, 131.10 - 130.11 (m), 130.66 - 127.18 (m), 129.56 - 129.05 (m), 52.78, 52.74, 48.65 (d, J = 8.7 Hz), 48.29 (d, J = 6.4 Hz), 47.52 (d, J = 3.2 Hz), 29.52 (d, J = 69.8 Hz), 28.49 (d, J = 69.6 Hz), 21.49, 20.06, 10.59, 10.45. HRMS (ESI-TOF) m / z calcd for C 19 H 25 NO3P ([M+H] + ) 345.1567, found: 345.1563.

[0373] Example 56: 3-Amino-4-(diphenylphosphoryl)-2-phenethylbutanoic acid methyl ester hydrochloride

[0374]

[0375] Following general procedure E, compound S7 and S 31 were used as substrates to give a pale yellow oil (85 mg, 62% yield, 1.9:1 dr).

[0376] 1 H NMR (400 MHz, CD3OD) δ 7.97 - 7.75 (m, 4H), 7.72 - 7.49 (m, 6H), 7.31 - 7.03 (m, 5H), 3.70 (d, J = 23.8 Hz, 4H), 3.09 - 2.75 (m, 3H), 2.64 - 2.32 (m, 2H), 2.14 - 1.72 (m, 2H). 31 P NMR (162 MHz, CD3OD) δ 35.37, 34.30. 13C NMR (101 MHz, CD3OD) δ 173.96, 173.64, 141.64, 141.49, 134.17 (dt, J = 6.5, 3.0 Hz), 132.86 (d, J = 6.0 Hz), 132.32 (d, J = 9.9 Hz), 132.15 (d, J = 10.0 Hz), 131.95 - 131.13 (m), 130.85 - 130.01 (m), 129.55, 129.48 (d, J = 5.4 Hz), 127.30, 53.08, 53.01, 49.79, 49.73 (d, J = 3.0 Hz), 48.25 (d, J = 9.0 Hz), 47.76 (d, J = 8.2 Hz), 34.11, 33.90, 30.93 (d, J = 69.1 Hz), 30.23, 29.83 (d, J = 68.8 Hz). HRMS (ESI-TOF) m / z calcd for C 25 H 29 NO3P ([M+H] + ) 422.1880, found: 422.1875.

[0377] Example 57: 3-Amino-4-(diphenylphosphoryl)-2-(thiophen-2-ylmethyl)butanoic acid methyl ester hydrochloride

[0378]

[0379] Following general procedure E, compound S8 and S 31 were used as substrates to give a brown solid (58 mg, 43% yield, 1.7:1 dr).

[0380] 1 H NMR (400 MHz, CD3OD) δ 8.00 - 7.48 (m, 11H), 7.20 (t, J = 5.6 Hz, 1H), 6.94 - 6.69 (m, 1.35H), 6.56 (d, J = 3.3 Hz, 0.65H), 3.73 (d, J = 4.3 Hz, 4H), 3.50 - 3.23 (m, 3H), 3.21 - 3.04 (m, 1H), 3.02 - 2.78 (m, 1H). 31 P NMR (162 MHz, CD3OD) δ 35.75, 34.44. 13C NMR (101 MHz, CD3OD) δ 173.09, 172.57, 139.94, 139.58, 135.07 - 133.95 (m), 133.20 - 130.73 (m), 132.44 (d, J = 9.9 Hz), 132.00 (d, J = 9.9 Hz), 130.63 - 129.96 (m), 128.06, 128.00, 127.74, 127.59, 125.91, 125.74, 53.20 (d, J = 2.9 Hz), 50.99 (d, J = 10.2 Hz), 50.51 (d, J = 7.4 Hz), 31.22 (d, J = 68.9 Hz), 29.44, 29.33, 28.76, 28.69. HRMS (ESI-TOF) m / z calcd for C 22 H 25 NO3P ([M+H] + ) 414.1287, found: 414.1283.

[0381] Example 58: Methyl 3-amino-4-(4-cyanophenyl)-2-methylbutanoate hydrochloride

[0382]

[0383] Following General Procedure F, compound S1 and S 40 were used as substrates to give a white solid (43 mg, 53% yield, 4.8:1 dr).

