Chiral β-germanyl-α-amino acid and synthesis method thereof

Abstract

The present invention belongs to the field of asymmetric synthesis, and discloses a chiral β-germanyl-α-amino acid and a synthesis method thereof. The chiral β-germanyl-α-amino acid has a structure or enantiomers or diastereomers of the general formula I: wherein PG is selected from Phth, Cbz, Boc, Fmoc, Tos, PMB, Bn, Alloc; R 1 Selected from alkyl, 1-adamantyl, phenyl, R 4 is selected from alkyl, halogen, alkoxy, cycloalkyl, phenyl; R 2 , R 3 Each is independently selected from one of the following structures: hydrogen, phenyl, benzyl, naphthyl, alkyl, alkoxy, halogen, trifluoromethyl, phenyl, trimethylsilyl, morpholinyl substituted phenyl, and R 2 , R 3 The present invention develops a copper-catalyzed asymmetric synthesis method of non-natural β-germanyl α-amino acids, and obtains various chiral β-germanyl α-amino acid derivatives, which have the advantages of high yield, good enantioselectivity, and a wide range of substrate applications; the compound structure of the invention is novel, and compounds with such skeletons are not disclosed in the prior art.

Description

Technical Field

[0001] The invention belongs to the field of asymmetric synthesis, and specifically relates to a chiral beta-germanyl-alpha-amino acid and a synthesis method thereof. Background Art

[0002] Unnatural α-amino acids are an important class of biologically active compounds with a wide range of applications in protein design, peptide modification, drug discovery, and materials science. Due to their diverse structures and functions, they are also widely used as chiral building blocks, auxiliary reagents, ligands, and intermediates in organic synthesis. In the past few decades, many asymmetric synthesis methods for unnatural α-amino acids have been developed, among which the introduction of heteroatoms at the β position of the α-amino acid side chain is particularly attractive because several natural α-amino acids contain β-heteroatoms. The addition of new β-heteroatoms to α-amino acids will change the chemical, physiological, and pharmacological properties and conformational structures of the compounds, thereby providing new natural α-amino acid analogs for application in various fields.

[0003] In recent years, interest in β-silyl α-amino acids has increased rapidly. Peptides containing silyl amino acids have enhanced proteolytic stability, lipophilicity, and membrane permeability, which are of great significance in peptide- and protein-based therapeutics. Germanium is located below silicon in the periodic table and is a congener of carbon. Organogermanium compounds have been used in drug discovery, materials science, and are also explored for their applications in synthesis and catalysis due to their relatively high stability, hydrophobicity, and low toxicity. From a synthetic perspective, the catalytic enantioselective hydrofunctionalization of dehydroalanine derivatives is the most direct and atom-economical approach to the synthesis of unnatural β-heteroatom α-amino acids. Although transition metal-catalyzed hydrosilylation has been reported, the catalytic enantioselective silylation of dehydroalanine is rare, with only one Rh-catalyzed asymmetric intramolecular silylation of dehydroalanine to generate cyclic chiral β-silyl α-amino acids reported.

[0004] Considering the application value of chiral β-germanyl-α-amino acids in improving the biological properties of peptides and developing new drugs, it is necessary to develop effective catalytic asymmetric synthesis methods for germanium-based amino acids. Summary of the invention

[0005] The purpose of the present invention is to provide a class of chiral β-germanyl-α-amino acids with novel structures.

[0006] Another object of the present invention is to provide a method for synthesizing chiral β-germanyl-α-amino acid.

[0007] In order to achieve one of the above purposes, the present invention adopts the following technical solution:

[0008] A chiral β-germanyl-α-amino acid having a structure or an enantiomer or a diastereomer of the general formula I:

[0009]

[0010] Wherein, PG is selected from Phth, Cbz, Boc, Fmoc, Tos, PMB, Bn, Alloc;

[0011] R 1 Selected from alkyl, 1-adamantyl, phenyl, R 4 Selected from alkyl, halogen, alkoxy, cycloalkyl, phenyl;

[0012] R 2 , R 3 Each is independently selected from one of the following structures: hydrogen, phenyl, benzyl, naphthyl, alkyl, alkoxy, halogen, trifluoromethyl, phenyl, trimethylsilyl, morpholinyl substituted phenyl, And R 2 , R 3 Not hydrogen at the same time.

[0013] Furthermore, the R 1 Selected from alkyl, 1-adamantyl, phenyl, R 4 Selected from alkyl, halogen.

[0014] Furthermore, the R 1 Selected from (C1-C4) alkyl, 1-adamantyl, phenyl, R 4 Selected from (C1-C4) alkyl and halogen.

[0015] Furthermore, the R 1 is selected from methyl, tert-butyl, 1-adamantyl, phenyl, R 4 Selected from methyl, isopropyl, chloro.

[0016] Furthermore, the R 1 for

[0017] Furthermore, the R 2 , R 3 Each is independently selected from one of the following structures: hydrogen, phenyl, benzyl, naphthyl, (C1-C4) alkyl, (C1-C4) alkoxy, halogen, trifluoromethyl, phenyl, trimethylsilyl, morpholinyl substituted phenyl, And R 2 , R 3 Not hydrogen at the same time.

[0018] Furthermore, the R 2 , R 3 Each is independently selected from one of the following structures: hydrogen, phenyl, benzyl, naphthyl, methyl, methoxy, fluorine, chlorine, trifluoromethyl, phenyl, trimethylsilyl, morpholinyl substituted phenyl, And R 2 , R 3 Not hydrogen at the same time.

[0019] Furthermore, the R 2 , R 3 Each is independently selected from one of the following structures: hydrogen, phenyl, benzyl, 2-naphthyl, 2-methylphenyl, 3,5-dimethylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 3-chlorophenyl, 4-trifluoromethylphenyl, 4-phenylphenyl, 4-trimethylsilylphenyl, And R 2 , R 3 Not hydrogen at the same time.

[0020] Furthermore, the R 2 Selected from one of the following structures: phenyl, benzyl, naphthyl, alkyl, alkoxy, halogen, trifluoromethyl, phenyl, trimethylsilyl, morpholinyl substituted phenyl,

[0021] The R 3 Selected from one of the following structures: hydrogen, phenyl, benzyl, naphthyl, alkyl, alkoxy, halogen, trifluoromethyl, phenyl substituted with phenyl,

[0022] Furthermore, the R 2 Selected from one of the following structures: phenyl, benzyl, naphthyl, (C1-C4) alkyl, (C1-C4) alkoxy, halogen, trifluoromethyl, phenyl, trimethylsilyl, morpholinyl substituted phenyl,

[0023] The R 3 One of the following structures: hydrogen, phenyl, benzyl, naphthyl, (C1-C4) alkyl, (C1-C4) alkoxy, halogen, trifluoromethyl, phenyl substituted with phenyl,

[0024] Furthermore, the R 2 Selected from one of the following structures: phenyl, benzyl, naphthyl, methyl, methoxy, fluorine, chlorine, trifluoromethyl, phenyl, trimethylsilyl, morpholinyl substituted phenyl,

[0025] The R3 Selected from one of the following structures: hydrogen, phenyl, benzyl, naphthyl, methyl, methoxy, fluorine, chlorine, trifluoromethyl, phenyl substituted with phenyl,

[0026] Furthermore, the R 2 Selected from one of the following structures: phenyl, benzyl, 2-naphthyl, 2-methylphenyl, 3,5-dimethylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 3-chlorophenyl, 4-trifluoromethylphenyl, 4-phenylphenyl, 4-trimethylsilylphenyl,

[0027] The R 3 Selected from one of the following structures: hydrogen, phenyl, benzyl, 2-naphthyl, 2-methylphenyl, 3,5-dimethylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 3-chlorophenyl, 4-trifluoromethylphenyl, 4-phenylphenyl,

[0028] Furthermore, the PG is Phth.

[0029] A chiral β-germanyl-α-amino acid selected from one of the following compounds:

[0030]

[0031] The synthesis method of chiral β-germanyl-α-amino acid comprises the following steps: in the presence of a ligand and a catalyst, compound 1 and compound 2 react as follows:

[0032]

[0033] The catalyst is selected from Cu(OAc)2, Cu(OAc), CuCl2, Cu(NO3)2, CuI, CuI2, Cu(CO2CF3)2.H2O, Cu(SO3CF3)2, copper bis(tert-butylacetoacetate), Cu(acac)2;

[0034] The ligand is selected from the following compounds:

[0035]

[0036] Furthermore, the catalyst is selected from Cu(OAc)2 and Cu(OAc).

[0037] Furthermore, the amount of the catalyst is at least 5 mol%.

[0038] Furthermore, the amount of the ligand is at least 5.5 mol%.

[0039] The basis for the amount of ligand and catalyst used is relative to the amount of compound 2. For example, if the amount of ligand is written in the form of 5.5 mol%, it means that 0.055 mol of ligand is used for every 1 mol of compound 2; if the amount of catalyst is written in the form of 5 mol%, it means that 0.05 mol of catalyst is used for every 1 mol of compound 2.

[0040] Furthermore, the molar ratio of compound 1 to compound 2 is (0.8-2):1.

[0041] Furthermore, the reaction uses at least one of toluene, 1,4-dioxane, THF, DCE, PhCl, 2-Me-THF, DME, MTBE, MeCN, ethyl acetate, acetone, and diethyl ether as solvent.

[0042] Furthermore, the reaction temperature is 0-40°C.

[0043] Furthermore, the reaction time is more than 12 hours.

[0044] As used herein, "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl.

[0045] As used herein, "cycloalkyl" refers to a non-aromatic carbocyclic ring having typically 3 to 12 ring carbon atoms, preferably 3 to 8 ring carbon atoms. The ring may be saturated or have one or more carbon-carbon double bonds. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl.

[0046] As used herein, "alkoxy" refers to -O-(alkyl) and -O-(cycloalkyl), wherein alkyl and cycloalkyl are as defined herein, and non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentoxy, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. Alkoxy groups typically have 1 to 7 carbon atoms connected by an oxygen bridge.

[0047] As used herein, "halogen" refers to fluorine, chlorine, bromine and iodine.

[0048] As used herein, "naphthyl" refers to Includes 1-naphthyl and 2-naphthyl.

[0049] As used herein, morpholinyl refers to

[0050] As used herein, benzyl refers to PhCH2-.

[0051] The substituents on the benzene ring may be monosubstituted or polysubstituted. When there are two or more substituents, the types of the substituents may be the same or different.

[0052] As used herein, the following words and phrases are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise: Phth refers to phthaloyl; Ad refers to adamantyl; Ph refers to phenyl; Cbz refers to benzyloxycarbonyl; Boc refers to tert-butyloxycarbonyl; Fmoc refers to t-methoxycarbonyl; Tos refers to p-toluenesulfonyl; PMB refers to p-methoxybenzyl; Bn refers to benzyl; Alloc refers to allyloxycarbonyl; MTBE refers to methyl tert-butyl ether; THF refers to tetrahydrofuran; DME refers to ethylene glycol dimethyl ether; and DCE refers to dichloroethane.

