Chiral alpha-amino acids and methods of preparation, methods of synthesis of a natural product of a cyclotriazadepside

Abstract

The present application relates to the technical field of organic synthesis, and particularly to chiral alpha-amino acid and a preparation method and a method for synthesizing a natural product of a phalloidin. t The asymmetric coupling is completed under the alkali and solvent system, the unactivated primary / secondary alkyl halide and alpha-carbonyl bromide are high enantioselectively converted, and a series of chiral unnatural alpha-amino acids are prepared. In addition, the present application first completes the total synthesis of the natural product of the phalloidin through a 4+3 linear synthesis strategy and a multi-step reaction by taking the chiral alpha-amino acid 3w as a key raw material, and expands the substrate range of the chiral alpha-amino acid, thereby providing a new path for the synthesis of the natural product of the cyclic peptide.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to chiral α-amino acids and their preparation methods, and methods for synthesizing natural products such as phalloidin. Background Technology

[0002] In recent years, peptide drugs have attracted widespread attention from researchers due to their advantages such as fewer side effects, high biological activity, and abundant targets. Among them, phalloidin, due to its unique structure and biological activity, can bind to filamentous actin, and its fluorescently labeled derivatives have wide applications in cell biology. Phaloidin natural products are mainly found in poisonous mushrooms of the genera *Amanita* and *Galerina*. Their basic structure is a bicyclic heptapeptide composed of six amino acids, but there are few reports on the total synthesis of phalloidin natural products.

[0003] In 2019, Süssmuth first reported the solid-phase total synthesis of phalloidin. Many researchers have also synthesized phalloidin derivatives and studied their bioactivity. However, other natural phalloidin products have not yet been synthesized chemically. Therefore, achieving the total synthesis of other natural phalloidin products is a pressing problem. The reason for the scarcity of reports on these natural products is mainly due to the inclusion of novel chiral non-natural amino acid structural units in their bicyclic heptapeptide basic structure. Phalloin is a natural product of phalloidin, and its bicyclic heptapeptide structure includes (S,S)-4-hydroxyproline, L-cysteine, D-threonine, L-alanine, L-tryptophan, and non-natural amino acids ... L-tryptophan. S )-2-amino-4-hydroxy-4-methylpentanoic acid. Due to the wide application of non-natural amino acids, numerous reports have been published to date. Asymmetric cross-coupling is undoubtedly one of the most important methods for forming chiral non-natural amino acids, but there is no information on ( S There are some reports on the asymmetric alkylation of diphenylimine-4-hydroxy-4-methylpentanoic acid. Since the 1990s, there have been some reports on the asymmetric alkylation of diphenylimine-4-hydroxy-4-methylpentanoic acid using phase-transfer catalysts, but problems such as lack of substrate universality still exist. The asymmetric allyl / benzyl alkylation of diphenylimine-4-hydroxy-4-methylpentanoic acid catalyzed by transition metals to prepare chiral α-non-natural amino acids has developed rapidly in the past decade, but there are few reports on the alkylation of diphenylimine-4-hydroxy-4-methylpentanoic acid tert-butyl ester. In 2023, Yin's group reported the copper-catalyzed asymmetric alkylation of diphenylimine-4-hydroxy-4-methylpentanoic acid tert-butyl ester, with substrates mainly consisting of allyl, propynyl, and benzyl halides. Although the yield was good and the enantioselectivity was high, only a limited number of unactivated primary alkyl iodides and α-carbonyl bromides were obtained. Summary of the Invention

[0004] To address the aforementioned problems, this invention provides chiral α-amino acids and their preparation methods, as well as a method for synthesizing phalloidin, a natural product. Using N-(diphenylmethylene)glycine tert-butyl ester as a substrate, an alkyl halide as a coupling agent, and a copper salt as a catalyst, [the method is described in the original text]. t Using BuFOXAP as a ligand, an asymmetric coupling reaction is carried out in a base and solvent system to yield chiral α-amino acids. This method utilizes readily available and inexpensive alkyl halides as coupling reagents, achieving highly enantioselective conversion of various primary and secondary unactivated alkyl halides, and even α-carbonyl bromides, into chiral glycine derivatives under mild conditions. This overcomes the problem of limited substrates in existing technologies.

[0005] To achieve the above objectives, the present invention adopts the following technical solution:

[0006] The first objective of this invention is to provide a method for preparing chiral α-amino acids, comprising the following steps:

[0007] Using N-(diphenylmethylene)glycine butyl ester as the substrate, alkyl halides as the coupling agent, and copper salts as the catalyst, t BuFOXAP is used as a ligand to undergo an asymmetric coupling reaction in a base and solvent system to obtain a chiral α-amino acid; the general structural formula of the alkyl halide is RX, where X is a halogen and the substituent R is an unactivated alkyl or α-carbonylalkyl group.

[0008] The t The structure of BuFOXAP is as follows: .

[0009] The synthetic routes for the above-mentioned chiral α-amino acids, i.e., chiral non-natural α-amino acids, are shown below:

[0010] .

[0011] It should be noted that in this invention, a novel synthetic methodology was designed to achieve the coupling reaction of N-(diphenylmethylene)glycine tert-butyl ester with alkyl halide, and the primary alkyl bromide and secondary alkyl iodide compounds used were not previously reported. Furthermore, this method was used for the first time to achieve the total synthesis of the natural product phalloidin.

[0012] In a preferred embodiment of the present invention, in the alkyl halide, X is bromine or iodine, and the unactivated alkyl group is a C1-C12 straight-chain or branched alkyl group, a C3-C8 cycloalkyl group, an aryl alkyl group, or an alkyl group containing an ether, ester, cyano, halogen, olefin, alkyne, or a protected hydroxyl functional group; in the α-carbonyl alkyl group, the substituent at the carbonyl α-position carbon is a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C6-C10 aryl group, or a nitrogen / oxygen heterocyclic group, and the substituent of the aryl or heterocyclic group is a halogen, a C1-C4 alkyl group, a C1-C4 alkoxy group, or a nitro group.

[0013] In a preferred embodiment of the present invention, the alkyl halide has any one of the following structures:

[0014] .

[0015] In a preferred embodiment of the present invention, the molar ratio of N-(diphenylmethylene)glycine tert-butyl ester to the alkyl halide is 1:2. The molar ratio of N-(diphenylmethylene)glycine tert-butyl ester to the copper salt is 40:1, and the copper salt is CuBr.

[0016] In a preferred embodiment of the present invention, the molar ratio of N-(diphenylmethylene)glycine tert-butyl ester to the ligand is 100:3; the molar ratio of N-(diphenylmethylene)glycine tert-butyl ester to the base is 1:2, and the base is tripotassium phosphate monohydrate or cesium carbonate. The molar volume ratio of N-(diphenylmethylene)glycine tert-butyl ester to the solvent is 0.2 mmol:1.0 mL, and the solvent is acetone or degassed acetone. The asymmetric coupling reaction is carried out at a temperature of 0°C to 35°C for 24 h to 36 h.

[0017] Specifically, when the product is 3a~3v, the base is tripotassium phosphate monohydrate, the solvent is acetone, the reaction temperature is 35℃, and the reaction time is 24h. When the product is 3w~3ah, the base is tripotassium phosphate monohydrate, the solvent is degassed acetone, the reaction temperature is 0℃, and the reaction time is 36h. When the product is 3ai~3an, the base is cesium carbonate, the solvent is degassed acetone, the reaction temperature is 35℃, and the reaction time is 24h.

[0018] A second objective of this invention is to provide a chiral α-amino acid obtained by the above method.

[0019] A third objective of this invention is to provide a method for synthesizing a natural product of phalloidin, comprising the following steps:

[0020] S1. The diphenylmethylene group of the chiral α-amino acid described above is removed, and Fmoc-L-tryptophan (compound 4) is added for coupling to obtain compound 5, wherein the chiral α-amino acid is compound 3w. The amino protecting group Fmoc of compound 5 is removed, and Fmoc-L-alanine (compound 6) is added for coupling to obtain compound 7. The Fmoc group of compound 7 is removed to obtain a tripeptide (compound 8).

[0021] The molar ratio of compound 3w to compound 4 is 5.7:6. The molar ratio of compound 5 to compound 6 is 6:6.3. In compound 7, which has the Fmoc group removed from alanine, the mass-to-volume ratio of compound 7 to the mixed solvent is 3g:30mL, and the mixed solvent is a 1:1 volume ratio solution of dichloromethane and diethylamine.

[0022] S2. Protect the amino, hydroxyl, and carboxyl groups of cis-L-4-hydroxyproline (compound 9) to obtain compound 10. Remove the Fmoc group from compound 10 to obtain compound 11. Using compound 11 and Fmoc-L-cysteine ​​(compound 12) as starting materials, perform amide condensation to obtain compound 13. Using compound 13 and Fmoc-D-threonine (compound 14) as starting materials, perform amide condensation to obtain compound 15. Remove the Fmoc group from compound 15 to obtain compound 16. Using compound 16 and Fmoc-L-alanine (compound 17) as starting materials, perform amide condensation to obtain compound 18. Protect the hydroxyl group of compound 18 to obtain compound 19. Remove the tert-butyl carboxyl protecting group from compound 19 to obtain the tetrapeptide (compound 20).