[0384] 1 H NMR (400 MHz, D20) δ 7.87 - 7.67 (m, 2H), 7.58 - 7.24 (m, 2H), 3.99 (ddd, J = 8.2, 6.8, 4.1 Hz, 1H), 3.69 (d, J = 16.1 Hz, 3H), 3.18 - 2.82 (m, 3H), 1.36 - 1.24 (m, 3H). 13 C NMR (100 MHz, D20) δ 175.37, 174.93, 141.18, 141.15, 133.04, 132.98, 130.26, 130.18, 119.46, 110.29, 53.83, 53.36, 52.81, 52.74, 40.44, 40.26, 35.94, 35.79, 11.76, 10.97. HRMS (ESI-TOF) m / z calcd for C 13 H 17 N2O2 ([M+H] + ) 233.1285, found: 233.1282.

[0385] Example 59: 3-Amino-2-methyl-4-(4-(methylsulfonyl)phenyl)butanoic acid methyl ester hydrochloride

[0386]

[0387] Following general procedure F with compound S1 and S 41 as substrates afforded a white solid (59 mg, 62% yield, 3.4: 1 dr).

[0388] 1 H NMR (400 MHz, D20) δ 7.97 (dd, J = 8.5, 2.2 Hz, 2H), 7.73 - 7.54 (m, 2H), 4.06 (td, J = 7.6, 4.2 Hz, 1H), 3.71 (d, J = 19.3 Hz, 3H), 3.30 (s, 3H), 3.25 - 3.10 (m, 2H), 2.98 (dqd, J = 14.7, 7.3, 4.2 Hz, 1H), 1.37 (dd, J = 7.4, 5.1 Hz, 3H). 13 C NMR (100 MHz, D20) δ 175.34, 174.86, 142.39, 142.35, 138.05, 138.03, 130.75, 130.67, 127.76, 127.68, 53.88, 53.40, 52.86, 52.76, 43.32, 40.43, 40.28, 35.81, 35.63, 11.76, 11.06. HRMS (ESI-TOF) m / z calcd for C 13 H 20 NO4S ([M+H] + ) 286.1108, found: 286.1104.

[0389] Example 60: 3-Amino-2-methyl-4-(l-oxo-2,3-dihydro-lH-inden-5-yl)butanoic acid methyl ester hydrochloride

[0390]

[0391] Following general procedure F with compound S1 and S 44 as substrates afforded a white solid (59 mg, 62% yield, 3.4: 1 dr).

[0392] 1H NMR (400 MHz, D20) δ 7.60 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 6.3 Hz, 1H), 7.31 (dd, J = 8.1, 5.1 Hz, 1H), 4.01 (td, J = 7.4, 3.9 Hz, 1H), 3.68 (d, J = 20.2 Hz, 3H), 3.14 - 3.02 (m, 4H), 3.01 - 2.88 (m, 1H), 2.72 - 2.55 (m, 2H), 1.34 (dd, J = 7.4, 4.4 Hz, 3H). 13 C NMR (100 MHz, D20) δ 212.16, 175.35, 174.90, 158.01, 157.94, 143.61, 143.56, 135.26, 128.72, 128.63, 127.91, 127.84, 123.96, 123.89, 53.96, 53.49, 52.81, 52.72, 40.41, 40.22, 36.34, 36.18, 36.01, 25.57, 11.75, 11.02. HRMS (ESI-TOF) m / z calcd for C 15 H 20 NO3 ([M+H] + ) 262.1438, found: 262.1435.

[0393] Example 61 : 3-amino-2-methyl-4-(l-oxo-l,3-dihydroisobenzofuran-5- yl)butanoic acid methyl ester hydrochloride

[0394]

[0395] Following General Procedure F, compound S1 and S 45 were used as substrates to give a white solid (44 mg, 49% yield, 3.5:1 dr).

[0396] 1 H NMR (400 MHz, D20) δ 7.78 (d, J = 7.9 Hz, 1H), 7.58 - 7.43 (m, 2H), 5.38 (s, 2H), 4.02 (td, J = 7.5, 4.0 Hz, 1H), 3.68 (d, J = 16.0 Hz, 3H), 3.27 - 3.05 (m, 2H), 2.96 (pd, J = 7.5, 4.1 Hz, 1H), 1.34 (dd, J = 7.4, 4.4 Hz, 3H). 13C NMR (100 MHz, D20) δ 175.36, 174.92, 173.99, 148.36, 148.31, 142.92, 142.89, 130.42, 130.34, 125.68, 125.62, 123.80, 123.78, 123.50, 123.42, 71.13, 54.03, 53.51, 52.83, 52.76, 40.42, 40.18, 36.09, 35.99, 11.85, 10.93. HRMS (ESI-TOF) m / z calcd for C 14 H 18 NO3([M+H] + ) 264.1230, found: 264.1227.