[0053] The present invention has the following beneficial effects: the present invention develops a copper-catalyzed asymmetric synthesis method of non-natural β-germanyl α-amino acids, and obtains various chiral β-germanyl-α-amino acid derivatives through enantioselective intermolecular hydrogen germanation of dehydroalanine derivatives with dihydrogermane and trihydrogermane, which has the advantages of high yield, good enantioselectivity, and a wide range of substrate applications. The compound structure of the present invention is novel, and compounds with such skeletons are not disclosed in the prior art. The products of the present invention can be converted into functional molecules containing germanium, which can be used in the fields of improving the biological properties of polypeptides and developing new drugs. DETAILED DESCRIPTION

[0054] Conventional reactions were carried out under magnetic stirring and argon protection; catalytic reactions were carried out in argon atmosphere in a colorless 10 mL microwave reaction tube. Anhydrous solvents (CH3CN, Et2O, CH2Cl2 and toluene) were obtained using an Inert Pure Solv solvent purification system or purchased from Energy Chemical. TLC was performed on a silica gel Huanghai HSGF254 plate and fluorescence quenching (λ max =254 nm) to visualize the chromatograms. GENERAR-REAGENT silica gel (200-300 mesh) was used for silica gel column chromatography. Unless otherwise stated, all reagents were purchased from commercial suppliers (Bide Pharmatech, Energy Chemical, TCI, Aldrich, Alfa and J&K) and used directly without further purification. Nuclear magnetic resonance (NMR) spectra were recorded at ambient temperature using a Bruker DPX 400 or Bruker DPX 600 instrument. 1H NMR is 400MHz or 600MHz, 13 C NMR is 101MHz or 151MHz, 19 F NMR is 376MHz or 565MHz, 31 P NMR is 162MHz or 243MHz. The unit of chemical shift (δ) is ppm, and the unit of coupling constant (J) is Hertz (Hz). NMR standards used are as follows: ( 1 H NMR)CDCl3=7.26ppm;( 13 C NMR)CDCl3=77.16ppm;( 1 H NMR) THF-d8 = 3.58 ppm; ( 13 C NMR)THF-d8=67.21ppm;( 1 HNMR) CD3OD = 3.31 ppm; ( 13 C NMR) CD3OD=49.00 ppm. 1 H NMR data are reported as follows: chemical shift (δ, ppm), s indicates singlet, d indicates doublet, t indicates triplet, q indicates quartet, m indicates multiplet, dd indicates doublet of doublets, and br indicates broad. 13 C NMR data are reported as chemical shifts (δ, ppm). HPLC analysis was performed on an Agilent 1260, and chiral columns OD-3, IA, IB, and IC were purchased from Daicel. High-resolution mass spectra (HRMS) were recorded on an Agilent Technologies 6230TOF LC / MS under electrospray ionization (ESI) conditions, using CH2Cl2 or THF as solvents. The samples were analyzed using a Bruker D8VENTURE (CuKα radiation, ) X-ray crystallographic data were recorded. Optical rotation was measured in CHCl3 at a concentration of 0.1 g / 100 mL using a Rudolph Autopol-I automatic polarimeter.

[0055] Example 1

[0056] Synthesis of Dihydrogermane and Trihydrogermane Substrates

[0057] Step A: Synthesis of dihydrogermane substrates 1b-1o, 1q.

[0058]

[0059] a) To a solution of Mg (1.2 eq.) and I2 (two crystals) in anhydrous THF, an aromatic bromide (1.0 eq., 1.0 M, THF) was added under argon atmosphere, and the mixture was stirred at 70°C for 3 hours to obtain a Grignard reagent. GeCl4 (1.2 eq.) and anhydrous Et2O (0.4-0.5 M) were added to a 500 mL Schlenk bottle under argon atmosphere, and the resulting mixture was cooled to -78°C; then the Grignard reagent was added dropwise to the mixture over 1 hour. The reaction was stirred at room temperature for 1 hour, and then refluxed at 46°C for 16 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue obtained was redissolved in anhydrous Et2O, the mixture was cooled to -78°C, and LiAlH4 (2.0 eq., 2.5 M, in THF) was added dropwise to the mixture. After 1 hour, the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with H2O at -78°C and extracted with Et2O; the combined organic phases were dried over anhydrous Na2SO4 and concentrated under vacuum to collect the residue to give crude trihydrogermane, which was used directly without further purification. The purity of dihydrogermane was determined by 1 H NMR measurement. Next, NCS (1.05 equivalents) and anhydrous THF (1.0 M) were added to a 150 mL Schlenk bottle under argon. Crude trihydrogermane (1.0 M, THF) was quickly added to the mixture at room temperature. After stirring at 60 ° C for 3 hours, the solvent was removed under vacuum, and the resulting residue was dissolved in petroleum ether, the resulting mixture was filtered, and the filtrate was concentrated in vacuo to obtain crude chlorogermanium S1, which was used directly without further purification.

[0060] b) Under argon, to a solution of Mg (1.2 eq.) and I2 (one crystal) in anhydrous tetrahydrofuran, is added bromoarene (1.0 eq., 1.0 M, THF), and the mixture is stirred at 70°C. After stirring for 3 hours, the reaction mixture is cooled to room temperature. Chlorogermanium S1 crude product (1.2 eq.) is quickly added. The mixture is stirred at 70°C for 12 hours, then the reaction is quenched with saturated aqueous NH4Cl solution, extracted with EtOAc, the combined organic phases are dried over anhydrous Na2SO4, concentrated in vacuo, and the residue is purified by silica gel column chromatography (usually 100% petroleum ether) to give dihydrogermane substrate 1.

[0061]

[0062] Compound 1b, 3.43 g, 61% yield, colorless liquid. 1 H NMR (400MHz, CDCl3) δ7.43 (d, J = 7.7 Hz, 4H), 7.19 (d, J = 7.6 Hz, 4H), 5.04 (s, 2H), 2.36 (s, 6H). 13C NMR (101MHz, CDCl3) δ139.0, 135.3, 130.6, 129.3, 21.6. HRMS(ESI,m / z)[MH] + Accurate mass calculation [C 14 H 15 [Ge] + :257.0380; measured value:257.0374.

[0063] Compound 1c, 2.15 g, 55% yield, colorless liquid. 1 H NMR (600MHz, CDCl3) δ7.56 (dd, J = 5.5, 1.9Hz, 4H), 7.43–7.35 (m, 6H), 5.12 (s, 2H). 13 C NMR (151MHz, CDCl3) δ135.3, 134.2, 129.2, 128.5. HRMS(ESI,m / z)[MH] + Accurate mass calculation [C 12 H 11 [Ge] + :229.0067; measured value:229.0063.

[0064] Compound 1d, 3.51 g, 62% yield, colorless liquid. 1 H NMR (600MHz, CDCl3) δ7.42 (d, J = 7.3 Hz, 2H), 7.30 (t, J = 7.4 Hz, 2H), 7.22 (d, J = 7.5 Hz, 2H), 7.16 (t, J = 7.3 Hz, 2H), 5.11 (s, 2H), 2.39 (s, 6H). 13 C NMR (151MHz, CDCl3) δ143.8,136.2,133.9,129.7,129.6,125.7,23.2. HRMS(ESI,m / z)[MH] + Accurate mass calculation [C 14 H 15 [Ge] + :257.0380; measured value:257.0375.

[0065] Compound 1e, 2.36 g, 55% yield, colorless liquid. 1 H NMR (600MHz, CDCl3) δ7.17(s,4H),7.02(s,2H),5.00(s,2H),2.31(s,12H). 13C NMR (151MHz, CDCl3) δ137.8, 134.0, 133.0, 130.9, 21.4. HRMS(ESI,m / z)[MH] + Accurate mass calculation [C 16 H 19 [Ge] + :285.0693; measured value:285.0682.

[0066] Compound 1f, 2.74 g, 59% yield, colorless solid. 1 H NMR (600MHz, CDCl3) δ7.45 (d, J = 7.4 Hz, 4H), 6.92 (d, J = 7.5 Hz, 4H), 5.03 (s, 2H), 3.82 (s, 6H). 13 C NMR (151MHz, CDCl3) δ160.6, 136.5, 125.1, 114.3, 55.2. HRMS(ESI,m / z)[MH] + Accurate mass calculation [C 14 H 15 GeO2] + :289.0278; measured value:289.0276.

[0067]

[0068] Compound 1g, 0.58g, 7% yield, colorless solid. 1 H NMR (400MHz, CDCl3) δ7.00 (d, J = 1.0 Hz, 1H), 6.98 (d, J = 1.0 Hz, 1H), 6.96 (s, 2H), 6.86 (s, 1H), 6.84 (s, 1H), 5.94 (s, 4H), 5.03 (s, 2H). 13 C NMR (101MHz, CDCl3) δ148.7,147.9,129.1,126.6,114.5,109.2,100.8. HRMS(ESI,m / z)[MH] + Accurate mass calculation [C 14 H 11 GeO4] + :316.9864; measured value:316.9864.

[0069] Compound 1h, 0.52 g, 22% yield, colorless liquid. 1 H NMR (600MHz, CDCl3) δ7.49 (t, J = 7.0 Hz, 4H), 7.08 (t, J = 8.6 Hz, 4H), 5.09 (s, 2H).13 C NMR (151MHz, CDCl3) δ 164.0 (d, J = 248.4Hz), 137.0 (d, J = 7.5Hz), 129.1 (d, J = 3.7Hz), 115.8 (d, J = 20.4Hz). 19 F NMR (376MHz, CDCl3) δ-111.65. HRMS(ESI,m / z)[MH] + Accurate mass calculation [C 12 H9F2Ge] + :264.9879; measured value:264.9875.

[0070] Compound 1i, 3.01 g, 46% yield, colorless liquid. 1 H NMR (600MHz, CDCl3) δ7.66 (d, J = 8.1 Hz, 4H), 7.63 (d, J = 8.1 Hz, 4H), 5.21 (s, 2H). 13 C NMR (151MHz, CDCl3) δ138.2, 135.6, 131.7 (q, J = 32.5Hz), 125.2 (q, J = 3.6Hz), 124.2 (q, J = 272.3Hz). 19 F NMR (376MHz, CDCl3) δ-63.03. HRMS(ESI,m / z)[MH] + Accurate mass calculation [C 14 H9F6Ge] + :364.9815; measured value:364.9814.

[0071] Compound 1j, 1.75 g, 68% yield, colorless liquid. 1 H NMR (400MHz, CDCl3) δ7.49 (s, 2H), 7.37 (dd, J = 8.0, 4.2Hz, 4H), 7.33–7.29 (m, 2H), 5.12 (s, 2H). 13 C NMR (101MHz, CDCl3) δ135.8, 134.9, 134.9, 133.2, 130.0, 129.7. HRMS(ESI,m / z)[MH] + Accurate mass calculation [C 12 H9Cl2Ge] + :296.9288; measured value:296.9263.

[0072] Compound 1k, 1.41 g, 48% yield, colorless solid. 1H NMR (600MHz, CDCl3) δ8.10(s,2H),7.85(d,J=8.2Hz,4H),7.82(d,J=6.8Hz,2H),7.64(d,J=8.1Hz,2H),7.53–7.48(m,4H),5.35(s,2H). 13 C NMR (151MHz, CDCl3) δ136.0,133.8,133.4,131.6,131.5,128.0,128.0,127.8,126.6,126.3. HRMS(ESI,m / z)[MH] + Accurate mass calculation [C 20 H 15 [Ge] + :329.0380; measured value:329.0377.

[0073]

[0074] Compound 11, 2.57 g, 45% yield, colorless solid. 1 H NMR (600MHz, CDCl3) δ7.66 (d, J = 7.8 Hz, 4H), 7.64–7.60 (m, 8H), 7.46 (t, J = 7.5 Hz, 4H), 7.37 (t, J = 7.1 Hz, 2H), 5.19 (s, 2H). 13 C NMR (151MHz, CDCl3) δ142.2,141.0,135.8,132.9,129.0,127.6,127.3,127.3. HRMS(ESI,m / z)[MH] + Accurate mass calculation [C 24 H 19 [Ge] + :381.0693; measured value:381.0685.

[0075] Compound 1m, 0.61 g, 25% yield, colorless liquid. 1 H NMR (600MHz, CDCl3) δ7.81 (s, 2H), 7.62 (d, J = 2.2Hz, 2H), 7.54 (d, J = 8.2Hz, 2H), 7.47 (dd, J = 8.2, 1.1Hz, 2H), 6.75 (dd, J = 2.2, 0.9Hz, 2H), 5.25 (s, 2H). 13 C NMR (151MHz, CDCl3) δ155.8,145.1,130.8,128.5,128.0,127.8,111.8,106.4. HRMS(ESI,m / z)[MH]+ Accurate mass calculation [C 16 H 11 GeO2] + :308.9965; measured value:308.9963.