[0023] In the group protection process of compound 9, Fmoc-su, acetyl chloride, and (Boc)₂O were used sequentially to protect the amino, hydroxyl, and carboxyl groups, respectively. The mass-to-volume ratio of compound 9 to Fmoc-su was 5 g:10 mL, the mass ratio of compound 9 to acetyl chloride was 5:9, and the mass ratio of compound 9 to (Boc)₂O was 5:16.6. In the removal of the Fmoc group from compound 10, the mass-to-volume ratio of compound 10 to the mixed solvent was 10 g:50 mL, and the mixed solvent was a 1:1 volume ratio of dichloromethane and diethylamine. The molar ratio of compound 11 to compound 12 was 17.4:18.3. The molar ratio of compound 13 to compound 14 was 12.5:13.2. In the removal of the Fmoc group from compound 15, the mass-to-volume ratio of compound 15 to the mixed solvent was 8 g:50 mL, and the mixed solvent was a 1:1 volume ratio of dichloromethane and diethylamine. The molar ratio of compound 16 to compound 17 was 7.4:7.8. The hydroxyl group of D-threonine in compound 18 is protected with acetyl chloride, and the molar ratio of compound 18 to acetyl chloride is 4.1:12.4. The carboxyl protecting group tert-butyl ester on proline in compound 19 is protected with trifluoroacetic acid, and the mass-to-volume ratio of compound 19 to trifluoroacetic acid is 4 g:30 mL.

[0024] S3. Using compounds 8 and 20 as starting materials, a condensation reaction is carried out to obtain compound 21. An intramolecular CS bond is formed in compound 21 under the action of I2 to obtain compound 22. The Fmoc group of compound 22 is removed to obtain compound 23. The tert-butyl ester group of compound 23 is removed to obtain compound 24. Compound 24 undergoes intramolecular amide condensation under the action of a condensing agent to obtain compound 25. The carbonyl group of compound 25 undergoes nucleophilic addition to obtain compound 26. The acetyl group of compound 26 is removed to obtain the natural product phalloidin.

[0025] The molar ratio of compound 8 to compound 20 is 2.7:2.8. When compound 21 undergoes intramolecular CS bond construction mediated by I2, the molar ratio of compound 21 to I2 is 1.6:6.4. In the removal of the Fmoc group from compound 22, the mass-to-volume ratio of compound 22 to the mixed solvent is 1.5 g:40 mL, and the mixed solvent is a 1:1 volume ratio of dichloromethane and diethylamine. The removal of the tert-butyl ester group from compound 23 is performed using trifluoroacetic acid, with a mass-to-volume ratio of compound 23 to trifluoroacetic acid of 1 g:10 mL. In the intramolecular amide condensation of compound 24, the molar ratio of compound 24 to the condensing agent HATU is 1:2. When performing nucleophilic addition to the carbonyl group of compound 25, magnesium methyl iodide was used, and the mass-to-volume ratio of compound 25 to magnesium methyl iodide was 50 mg: 0.1 mL; when removing the acetyl protecting groups of the two alcohol hydroxyl groups of compound 26, a methanol solution of amine was used, and the mass-to-volume ratio of compound 26 to the methanol solution of amine was 8 mg: 3 mL.

[0026] In the synthesis of Phalloin, this invention designs a [4+3] strategy to synthesize linear heptapeptide compounds. The bicyclic heptapeptide framework is constructed by constructing intramolecular CS bonds through iodine-mediated synthesis and selecting intramolecular amide condensation from the non-natural amino acid and alanine end.

[0027] Compared with the prior art, the beneficial effects of the present invention are:

[0028] 1. This invention provides a method for preparing chiral α-amino acids. The method uses readily available and inexpensive alkyl halides as coupling reagents, and achieves highly enantioselective conversion of various primary and secondary unactivated alkyl halides, and even α-carbonyl bromide compounds, into chiral glycine derivatives under mild conditions.

[0029] 2. This invention enables the asymmetric alkylation reaction of diphenylimine glycine tert-butyl ester using unactivated alkyl bromide or iodine compounds and carbonyl α-bromine compounds. This approach expands the substrate range of chiral α-non-natural amino acids and also solves the problem of (…). S The gram-scale synthesis of 2-amino-4-hydroxy-4-methylpentanoic acid was solved, and the total synthesis of the natural product phalloidin was achieved through a 4+3 linear synthesis strategy. Attached Figure Description

[0030] Figure 1 This is the proton NMR spectrum of the chiral α-amino acid 3w of this invention. Detailed Implementation

[0031] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0032] It should be noted that the technical terms used in this invention are only for the purpose of describing specific embodiments and are not intended to limit the scope of protection of this invention. Unless otherwise specified, all raw materials, reagents, instruments and equipment used in the following embodiments of this invention can be purchased from the market or prepared by existing methods.

[0033] The following specific examples will provide further explanation.

[0034] In this invention, the English abbreviation for 1-hydroxybenzotriazole is HOBT, the English abbreviation for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is EDC, the English abbreviation for diisopropylethylamine is DIPEA, and the English abbreviation for 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate is HATU.

[0035] Example 1

[0036] A method for preparing a chiral, non-natural α-amino acid 3a includes the following steps:

[0037] In a glove box, add 0.2 mmol (1.0 equivalent) of N-(diphenylmethylene)glycine tert-butyl ester, 0.4 mmol (2.0 equivalent) of bromoisobutane, 0.4 mmol (2.0 equivalent) of tripotassium phosphate monohydrate, 0.005 mmol of CuBr (2.5 mol%), and 0.006 mmol of [unspecified substance] (3 mol%). t The BuFOXAP was weighed and placed in an 8 mL Shrek vial. 1.0 mL of acetone was added to the vial and stirred for 1 min. The vial was then removed. The resulting mixture was stirred in an oil bath at 35°C for 24 h. After cooling to room temperature, the solvent was removed by vacuum distillation, and the product was purified by silica gel column chromatography using a 5:95 mixture of ethyl acetate and petroleum ether to give product 3a, with the structure shown below:

[0038] .

[0039] 3a was a white solid with a yield of 59 mg, representing a yield of 84% and an enantiomeric excess (ee) of 96%. The determination of 3a yielded the following results: 1H NMR (600MHz, CDCl3) δ 7.67 (s, 2H), 7.48 – 7.43 (m, 3H), 7.42 – 7.38(m, 1H), 7.37 – 7.32 (m, 2H), 7.21 (d, J=7.0Hz, 2H), 3.98 (dd, J=8.8, 4.9Hz,1H), 1.87 (ddd, J=13.9, 8.8, 5.3Hz, 1H), 1.77 (ddd, J=13.5, 8.6, 4.9Hz, 1H),1.67 – 1.57 (m, 1H), 1.48 (s, 9H), 0.88 (d, J=6.7Hz, 3H), 0.71 (d, J = 6.6 Hz, 3H.

[0040] Example 2

[0041] The difference from Example 1 is that the alkyl halide is n-butyl bromide, and the product is 3b. The structure is as follows:

[0042] .

[0043] 3b is a white solid with a yield of 69 mg, a yield of 99%, and an ee of 96%. The results of the determination of 3b are as follows: 1 HNMR (600MHz, CDCl3) δ 7.68 (d, J=7.1Hz, 2H), 7.46 (d, J=7.2Hz, 3H), 7.40 (t,J=7.3Hz, 1H), 7.35 (t, J=7.6Hz, 2H), 7.20 (d, J=5.4Hz, 2H), 3.93 (t, J=6.6Hz,1H), 1.91 (q, J=6.3Hz, 2H), 1.47 (s, 9H), 1.33 – 1.26 (m, 4H), 0.89 (t, J=7.1Hz, 3H).

[0044] Example 3

[0045] The difference from Example 1 is that the alkyl halide is bromomethylcyclopropane, and the product is 3c. The structure is as follows:

[0046] .

[0047] 3C is a colorless oily substance with a yield of 65 mg, a yield of 93%, and an ee of 99%. The results of 3C determination are as follows: 1HNMR (600MHz, CDCl3) δ 7.67 (d, J=7.0Hz, 2H), 7.47 – 7.41 (m, 3H), 7.38 (t, J=7.3Hz, 1H), 7.33 (d, J=7.8Hz, 2H), 7.21 (dd, J=7.6, 1.8Hz, 2H), 4.06 (dd, J=8.4, 4.7Hz, 1H), 1.89 (ddd, J=14.6, 8.4, 6.7Hz, 1H), 1.73 (ddd, J=13.8, 7.5,4.7Hz, 1H), 1.46 (s, 9H), 0.68 (ddt, J=10.3, 7.5, 3.8Hz, 1H), 0.46 – 0.38 (m,1H), 0.36 – 0.26 (m, 1H), 0.10 (dq, J=9.6, 4.9Hz, 1H), -0.03 (dq, J=9.5,4.9Hz, 1H).

[0048] Example 4

[0049] The difference from Example 1 is that the alkyl halide is bromomethylcyclohexane, and the product is 3d. The structure is as follows:

[0050] .