[0397] Example 62: Methyl 3-amino-4-(3,4-dicyanophenyl)-2-methylbutanoate hydrochloride

[0398]

[0399] Following general procedure F, compound S1 and S 46 gave white solid (58 mg, 68% yield, 3.5: 1 dr).

[0400] 1 H NMR (400 MHz, D20) δ 8.08 - 7.95 (m, 1.81H), 7.92 - 7.76 (m, 1.19H), 4.17 - 3.97 (m, 1H), 3.82 - 3.68 (m, 3H), 3.34 - 3.15 (m, 2H), 3.06 - 2.90 (m, 1H), 1.41 - 1.32 (m, 3H). 13 C NMR (101 MHz, D20) δ 177.70, 177.24, 144.97, 137.63, 137.56, 137.32, 137.26, 137.04, 136.98, 118.73, 118.62, 118.03, 116.56, 116.53, 56.09, 55.54, 55.49, 55.43, 42.95, 42.69, 38.12, 14.49, 13.46. HRMS (ESI-TOF) m / z calcd for C 14 H 16 N3O2([M+H] + ) 258.1237, found: 258.1235.

[0401] Example 63: Dimethyl 5-(2-amino-4-methoxy-3-methyl-4-oxobutyl)isophthalate hydrochloride

[0402]

[0403] With compounds S1 and S 48 The substrate was prepared according to the general procedure F to obtain a white solid (65 mg, 60% yield, 3.5:1 dr).

[0404] 1 H NMR(400MHz,D2O)δ8.28–7.57(m,3H),4.01(td,J=7.5,3.8Hz,1H),3.93(d,J=3.3Hz,6H),3.71 (d,J=17.5Hz,3H),3.16–2.99(m,2H),2.89(qt,J=7.4,4.0Hz,1H),1.37(dd,J=6.7,3.6Hz,3H). 13 C NMR(100MHz,D2O)δ175.20,174.71,167.08,167.05,136.56,136.49,134.64,134.51,130.33,130.2 7,129.11,53.94,53.24,52.97,52.85,52.74,39.94,39.79,35.31,12.05,10.80.HRMS(ESI-TOF)m / z calcd.for C 16 H 22 NO6([M+H] + )324.1442,found:324.1438.

[0405] Example 64: Methyl 3-amino-2-methyl-4-(pyridin-4-yl)butyrate hydrochloride

[0406]

[0407] With compounds S1 and S 50 The substrate was prepared according to the general procedure F to obtain a brown solid (42 mg, 57% yield, 4.1:1 dr).

[0408] 1H NMR (400 MHz, D20) δ 8.91 - 8.71 (m, 2H), 8.10 (dt, J = 6.3, 3.2 Hz, 2H), 4.28 - 4.13 (m, 1H), 3.76 (d, J = 2.2 Hz, 3H), 3.54 - 3.31 (m, 2H), 3.03 (qd, J = 7.2, 3.5 Hz, 1H), 1.37 (dd, J = 7.3, 4.1 Hz, 3H). 13 C NMR (101 MHz, D20) δ 174.90, 174.56, 157.45, 157.37, 141.34, 141.29, 128.26, 128.21, 52.97, 52.92, 52.86, 52.25, 40.63, 40.35, 36.15, 35.87, 12.23, 10.84. HRMS (ESI-TOF) m / z calcd for C 11 H 17 N2O2 ([M+H] + ) 209.1285, found: 209.1282.

[0409] Example 65: 3-amino-2-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)butanoic acid methyl ester hydrochloride

[0410]

[0411] Following general procedure F, compound S1 and S 51 were used as substrates to give a white solid (49 mg, 52% yield, 3.1:1 dr).

[0412] 1 H NMR (400 MHz, D20) δ 8.98 (d, J = 2.5 Hz, 1H), 8.36 (dd, J = 8.4, 2.4 Hz, 1H), 7.78 (dd, J = 8.4, 3.5 Hz, 1H), 4.24 - 4.12 (m, 1H), 3.71 (d, J = 10.5 Hz, 3H), 3.50 - 3.30 (m, 2H), 3.09 - 2.97 (m, 1H), 1.40 - 1.22 (m, 3H). 19 F NMR (376 MHz, D20) δ -62.60. 13C NMR (101 MHz, D20) δ 174.98, 174.82, 158.38, 158.30, 144.71 (q, J = 4.1 Hz), 137.82 (q, J = 3.4 Hz), 126.30 (q, J = 34.34 Hz), 125.91, 122.85 (q, J = 271.9 Hz), 52.88, 52.86, 52.37, 52.03, 40.67, 40.60, 35.91, 35.87, 12.13, 11.41. HRMS (ESI-TOF) m / z calcd for C 12 H 16 F3N2O2([M+H] + ) 277.1158, found: 277.1153.