[0076] Compound 1n, 0.31 g, 7% yield, colorless solid. 1 H NMR (400MHz, CDCl3) δ8.39 (s, 2H), 8.16 (d, J = 6.5Hz, 2H), 7.88 (t, J = 9.1Hz, 4H), 7.64 (d, J = 7.8Hz, 2H), 7.50–7.41 (m, 4H), 5.39 (s, 2H). 13 C NMR (151MHz, CDCl3) δ140.9,139.4,135.8,135.3,133.0,129.5,128.6,127.1,124.6,123.0,123.0,121.8. HRMS(ESI,m / z)[MH] + Accurate mass calculation [C 24 H 15 GeS2] + :440.9821; measured value:440.9825.

[0077] Compound 1o, 1.60 g, 51% yield, colorless liquid. 1 H NMR (600MHz, CDCl3) δ7.66 (d, J = 4.8 Hz, 2H), 7.36 (d, J = 3.3 Hz, 2H), 7.23 (dd, J = 4.6, 3.5 Hz, 2H), 5.35 (s, 2H). 13 C NMR (151MHz, CDCl3) δ136.3, 131.6, 129.8, 128.4. HRMS(ESI,m / z)[MH] + Exact mass calculation [C8H7GeS2] + :240.9195; measured value:240.9194.

[0078] Compound 1q, 1.31 g, 50% yield, colorless solid. 1 H NMR(400MHz, CDCl3) δ8.07(s,1H),7.84(dd,J=12.3,4.8Hz,3H),7.61(dd,J=8.1 ,0.9Hz,1H),7.53–7.46(m,4H),7.21(d,J=7.5Hz,2H),5.20(s,2H),2.38(s,3H). 13C NMR (101MHz, CDCl3) δ139.2,135.9,135.3,133.7,133.4,131.9,131.5,130.3,129.4,128.0,127.9,127.7,126.5,126.2,21.6. HRMS(ESI,m / z)[MH] + Accurate mass calculation [C 17 H 15 [Ge] + :293.0380; measured value:293.0375.

[0079] Step B: Synthesis of dihydrogermane substrate 1p.

[0080]

[0081] References [M. Kamitani, K. Fukumoto, R. Tada, M. Itazaki, H. Nakazawa, Organometallics 2012, 31, 2957-2960.] A magnetic stirring bar and magnesium powder (48.0 mmol, 3.2 equiv) were placed in a dry 100 mL round-bottom flask, the flask was purged with argon, and then I2 (one pellet), anhydrous THF (0.5 M) and GeCl4 (15.0 mmol, 1.0 equiv) were added. Benzyl bromide (40.5 mmol, 2.7 equiv) was added dropwise to the mixture at room temperature, and the resulting mixture was stirred at 60 ° C overnight. LiAlH4 (2.5 M, in THF, 30.0 mmol, 2.0 equiv) was added at -78 ° C, and then stirred at room temperature overnight. After the reaction was completed, the reaction was quenched with saturated NH4Cl aqueous solution and extracted with EtOAc. The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo, and the residue was purified by silica gel (petroleum ether 100%) column chromatography to obtain compound 0.42 g 1p, 11% yield, as a colorless liquid. 1 H NMR (400MHz, CDCl3) δ7.26–7.21(m,4H),7.13–7.04(m,6H),4.07(p,J=3.2Hz,2H),2.39(t,J=3.1Hz,4H). 13 C NMR (101MHz, CDCl3) δ140.9, 128.7, 128.1, 124.8, 19.3.

[0082] Step C: Synthesis of trihydrogermane substrates 4a, 4b.

[0083]

[0084] Under argon protection, to a solution of Mg (1.2 equiv) and I2 (two crystals) in anhydrous THF, bromoarene (1.0 equiv, 1.0 M, THF) was added, and the mixture was stirred at 70°C for 3 hours to obtain a Grignard reagent. Under argon protection, GeCl4 (1.2 equiv) and anhydrous Et2O (0.4-0.5 M) were added to a 500 mL Schlenk bottle, and the resulting mixture was cooled to -78°C, and then the Grignard reagent was added dropwise to the mixture within 1 hour. Thereafter, the mixture was stirred at room temperature for 1 hour, and then refluxed at 46°C for 16 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was redissolved in anhydrous Et2O and cooled to -78°C, and LiAlH4 (2.0 equiv, 2.5 M, in THF) was added dropwise to the mixture. After 1 hour, the reaction mixture was stirred at room temperature overnight. The reaction was quenched with H2O at -78°C and extracted with Et2O. The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was collected to obtain crude trihydrogermane, which was distilled at normal pressure to obtain trihydrogermane 4.

[0085]

[0086] Compound 4a, 2.95 g, 59% yield, colorless liquid, distillation temperature 215°C. 1 H NMR (600MHz, CDCl3) δ7.43 (d, J = 7.1 Hz, 2H), 7.18 (d, J = 7.1 Hz, 2H), 4.26 (s, 3H), 2.36 (s, 3H). 13 C NMR (101MHz, CDCl3) δ139.0, 135.5, 130.9, 129.3, 21.5. HRMS(ESI,m / z)[MH] + Exact mass calculation [C7H9Ge] + :166.9911; measured value:166.9910.

[0087] Compound 4b, 3.71 g, 56% yield, colorless liquid, distillation temperature 205°C. 1 H NMR (600MHz, CDCl3) δ7.66 (d, J = 7.7 Hz, 2H), 7.59 (d, J = 7.9 Hz, 2H), 4.33 (s, 3H). 13 C NMR (151MHz, CDCl3) δ 136.6, 135.9, 131.3 (q, J = 32.3Hz), 124.9 (q, J = 3.9Hz), 124.3 (q, J = 272.2Hz). 19F NMR (565MHz, CDCl3) δ-62.99. HRMS(ESI,m / z)[MH] - Exact mass calculation [C7H6F3Ge] - :220.9639; measured value:220.9631.

[0088] Step D: Synthesis of trihydrogermane substrates 4c-4e.

[0089]

[0090] Under argon protection, to a solution of Mg (1.2 equiv) and I2 (two crystals) in anhydrous THF, aromatic bromide (1.0 equiv, 1.0 M, THF) was added, and the mixture was stirred at 70°C for 3 hours to obtain a Grignard reagent. Under argon protection, GeCl4 (1.2 equiv) and anhydrous Et2O (0.4-0.5 M) were added to a 500 mL Schlenk bottle, and the resulting mixture was cooled to -78°C, and then the Grignard reagent was added dropwise to the mixture within 1 hour. Thereafter, the mixture was stirred at room temperature for 1 hour, and then refluxed at 46°C for 16 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was redissolved in anhydrous Et2O and cooled to -78°C, and LiAlH4 (2.0 equiv, 2.5 M, in THF) was added dropwise to the resulting mixture. After 1 hour, the reaction mixture was stirred at room temperature overnight. The reaction was quenched with H2O at -78°C and extracted with Et2O. The combined organic phases were dried over anhydrous Na2SO4 and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography to afford trihydrogermane 4.

[0091]

[0092] Compound 4c, 2.38 g, 53% yield, colorless liquid. 1 HNMR(400MHz, CDCl3) δ7.56–7.45(m,4H),4.27(s,3H),0.28(s,9H). 13 C NMR (101MHz, CDCl3) δ141.5, 134.9, 133.3, 131.0, -1.1. HRMS(ESI,m / z)[MH] - Accurate mass calculation [C9H 15 GeSi] - :225.0160; measured value:225.0157.

[0093] Compound 4d, 2.90 g, 61% yield, colorless solid. 1H NMR (400MHz, CDCl3) δ7.42 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 8.5 Hz, 2H), 4.22 (s, 3H), 3.89–3.82 (m, 4H), 3.21–3.14 (m, 4H). 13 C NMR (101MHz, CDCl3) δ152.0, 136.5, 120.5, 115.6, 67.0, 49.0. HRMS(ESI,m / z)[M+H] + Accurate mass calculation [C 10 H 16 GeNO] + :240.0438; measured value:240.0435.

[0094] Compound 4e, 1.03 g, 25% yield, colorless solid. 1 H NMR (400MHz, CDCl3) δ7.83 (s, 1H), 7.35 (s, 2H), 7.06 (d, J = 3.1Hz, 1H), 6.48 (d, J = 2.6Hz, 1H), 4.35 (s, 3H), 3.80 (s, 3H). 13 C NMR (101MHz, CDCl3) δ137.2,129.1,128.6,127.9,119.7,109.5,100.9,32.9. HRMS(ESI,m / z)[M+H] + Accurate mass calculation [C9H 12 [GeN] + :208.0176; measured value:208.0175.

[0095] Example 2

[0096] Step E: Synthesis of dehydroalanine derivatives 2a, 2b, 2c.

[0097]

[0098] Prepared according to the literature [M.-Y. Chang, S.-T. Chen, N.-C. Chang, Synth. Commun. 2003, 33, 1375-1382.]. A toluene (0.5 M) solution of H-NPhth (10.0 mmol, 1.0 equiv), PPh3 (1.0 mmol, 10 mol%) and NaOAc (5.0 mmol, 50 mol%) was stirred and heated at reflux temperature for 10 min. HOAc (10.0 mmol, 1.0 equiv) and propanoate (10.0 mmol, 1.0 equiv) were added to the above solution. The reaction mixture was refluxed for 18 h. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (generally CH2Cl2 100%) to obtain dehydroalanine substrates 2a, 2b, 2c.

[0099]

[0100] Compound 2a, 1.73 g, 75% yield, colorless solid. 1 H NMR (600MHz, CDCl3) δ7.92 (dd, J = 5.4, 3.1 Hz, 2H), 7.78 (dd, J = 5.5, 3.0 Hz, 2H), 6.69 (s, 1H), 6.00 (s, 1H), 3.82 (s, 3H). 13 C NMR (151MHz, CDCl3) δ166.6,162.9,134.6,132.0,129.2,128.3,124.1,53.0.

[0101] Compound 2b, 2.01 g, 73% yield, colorless solid. 1 H NMR (600MHz, CDCl3) δ7.91 (dd, J = 5.4, 3.0 Hz, 2H), 7.77 (dd, J = 5.4, 3.1 Hz, 2H), 6.58 (s, 1H), 5.91 (s, 1H), 1.48 (s, 9H). 13 C NMR (151MHz, CDCl3) δ166.7,161.3,134.6,132.0,130.7,126.8,124.0,82.9,28.0.

[0102] Compound 2c, 1.31 g, 74% yield, colorless solid. 1H NMR (600MHz, CDCl3) δ7.90(dd,J=7.6,3.8Hz,2H),7.76(dd,J=7.8,3.9Hz,2H),6.58(s,1H),5.90(s,1H),2.16(s,3H),2.13(s,6H),1.68–1.61(m,6H). 13 C NMR (151MHz, CDCl3) δ166.7,160.9,134.5,132.0,130.7,126.9,124.0,82.9,41.2,36.2,31.0. HRMS(ESI,m / z)[M+H] + Accurate mass calculation [C 21 H 22 NO4] + :352.1543; measured value:352.1542.

[0103] Step F: Synthesis of dehydroalanine derivatives 2d, 2e, 2f, 2g.