[0051] The 3d product was a colorless oily substance with a yield of 72 mg, a yield of 92%, and an ee of 95%. The 3d product was analyzed, and the results are as follows: 1 HNMR (600MHz, CDCl3) δ 7.68 (d, J=8.2Hz, 2H), 7.49 – 7.44 (m, 3H), 7.41 (t, J=7.3Hz, 1H), 7.35 (t, J=7.5Hz, 2H), 7.21 (dd, J=7.4, 2.1Hz, 2H), 4.03 (dd, J=8.5, 5.2Hz, 1H), 1.87 – 1.76 (m, 2H), 1.69 – 1.57 (m, 4H), 1.48 (s, 9H), 1.42– 1.36 (m, 1H), 1.27 – 1.17 (m, 2H), 1.12 (td, J=9.1, 4.0Hz, 2H), 0.97 – 0.84(m, 1H), 0.73 (dd, J=11.5, 3.1Hz, 1H).

[0052] Example 5

[0053] The difference from Example 1 is that the alkyl halide is β-bromophenylethane, and the product is 3e. The structure is as follows:

[0054] .

[0055] 3e was a yellow oily substance with a yield of 74 mg, a yield of 93%, and an ee of 94%. The results of 3e determination are as follows: 1 HNMR (600MHz, CDCl3) δ 7.74 (d, J=7.0Hz, 2H), 7.48 – 7.42 (m, 4H), 7.39 (t, J=7.5Hz, 2H), 7.29 (t, J=7.6Hz, 2H), 7.23 – 7.16 (m, 5H), 4.05 (t, J=6.5Hz, 1H), 2.76 – 2.68 (m, 1H), 2.65 (t, J=8.2Hz, 1H), 2.32 – 2.25 (m, 2H), 1.51 (s, 9H).

[0056] Example 6

[0057] The difference from Example 1 is that the alkyl halide is 4-phenyl-1-butyl bromide, and the product is 3f. The structure is as follows:

[0058] .

[0059] 3f is a yellow oily substance with a yield of 82 mg, a yield of 96%, and an ee of 96%. The results of the determination of 3f are as follows: 1 HNMR (600MHz, CDCl3) δ 7.69 (d, J=7.7Hz, 2H), 7.46 (d, J=5.7Hz, 3H), 7.42 (t,J=7.1Hz, 1H), 7.36 (t, J=7.6Hz, 2H), 7.28 (t, J=7.4Hz, 2H), 7.22 – 7.14 (m,5H), 3.95 (t, J=6.5Hz, 1H), 2.62 (qt, J=7.5, 4.7, 3.3Hz, 2H), 1.96 (q, J=7.5Hz, 2H), 1.61 (p, J=8.3Hz, 2H), 1.48 (s, 9H), 1.41 (dd, J=14.0, 7.4Hz, 1H), 1.32 (p, J=8.7, 7.7Hz, 1H).

[0060] Example 7

[0061] The difference from Example 1 is that the alkyl halide is 2-bromoethyl acetate, and the product is 3g. The structure is as follows:

[0062] .

[0063] 3g was a yellow oily substance, with a yield of 65mg, a yield rate of 86%, and an ee of 96%. The results of the determination of 3g were as follows: 1 HNMR (600MHz, CDCl3) δ 7.66 (d, J=7.0Hz, 2H), 7.46 (dd, J=5.1, 1.9Hz, 3H), 7.41 (t, J=7.3Hz, 1H), 7.35 (t, J=7.6Hz, 2H), 7.21 (dd, J=6.4, 3.2Hz, 2H), 4.16 (dt, J=11.2, 5.7Hz, 1H), 4.09 (dd, J=8.5, 4.7Hz, 1H), 4.03 (ddd, J=11.0,8.4, 5.7Hz, 1H), 2.26 (dddd, J=17.0, 14.1, 8.4, 5.1Hz, 2H), 1.92 (s, 3H), 1.48 (s, 9H).

[0064] Example 8

[0065] The difference from Example 1 is that the alkyl halide is 1-BOC-4-bromomethylpiperidine, and the product is 3h. The structure is shown below:

[0066] .

[0067] The 3-hour product was a colorless oily substance with a yield of 83 mg, a yield of 84%, and an ee of 96%. The results of the 3-hour product analysis are as follows: 1HNMR (600MHz, CDCl3) δ 7.67 (d, J=6.8Hz, 2H), 7.47 (d, J=3.2Hz, 3H), 7.41 (t,J=7.3Hz, 1H), 7.35 (t, J=7.6Hz, 2H), 7.19 (dd, J=6.6, 2.9Hz, 2H), 4.12 – 3.90(m, 3H), 2.62 (d, J=39.0Hz, 2H), 1.84 (td, J=14.8, 7.4Hz, 2H), 1.63 – 1.54(m, 1H), 1.46 (d, J=9.9Hz, 18H), 1.34 (dt, J=13.2, 3.4Hz, 1H), 1.08 (td, J=12.3, 4.3Hz, 1H), 1.01 – 0.85 (m, 2H).

[0068] Example 9

[0069] The difference from Example 1 is that the alkyl halide is 1,2-dibromoethane, and the product is 3i. The structure is as follows:

[0070] .

[0071] 3i is a yellow oily substance with a yield of 79 mg, a yield of 99%, and an ee of 96%. The results of the determination of 3i are as follows: 1 HNMR (600MHz, CDCl3) δ 7.68 (d, J=7.1Hz, 2H), 7.48 (d, J=5.1Hz, 3H), 7.43 (t,J=7.3Hz, 1H), 7.36 (t, J=7.7Hz, 2H), 7.26 (d, J=7.5Hz, 2H), 4.14 (dd, J=8.6,4.2Hz, 1H), 3.52 (ddd, J=10.0, 7.0, 5.0Hz, 1H), 3.42 (ddd, J=10.0, 8.6,6.5Hz, 1H), 2.56 (dddd, J=14.0, 8.7, 6.5, 5.1Hz, 1H), 2.48 – 2.41 (m, 1H), 1.47 (s, 9H).

[0072] Example 10

[0073] The difference from Example 1 is that the alkyl halide is 1,4-dibromobutane, and the product is 3j. The structure is as follows:

[0074] .

[0075] 3j is a yellow oily substance with a yield of 45 mg, a yield rate of 52%, and an ee of 96%. The results of the determination of 3j are as follows: 1 HNMR (600MHz, CDCl3) δ 7.68 (d, J=7.0Hz, 2H), 7.47 (d, J=7.5Hz, 3H), 7.41 (t,J=7.3Hz, 1H), 7.36 (d, J=7.9Hz, 2H), 7.21 (d, J=7.8Hz, 2H), 3.99 – 3.91 (m,1H), 3.39 (td, J=6.8, 2.7Hz, 2H), 1.93 (tdd, J=8.7, 5.9, 2.1Hz, 2H), 1.83 (dddd, J=13.2, 8.4, 6.8, 4.0Hz, 2H), 1.48 (s, 11H).

[0076] Example 11

[0077] The difference from Example 1 is that the alkyl halide is 1,5-dibromopentane, and the product is 3k. The structure is as follows:

[0078] .

[0079] 3k was a yellow oily substance with a yield of 67 mg, a yield of 75%, and an ee of 96%. The results of the determination of 3k are as follows: 1 HNMR (600MHz, CDCl3) δ 7.67 (d, J=7.0Hz, 2H), 7.47 (d, J=7.3Hz, 3H), 7.40 (d,J=7.3Hz, 1H), 7.35 (t, J=7.5Hz, 2H), 7.20 (d, J=7.6Hz, 2H), 3.94 (t, J=6.5Hz,1H), 3.39 (t, J=6.8Hz, 2H), 1.92 (q, J=7.9, 6.8Hz, 2H), 1.88 – 1.81 (m, 2H), 1.47 (s, 9H), 1.41 – 1.26 (m, 4H).

[0080] Example 12

[0081] The difference from Example 1 is that the alkyl halide is 2-phenoxyethyl bromide, and the product is 3l. The structure is as follows:

[0082] .

[0083] 3L was a brown solid, with a yield of 82 mg, a yield of 99%, and an ee of 92%. The determination of 3L yielded the following results: 1 HNMR (600MHz, CDCl3) δ 7.69 (d, J=7.7Hz, 2H), 7.40 (ddt, J=31.4, 24.0, 7.5Hz, 6H), 7.29 (t, J=7.8Hz, 2H), 7.13 (d, J=7.4Hz, 2H), 6.96 (t, J=7.4Hz, 1H), 6.83 (d, J=8.1Hz, 2H), 4.32 (dd, J=9.0, 4.2Hz, 1H), 4.12 – 4.05 (m, 1H), 3.99 (td, J=9.1, 5.0Hz, 1H), 2.45 (dddd, J=34.8, 13.9, 9.0, 4.5Hz, 2H), 1.50 (s, 9H).

[0084] Example 13

[0085] The difference from Example 1 is that the alkyl halide is 2-(2-ethoxyphenoxy)bromoethane, and the product is 3m. The structure is shown below:

[0086] .

[0087] 3m is a colorless oily substance with a yield of 85 mg, a yield rate of 93%, and an ee of 96%. The results of the determination of 3m are as follows: 1 HNMR (600MHz, CDCl3) δ 7.67 (d, J=7.0Hz, 2H), 7.44 – 7.37 (m, 4H), 7.35 (t, J=7.5Hz, 2H), 7.17 (d, J=6.5Hz, 2H), 6.93 – 6.85 (m, 4H), 4.28 (dd, J=8.5,4.4Hz, 1H), 4.14 – 4.06 (m, 2H), 4.05 – 3.94 (m, 2H), 2.55 – 2.40 (m, 2H), 1.47 (s, 9H), 1.36 (t, J=7.0Hz, 3H).