[0413] Example 66: 3-Amino-2-methyl-4-(pyrimidin-2-yl)butanoic acid methyl ester hydrochloride

[0414]

[0415] Following General Procedure F, compound S1 and S 52 were used as substrates to give a white solid (41 mg, 56% yield, 3.7:1 dr).

[0416] 1 H NMR (400 MHz, D20) δ 9.00 - 8.88 (m, 2H), 7.75 - 7.64 (m, 1H), 4.32 - 4.19 (m, 1H), 3.73 (d, J = 7.3 Hz, 3H), 3.52 - 3.43 (m, 2H), 3.16 - 3.05 (m, 1H), 1.33 (dd, J = 7.3, 4.8 Hz, 3H). 13 C NMR (101 MHz, D20) δ 174.94, 163.51, 157.93, 157.90, 121.02, 52.91, 51.09, 50.85, 40.77, 40.69, 36.43, 36.26, 12.39, 11.65. HRMS (ESI-TOF) m / z calcd for C 10 H 16 N3O2([M+H] + ) 210.1237, found: 210.1234.

[0417] Example 67: 3-Amino-2-methyl-4-(quinolin-3-yl)butanoic acid methyl ester hydrochloride

[0418]

[0419] With compounds S1 and S 53 The substrate was prepared according to the general procedure F to obtain a brown solid (36 mg, 41% yield, 3.7:1 d).

[0420] 1 H NMR(400MHz,D2O)δ9.25–9.06(m,2H),8.36–8.09(m,3H),8.04–7.90(m,1H),4.28–4.11(m,1H),3.69(d, J=11.9Hz,3H),3.50(dt,J=15.3,7.6Hz,2H),3.07(ddt,J=11.4,7.4,3.5Hz,1H),1.41(d,J=7.4Hz,3H). 13 C NMR(100MHz,D2O)δ175.10,174.63,147.69,144.90,144.83,136.86,135.43,130.61,129.67,129.00 ,128.89,120.20,53.57,52.94,40.39,40.22,32.87,32.83,11.97,11.04,11.01.HRMS(ESI-TOF)m / z calcd.forC 15 H 19 N₂O₂([M+H)) + )259.1441,found:259.1437.

[0421] Figure 24 and Figure 25 These are the hydrogen and carbon spectra of methyl 3-amino-2-methyl-4-(quinoline-3-yl)butyrate hydrochloride, respectively.

[0422] Example 68: Methyl 3-amino-2-methyl-4-(quinoline-4-yl)butyrate hydrochloride

[0423]

[0424] With compounds S1 and S 54 The substrate was prepared according to the general procedure F to obtain a brown solid (54 mg, 61% yield, 3.7:1 dr).

[0425] 1H NMR (400 MHz, D20) δ 9.20 - 8.91 (m, 1H), 8.42 (d, J = 8.4 Hz, 1H), 8.25 (d, J = 8.5 Hz, 1H), 8.17 (t, J = 7.7 Hz, 1H), 8.12 - 8.00 (m, 2H), 4.35 - 4.20 (m, 1H), 3.97 - 3.84 (m, 1H), 3.77 (dd, J = 13.4, 8.5 Hz, 1H), 3.68 (d, J = 1.9 Hz, 3H), 3.13 - 3.02 (m, 1H), 1.43 (dt, J = 6.7, 3.4 Hz, 3H). 13 C NMR (100 MHz, D20) δ 174.90, 174.54, 154.99, 154.84, 143.44, 143.41, 137.37, 135.31, 130.80, 130.74, 128.03, 127.96, 124.80, 124.72, 123.22, 123.13, 121.35, 52.97, 52.90, 52.66, 52.22, 40.73, 40.66, 33.37, 33.16, 11.80, 11.27. HRMS (ESI-TOF) m / z calcd for C 15 H 19 N2O2([M+H] + ) 259.1441, found: 259.1438.