[0104]

[0105] Compound S2 was synthesized using DL-serine according to the literature [TJ Donohoe, CR Jones, LCA Barbosa, J. Am. Chem. Soc. 2011, 133, 16418-16421.]. Compound S2 was prepared according to the literature [N. Obara, T. Watanabe, T. Asakawa, T. Kan, T. Tanaka, Synlett 2017, 28, 1183-1186.] 2d, 2e, 2f, 2g. ArOH (7.5 mmol, 1.5 equiv) and 4-dimethylaminopyridine (0.5 mmol, 10 mol%) were added to a solution of S2 (5.0 mmol, 1.0 equiv) in anhydrous CH2Cl2 (0.5 M) at 0°C under argon protection. Subsequently, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.5 mmol, 1.5 equiv) was added to the reaction mixture. After 20 minutes, the reaction mixture was moved to room temperature for 1 to 2 hours. The reaction was quenched with saturated brine and extracted with EtOAc; the combined organic phases were dried over anhydrous Na2SO4, the solvent was removed under vacuum, and the resulting residue was purified by silica gel column chromatography (generally CH2Cl2 100%) to obtain dehydroalanine substrates 2d, 2e, 2f and 2g.

[0106]

[0107] Compound 2d, 0.80 g, 55% yield, colorless solid.1 HNMR (400MHz, CDCl3) δ7.94 (dd, J=5.5, 3.1Hz, 2H), 7.79 (dd, J=5.5, 3.1Hz, 2H), 7 .42–7.34(m,2H),7.27–7.20(m,1H),7.19–7.12(m,2H),6.87(s,1H),6.15(s,1H). 13 C NMR (101MHz, CDCl3) δ166.5,161.2,150.6,134.8,131.9,129.6,129.0,126.4,124.2,121.6.

[0108] Compound 2e, 0.71 g, 44% yield, colorless solid. 1 H NMR (400MHz, CDCl3) δ7.94 (dd, J=5.5, 3.1Hz, 2H), 7.78 (dd, J=5.5, 3.1Hz, 2H), 7.06 (s, 3H), 6.95 (s, 1H), 6.17 (s, 1H), 2.20 (s, 6H). 13 C NMR (101MHz, CDCl3) δ166.5,160.2,147.9,134.7,132.0,130.4,129.6,128.8,128.8,126.4,124.1,16.4. HRMS(ESI,m / z)[M+H] + Accurate mass calculation [C 19 H 16 NO4] + :322.1074; measured value:322.1073.

[0109] Compound 2f, 0.27 g, 14% yield, colorless solid. 1 H NMR (600MHz, CDCl3) δ7.94 (dd, J=5.4, 3.1Hz, 2H), 7.78 (dd, J=5.5, 3.0Hz, 2H), 7.22 (dd, J=8.4, 6.8Hz, 1 H), 7.16 (d, J = 7.4Hz, 2H), 6.96 (s, 1H), 6.19 (s, 1H), 3.02 (hept, J = 6.9Hz, 2H), 1.20 (d, J = 19.8Hz, 12H). 13 C NMR (151MHz, CDCl3) δ166.5,161.0,145.4,140.6,134.7,132.0,129.7,129.0,127.0,124.2,124.1,27.6,24.0,22.8. HRMS(ESI,m / z)[M+H]+ Accurate mass calculation [C 23 H 24 NO4] + :378.1700; measured value:378.1698.

[0110] Compound 2g, 1.49g, 82% yield, colorless solid. 1 H NMR (400MHz, CDCl3) δ7.94 (dd, J=5.5, 3.1Hz, 2H), 7.79 (dd, J=5.5, 3.1Hz, 2H) ,7.37(d,J=8.1Hz,2H),7.16(dd,J=8.4,7.9Hz,1H),7.04(s,1H),6.27(s,1H). 13 C NMR (101MHz, CDCl3) δ166.2,158.9,143.7,134.7,131.9,130.7,129.2,128.8,127.9,127.7,124.2. HRMS(ESI,m / z)[M+H] + Accurate mass calculation [C 17 H 10 Cl2NO4] + :361.9981; measured value:361.9980.

[0111] Example 3

[0112] Step G: In a glove box filled with argon, the catalyst (5.0 mol%), ligand (5.5 mol%) and solvent (1.0 mL) were loaded into a dry 10.0 mL microwave reaction tube, and the resulting mixture was stirred at room temperature for 15 minutes, and then compound 1 (0.18 mmol, 1.2 equiv) and compound 2 (0.15 mmol, 1.0 equiv) were added. Cover the lid, remove from the glove box, and stir at room temperature for 24 hours. The reaction mixture was concentrated and purified by silica gel column chromatography using dichloromethane / petroleum ether (1:1 to 2:1) as the eluent to obtain product 3. Using Cu (OAc) as a catalyst and chiral diphosphine ligand L2, dehydroalanine derivative 2a reacted with dihydrogermane 1b to obtain β-germanyl α-amino acid product 3ba, 70.3 mg, yield 95%, ee 35%, colorless oil.

[0113]

[0114] [α] D 25.0= +12.0 (c = 0.1, CHCl3). HLPC conditions: Daicel Chiralpak OD-3 column, n-hexane / isopropanol = 98:02, 1.0 mL / min), λ = 280 nm, temperature = 28°C, t (minor) = 16.48 min, t (major) = 28.98 min. 1 H NMR (400MHz, CDCl3) δ7.66–7.60(m,4H),7.32(d,J=7.9Hz,2H),7.27(d,J=7.9Hz,2H),7.08(d,J=7.5Hz,2H),6.89(d,J=7.5Hz,2H),5.12(dd,J=12.1,4 .6Hz,1H),5.05(dd,J=5.0,1.6Hz,1H),3.71(s,3H),2.43(ddd,J=14.2,12. 1,5.0Hz,1H),2.27(s,3H),2.24(ddd,J=14.2,4.7,1.8Hz,1H),2.12(s,3H). 13 C NMR (101MHz, CDCl3) δ170.7,167.3,139.0,138.7,134.6,134.4,133.6,131.8,131.8,131.3,129.2,129.0,123.3,52.9,50.1,21.5,21.4,14.3. HRMS(ESI,m / z)[M+Na] + Accurate mass calculation [C 26 H 25 GeNO4Na] + :512.0888; measured value:512.0898.

[0115] The reaction conditions were further optimized to improve enantioselectivity. After screening copper catalysts, chiral ligands, solvents and temperature, the ee value of the target product still did not increase much.

[0116] Screening of copper catalyst: Cu(OAc)2 was used as catalyst with a yield of 93% and an ee of 32%.

[0117] Screening of chiral ligands (using Cu(OAc)2 catalyst and THF solvent)

[0118]

[0119] Ligand Yield (%) ee(%) 1 L3 17 15 2 L4 16 3 3 L5 17 4 4 L6 94 4 5 L7 93 3 6 L8 96 4

[0120] Solvent screening

[0121]

[0122] 2(R) Solvents Yield (%) ee(%) 1 2a(R=Me) Toluene 91 2 2 2a(R=Me) 1,4-Dioxane 95 30 3 2a(R=Me) DCE 83 13 4 2a(R=Me) PhCl 97 9 5 2a(R=Me) 2-Me-THF 50 2 6 <![CDATA[2b(R= t This)]]> THF 83 49 7 <![CDATA[2b(R= t This)]]> EtOAc 29 14 8 <![CDATA[2b(R= t This)]]> DME 85 46 9 <![CDATA[2b(R= t This)]]> Methyl tert-butyl ether 52 5 10 <![CDATA[2b(R= t This)]]> MeCN 74 15 11 <![CDATA[2b(R= t This)]]> acetone 42 3 12 <![CDATA[2b(R= t This)]]> Ether 36 16

[0123] Temperature screening

[0124]

[0125] 3bb, colorless oil, 76.3 mg. [α] D 25.0 =+26.0 (c=0.1, CHCl3). HPLC conditions: Daicel Chiralpak OD-3 column, n-hexane / isopropanol=98:02, 1.0 mL / min), λ=280 nm, temperature=28°C, t(minor)=9.01 min, t(major)=11.80 min. 1 H NMR (400MHz, CDCl3) δ7.65–7.59(m,4H),7.33(d,J=7.9Hz,2H),7.27(d,J=7.9Hz,2H),7.08(d,J=7.5Hz,2H),6.88(d,J=7.5Hz,2H), 5.06–4.98(m,2H),2.42(ddd,J=14.2,12.3,5.1Hz,1H),2.27(s,3H),2.18(ddd,J=14.2,4.5,1.7Hz,1H),2.12(s,3H),1.42(s,9H). 13 C NMR (101MHz, CDCl3) δ169.1,167.5,138.9,138.6,134.6,134.4,133.5,132 .0,131.8,131.5,129.1,129.0,123.1,82.5,50.9,28.0,21.5,21.4,14.3. HRMS(ESI,m / z)[M+Na] + Accurate mass calculation [C 29 H 31 GeNO4Na] + :554.1357; measured value:554.1370.

[0126] temperature Yield (%) ee(%) 1 rt 96 59 2 15 95 59 3 0 19 60

[0127] Considering that the ester group of substrate 2a may affect the enantioselectivity of the reaction, the ee value can be significantly improved by increasing the steric hindrance of the ester group R'. When R' is 2,6-dichlorophenyl, product 3bg is obtained with a yield of 96% and 90% ee.

[0128]

[0129]

[0130]

[0131] Colorless foam, 87.6 mg, 96% yield, 67% ee. [α] D 25.0 = +22.0 (c = 0.1, CHCl3). HPLC conditions: Daicel Chiralpak OD-3 column, n-hexane / isopropanol = 98:02, 1.0 mL / min), λ = 280 nm, temperature = 28°C, t (minor) = 6.84 min, t (major) = 9.22 min. 1 H NMR (400MHz, CDCl3) δ7.65–7.58(m,4H),7.32(d,J=7.9Hz,2H),7.26(d,J=7.8Hz,2H),7.07(d,J=7.6Hz,2H),6.88(d,J=7.5Hz,2H),5.03(dd,J =5.0,1.6Hz,1H),4.99(dd,J=12.2,4.5Hz,1H),2.40(ddd,J=14.2,12.2,5.1Hz,1H),2.26(s,3H),2.20–2.10(m,7H),2.05(s,6H),1.61(s,6H). 13 C NMR (101MHz, CDCl3) δ168.8,167.5,138.9,138.6,134.7,134.4,133.5,132.1,13 1.9,131.6,129.1,129.0,123.2,82.6,50.9,41.2,36.2,31.0,21.5,21.4,14.4. HRMS(ESI,m / z)[M+Na] + Accurate mass calculation [C 35 H 37 GeNO4Na] + :632.1826; measured value:632.1842.

[0132]

[0133] Colorless oil, 76.8 mg, 93% yield, 63% ee. [α] D 25.0= +3.0 (c = 0.1, CHCl3). HPLC conditions: Daicel Chiralpak OD-3 column, n-hexane / isopropanol = 98:02, 1.0 mL / min), λ = 280 nm, temperature = 28°C, t (minor) = 14.34 min, t (major) = 24.22 min. 1 H NMR (400MHz, CDCl3) δ7.68–7.61(m,4H),7.37–7.28(m,6H),7.21(t,J=7.4Hz,1H),7.07(dd,J=14.4,7.9Hz,4H),6.91(d,J=7.5Hz,2 H),5.34(ddd,J=6.7,4.7,1.5Hz,1H),5.11(dd,J=4.9,1.9Hz,1H),2.55–2.45(m,1H),2.37–2.29(m,1H),2.27(s,3H),2.13(s,3H). 13 C NMR (101MHz, CDCl3) δ169.1,167.3,150.8,139.1,138.8,134.7,134.4,133.7,1 31.8,131.2,129.6,129.2,129.1,126.2,123.4,121.5,50.2,21.5,21.4,14.6. HRMS(ESI,m / z)[M+Na] + Accurate mass calculation [C 31 H 27 GeNO4Na] + :574.1044; measured value:574.1057.