[0088] Example 14

[0089] The difference from Example 1 is that the alkyl halide is 4-bromo-1-butene, and the product is 3n. The structure is as follows:

[0090] .

[0091] 3n was a colorless oily substance with a yield of 67 mg, a yield of 96%, and an ee of 97%. The results of 3n determination are as follows: 1 HNMR (600MHz, CDCl3) δ 7.69 (d, J=7.1Hz, 2H), 7.46 (d, J=6.3Hz, 3H), 7.41 (d,J=7.0Hz, 1H), 7.35 (t, J=7.5Hz, 2H), 7.21 (d, J=7.5Hz, 2H), 5.77 (td, J=10.6,5.0Hz, 1H), 5.00 (d, J=17.1Hz, 1H), 4.93 (d, J=10.2Hz, 1H), 3.96 (t, J=6.0Hz,1H), 2.10 (dd, J=16.6, 8.3Hz, 1H), 2.03 (p, J=5.5Hz, 3H), 1.47 (s, 9H).

[0092] Example 15

[0093] The difference from Example 1 is that the alkyl halide is 5-bromo-1-pentene, and the product is 3o. The structure is as follows:

[0094] .

[0095] 3O was a colorless oily substance with a yield of 69 mg, a yield of 95%, and an ee of 96%. The determination of 3O yielded the following results: 1 HNMR (600MHz, CDCl3) δ 7.69 (d, J=8.4Hz, 2H), 7.47 (q, J=6.9Hz, 3H), 7.40 (d,J=7.4Hz, 1H), 7.35 (t, J=7.5Hz, 2H), 7.21 (d, J=8.1Hz, 2H), 5.80 (ddd, J=17.0, 10.4, 1.4Hz, 1H), 5.04 – 4.91 (m, 2H), 3.96 (t, J=6.6Hz, 1H), 2.03 (q,J=7.1Hz, 2H), 1.95 (q, J=7.3, 6.4Hz, 2H), 1.49 (s, 9H).

[0096] Example 16

[0097] The difference from Example 1 is that the alkyl halide is 6-bromo-1-hexene, and the product is 3p. The structure is as follows:

[0098] .

[0099] 3p is a colorless oily substance with a yield of 70 mg, a yield of 93%, and an ee of 96%. The 3p spectroscopy was measured, and the results are as follows: ¹H NMR (600MHz, CDCl₃) δ 7.69 (d, J=7.0Hz, 2H), 7.50 – 7.44 (m, 3H), 7.41 (t, J=7.3Hz, 1H), 7.35 (t, J=7.5Hz, 2H), 7.21 (dd, J=7.5, 1.9Hz, 2H), 5.80 (ddt, J=17.0, 10.2, 6.7Hz, 1H), 5.05 – 4.91 (m, 2H), 3.95 (t, J=6.5Hz, 1H), 2.11 –2.01 (m, 2H), 1.97 – 1.87 (m, 2H), 1.48 (s, 9H).

[0100] Example 17

[0101] The difference from Example 1 is that the alkyl halide is 4-bromobutyloxy-tert-butyldimethylsilane, and the product is 3q. The structure is shown below:

[0102] .

[0103] 3q was a colorless oily substance with a yield of 89 mg, a yield of 93%, and an ee of 96%. The determination of 3q yielded the following results: 1 HNMR (600MHz, CDCl3) δ 7.68 (d, J=8.1Hz, 2H), 7.46 (d, J=7.1Hz, 3H), 7.40 (d,J=14.6Hz, 1H), 7.35 (t, J=7.5Hz, 2H), 7.21 (d, J=7.7Hz, 2H), 3.95 (t, J=6.6Hz, 1H), 3.65 – 3.56 (m, 2H), 1.99 – 1.91 (m, 2H), 1.50 (t, J=7.0Hz, 2H), 1.48 (s, 9H), 1.34 – 1.25 (m, 2H), 0.90 (s, 9H), 0.05 (s, 6H).

[0104] Example 18

[0105] The difference from Example 1 is that the alkyl halide is 4-bromobutyronitrile, and the product is 3r. The structure is as follows:

[0106] .

[0107] 3r was a brown oily substance with a yield of 70 mg, a yield of 97%, and an ee of 96%. The results of the determination of 3r are as follows: 1 HNMR (600MHz, CDCl3) δ 7.67 (d, J=5.2Hz, 2H), 7.52 – 7.45 (m, 3H), 7.42 (t, J=7.3Hz, 1H), 7.38 – 7.33 (m, 2H), 7.20 (d, J=5.7Hz, 2H), 3.98 (dd, J=7.7,4.7Hz, 1H), 2.41 – 2.29 (m, 2H), 2.13 – 1.95 (m, 2H), 1.81 – 1.65 (m, 2H), 1.47 (s, 9H).

[0108] Example 19

[0109] The difference from Example 1 is that the alkyl halide is 6-bromo-2-hexanone, and the product is 3S. The structure is as follows:

[0110] .

[0111] 3s is a yellow oily substance with a yield of 70 mg, a yield of 89%, and an ee of 94%. The results of 3s determination are as follows: 1 HNMR (600MHz, CDCl3) δ 7.66 (d, J=7.0Hz, 2H), 7.48 – 7.44 (m, 3H), 7.40 (t, J=7.3Hz, 1H), 7.34 (t, J=7.5Hz, 2H), 7.19 (d, J=9.4Hz, 2H), 3.93 (t, J=6.5Hz,1H), 2.41 (t, J=7.6Hz, 2H), 2.12 (s, 3H), 1.94 – 1.88 (m, 2H), 1.55 (p, J=7.6Hz, 2H), 1.46 (s, 9H), 1.37 – 1.32 (m, 1H), 1.30 – 1.25 (m, 1H).

[0112] Example 20

[0113] The difference from Example 1 is that the alkyl halide is methyl 6-bromohexanoate, and the product is 3t. The structure is as follows:

[0114] .

[0115] 3t is a yellow oily substance with a yield of 75 mg, a yield rate of 89%, and an ee of 91%. The results of the analysis of 3t are as follows: 1 HNMR (600MHz, CDCl3) δ 7.67 (d, J=7.7Hz, 2H), 7.46 (d, J=7.2Hz, 3H), 7.40 (t,J=7.3Hz, 1H), 7.34 (t, J=7.6Hz, 2H), 7.19 (d, J=6.8Hz, 2H), 3.93 (t, J=6.5Hz,1H), 3.66 (s, 3H), 2.28 (t, J=7.6Hz, 2H), 1.91 (q, J=7.3Hz, 2H), 1.62 (p, J=7.4Hz, 2H), 1.47 (s, 9H), 1.28 (d, J=8.2Hz, 2H).

[0116] Example 21

[0117] The difference from Example 1 is that the alkyl halide is (4-bromo-1-butynyl)trimethylsilane, and the product is 3u. The structure is shown below:

[0118] .

[0119] 3u was a colorless oily substance with a yield of 40 mg, a yield rate of 48%, and an ee of 92%. The results of the determination of 3u are as follows: 1 HNMR (600MHz, CDCl3) δ 7.67 (d, J=8.6Hz, 2H), 7.46 (d, J=6.1Hz, 3H), 7.41 (t,J=7.3Hz, 1H), 7.35 (t, J=7.5Hz, 2H), 7.22 (d, J=9.6Hz, 2H), 4.06 (dd, J=8.3,4.7Hz, 1H), 2.39 – 2.23 (m, 2H), 2.16 (ddt, J=11.3, 8.9, 4.4Hz, 2H), 1.47 (s,9H), 0.12 (s, 9H).

[0120] Example 22

[0121] The difference from Example 1 is that the alkyl halide is N-(3-bromopropyl)phenylenediamine, and the product is 3v. The structure is shown below:

[0122] .

[0123] 3v was a colorless oily substance with a yield of 89 mg, a yield rate of 92%, and an ee of 97%. The results of the 3v determination are as follows: 1 HNMR (600MHz, CDCl3) δ 7.83 (d, J=8.5Hz, 2H), 7.71 (d, J=4.5Hz, 2H), 7.65 (d,J=7.7Hz, 2H), 7.44 (q, J=7.1, 6.7Hz, 3H), 7.38 (t, J=7.3Hz, 1H), 7.32 (t, J=7.6Hz, 2H), 7.21 (d, J=6.9Hz, 2H), 4.00 – 3.93 (m, 1H), 3.68 (t, J=7.3Hz, 2H), 1.98 (qd, J=10.4, 6.7Hz, 2H), 1.79 – 1.66 (m, 2H), 1.45 (s, 9H).

[0124] Example 23

[0125] A method for preparing a chiral, non-natural α-amino acid 3w includes the following steps:

[0126] In a glove box, add 0.2 mmol (1.0 equivalent) of N-(diphenylmethylene)glycine butyl ester, 0.4 mmol (2.0 equivalent) of bromoacetone, 0.4 mmol (2.0 equivalent) of tripotassium phosphate monohydrate, 0.005 mmol of CuBr (2.5 mol%), and 0.006 mmol of [unspecified ingredient] (3 mol%). t BuFOXAP was weighed and placed in an 8 mL Shrek vial. 1.0 mL of degassed acetone was added to the vial, and the mixture was stirred for 1 min before being removed. The resulting mixture was stirred in an oil bath at 0 °C for 36 h. After cooling to room temperature, the solvent was removed by vacuum distillation, and the product was purified by silica gel column chromatography to obtain product 3w. The structure is shown below:

[0127] .