[0426] Example 69: methyl 3-amino-4-(3,4-dicyanophenyl)-2-methylbutanoate hydrochloride

[0427]

[0428] Following general procedure F, compound S3 and S 46 were used as substrates to give a white solid (48 mg, 50% yield, 2.6:1 dr).

[0429] 1H NMR (400 MHz, D20) δ 8.02 (dd, J = 8.1, 1.8 Hz, 1H), 7.97 (d, J = 2.1 Hz, 1H), 7.84 (dd, J = 8.2, 1.9 Hz, 1H), 4.09 - 3.94 (m, 1H), 3.87 (s, 0.83H), 3.76 (s, 2.17H), 3.28 (ddd, J = 44.4, 14.6, 5.9 Hz, 1H), 3.11 (td, J = 15.8, 9.0 Hz, 1H), 2.78 - 2.71 (m, 0.72H), 2.41 - 2.32 (m, 0.28H), 2.16 - 2.02 (m, 1H), 1.15 - 0.83 (m, 6H). 13 C NMR (101 MHz, D20) δ 174.57, 173.46, 142.36, 142.00, 134.97, 134.85, 134.72, 134.57, 134.45, 134.38, 116.20, 116.08, 115.61, 115.53, 114.17, 53.98, 52.92, 52.74, 52.55, 51.52, 50.82, 37.01, 35.48, 27.21, 26.66, 19.79, 19.73, 19.14, 18.77. HRMS (ESI-TOF) m / z calcd for C 16 H 20 N3O2 ([M+H] + ) 286.1550, found: 286.1547.

[0430] Example 70: Methyl 4-(2-amino-4-methoxy-3-methyl-4-oxobutyl)benzoate hydrochloride

[0431]

[0432] Following General Procedure F, compound S9 and S 42 were used as substrates to give a white solid (70 mg, 62% yield, 4.2: 1 dr). 1 H NMR (400 MHz, D20) δ 7.95 - 7.73 (m, 2H), 7.33 - 6.93 (m, 7H), 3.90 - 3.72 (m, 4H), 3.57 (d, J = 35.6 Hz, 3H), 3.17 - 2.81 (m, 5H). 13C NMR (101 MHz, D20) δ 173.49, 173.46, 168.48, 168.44, 140.84, 137.22, 136.99, 130.00, 129.95, 129.59, 129.51, 128.82, 128.72, 128.59, 127.08, 127.04, 52.67, 52.62, 52.53, 52.49, 48.34, 47.46, 35.40, 34.75, 34.45, 33.00. HRMS (ESI-TOF) m / z calcd for C 20 H 24 NO4 ([M+H] + ) 342.1700, found: 342.1697.

[0433] Example 71 : Methyl 4-(2-amino-3-(methoxycarbonyl)-5-phenylpentyl)benzoate hydrochloride

[0434]

[0435] Following General Procedure F, compound S7 and S 42 were used as substrates to give a white solid (63 mg, 54% yield, 6.2: 1 dr). 1 H NMR (400 MHz, CD3OD) δ 7.92 (d, J = 7.1 Hz, 2H), 7.43 - 7.04 (m, 7H), 3.98 - 3.81 (m, 4H), 3.76 (d, J = 12.7 Hz, 3H), 3.05 - 2.96 (m, 1.83H), 2.85 - 2.48 (m, 3.17H), 2.13 - 1.87 (m, 2H). 13 C NMR (100 MHz, CD3OD) δ 174.38, 168.11, 142.12, 141.78, 131.08, 130.74, 130.68, 130.44, 129.76, 129.62, 127.38, 54.88, 53.01, 52.71, 46.02, 37.13, 34.26, 29.94. HRMS (ESI-TOF) m / z calcd for C 21 H 26 NO4 ([M+H] + ) 356.1856, found: 356.1852.

[0436] Example 72: Methyl 4-(2-amino-4-methoxy-4-oxo-3-(thiophen-2-ylmethyl)butyl)benzoate hydrochloride

[0437]

[0438] Compound S8 and aryl bromide S 42 was subjected to the general procedure F to give brown solid (65 mg, 54% yield, 3.7:1 dr).