[0134]

[0135] Colorless oil, 79.9 mg, 92% yield, 86% ee. [α] D 25.0 = +27.0 (c = 0.1, CHCl3). HPLC conditions: Daicel Chiralpak OD-3 column, n-hexane / isopropanol = 98:02, 1.0 mL / min), λ = 280 nm, temperature = 28°C, t (major) = 14.46 min, t (minor) = 19.66 min. 1H NMR (400MHz, CDCl3) δ7.68–7.61(m,4H),7.36(d,J=7.7Hz,2H),7.31(d,J=7. 7Hz,2H),7.11(d,J=7.7Hz,2H),7.03(s,3H),6.89(d,J=7.7Hz,2H),5.42(dd, J=12.4,4.4Hz,1H),5.13(d,J=5.0Hz,1H),2.68(ddd,J=13.9,12.6,5.4Hz,1H ), 2.42 (ddd, J = 14.1, 4.3, 0.9Hz, 1H), 2.29 (s, 3H), 2.14 (s, 6H), 2.12 (s, 3H). 13 CNMR (101MHz, CDCl3) δ168.2,167.4,148.1,139.1,138.8,134.7,134.4,133.7,131.8, 131.7,131.2,130.3,129.2,129.1,128.7,126.2,123.3,50.1,21.5,21.4,16.5,14.3. HRMS(ESI,m / z)[M+Na] + Accurate mass calculation [C 33 H 31 GeNO4Na] + :602.1357; measured value:602.1370.

[0136]

[0137] Colorless oil, 90.4 mg, 95% yield, 89% ee. [α] D 25.0 = +24.0 (c = 0.1, CHCl3). HPLC conditions: Daicel Chiralpak OD-3 column, n-hexane / isopropanol = 98:02, 1.0 mL / min), λ = 280 nm, temperature = 28°C, t (major) = 5.26 min, t (minor) = 6.75 min. 1H NMR (400MHz, CDCl3) δ7.67–7.60(m,4H),7.37(d,J=7.9Hz,2H),7.31(d,J=7.8Hz,2H),7.20(d d,J=8.7,6.3Hz,1H),7.13(dd,J=8.1,7.0Hz,4H),6.89(d,J=7.5Hz,2H),5.44(dd,J=12.6,4.3 Hz,1H),5.14(dd,J=5.6,1.3Hz,1H),2.94(hept,J=6.8Hz,2H),2.72(ddd,J=14.1,12.6,5.5H z, 1H), 2.43 (ddd, J = 14.1, 4.3, 1.3Hz, 1H), 2.30 (s, 3H), 2.12 (s, 3H), 1.13 (d, J = 45.4Hz, 12H). 13 C NMR (101MHz, CDCl3) δ169.0,167.3,145.7,139.1,138.7,134.7,134.4,133.7,131.8,13 1.7,131.2,129.2,129.1,126.8,124.0,123.3,50.3,27.6,23.9,22.7,21.5,21.4,14.1. HRMS(ESI,m / z)[M+Na] + Accurate mass calculation [C 37 H 39 GeNO4Na] + :658.1983; measured value:658.1996.

[0138]

[0139] Colorless foam, 89.2 mg, 96% yield, 90% ee. [α] D 25.0 = +32.0 (c = 0.1, CHCl3). HPLC conditions: Daicel Chiralpak OD-3 column, n-hexane / isopropanol = 98.5:1.5, 0.35 mL / min), λ = 280 nm, temperature = 28°C, t (minor) = 39.08 min, t (major) = 40.82 min. 1H NMR (600MHz, CDCl3) δ7.66–7.60(m,4H),7.33(dd,J=14.6,8.0Hz,4H),7.28(d,J=7.7Hz,2H),7.11(dd,J=16.4,8.0Hz,3H),6.87(d,J=7.6Hz,2H),5. 49(dd,J=12.7,4.3Hz,1H),5.10(d,J=4.4Hz,1H),2.75(ddd,J=14.1,12.8 ,5.4Hz,1H),2.38(ddd,J=14.2,4.2,1.2Hz,1H),2.27(s,3H),2.10(s,3H). 13 CNMR (151MHz, CDCl3) δ167.1,167.0,143.9,139.2,138.8,134.7,134.4,133.7,131 .7,131.6,131.0,129.3,129.1,129.0,128.8,127.5,123.4,50.1,21.5,21.4,14.2. HRMS(ESI,m / z)[M+Na] + Accurate mass calculation [C 31 H 25 Cl2GeNO4Na] + :642.0264; measured value:642.0256.

[0140] After obtaining the optimal reaction conditions, Examples 4 to 23 expanded the substrates. Dihydrogermanes containing various functional groups of benzene rings, including electron-donating methyl (1d), 3,5-dimethyl (1e), methoxy (1f), 3,4-dioxolane (1g), electron-donating fluorine (1h), trifluoromethyl (1i), chlorine (1j), as well as phenyl (1l), naphthyl (1k), can react smoothly with dehydroalanine 2g to obtain β-germanyl α-amino acids 3cg-3lg with good yields (61-98%) and excellent enantioselectivity (82-91%e). Heterocycles, such as benzofuran (1m), dibenzothiophene (1n) and thiophene (1o), can also be converted into β-germanyl α-amino acids with yields of 50-73% and 74-92%ee. Phenyl replaced with benzyl (1p) is also a suitable substrate to obtain the corresponding product 3pg. Under the condition that the germanium substituents were different, the chiral product 3qg containing carbon center and germanium center was successfully constructed with a yield of 97%, a dr ratio of 1:1, 90% ee and 90% ee. Trihydrogermane can react smoothly with 2g to obtain the corresponding β-germanyl α-amino acid with a high yield and an ee value of about 85%. Trihydrogermane with methyl (4a), trifluoromethyl (4b), trimethylsilyl (4c) and morpholinyl (4d) on the benzene ring, as well as N-methylindole can react.

[0141]

[0142] Step G: In a glove box filled with argon, add Cu(OAc) (5.0 mol%), (S,S)-Ph-BPE (5.5 mol%) and anhydrous THF (1.0 mL) to a dry 10.0 mL microwave reaction tube. The resulting mixture was stirred at room temperature for 15 minutes, and then 1 or 4 (0.18 mmol, 1.2 equiv) and 2 (0.15 mmol, 1.0 equiv) were added. The reaction tube was capped, removed from the glove box, and stirred at room temperature for 24 hours. The reaction mixture was concentrated and purified by column chromatography using dichloromethane / petroleum ether (from 1:1 to 1:0) as the eluent to obtain the desired product 3.

[0143] Synthesis of racemic compound 3: Replace the ligand in step G with Xantphos, and keep other conditions unchanged.

[0144] Example 4

[0145]

[0146] Colorless foam, 84.2 mg, 95% yield, 90% ee. [α] D 25.0 = +31.0 (c = 0.1, CHCl3). HPLC conditions: Daicel Chiralpak OD-3 column, n-hexane / isopropanol = 98:02, 0.5 mL / min), λ = 280 nm, temperature = 28°C, t (minor) = 30.89 min, t (major) = 33.95 min. 1 H NMR (600MHz, CDCl3) δ7.68–7.60(m,4H),7.47(dd,J=6.4,2.9Hz,2H),7.41(d,J=6. 7Hz,2H),7.32(d,J=8.1Hz,2H),7.30–7.27(m,3H),7.11(t,J=8.2Hz,1H),7.08(t,J =7.2Hz,2H),7.04(t,J=7.3Hz,1H),5.50(dd,J=12.4,4.5Hz,1H),5.16(dd,J=5.0,1 .2Hz, 1H), 2.78 (ddd, J=14.2, 12.5, 5.2Hz, 1H), 2.44 (ddd, J=14.2, 4.5, 1.5Hz, 1H). 13C NMR (151MHz, CDCl3) δ167.1,166.9,143.9,135.1,134.7,134.5,134.5,133.9 ,131.7,129.3,129.0,129.0,128.8,128.5,128.3,127.6,123.5,50.0,14.3. HRMS(ESI,m / z)[M+Na] + Accurate mass calculation [C 29 H 21 Cl2GeNO4Na] + :613.9951; measured value:613.9946.

[0147] Example 5

[0148]

[0149] Colorless foam, 56.8 mg, 61% yield, 82% ee. [α] D 25.0 = +48.0 (c = 0.1, CHCl3). HPLC conditions: Daicel Chiralpak OD-3 column, n-hexane / isopropanol = 98:02, 0.5 mL / min), λ = 280 nm, temperature = 28°C, t (minor) = 22.65 min, t (major) = 29.66 min. 1 H NMR(600MHz, CDCl3)δ7.65(dt,J=7.0,3.6Hz,2H),7.63–7.60(m,2H),7.42(d,J=7.2Hz,1 H),7.33(dd,J=7.4,4.7Hz,3H),7.23(t,J=7.4Hz,1H),7.16–7.09(m,3H),6.90–6.84(m,2 H),6.80(t,J=7.1Hz,1H),5.52(dd,J=12.4,4.5Hz,1H),5.28(d,J=4.9Hz,1H),2.92(ddd ,J=14.0,12.6,5.6Hz,1H),2.51(ddd,J=14.4,4.6,1.2Hz,1H),2.29(s,3H),2.23(s,3H). 13C NMR (151MHz, CDCl3) δ167.0,166.9,143.9,143.4,143.2,135.4,134.8,134.6,134.5,133.8,131. 7,129.9,129.7,129.6,129.1,128.9,128.8,127.5,125.6,125.4,123.4,50.2,23.0,23.0,13.4. HRMS(ESI,m / z)[M+Na] + Accurate mass calculation [C 31 H 25 Cl2GeNO4Na] + :642.0264; measured value:642.0257.

[0150] Example 6

[0151]

[0152] Colorless foam, 89.3 mg, 92% yield, 91% ee. [α] D 25.0 = +36.0 (c = 0.1, CHCl3). HPLC conditions: Daicel Chiralpak OD-3 column, n-hexane / isopropanol = 98:02, 0.5 mL / min), λ = 280 nm, temperature = 28°C, t (minor) = 16.09 min, t (major) = 23.29 min. 1 H NMR (600MHz, CDCl3) δ7.67–7.63(m,2H),7.63–7.61(m,2H),7.32(d,J=8.1Hz,2H),7.11(t,J=8.1Hz,1H),7.09(s,2H),7.00(s,2H),6.92(s,1H ), 6.52(s,1H),5.51(dd,J=12.8,4.1Hz,1H),5.09(d,J=5.6Hz,1H),2.83–2.75(m,1H),2.39(dd,J=14.2,3.9Hz,1H),2.26(s,6H),2.10(s,6H). 13 C NMR (151MHz, CDCl3) δ167.0,167.0,143.9,137.8,137.5,135.0,134.4,133.6,132. 4,132.1,131.5,131.0,130.4,128.9,128.7,127.5,123.0,50.1,21.4,21.3,14.0. HRMS(ESI,m / z)[M+Na] +Accurate mass calculation [C 33 H 29 Cl2GeNO4Na] + :670.0577; measured value:670.0568.

[0153] Example 7

[0154]

[0155] Colorless foam, 91.8 mg, 94% yield, 90% ee. [α] D 25.0 = +30.0 (c = 0.1, CHCl3). HPLC conditions: Daicel Chiralpak OD-3 column, n-hexane / isopropanol = 98:02, 1.0 mL / min), λ = 280 nm, temperature = 28°C, t (major) = 29.83 min, t (minor) = 36.67 min. 1 H NMR(600MHz, CDCl3)δ7.65(dt,J=7.1,3.7Hz,2H),7.64–7.61(m,2H),7.36(d,J=8.5 Hz,2H),7.31(t,J=8.5Hz,4H),7.11(t,J=8.1Hz,1H),6.83(d,J=8.5Hz,2H),6.61(d ,J=8.4Hz,2H),5.49(dd,J=12.6,4.3Hz,1H),5.09(d,J=5.1Hz,1H),3.75(s,3H),3. 63(s,3H),2.73(ddd,J=14.1,12.7,5.3Hz,1H),2.36(ddd,J=14.2,4.3,1.0Hz,1H). 13 C NMR (151MHz, CDCl3) δ167.1,167.0,160.6,160.3,143.9,136.0,135.7,133.7,131. 8,129.0,128.8,127.5,126.0,125.4,123.4,114.2,114.0,55.1,54.9,50.1,14.3. HRMS(ESI,m / z)[M+Na] + Accurate mass calculation [C 31 H 25 Cl2GeNO6Na] + :674.0163; measured value:674.0154.