[0128] 3w was a yellow solid with a yield of 68 mg, a yield of 97%, and an ee of 98%. The 1H NMR spectrum of 3w was analyzed as follows: Figure 1 As shown, the results are as follows: 1H NMR (600MHz, CDCl3) δ 7.62 (d, J=8.0Hz, 2H), 7.47 (q, J=7.6, 6.9Hz, 3H), 7.40 (t, J=8.0Hz, 1H), 7.36 – 7.31 (m, 2H), 7.29 (d, J=7.8Hz, 2H), 4.48 (t, J=7.1Hz, 1H), 3.16 (dd, J=17.0, 5.8Hz, 1H), 2.96 (dd, J=17.0, 7.2Hz, 1H), 2.18 (s, 3H), 1.46 (s, 9H).

[0129] Example 24

[0130] The difference from Example 23 is that the alkyl halide is 1-bromopinazone, and the product is 3x. The structure is as follows:

[0131] .

[0132] 3x was a colorless oily substance with a yield of 76 mg, a yield of 97%, and an ee of 84%. The results of the determination of 3x are as follows: 1 HNMR (600MHz, CDCl3) δ 7.62 (d, J=7.1Hz, 2H), 7.50 – 7.44 (m, 3H), 7.39 (t, J=7.3Hz, 1H), 7.35 – 7.28 (m, 4H), 4.49 (t, J=6.4Hz, 1H), 3.20 – 3.09 (m, 2H), 1.46 (s, 9H), 1.17 (s, 9H).

[0133] Example 25

[0134] The difference from Example 23 is that the alkyl halide is 1-bromo-3-methyl-2-butanone, and the product is 3y. The structure is shown below:

[0135] .

[0136] 3y is a colorless oily substance with a yield of 71 mg, a yield of 93%, and an ee of 91%. The results of the determination of 3y are as follows: 1HNMR (600MHz, CDCl3) δ 7.62 (d, J=7.4Hz, 2H), 7.51 – 7.44 (m, 3H), 7.39 (t, J=7.4Hz, 1H), 7.31 (dt, J=17.6, 7.2Hz, 4H), 4.51 (dd, J=7.4, 5.6Hz, 1H), 3.16(dd, J=17.1, 5.6Hz, 1H), 3.04 (dd, J=17.1, 7.4Hz, 1H), 2.64 (p, J=6.9Hz, 1H), 1.46 (s, 9H), 1.12 (dd, J=7.0, 4.5Hz, 6H).

[0137] Example 26

[0138] The difference from Example 23 is that the alkyl halide is 1-adamantane-2-bromoethylone, and the product is 3z. The structure is shown below:

[0139] .

[0140] 3z was a colorless oily substance with a yield of 69 mg, a yield rate of 73%, and an ee of 94%. The results of the determination of 3z are as follows: 1 HNMR (600MHz, CDCl3) δ 7.62 (d, J=7.5Hz, 2H), 7.46 (dd, J=11.8, 6.9Hz, 3H), 7.39 (t, J=7.5Hz, 1H), 7.31 (dt, J=17.8, 6.5Hz, 4H), 4.49 (dd, , 1.45 (s, 9H).

[0141] Example 27

[0142] The difference from Example 23 is that the alkyl halide is 2-bromo-1-(tetrahydro-2H-pyran-4-yl)ethyl ketone, and the product is 3aa. The structure is shown below:

[0143] .

[0144] 3aa was a white solid, with a yield of 81 mg, a yield of 96%, and an ee of 94%. The determination of 3aa yielded the following results:1 HNMR (600MHz, CDCl3) δ 7.61 (d, J=7.8Hz, 2H), 7.47 (td, J=10.0, 9.6, 4.7Hz, 3H), 7.39 (t, J=7.4Hz, 1H), 7.32 (t, J=7.6Hz, 2H), 7.28 (d, J=7.2Hz, 2H), 4.51 (t, J=6.5Hz, 1H), 3.98 (t, J=10.6Hz, 2H), 3.42 (q, J=9.3Hz, 2H), 3.15 (dd, J=17.0, 5.7Hz, 1H), 3.00 (dd, J=16.9, 7.3Hz, 1H), 2.60 (tt, J=11.3,4.1Hz, 1H), 1.79 (d, J=13.7Hz, 2H), 1.69 (dqd, J=24.5, 11.5, 4.2Hz, 2H), 1.44(s, 9H).

[0145] Example 28

[0146] The difference from Example 23 is that the alkyl halide is tert-butyl 4-(bromoacetyl)piperidine-1-carboxylate, and the product is 3ab. The structure is shown below:

[0147] .

[0148] 3ab is a yellow oily substance with a yield of 98 mg, a yield rate of 94%, and an ee of 95%. The results of the determination of 3ab are as follows: 1H NMR (600MHz, CDCl3) δ 7.60 (d, J=7.8Hz, 2H), 7.46 (q, J=7.7Hz, 3H), 7.38(t, J=7.3Hz, 1H), 7.32 (t, J=7.6Hz, 2H), 7.27 (d, J=7.3Hz, 2H), 4.49 (t, J=6.5Hz, 1H), 4.15 – 4.02 (m, 2H), 3.15 (dd, J=17.0, 5.8Hz, 1H), 2.99 (dd, J=17.0, 7.3Hz, 1H), 2.79 (d, J=11.3Hz, 2H), 2.51 (ddd, J=11.2, 7.5, 3.8Hz, 1H), 1.83 (d, J=13.6Hz, 2H), 1.53 (td, J=12.2, 11.8, 4.4Hz, 2H), 1.46 (s, 9H), 1.44 (s, 9H).

[0149] Example 29

[0150] The difference from Example 23 is that the alkyl halide is tert-butyl bromoacetate, and the product is 3ac. The structure is as follows:

[0151] .

[0152] 3ac was a colorless oily substance with a yield of 52 mg, a yield rate of 64%, and an ee of 92%. The results of the determination of 3ac are as follows: 1 H NMR (600MHz, CDCl3) δ 7.64 (d, J=7.0Hz, 2H), 7.47 (d, J=7.3Hz, 3H), 7.40 (t, J=7.3Hz, 1H), 7.34 (t, J=7.5Hz, 2H), 7.28 (dd, J=7.6, 1.8Hz, 2H), 4.40(dd, J=7.7, 5.7Hz, 1H), 2.94 (dd, J=15.6, 5.7Hz, 1H), 2.79 (dd, J=15.7,7.7Hz, 1H), 1.46 (s, 9H), 1.43 (s, 9H).

[0153] Example 30

[0154] The difference from Example 23 is that the alkyl halide is 2-bromoacetophenone, and the product is 3ad. The structure is as follows:

[0155] .

[0156] 3ad is a yellow oily substance with a yield of 75 mg, a yield of 95%, and an ee of 92%. The results of the determination of 3ad are as follows: 1 H NMR (600MHz, CDCl3) δ 8.00 (d, J=7.5Hz, 2H), 7.63 (d, J=7.4Hz, 2H), 7.57(t, J=7.4Hz, 1H), 7.48 (p, J=7.7, 7.0Hz, 5H), 7.42 – 7.37 (m, 1H), 7.35 –7.31 (m, 4H), 4.75 – 4.67 (m, 1H), 3.76 (dd, J=17.0, 5.9Hz, 1H), 3.53 (dd, J=17.0, 7.1Hz, 1H), 1.48 (s, 9H).

[0157] Example 31

[0158] The difference from Example 23 is that the alkyl halide is 2-bromo-4'-fluoroacetophenone, and the product is 3ae. The structure is shown below:

[0159] .

[0160] 3ae was a yellow oily substance with a yield of 83 mg, a yield of 96%, and an ee of 91%. The proton and carbon NMR spectra of 3ae were determined, and the results are as follows: 1 H NMR (600MHz CDCl3) δ 8.06 – 7.98 (m, 2H), 7.62 (d, J=8.2Hz, 2H), 7.48 (d, J=7.8Hz, 3H), 7.39 (t, J=7.3Hz, 1H), 7.32 (t, J=7.8Hz, 4H), 7.13 (t, J=8.5Hz, 2H), 4.70 (t, J=6.5Hz, 1H), 3.71 (dd, J=16.9, 5.9Hz, 1H), 3.48 (dd, J=16.9, 7.1Hz, 1H), 1.47 (s, 10H).

[0161] Example 32

[0162] The difference from Example 23 is that the alkyl halide is 2-bromo-4'-methoxyacetophenone, and the product is 3af. The structure is shown below:

[0163] .

[0164] 3af was a colorless oily substance with a yield of 71 mg, a yield of 80%, and an ee of 96%. The results of the determination of 3af are as follows: 1 H NMR (600MHz, CDCl3) δ 7.98 (d, J=8.8Hz, 2H), 7.62 (d, J=8.4Hz, 2H), 7.47(q, J=8.1, 7.3Hz, 3H), 7.38 (t, J=7.3Hz, 1H), 7.34 – 7.29 (m, 4H), 6.94 (d, J=6.8Hz, 2H), 4.69 (dd, J=7.1, 5.9Hz, 1H), 3.87 (s, 3H), 3.68 (dd, J=16.8,5.9Hz, 1H), 3.47 (dd, J=16.8, 7.1Hz, 1H), 1.47 (s, 9H).