[0439] 1 H NMR (400 MHz, CD3OD) δ 8.00 (t, J = 8.5 Hz, 2H), 7.60 - 7.16 (m, 3H), 7.10 - 6.73 (m, 2H), 3.90 (s, 3H), 3.81 (s, 1H), 3.73 (d, J = 22.1 Hz, 3H), 3.34 - 3.29 (m, 1H), 3.27 - 3.11 (m, 3H), 3.13 - 2.95 (m, 1H). 13 C NMR (100 MHz, CD3OD) δ 173.22, 173.04, 168.15, 142.19, 142.09, 140.76, 140.32, 131.18, 131.12, 130.80, 130.74, 130.70, 128.07, 128.03, 127.56, 127.49, 125.80, 125.70, 54.31, 54.00, 53.10, 53.05, 52.71, 50.56, 38.24, 36.59, 29.87, 29.04. HRMS (ESI-TOF) m / z calcd. for C 18 H 22 NO4S ([M+H] + ) 348.1264, found: 348.1259.

[0440] The above-described embodiments detail the technical solutions and beneficial effects of the present application. It should be understood that the above-described embodiments are only specific embodiments of the present application and are not intended to limit the present application. Any modifications, supplements, and equivalent replacements made within the principle range of the present application shall be included in the protection range of the present application.

Claims

1. A class of imine compounds, characterized in that, Its structural formula is shown in equation (I): ； Wherein, R is selected from halogen, methyl, ethyl, propyl, isopropyl, isobutyl, cyclohexyl, phenyl, p-fluorophenyl, p-chlorophenyl, benzyl, p-methylbenzyl, p-methoxybenzyl, phenethyl, thiophenemethyl, tert-butoxymethyl, etc. , .

2. The imine compound according to claim 1, characterized in that, Its preparation methods include: Benzoyl group protection α Starting from amino acids, the imine compound shown in formula (I) is synthesized through a multi-step reaction involving DCC condensation, alkynylation, ring opening, and Lindlar reductive hydrogenation. Or from α Starting with an amino acid hydrochloride, it undergoes condensation with an aldehyde, nucleophilic substitution with 1,2-dibromoethane, and finally elimination to obtain the imine shown in formula (I).

3. A class of products with multiple functional groups β A method for synthesizing amino acid esters, characterized in that, Includes the following steps: The imine compound of formula (I) according to claim 1 and the free radical precursor of formula (II), (III), (IV) or (V) are dissolved in an organic solvent and photocatalytically reacted in an inert atmosphere under the action of photosensitizer, alkali and light. After the reaction is completed, the reaction system is separated and purified to obtain an intermediate. Acidification of the intermediate yields the product shown in formulas (VI), (VII), (VIII), or (IX). β -Amino acid esters; ； ； ； When X is 0, Y is 1 and Z is 3, or Y is 4 and Z is 9; when X is 1, Y is 1 and Z is 2. R1 is selected from cyclopropyl, phenyl, p-methylphenyl, p-ethylphenyl, p-methoxyphenyl, 2,5-dimethoxyphenyl, 3-chloro-4-fluorophenyl, p-methoxycarbonylphenyl, and benzodioxanepentyl. R2 is selected from phenyl, p-methylphenyl, p-methoxyphenyl, p-fluorophenyl, p-chlorophenyl, 2-methoxyphenyl, 3-methylphenyl, 3,5-dimethylphenyl, and biphenyl; R3 is selected from p-cyanophenyl, p-methanesulfonylphenyl, p-methoxycarbonylphenyl, 3-acetylphenyl, indanone, benzofuran-1(3H)one, 3,4-dicyanophenyl, 3,5-dicyanophenyl, 3,5-dimethoxycarbonylphenyl, 3-cyano-5-chlorophenyl, pyridyl, trifluoromethylpyridyl, pyrimidinyl, and benzopyridyl.

4. The method according to claim 3 β A method for synthesizing amino acid esters, characterized in that, The free radical precursor shown in formula (II) is selected from sodium trifluoromethyl sulfinate, sodium difluoromethyl sulfinate, and sodium perfluorobutyl sulfinate.

5. The method according to claim 3 β A method for synthesizing amino acid esters, characterized in that, The photosensitizer is selected from... fac -tris(2-phenylpyridine) iridium, (4,4'-Di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III)hexafluorophosphate, bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridiumhexafluorophosphate, sodium eosin, 3,6-di-tert-butyl-9-trimethylmethyl-10-phenylacridin-10-onium tetrafluoroborate, 2,4,5,6-tetracarbazolyl-1,3-dicyanophenyl, tris(2,2'-bipyridine)ruthenium di(hexafluorophosphate) salt.

6. The method according to claim 3 β A method for synthesizing amino acid esters, characterized in that, The light wavelength is 370-467nm; the reaction time is 2-50h; and the reaction temperature is room temperature.

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