[0156] Example 8

[0157]

[0158] Colorless foam, 75.4 mg, 74% yield, 90% ee. [α] D 25.0 =+37.0 (c=0.1, CHCl3). HPLC conditions: Daicel Chiralpak OD-3 column, n-hexane / isopropanol=95:05, 1.0 mL / min), λ=280 nm, temperature=28°C, t(major)=45.17 min, t(minor)=54.73 min. 1 H NMR(400MHz, CDCl3)δ7.70(dt,J=6.7,3.5Hz,2H),7.67–7.63(m,2H),7.32(d, J=8.1Hz,2H),7.12(t,J=8.1Hz,1H),6.88(dd,J=18.9,9.0Hz,3H),6.82–6.74( m,2H),6.56(d,J=7.6Hz,1H),5.88(s,2H),5.75(s,2H),5.48(dd,J=12.6,4.3H z,1H),5.10(d,J=4.9Hz,1H),2.77–2.66(m,1H),2.35(dd,J=14.1,4.1Hz,1H). 13 C NMR (101MHz, CDCl3) δ167.0,166.8,148.7,148.3,147.8,147.5,143.8,133.8,131.6,128.9,128.8 ,128.7,128.2,127.6,127.5,127.0,123.4,113.9,113.7,109.1,109.0,100.8,100.6,49.9,14.4. HRMS(ESI,m / z)[M+Na] + Accurate mass calculation [C 31 H 21 Cl2GeNO8Na] + :701.9748; measured value:701.9741.

[0159] Example 9

[0160]

[0161] Colorless foam, 89.4 mg, 95% yield, 88% ee. [α] D 25.0= +28.0 (c = 0.1, CHCl3). HPLC conditions: Daicel Chiralpak IC column, n-hexane / isopropanol = 98:02, 1.0 mL / min), λ = 280 nm, temperature = 28°C, t (minor) = 12.21 min, t (major) = 16.38 min. 1 H NMR (400MHz, CDCl3) δ7.67(s,4H),7.42(d,J=6.1Hz,1H),7.40(d,J=6.1Hz,1H),7.37( d,J=6.1Hz,1H),7.35(d,J=6.1Hz,1H),7.33(s,1H),7.31(s,1H),7.12(t,J=8.1Hz,1H ),7.00(t,J=8.9Hz,2H),6.79(t,J=8.9Hz,2H),5.48(dd,J=12.3,4.6Hz,1H),5.17(d, J=5.1Hz, 1H), 2.74 (ddd, J=14.2, 12.3, 5.3Hz, 1H), 2.42 (ddd, J= 14.2, 4.6, 1.4Hz, 1H). 13C NMR (151MHz, CDCl3) δ167.1, 166.7, 163.9 (d, J = 249.0Hz), 163.7 (d, J = 249.1Hz), 143.8, 136.5 (d, J = 7.3Hz), 136.2 (d, J = 7.5Hz), 134. 2,131.6,130.1(d,J=3.8Hz),129.7(d,J=3.7Hz),128.9,128.8,127.6,123.5,115.8(d,J=20.4Hz),115.6(d,J=20.1Hz),49.8,14.4. 19 F NMR (376MHz, CDCl3) δ-111.24,-111.36. HRMS(ESI,m / z)[M+Na] + Accurate mass calculation [C 29 H 19 Cl2F2GeNO4Na] + :649.9763; measured value:649.9754.

[0162] Example 10

[0163]

[0164] Colorless foam, 102.3 mg, 94% yield, 90% ee. [α] D 25.0= +29.0 (c = 0.1, CHCl3). HPLC conditions: Daicel Chiralpak IC column, n-hexane / isopropanol = 98:02, 1.0 mL / min), λ = 280 nm, temperature = 28°C, t (minor) = 7.51 min, t (major) = 11.93 min. 1 H NMR (600MHz, CDCl3) δ7.64(s,4H),7.58(d,J=8.0Hz,2H),7.54(dd,J=7.8,4.5Hz,4H),7.33(t,J=7.5Hz,4H),7.12(t,J=8.1Hz ,1H),5.53(dd,J=12.2,4.6Hz,1H),5.31(d,J=5.3Hz,1H),2.84(ddd,J=14.3,12.3,5.7Hz,1H),2.53(dd,J=14.0,4.4Hz,1H). 13 C NMR (151MHz, CDCl3) δ167.0,166.4,143.7,139.2,138.8.135.1,134.8,134.4,131.7(q,J=32.4Hz),131.5(q,J=32.4Hz),13 1.3, 128.8, 127.7, 125.1 (q, J = 3.3Hz), 124.9 (q, J = 3.8Hz), 123.9 (q, J = 272.4Hz), 123.8 (q, J = 272.4Hz), 123.4, 49.6, 14.3. 19 F NMR (376MHz, CDCl3) δ-62.90,-62.99. HRMS(ESI,m / z)[M+Na] + Accurate mass calculation [C 31 H 19 Cl2F6GeNO4Na] + :749.9699; Measured value:749.9694.

[0165] Embodiment 11

[0166]

[0167] Colorless foam, 90.2 mg, 91% yield, 92% ee. [α] D 25.0= +37.0 (c = 0.1, CHCl3). HPLC conditions: Daicel Chiralpak OD-3 column, n-hexane / isopropanol = 98:02, 1.0 mL / min), λ = 280 nm, temperature = 28°C, t (minor) = 15.81 min, t (major) = 19.07 min. 1 H NMR (400MHz, CDCl3) δ7.77–7.66(m,4H),7.43(s,1H),7.36(d,J=7.9Hz,4H),7.33–7.27(m,3H),7.16(t,J=8.1Hz,1H),7.08(t,J=7.6Hz,1H), 7.02(d,J=8.1Hz,1H), 5.52(dd,J=12.2,4.7Hz,1H), 5.24(d,J=5.3Hz,1H), 2.81(ddd,J=14.2,12.5,5.6Hz,1H), 2.50(dd,J=14.2,4.3Hz,1H). 13 C NMR (101MHz, CDCl3) δ167.0,166.5,143.7,136.9,136.4,134.9,134.8,134.4,134.1,134.1 ,132.6,132.3,131.3,130.0,129.8,129.7,129.3,128.9,128.8,127.7,123.5,49.7,14.3. HRMS(ESI,m / z)[M+Na] + Accurate mass calculation [C 29 H 19 Cl4GeNO4Na] + :681.9172; measured value:681.9161.

[0168] Example 12

[0169]

[0170] Colorless foam, 100.1 mg, 97% yield, 90% ee. [α] D 25.0 = +57.0 (c = 0.1, CHCl3). HPLC conditions: Daicel Chiralpak IC column, n-hexane / isopropanol = 98:02, 1.0 mL / min), λ = 280 nm, temperature = 28°C, t (minor) = 27.15 min, t (major) = 35.67 min. 1H NMR (600MHz, CDCl3) δ8.01(s,1H),7.96(s,1H),7.77(d,J=7.9Hz,3H),7.68(d,J=7.9Hz,1H ),7.60–7.54(m,3H),7.52(d,J=8.1Hz,1H),7.47(dd,J=6.2,3.2Hz,2H),7.40(dt,J=15.0,6 .8Hz,2H),7.32(dd,J=8.2,2.6Hz,4H),7.21–7.17(m,2H),7.10(t,J=8.1Hz,1H),5.64(dd, J=12.7,3.9Hz,1H),5.46(d,J=5.6Hz,1H),3.05–2.97(m,1H),2.60(dd,J=14.3,3.4Hz,1H). 13 C NMR (151MHz, CDCl3) δ167.1,166.9,143.8,135.7,135.1,133.7,133.4,133.2,133.0,132.5,132.1,130.8 ,130.7,130.5,128.9,128.7,128.0,127.8,127.7,127.5,126.6,126.3,126.3,126.1,122.7,49.9,14.1. HRMS(ESI,m / z)[M+Na] + Accurate mass calculation [C 37 H 25 Cl2GeNO4Na] + :714.0264; measured value:714.0261.

[0171] The absolute configuration of compound 3kg (in dichloromethane / petroleum ether solution) was determined by X-ray diffraction analysis. The relevant data are deposited in the Cambridge Crystallographic Data Center with the deposit number CCDC 2132574. The detailed information is shown in the following table:

[0172]

[0173]

[0174] Example 13

[0175]

[0176] Colorless foam, 109.6 mg, 98% yield, 90% ee. [α] D 25.0= +34.0 (c = 0.1, CHCl3). HPLC conditions: Daicel Chiralpak IC column, n-hexane / isopropanol = 98:02, 1.0 mL / min), λ = 280 nm, temperature = 28°C, t (minor) = 28.45 min, t (major) = 37.73 min. 1 H NMR (600MHz, CDCl3) δ7.64(dd,J=5.1,2.9Hz,2H),7.60(d,J=7.9Hz,2H),7.55(dd,J=10.0,7.9Hz,6H),7.49–7.42(m,8H),7.35(dd,J=17.8,9.4 Hz, 6H), 7.12 (t, J = 8.1Hz, 1H), 5.61 (dd, J = 12.5, 4.2Hz, 1H), 5.29 (d, J = 5.2Hz, 1H), 2.90 (td, J = 13.5, 5.5Hz, 1H), 2.53 (dd, J = 14.2, 3.9Hz, 1H). 13 C NMR (151MHz, CDCl3) δ167.1,166.8,143.8,142.2,141.7,140.8,140.5,135.3,134.9,133.9,133.9 ,133.4,131.6,128.9,128.9,128.8,127.6,127.6,127.2,127.2,127.1,126.9,123.3,50.0,14.3. HRMS(ESI,m / z)[M+Na] + Accurate mass calculation [C 41 H 29 Cl2GeNO4Na] + :766.0577; measured value:766.0575.

[0177] Embodiment 14

[0178]

[0179] Colorless foam, 73.5 mg, 73% yield, 92% ee. [α] D 25.0 = +33.0 (c = 0.1, CHCl3). HPLC conditions: Daicel Chiralpak IC column, n-hexane / isopropanol = 98:02, 1.0 mL / min), λ = 280 nm, temperature = 28°C, t (minor) = 25.42 min, t (major) = 34.78 min. 1H NMR(600MHz, CDCl3)δ7.71(s,1H),7.67(s,1H),7.57(s,1H),7.49–7.42(m,6H) ,7.38(d,J=8.2Hz,1H),7.32(dd,J=7.8,5.2Hz,3H),7.19(d,J=8.1Hz,1H),7.1 1(t,J=8.1Hz,1H),6.70(s,1H),6.61(s,1H),5.56(dd,J=12.8,3.9Hz,1H),5.3 2(d,J=5.7Hz,1H), 2.87(td,J=13.5,5.8Hz,1H), 2.48(dd,J=14.3,4.0Hz,1H). 13 C NMR (151MHz, CDCl3) δ167.1,166.9,155.7,155.4,145.1,144.7,143.9,133.5,131.1,130.3,130.0,129.0 ,128.8,128.7,128.3,128.1,127.9,127.7,127.6,127.6,123.0,111.8,111.6,106.5,106.5,50.0,14.5. HRMS(ESI,m / z)[M+Na] + Accurate mass calculation [C 33 H 21 Cl2GeNO6Na] + :693.9850; measured value:693.9845.