[0165] Example 33

[0166] The difference from Example 23 is that the alkyl halide is 2-bromo-4'-methylacetophenone, and the product is 3 ag. The structure is shown below:

[0167] .

[0168] 3ag was a yellow oily substance with a yield of 69mg, a yield rate of 81%, and an ee of 92%. The results of the determination of 3ag are as follows: 1 H NMR (600MHz, CDCl3) δ 7.89 (d, J=8.2Hz, 2H), 7.62 (d, J=8.4Hz, 2H), 7.50 –7.45 (m, 3H), 7.42 – 7.36 (m, 1H), 7.34 – 7.29 (m, 4H), 7.26 (d, J=8.0Hz,2H), 4.69 (dd, J=7.1, 5.9Hz, 1H), 3.71 (dd, J=16.9, 5.9Hz, 1H), 3.50 (dd, J=16.9, 7.1Hz, 1H), 2.42 (s, 3H), 1.47 (s, 9H).

[0169] Example 34

[0170] The difference from Example 23 is that the alkyl halide is 2-bromo-4'-nitroacetophenone, and the product is 3ah. The structure is shown below:

[0171] .

[0172] 3ah is a yellow oily substance with a yield of 30 mg, a yield rate of 33%, and an ee of 99%. The results of the determination of 3ah are as follows: 1 H NMR (600MHz, CDCl3) δ 8.31 (d, J=8.4Hz, 2H), 8.13 (d, J=8.4Hz, 2H), 7.60 (d, J=7.8Hz, 2H), 7.49 (d, J=6.6Hz, 3H), 7.40 (t, J=7.5Hz, 1H), 7.35 – 7.28(m, 4H), 4.69 (t, J=6.5Hz, 1H), 3.75 (dd, J=17.0, 5.9Hz, 1H), 3.52 (dd, J=17.0, 7.1Hz, 1H).

[0173] Example 35

[0174] A method for preparing a chiral, non-natural α-amino acid 3ai includes the following steps:

[0175] In a glove box, 0.2 mmol (1.0 equivalent) of N-(diphenylmethylene)glycine butyl ester, 0.4 mmol (2.0 equivalent) of 2-iodopropane, 0.4 mmol (2.0 equivalent) of cesium carbonate, 0.005 mmol of CuBr (2.5 mol%), and 0.006 mmol of [unspecified substance] (3 mol%) were placed in the glove box. t BuFOXAP was weighed and placed in an 8 mL Shrek vial. 1.0 mL of degassed acetone was added to the vial, and the mixture was stirred for 1 min before being removed. The resulting mixture was stirred in an oil bath at 35 °C for 24 h. After cooling to room temperature, the solvent was removed by vacuum distillation, and the product was purified by silica gel column chromatography to obtain product 3ai. Its structure is shown below:

[0176] .

[0177] 3ai was a white solid, with a yield of 64 mg, a yield of 95%, and an ee of 80%. The results of the determination of 3ai are as follows: 1HNMR (600MHz, CDCl3) δ 7.70 (d, J=7.0Hz, 2H), 7.45 (d, J=5.2Hz, 3H), 7.40 (d,J=7.3Hz, 1H), 7.35 (t, J=7.4Hz, 2H), 7.18 (dd, J=7.4, 2.0Hz, 2H), 3.72 (d, J=5.9Hz, 1H), 2.42 – 2.32 (m, 1H), 1.48 (s, 9H), 1.03 (d, J=6.8Hz, 3H), 0.90 (d, J=6.8Hz, 3H).

[0178] Example 36

[0179] The difference from Example 35 is that the alkyl halide is iodocyclopentane, and the product is 3aj. The structure is as follows:

[0180] .

[0181] 3aj was a white solid, with a yield of 67.6 mg, a yield of 93%, and an ee of 98%. The determination of 3aj yielded the following results: 1 H NMR (600MHz, CDCl3) δ 7.68 (d, J=7.0Hz, 2H), 7.46 (d, J=7.2Hz, 3H), 7.40 (t, J=7.3Hz, 1H), 7.34 (t, J=7.4Hz, 2H), 7.20 (d, J=7.8Hz, 2H), 3.84 (d, J=7.3Hz, 1H), 2.61 (q, J=8.1Hz, 1H), 1.81 – 1.68 (m, 2H), 1.62 – 1.51 (m, 4H), 1.48 (s, 9H), 1.45 – 1.39 (m, 1H), 1.21 (dt, J=13.7, 8.1Hz, 1H).

[0182] Example 37

[0183] The difference from Example 35 is that the alkyl halide is iodocyclohexane, and the product is 3ak. The structure is as follows:

[0184] .

[0185] 3ak was a white solid, with a yield of 67 mg, a yield of 89%, and an ee of 90%. The determination of 3ak yielded the following results: 1HNMR (600MHz, CDCl3) δ 7.70 (d, J=8.0Hz, 2H), 7.49 – 7.43 (m, 3H), 7.40 (t, J=7.3Hz, 1H), 7.35 (t, J=7.5Hz, 2H), 7.17 (d, J=5.8Hz, 2H), 3.73 (d, J=6.5Hz,1H), 2.07 (dd, J=6.6, 3.3Hz, 1H), 1.80 – 1.64 (m, 4H), 1.61 – 1.53 (m, 1H),1.48 (s, 9H), 1.28 (ddq, J=12.8, 8.8, 3.9Hz, 2H), 1.23 – 1.10 (m, 2H), 1.01(dd, J=12.3, 3.6Hz, 1H).

[0186] Example 38

[0187] The difference from Example 35 is that the alkyl halide is 4-iodotetrahydropyran, and the product is 3al. The structure is as follows:

[0188] .

[0189] 3al was a white solid, with a yield of 74 mg, a yield of 97%, and an ee of 96%. The determination of 3al yielded the following results: 1 HNMR (600MHz, CDCl3) δ 7.69 (d, J=8.6Hz, 2H), 7.50 – 7.44 (m, 3H), 7.43 – 7.38 (m, 1H), 7.35 (d, J=7.9Hz, 2H), 7.18 (d, J=7.6Hz, 2H), 4.04 – 3.93 (m, 2H), 3.77 (d, J=6.7Hz, 1H), 3.43 (t, J=12.1Hz, 2H), 2.34 (tdt, J=11.1, 6.9, 3.9Hz, 1H), 1.67 – 1.56 (m, 2H), 1.50 (s, 1H), 1.48 (s, 9H), 1.42 – 1.35 (m, 1H).

[0190] Example 39

[0191] The difference from Example 35 is that the alkyl halide is 1-CBZ-4-iodopiperidine, and the product is 3am. The structure is shown below:

[0192] .

[0193] 3am is a colorless oily substance with a yield of 97 mg, a yield rate of 95%, and an ee of 87%. The results of the determination of 3am are as follows: 1 H NMR (600MHz, CDCl3) δ 7.68 (d, J=7.3Hz, 2H), 7.51 – 7.44 (m, 3H), 7.42 (t,J=7.3Hz, 1H), 7.40 – 7.29 (m, 7H), 7.16 (dd, J=7.3, 2.2Hz, 2H), 5.15 (s, 2H), 4.34 – 4.14 (m, 2H), 3.77 (d, J=6.6Hz, 1H), 2.81 (s, 2H), 2.26 (td, J=5.8,5.1, 2.5Hz, 1H), 1.75 (d, J=13.2Hz, 1H), 1.57 (dp, J=8.8, 2.8Hz, 1H), 1.44 –1.38 (m, 1H), 1.22 (t, J=8.8Hz, 1H).

[0194] Example 40

[0195] The difference from Example 35 is that the alkyl halide is N-Boc-4-iodopiperidine, and the product is 3an. The structure is shown below:

[0196] .

[0197] 3an was a white solid, with a yield of 90 mg, a yield of 94%, and an ee of 88%. The determination of 3an yielded the following results: 1 HNMR (600MHz, CDCl3) δ 7.67 (d, J=7.2Hz, 2H), 7.46 (d, J=6.9Hz, 3H), 7.40 (t,J=7.3Hz, 1H), 7.33 (t, J=7.6Hz, 2H), 7.16 (d, J=7.6Hz, 2H), 4.12 (s, 2H),3.76 (d, J=6.6Hz, 1H), 2.71 (s, 2H), 2.23 (tdd, J=8.7, 6.0, 3.5Hz, 1H), 1.71(d, J=13.1Hz, 1H), 1.53 (d, J=14.6Hz, 1H), 1.47 (s, 18H).

[0198] Next, the present invention synthesized the natural product phalloidin, and the specific synthesis process is as follows:

[0199] The synthetic routes for S1 and compound 8 are shown below:

[0200] .

[0201] 2.0 g (5.7 mmol, equivalent to 1.0 equivalent of purified 3w) was dissolved in tetrahydrofuran, and the pH was adjusted to 1 with 2M hydrochloric acid. The mixture was stirred for 10 min, and the pH was adjusted to 7 with saturated sodium carbonate solution. Excess solvent was removed by concentration under reduced pressure. The residue was dissolved in dichloromethane, and 2.6 g (6 mmol, equivalent to 1.05 equivalent of Fmoc-L-tryptophan) and 808 mg (6 mmol, equivalent to 1.05 equivalent of 1-hydroxybenzotriazole HOBT) were added sequentially to obtain a mixture. 1.1 g (6 mmol, equivalent to 1.05 equivalent of EDC) in dichloromethane solution was slowly added at 0 °C. After 3 h, the mixture was extracted with saturated sodium bicarbonate solution, and the organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography with CH2Cl2 / MeOH = 20 / 1, yielding 5 g of white solid. The yield was 2.8 g, with a molar weight of 4.8 mmol, and a yield of 84%.