[0180] Embodiment 15

[0181]

[0182] Colorless foam, 74.9 mg, 62% yield, 90% ee. [α] D 25.0 = +34.0 (c = 0.1, CHCl3). HPLC conditions: Daicel Chiralpak OD-3 column, n-hexane / isopropanol = 85:15, 1.0 mL / min), λ = 280 nm, temperature = 28°C, t (minor) = 15.08 min, t (major) = 28.79 min. 1H NMR(400MHz, CDCl3)δ8.27(s,1H),8.22(s,1H),8.14–8.09(m,2H),7.85–7.78(m,3H),7. 63(d,J=7.9Hz,1H),7.55(t,J=7.3Hz,2H),7.49–7.41(m,4H),7.32(d,J=8.1Hz,2H),7.1 9(dd,J=5.4,3.1Hz,2H),7.11(t,J=8.1Hz,1H),7.04(dd,J=5.4,3.0Hz,2H),5.65(dd,J= 13.0, 3.8Hz, 1H), 5.49 (d, J = 6.0Hz, 1H), 3.08–2.98 (m, 1H), 2.59 (dd, J = 14.3, 3.8Hz, 1H). 13 C NMR (101MHz, CDCl3) δ167.2,166.9,143.9,140.9,140.6,139.3,139.1,135.7,135.5,135.2,133.3,132.6,132.1,130.7 ,130.4,130.0,128.9,128.8,128.1,127.6,127.0,124.6,124.6,123.0,123.0,122.8,122.7,122.0,121.9,49.9,14.2. HRMS(ESI,m / z)[M+Na] + Accurate mass calculation [C 41 H 25 Cl2GeNO4S2Na] + :825.9706; measured value:825.9717.

[0183] Example 16

[0184]

[0185] Colorless foam, 45.3 mg, 50% yield, 74% ee. [α] D 25.0 = +13.0 (c = 0.1, CHCl3). HPLC conditions: Daicel Chiralpak OD-3 column, n-hexane / isopropanol = 98:02, 0.5 mL / min), λ = 280 nm, temperature = 28°C, t (minor) = 32.65 min, t (major) = 40.03 min. 1H NMR (400MHz, CDCl3) δ7.76(dd,J=5.4,3.1Hz,2H),7.68(dd,J=5.5,3.1Hz,2H),7.54(d,J=4.8Hz,1H),7.43(d,J=4.8Hz,1H),7.3 4–7.28(m,4H),7.14–7.09(m,2H),7.03–6.99(m,1H),5.54–5.47(m,2H),2.81–2.72(m,1H),2.54(ddd,J=14.3,5.3,1.7Hz,1H). 13 C NMR (101MHz, CDCl3) δ167.1,166.6,143.8,136.0,135.7,134.1,131.7,131.5 ,131.4,131.3,130.7,128.9,128.8,128.3,128.2,127.6,123.6,49.6,16.8. HRMS(ESI,m / z)[M+Na] + Accurate mass calculation [C 25 H 17 Cl2GeNO4S2Na] + :625.9080; measured value:625.9072.

[0186] Embodiment 17

[0187]

[0188] Colorless foam, 27.9 mg, 30% yield, 65% ee. [α] D 25.0 =-8.0 (c = 0.1, CHCl3). HPLC conditions: Daicel Chiralpak IA column, n-hexane / isopropanol = 98:02, 1.0 mL / min), λ = 250 nm, temperature = 28°C, t (minor) = 17.21 min, t (major) = 18.76 min. 1H NMR (400MHz, CDCl3) δ8.03 (dd, J=5.1, 3.2Hz, 2H), 7.89 (dd, J=5.2, 3.1Hz, 2H ),7.46(d,J=8.1Hz,2H),7.41–7.27(m,5H),7.23(d,J=6.1Hz,1H),7.19(d,J =7.3Hz,3H),7.14(d,J=7.6Hz,2H),5.37(dd,J=10.4,6.4Hz,1H),4.28(d,J= 4.7Hz, 1H), 2.55 (d, J = 2.3Hz, 2H), 2.49 (d, J = 2.5Hz, 2H), 2.21–2.06 (m, 2H). 13 C NMR (101MHz, CDCl3) δ167.3,166.8,143.8,139.8,139.8,134.4,131.8,128.9,128. 8,128.8,128.7,128.2,128.1,127.6,124.8,124.8,123.8,50.2,21.0,20.9,13.1. HRMS(ESI,m / z)[M+Na] + Accurate mass calculation [C 31 H 25 Cl2GeNO4Na] + :642.0264; measured value:642.0274.

[0189] Embodiment 18

[0190]

[0191] Colorless foam, 95.0 mg, 97% yield, dr = 1:1, 90% ee, 90% ee. [α] D 25.0 = +33.0 (c = 0.1, CHCl3). HPLC conditions: Daicel Chiralpak IB column, n-hexane / isopropanol = 99:01, 0.3 mL / min), λ = 280 nm, temperature = 28°C, t(major) = 38.47 min, t(minor) = 40.44 min, t(minor) = 45.13 min, t(major) = 50.26 min. 1H NMR(400MHz, CDCl3)δ7.94(s,1H),7.86(s,1H),7.76–7.69(m,3H),7.63(d,J=7.5Hz,1H),7.5 9–7.55(m,2H),7.54–7.49(m,4H),7.46–7.37(m,7H),7.37–7.29(m,9H),7.22(dd,J=5.5,3.0H z,2H),7.15–7.08(m,4H),6.94(d,J=7.6Hz,2H),5.55(dt,J=9.2,4.4Hz,2H),5.27(dd,J=8.8 ,4.9Hz,2H),2.93–2.81(m,2H),2.48(ddd,J=17.9,9.0,2.6Hz,2H),2.30(s,3H),2.14(s,3H). 13 C NMR (101MHz, CDCl3) δ167.1,167.1,166.9,166.9,143.9,143.9,139.3,139.0,135.5,1 35.0,134.8,134.4,133.7,133.4,133.3,133.2,132.9,132.7,132.4,131.5,131.4,130 .9,130.8,130.7,130.6,129.4,129.2,128.9,128.8,128.0,128.0,127.8,127.7,127.7 ,127.7,127.5,126.5,126.2,126.2,126.0,123.2,122.8,50.0,21.5,21.5,14.1,14.1. HRMS(ESI,m / z)[M+Na] + Accurate mass calculation [C 34 H 25 Cl2GeNO4Na] + :678.0264; measured value:678.0274.

[0192] Embodiment 19

[0193]

[0194] Colorless foam, 61.9 mg, 78% yield, 84% ee. [α] D 25.0= +10.0 (c = 0.1, CHCl3). HPLC conditions: Daicel Chiralpak OD-3 column, n-hexane / isopropanol = 98:02, 1.0 mL / min), λ = 280 nm, temperature = 28°C, t (major) = 15.90 min, t (minor) = 19.92 min. 1 H NMR (400MHz, CDCl3) δ7.74(dd,J=5.5,3.1Hz,2H),7.67(dd,J=5.5,3.1Hz,2H),7.32(d,J=8.1Hz,2H),7.27(d,J=7.8Hz,2H),7.11(t,J= 8.1Hz,1H),6.92(d,J=7.6Hz,2H),5.42(dd,J=11.9,5.2Hz,1H),4.56–4.42(m,2H),2.58–2.50(m,1H),2.31–2.24(m,1H),2.15(s,3H). 13 C NMR (101MHz, CDCl3) δ167.2,166.8,143.8,138.9,134.8,134.0,131.7,129.2,129.1,128.9,128.8,127.6,123.6,50.5,21.4,12.4. HRMS(ESI,m / z)[MH] + Accurate mass calculation [C 24 H 18 Cl2GeNO4] + :527.9819; measured value:527.9811.

[0195] Embodiment 20

[0196]

[0197] Colorless foam, 70.6 mg, 81% yield, 82% ee. [α] D 25.0 = +8.0 (c = 0.1, CHCl3). HPLC conditions: Daicel Chiralpak OD-3 column, n-hexane / isopropanol = 90:10, 1.0 mL / min), λ = 250 nm, temperature = 28°C, t (major) = 13.20 min, t (minor) = 27.02 min. 1H NMR (600MHz, CDCl3) δ7.71(dd,J=5.5,3.1Hz,2H),7.66(dd,J=5.5,3.0Hz,2H),7.50(d,J=7.7Hz,2H),7.31(dd,J=7.9,3 .8Hz,4H),7.12(t,J=8.1Hz,1H),5.42(dd,J=11.7,5.3Hz,1H),4.66–4.53(m,2H),2.61–2.55(m,1H),2.37–2.32(m,1H). 13 C NMR (151MHz, CDCl3) δ167.1,166.5,143.7,138.1,135.2,134.4,131.5,131.1(q,J=32.2 Hz), 128.9, 128.8, 127.7, 124.7 (q, J = 3.3Hz), 124.0 (q, J = 272.3Hz), 123.5, 50.3, 12.5. 19 F NMR (565MHz, CDCl3) δ-62.87. HRMS(ESI,m / z)[M+H] + Accurate mass calculation [C 24 H 17 Cl2F3GeNO4] + :583.9693; measured value:583.9683.

[0198] Embodiment 21

[0199]

[0200] Colorless foam, 63.3 mg, 72% yield, 84% ee. [α] D 25.0 = +7.0 (c = 0.1, CHCl3). HPLC conditions: Daicel Chiralpak OD-3 column, n-hexane / isopropanol = 98:02, 1.0 mL / min), λ = 280 nm, temperature = 28°C, t (major) = 9.40 min, t (minor) = 14.12 min. 1H NMR (400MHz, CDCl3) δ7.76(dd,J=5.4,3.1Hz,2H),7.67(dd,J=5.5,3.0Hz,2H),7.39(d,J=7.7Hz,2H),7.31(t,J=8.0Hz,4H) ,7.12(t,J=8.1Hz,1H),5.45(dd,J=11.7,5.4Hz,1H),4.58–4.43(m,2H),2.60–2.51(m,1H),2.35–2.28(m,1H),0.19(s,9H). 13 C NMR (101MHz, CDCl3) δ167.2,166.7,143.8,141.4,134.2,134.1,133.6,133.1,131.7,128.9,128.8,127.6,123.6,50.6,12.5,-1.1. HRMS(ESI,m / z)[MH] + Accurate mass calculation [C 26 H 24 Cl2GeNO4Si] + :586.0058; measured value:586.0050.

[0201] Embodiment 22

[0202]

[0203] Yellow foam, 81.0 mg, 90% yield, 86% ee. [α] D 25.0 = +7.0 (c = 0.1, CHCl3). HPLC conditions: Daicel Chiralpak IC column, n-hexane / isopropanol = 90:10, 1.0 mL / min), λ = 280 nm, temperature = 28°C, t (minor) = 36.86 min, t (major) = 43.10 min. 1 H NMR (400MHz, CDCl3) δ7.76(dd,J=5.5,3.0Hz,2H),7.67(dd,J=5.5,3.1Hz,2H),7.30(dd,J=15.0,8.4Hz,4H),7.14–7.09(m,1H),6.66(d,J =8.6Hz,2H),5.41(dd,J=11.8,5.3Hz,1H),4.54–4.38(m,2H),3.83–3.80(m,4H),3.05–3.02(m,4H),2.56–2.47(m,1H),2.29–2.22(m,1H). 13C NMR (101MHz, CDCl3) δ167.2,166.8,151.7,143.8,135.8,134.1,131.8,128.9,128.8,127.6,123.6,122.0,115.1,66.9,50.6,48.6,12.6. HRMS(ESI,m / z)[M+H] + Accurate mass calculation [C 27 H 25 Cl2GeN2O5] + :601.0347; measured value:601.0340.

[0204] The X-ray diffraction analysis confirmed that compound 5dg (in dichloromethane / i The absolute configuration of PrOH / n-hexane = 1:1:15 solution) is deposited in the Cambridge Crystallographic Data Center with the deposit number CCDC 2175369. The detailed information is shown in the following table:

[0205]

[0206] Embodiment 23

[0207]

[0208] Colorless foam, 65.6 mg, 77% yield, 87% ee. [α] D 25.0 = +4.0 (c = 0.1, CHCl3). HPLC conditions: Daicel Chiralpak IC column, n-hexane / isopropanol = 90:10, 0.35 mL / min), λ = 280 nm, temperature = 28°C, t (minor) = 60.87 min, t (major) = 63.94 min. 1 H NMR (400MHz, CDCl3) δ7.63(s,1H),7.56(dd,J=5.5,3.1Hz,2H),7.47(dd,J=5.5,3.1 Hz,2H),7.31(d,J=8.1Hz,2H),7.17(dd,J=8.1,0.8Hz,1H),7.11(t,J=8.1Hz,1H),7 .01(d,J=8.2Hz,1H),6.91(d,J=3.1Hz,1H),6.34(d,J=3.1Hz,1H),5.44(dd,J=12.3 ,4.8Hz,1H),4.66–4.51(m,2H),3.63(s,3H),2.67–2.57(m,1H),2.31–2.24(m,1H). 13C NMR (101MHz, CDCl3) δ167.2,166.9,143.9,136.9,133.3,131.4,129.0,128. 8,128.8,128.1,127.5,127.1,123.1,121.4,109.4,101.1,50.6,32.7,12.5. HRMS(ESI,m / z)[M+H] + Accurate mass calculation [C 26 H 21 Cl2GeN2O4] + :569.0085; measured value:569.0072.

[0209] Embodiment 24

[0210] Scale-up experiment: Gram-scale reaction of 2 g of dehydroalanine with 1 b of dihydroheptane

[0211]

[0212] In a glove box filled with argon, Cu(OAc) (0.1 mmol, 12.3 mg, 5.0 mol%), (S,S)-Ph-BPE (0.11 mmol, 55.7 mg, 5.5 mol%) and anhydrous THF (13.0 mL) were added to a dry 50.0 mL Schlenk bottle. The resulting mixture was stirred at room temperature for 15 min, and then 1b (2.4 mmol, 1.2 equiv) and 2g (2.0 mmol, 1.0 equiv) were added. The reaction tube was capped, removed from the glove box, and stirred at room temperature for 24 h. The reaction mixture was concentrated and purified by column chromatography using dichloromethane / petroleum ether (1:1) as the eluent to obtain the target product 3bg, 1.16 g, with a yield of 94% and 86% ee. After recrystallization from dichloromethane and petroleum ether, the ee value increased to 95%.

[0213] Embodiment 25

[0214] In order to prove the application value of the compound of the present invention, a series of derivatizations were performed on compound 3bg. 3bg was deprotected with hydrazine hydrate, and changing the amount of hydrazine hydrate used in the hydrazinolysis process could selectively obtain N-protected β-germanyl α-amino acid 6 or completely unprotected β-germanyl α-amino acid 7 with good yields and without affecting the original stereoisomer purity.

[0215]

[0216] Under air atmosphere, 3bg (92.9 mg, 0.15 mmol) and CH2Cl2 (1.5 mL) were added to a 10.0 mL microwave reaction tube, followed by N2H4·H2O (9.0 mg, 0.18 mmol, 1.2 equiv) and MeOH (0.15 mL). The reaction tube was covered and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and purified by column chromatography using ethyl acetate / petroleum ether (2:1) as the eluent to obtain the target product 6 as a colorless foam, 62.6 mg. [α] D 25.0 = +24.0 (c = 0.1, CHCl3). HPLC conditions: Daicel Chiralpak IC column, n-hexane / isopropanol = 50:50, 1.0 mL / min), λ = 250 nm, temperature = 28°C, t (major) = 34.20 min, t (minor) = 88.24 min. 1 H NMR (400MHz, CD3OD) δ7.69–7.63(m,2H),7.59–7.53(m,2H),7.26(d,J=7.6Hz,2H),7.16(d,J=7.4Hz,2H),7.05(d,J=7.5Hz,2H),6.80(d,J=7.5Hz,2 H),5.05(dd,J=13.0,3.8Hz,1H),4.92(d,J=5.2Hz,1H),2.45(td,J=13.5, 5.7Hz, 1H), 2.23 (s, 3H), 2.12 (ddd, J = 14.2, 3.9, 0.8Hz, 1H), 2.06 (s, 3H). 13 C NMR (101MHz, CD3OD) δ171.7,169.1,140.1,139.9,135.5,135.2,134.9,133.0,132.3,130.1,130.0,124.1,51.5,21.4,14.8. HRMS(ESI,m / z)[MH] + Accurate mass calculation [C 25 H 22 GeNO4] + :474.0755; measured value:474.0749.

[0217]

[0218] Under air atmosphere, 3bg (92.9 mg, 0.15 mmol) and CH2Cl2 (1.5 mL) were added to a 10.0 mL microwave reaction tube, followed by N2H4·H2O (37.5 mg, 0.75 mmol, 5.0 equiv) and MeOH (0.15 mL). The reaction tube was capped and the reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with H2O, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography using ethyl acetate / MeOH (4:1) as the eluent to obtain the desired product 7 as a light brown oil, 38.2 mg. [α] D 25.0 =-3.0 (c = 0.1, CHCl3). HPLC conditions: Daicel Chiralpak IC column, n-hexane / isopropanol = 0:100, 0.2 mL / min), λ = 250 nm, temperature = 28°C, t (major) = 42.64 min, t (minor) = 51.13 min. 1 H NMR (600MHz, CDCl3) δ8.07(br,1H),7.41(dd,J=7.0,5.4Hz,4H),7.18(d,J=7.4Hz,4H),5.12(t,J=3.2H z,1H),3.61(dd,J=8.7,5.2Hz,1H),2.34(s,6H),2.21–1.70(m,3H),1.61(ddd,J=12.5,8.8,3.1Hz,1H). 13 C NMR (151MHz, CDCl3) δ175.7,139.2,134.7,134.7,132.3,132.2,129.4,52.6,21.6,21.0. HRMS(ESI,m / z)[MH] + Accurate mass calculation [C 17 H 20 GeNO2] + :344.0700; measured value:344.0708.

[0219] Treatment of 3bg with excess NaBH4 afforded the diol product 8 in 87% yield with unchanged ee value.

[0220]

[0221] In a glove box filled with argon, 3bg (92.9 mg, 0.15 mmol) and NaBH4 (56.7 mg, 1,50 mmol, 10.0 equiv) were added to a 10.0 mL microwave reaction tube. The tube was capped and removed from the glove box. iPrOH (1.8 mL) and H2O (0.3 mL) were then added in sequence. The reaction mixture was stirred at room temperature for 9 hours, quenched with brine, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (2:1) as the eluent to obtain the target product 8 as a colorless solid, 60.8 mg. [α] D 25.0 =-15.0 (c = 0.1, CHCl3). HPLC conditions: Daicel Chiralpak OD-3 column, n-hexane / isopropanol = 95:5, 1.0 mL / min), λ = 250 nm, temperature = 28°C, t (major) = 24.06 min, t (minor) = 35.91 min. 1 H NMR (400MHz, CDCl3) δ7.39 (t, J=7.0Hz, 4H), 7.34 (dd, J=7.4, 0.7Hz, 1H), 7.26 (d, J=7.0Hz,1H),7.15(d,J=7.7Hz,5H),7.04(d,J=7.3Hz,1H),6.59(d,J=8.0Hz,1H) ,5.12(t,J=3.0Hz,1H),4.55–4.46(m,3H),4.40(br,1H),3.73(dd,J=11.1,3.5Hz ,1H),3.58(dd,J=11.1,5.7Hz,1H),3.16(br,1H),2.33(s,6H),1.68–1.63(m,2H). 13 C NMR (101MHz, CDCl3) δ170.2,139.6,139.2,135.6,134.7,134.5,132.4,132 .1,131.0,130.5,129.4,129.4,128.0,127.6,67.0,64.5,50.8,21.5,16.5. HRMS(ESI,m / z)[MH] + Accurate mass calculation [C 25 H 28 GeNO3] + :464.1275; measured value:464.1276.

[0222] Using Pd(tBu3P)2 catalyst, 3bg was coupled with 4-iodoanisole to afford tetrasubstituted germanium compound 9 in 48% yield and 84% ee.

[0223]

[0224] In a glove box filled with argon, add Pd(tBu3P)2 (3.8 mg, 5.0 mol%), DABCO (16.8 mg, 0.15 mmol, 1.0 equiv), 4-iodoanisole (105.3 mg, 0.45 mmol, 3.0 equiv), 3bg (92.9 mg, 0.15 mmol, 1.0 equiv) and anhydrous tetrahydrofuran (1.5 mL) to a dry 10.0 mL microwave reaction tube. Cap the tube and remove from the glove box. The reaction mixture is stirred at room temperature for 5 h. The reaction is quenched with H2O and extracted with CH2Cl2. The combined organic phases are dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by silica gel column chromatography using CH2Cl2 / petroleum ether (1:1) as eluent to obtain the desired product 9 as a colorless foam, 52.1 mg. [α] D 25.0 =-16.0 (c = 0.1, CHCl3). HPLC conditions: Daicel Chiralpak OD-3 column, n-hexane / isopropanol = 98:2, 0.5 mL / min), λ = 250 nm, temperature = 28°C, t (major) = 25.65 min, t (minor) = 29.90 min. 1 H NMR (400MHz, CDCl3) δ7.59(s,4H),7.43–7.40(m,2H),7.38(dd,J=8.1,1.0Hz,4H),7.31(d,J=8.1Hz,2H),7.13–7.08(m,1H),7.05(dd,J=7.6,2.8Hz,4H ),6.81–6.76(m,2H),5.59(dd,J=13.4,3.4Hz,1H),3.72(s,3H),3.02(dd,J =14.3, 13.5Hz, 1H), 2.59 (dd, J = 14.4, 3.4Hz, 1H), 2.23 (s, 3H), 2.22 (s, 3H). 13C NMR (101MHz, CDCl3) δ167.2,167.2,160.4,143.9,138.9,138.8,136.2,134.8,133.5,1 32.2,131.8,129.2,128.9,128.7,127.5,126.4,123.2,114.1,55.0,49.6,21.5,14.1. HRMS(ESI,m / z)[M+Na] + Accurate mass calculation [C 38 H 31 Cl2GeNO5Na] + :748.0683; measured value:748.0671.

[0225] The above is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any changes or substitutions that can be easily thought of by a person skilled in the art within the technical scope disclosed by the present invention should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope of the claims.

Claims

1. A method for synthesizing a chiral β-germanyl-α-amino acid, characterized in that: The method comprises the following steps: in the presence of a ligand and a catalyst, compound 1 and compound 2 react as follows: Among them, PG is Phth; R 1 is selected from methyl, tert-butyl, 1-adamantyl, phenyl, , R 4 Selected from methyl, isopropyl, chloro; R 2 , R 3 Each is independently selected from one of the following structures: hydrogen, phenyl, benzyl, 2-naphthyl, 2-methylphenyl, 3,5-dimethylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 3-chlorophenyl, 4-trifluoromethylphenyl, 4-phenylphenyl, 4-trimethylsilylphenyl, , , , , , , And R 2 , R 3 Different from hydrogen, The catalyst is selected from Cu(OAc)2, Cu(OAc), and the ligand is The reaction uses at least one of 1,4-dioxane, THF and DME as solvent; and the reaction temperature is 15-40°C.

2. The synthesis method according to claim 1, characterized in that The amount of the catalyst used is at least 5 mol%; the amount of the ligand used is at least 5.5 mol%; the molar ratio of compound 1 to compound 2 is (0.8-2):1; and the reaction time is more than 12 hours.

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