[0202] 3.6 g (6 mmol, equivalent to 1.0 equivalent) of compound 5 was dissolved in 30 mL of a 1:1 mixture of dichloromethane and diethylamine. The mixture was stirred at room temperature for 30 min, and the diethylamine was removed by vacuum concentration. Then, 2.0 g (6.3 mmol, equivalent to 1.05 equivalent) of Fmoc-Ala-OH6 and 857 mg (6.3 mmol, equivalent to 1.05 equivalent) of HOBT were added sequentially. The resulting mixture was then slowly added at 0 °C to a dichloromethane solution containing 1.2 g (6.3 mmol, equivalent to 1.05 equivalent) of EDC. After 3 h, the mixture was extracted with saturated sodium bicarbonate solution, the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography with CH2Cl2 / MeOH = 20 / 1, yielding a white solid 7. The yield was 3.6 g (5.4 mmol), or 90%.

[0203] 3 g (4.5 mmol, equivalent to 1.0 equivalent) of compound 7 was dissolved in 30 mL of a 1:1 mixture of dichloromethane and diethylamine. The mixture was stirred at room temperature for 30 min, concentrated under reduced pressure, and then separated by column chromatography with CH2Cl2 / MeOH as the eluent (9 / 1). The yield was 1.9 g (4.2 mmol) and the molar weight was 94%.

[0204] The results of the determination of compound 8 are as follows: 1H NMR (600MHz, DMSO-d6) δ 10.82 (s, 1H), 8.34 (d, J=7.6Hz, 1H), 7.98 (d, J=8.5Hz, 1H), 7.58 (d, J=7.9Hz, 1H), 7.33 (d,J=8.1Hz, 1H), 7.15 (s, 1H), 7.06 (t, J=7.1Hz, 1H), 6.98 (t, J=7.4Hz, 1H), 4.58 (d, J=6.3Hz, 1H), 4.52 (q, J=6.9Hz, 1H), 3.24 (q, J=6.8Hz, 1H), 3.16(dd, J=14.7, 4.9Hz, 1H), 2.99 (dd, J=14.7, 8.2Hz, 1H), 2.90 (dd, J=17.3,5.9Hz, 1H), 2.73 (dd, J=17.4, 6.9Hz, 1H), 2.11 (s, 3H), 1.40 (s, 9H), 1.04(d, J=7.0Hz, 3H).

[0205] The synthetic routes for S2 and compound 20 are shown below:

[0206] .

[0207] 5.0 g (38 mmol, equivalent to 1.0 equivalent) of cis-L-4-hydroxyproline was dissolved in 60 mL of 1,4-dioxane to obtain a solution. 60 mL of 1M sodium carbonate aqueous solution was added dropwise to the solution under ice bath conditions, followed by 10 mL of 4M Fmoc-Su dissolved in 1,4-dioxane. After stirring at room temperature for 1 h, the pH was adjusted to 1 with 2M hydrochloric acid solution, and the mixture was extracted with 50 mL of dichloromethane. The organic phase was separated, washed with water, dried over sodium sulfate, and concentrated. The residue was dissolved in dichloromethane, and 6.0 g (76.2 mmol, equivalent to 2.0 equivalent) of pyridine and 9.0 g (114 mmol, equivalent to 3.0 equivalent) of acyl chloride were added sequentially under ice bath conditions. After reacting for 1 h, the pH was adjusted to 3 with 2M hydrochloric acid solution, and the mixture was extracted sequentially with 20 mL of saturated ammonium chloride solution and 20 mL of dichloromethane. The organic phase was separated, washed with water, dried over sodium sulfate, and concentrated. The residue was dissolved in 60 mL of tert-butanol, and 1.4 g (11.4 mmol, equivalent to 0.3 equivalents of dimethylimine) and 16.6 g (76 mmol, equivalent to 2.0 equivalents of (BOC)₂O) were added sequentially at room temperature. After reacting for 1 h, the mixture was concentrated under reduced pressure and extracted with 40 mL of saturated ammonium chloride solution and 40 mL of ethyl acetate. The organic phase was separated, washed with water, dried over sodium sulfate, concentrated, and purified by column chromatography with hexane / ethyl acetate as the eluent in a 4 / 1 ratio, yielding a white solid product 10, with a yield of 13.7 g and a molar weight of 30.5 mmol. The overall yield of the three steps was 80%.

[0208] 10.0 g (22.1 mmol, equivalent to 1.0 equivalent) of compound 10 was dissolved in 50 mL of a 1:1 mixture of dichloromethane and diethylamine to obtain a mixture. The mixture was stirred at room temperature for 30 min, concentrated under reduced pressure, and then separated by column chromatography with CH2Cl2 / MeOH as the eluent (20 / 10). The yield was 4.6 g of white solid 11, with a molar weight of 19.9 mmol and a yield of 90%.

[0209] 4.0 g (17.4 mmol, equivalent to 1.0 equivalent) of purified compound 11 was dissolved in dichloromethane. Then, 10.7 g (18.3 mmol, equivalent to 1.05 equivalent) of Fmoc-L-cysteine ​​12 and 2.5 g (18.3 mmol, equivalent to 1.05 equivalent) of HOBT were added sequentially to obtain a mixture. At 0°C, 3.5 g (18.3 mmol, equivalent to 1.05 equivalent) of a dichloromethane solution of EDC was slowly added. After 3 h, the mixture was extracted with saturated sodium bicarbonate solution. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography with CH2Cl2 / MeOH = 20 / 1, yielding a white solid 13. The yield was 12.8 g, with a molar weight of 16.0 mmol, and a yield of 92%.

[0210] 10.0 g (12.5 mmol, equivalent to 1.0 equivalent) of compound 13 was dissolved in 50 mL of a 1:1 mixture of dichloromethane and diethylamine to obtain a mixture. The mixture was stirred at room temperature for 30 min, and the diethylamine was removed by vacuum concentration. The residue was dissolved in dichloromethane, and 4.5 g (13.2 mmol, equivalent to 1.05 equivalent) of Fmoc-D-Thr-OH (compound 14) and 1.8 g (13.2 mmol, equivalent to 1.05 equivalent) of HOBT were added sequentially to obtain a mixture. 2.5 g (13.2 mmol, equivalent to 1.05 equivalent) of EDC in dichloromethane solution was slowly added at 0°C. After 3 h, the mixture was extracted with saturated sodium bicarbonate solution, the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography with CH2Cl2 / MeOH = 20 / 1 to give a white solid 15. The yield was 9.8 g, the molar weight was 10.9 mmol, and the yield was 87%.

[0211] 8.0 g (8.9 mmol, equivalent to 1.0 equivalent) of compound 15 was dissolved in 50 mL of a 1:1 mixture of dichloromethane and diethylamine to obtain a mixture. The mixture was stirred at room temperature for 30 min, concentrated under reduced pressure, and then separated by column chromatography with CH2Cl2 / MeOH as the eluent (20 / 10). The result was a white solid 16 with a yield of 5.7 g (8.4 mmol) and a molar weight of 94%.

[0212] 5.0 g (7.4 mmol, equivalent to 1.0 equivalent) of purified compound 16 was dissolved in dichloromethane. Then, 2.6 g (7.8 mmol, equivalent to 1.05 equivalent) of Fmoc-Ala-OH (compound 17) and 1.1 g (7.8 mmol, equivalent to 1.05 equivalent) of HOBT were added sequentially to obtain a mixture. A solution of 1.5 g (7.8 mmol, equivalent to 1.05 equivalent) of EDC in dichloromethane was slowly added at 0°C. After 3 hours, the mixture was extracted with saturated sodium bicarbonate solution. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography with CH2Cl2 / MeOH = 20 / 1, yielding a white solid 18. The yield was 6.2 g (6.4 mmol), representing a yield of 87%.

[0213] 4.0 g (4.1 mmol, equivalent to 1.0 equivalent) of purified 18 was dissolved in dichloromethane. Under ice bath conditions, 653 mg (8.3 mmol, equivalent to 2.0 equivalent) of pyridine and 972 mg (12.4 mmol, equivalent to 3.0 equivalent) of acyl chloride were added sequentially. After reacting for 1 h, the pH was adjusted to 3 with 2 M hydrochloric acid solution. The organic phase was extracted with 20 mL of saturated ammonium chloride solution and 20 mL of dichloromethane, washed with water, dried over sodium sulfate, concentrated, and separated by column chromatography with eluent CH2Cl2 / MeOH = 20 / 1, yielding a white solid 19 with a yield of 4.0 g (4.0 mmol, 97%).

[0214] 4.0 g (4.0 mmol) of purified 19, equivalent to 1.0 equivalent, was dissolved in 30 mL of trifluoroacetic acid. After stirring for 1 h, the trifluoroacetic acid was removed by vacuum concentration, and then separated by column chromatography with CH2Cl2 / MeOH = 20 / 1 as the eluent, yielding a white solid 20 with a yield of 3.5 g and a molar amount of 3.6 mmol, resulting in a yield of 92%.

[0215] The results of the determination of compound 20 are as follows: 1 H NMR (600MHz, DMSO-d6) δ 8.67 (d, J=8.5Hz, 1H), 8.00 (d, J=9.1Hz, 1H), 7.89 (d, J=7.6Hz, 2H), 7.72 (dd, J=15.3,7.5Hz, 2H), 7.52 (d, J=7.5Hz, 1H), 7.42 (t, J=7.5Hz, 2H), 7.32 (d, J=8.4Hz,14H), 7.22 (t, J=7.3Hz, 3H), 5.17 – 5.05 (m, 2H), 4.54 (dd, J=9.0, 5.6Hz,1H), 4.36 (dd, J=23.3, 8.5Hz, 2H), 4.29 – 4.13 (m, 5H), 3.70 – 3.64 (m, 1H), 3.04 (d, J=11.6Hz, 1H), 2.43 (t, J=8.Hz, 1H), 2.38 (dd, J=13.9, 6.6Hz, 1H), 1.96 (s, 4H), 1.82 (s, 3H), 1.22 (d, J=7.2Hz, 3H), 1.10 (d, J=6.3Hz, 3H).

[0216] The synthesis route for S3 and Phalloin is shown below:

[0217] .

[0218] 1.2 g (2.7 mmol, equivalent to 1.0 equivalent) of purified compound 8 was dissolved in dichloromethane. Then, 2.7 g (2.8 mmol, equivalent to 1.05 equivalent) of tetrapeptide compound 20 and 384 mg (2.8 mmol, equivalent to 1.05 equivalent) of HOBT were added sequentially to obtain a mixture. At 0°C, 544 mg (2.8 mmol, equivalent to 1.05 equivalent) of EDC in dichloromethane was slowly added. After 3 h, the mixture was extracted with saturated sodium bicarbonate solution. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography with CH2Cl2 / MeOH = 20 / 1, yielding a white solid 21. The yield was 3.2 g, with a molar mass of 2.4 mmol, and a yield of 92%.

[0219] 2.2 g (1.6 mmol, equivalent to 1.0 equivalent) of heptapeptide 21 was dissolved in 50 mL of DMF to form a solution. At room temperature, a mixture of 2.2 L of dry DMF containing 1.6 g (6.4 mmol, equivalent to 4.0 equivalent) of I2 was added in portions over 50 min. The mixture was then stirred for 3 h. The reaction was quenched with sodium thiosulfate solution, and the solution was concentrated under reduced pressure to give a yellow crude product. The crude product was extracted with ethyl acetate and 20% sodium chloride solution, and the combined organic layers were dried over anhydrous sodium sulfate. After concentration, the product was separated by column chromatography with CH2Cl2 / MeOH = 20 / 1, yielding a white solid 22. The yield was 1.29 g (1.3 mmol), with a yield of 80%.

[0220] 1.5 g (1.3 mmol, equivalent to 1.0 equivalent) of compound 22 was dissolved in 40 mL of a 1:1 mixture of dichloromethane and diethylamine to obtain a mixture. The mixture was stirred at room temperature for 2 h, concentrated under reduced pressure, and then separated by column chromatography with CH2Cl2 / MeOH as the eluent (10 / 1) to give a white solid 23. The yield was 1.1 g, the molar amount was 1.2 mmol, and the yield was 92%.

[0221] 1.0 g (1.1 mmol, equivalent to 1.0 equivalent) of purified product 23 was dissolved in 10 mL of trifluoroacetic acid. After stirring for 1 h, the product was concentrated under vacuum to remove trifluoroacetic acid. The product was then separated by column chromatography with CH2Cl2 / MeOH as the eluent (1 / 1) to obtain the orange crude product 24. The yield was 882.0 mg, the molar amount was 1.0 mmol, and the yield was 94%.

[0222] 882.0 mg (1.0 mmol, equivalent to 1.0 equivalent) of crude product 24 was dissolved in 700 mL of DMF, and 258.0 mg (2.0 mmol, equivalent to 2.0 equivalent) of DIPEA was added. Then, 570.3 mg (1.5 mmol, equivalent to 1.5 equivalent) of HATU in 200 mL of DMF solution was slowly added dropwise at 0°C. After reacting for 12 h, the mixture was concentrated under reduced pressure to obtain a yellow crude product. This product was extracted with ethyl acetate and 20 wt% sodium chloride solution. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The product was then separated by column chromatography with CH2Cl2 / MeOH as the eluent (10 / 1) to obtain a yellow solid 25. The yield was 276.3 mg, the molar amount was 3.3 mmol, and the yield was 32%.

[0223] 50 mg (0.06 mmol, equivalent to 1.0 equivalent) of dicyclic heptapeptide 25 was dissolved in 2 mL of dry tetrahydrofuran. 0.1 mL of 3M methyl magnesium iodide (equivalent to 5.0 equivalent) was slowly added at -30°C over 5 min to obtain a mixture. After stirring for 18 h, the mixture was quenched with water, extracted with ethyl acetate and 20% sodium chloride solution, and the organic layers were combined. The mixture was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography with CH2Cl2 / MeOH = 10 / 1 to give a white solid 26. The yield was 11 mg, the molar amount was 0.013 mmol, and the yield was 22%.

[0224] 8 mg (0.009 mmol, equivalent to 1.0 equivalent) of compound 26 was dissolved in 3 mL of a 1 M NH3 / MeOH mixed solution to obtain a mixture. The mixture was stirred at room temperature for 5 h, concentrated under reduced pressure, and then separated by column chromatography with CH2Cl2 / MeOH as the eluent (5 / 1) to give a white solid, Phalloin, with a yield of 6.1 mg, a molar amount of 0.008 mmol, and a yield of 84%.

[0225] The results of the determination of the compound Phalloin are as follows: 1H NMR (600MHz, DMSO-d6) δ 11.27(s, 1H), 8.70 (d, J=7.5Hz, 1H), 8.28 (s, 1H), 7.79 (s, 1H), 7.65 (dd, J=17.8,7.4Hz, 2H), 7.33 (s, 2H), 7.24 (d, J=8.1Hz, 1H), 7.13 – 7.06 (m, 1H), 7.00 –6.94 (m, 1H), 5.60 (d, J=3.9Hz, 1H), 4.86 (d, J=5.9Hz, 1H), 4.74 (td, J=7.1,4.8Hz, 2H), 4.49 (t, J=6.5Hz, 1H), 4.35 (q, J=4.5Hz, 1H), 4.22 (td, J=6.3,4.1Hz, 1H), 4.16 (dd, J=9.0, 5.8Hz, 1H), 4.04 – 3.93 (m, 2H), 3.87 (p, J=7.2Hz, 1H), 3.77 (dd, J=10.3, 5.1Hz, 1H), 3.55 (dd, J=10.4, 3.9Hz, 2H), 3.24(s, 1H), 3.14 (dd, J=15.0, 12.3Hz, 1H), 2.29 (ddd, J=13.4, 9.0, 4.8Hz, 1H),1.82 (dt, J=11.3, 5.3Hz, 1H), 1.76 (s, 1H), 1.21 (d, J=6.6Hz, 3H), 1.08 (t, J=5.4Hz, 9H), 0.75 (s, 3H).

[0226] It should be noted that when numerical ranges are involved in this invention, it should be understood that both endpoints of each numerical range, as well as any value between the two endpoints, can be selected. Since the steps and methods used are the same as in the embodiments, preferred embodiments are described here to avoid redundancy. Although preferred embodiments of this invention have been described, those skilled in the art, once they understand the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the appended scope of protection is intended to be interpreted as including the preferred embodiments and all changes and modifications falling within the scope of this invention.

[0227] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of protection of this invention and its equivalents, this invention also intends to include these modifications and variations.

Claims

1. A method for synthesizing a natural product called phalloidin, characterized in that, Includes the following steps: The diphenylmethylene group of the chiral α-amino acid was removed, and Fmoc-L-tryptophan (compound 4) was added for coupling to obtain compound 5; the chiral α-amino acid was compound 3w. The amino Fmoc group of compound 5 was removed, and Fmoc-L-alanine, i.e. compound 6, was added and coupled to obtain compound 7. The Fmoc group of compound 7 was removed to obtain a tripeptide, namely compound 8; The structures of compounds 3w, 5, 7, and 8 are shown below: ； Using compounds 8 and 20 as raw materials, a condensation reaction was carried out to obtain compound 21; Under the action of I2, an intramolecular CS bond was formed on compound 21 to obtain compound 22; The Fmoc group of compound 22 was removed to obtain compound 23; The tert-butyl ester group of compound 23 was removed to obtain compound 24; Compound 24 was subjected to intramolecular amide condensation under the action of a condensing agent to obtain compound 25; Nucleophilic addition to the carbonyl group of compound 25 yields compound 26; The acetyl group of compound 26 was removed to obtain the natural product phalloidin. The structures of compounds 8, 20-26, and the natural product phalloidin are shown below: 。 2. The method for synthesizing the natural product phalloidin according to claim 1, characterized in that, A method for preparing chiral α-amino acids includes the following steps: Using N-(diphenylmethylene)glycine tert-butyl ester as the substrate, alkyl halides as the coupling agent, and copper salts as the catalyst, t Using BuFOXAP as a ligand, an asymmetric coupling reaction is carried out in a base and solvent system to yield a chiral α-amino acid; the alkyl halide has the structure shown below: ； The copper salt is CuBr, the base is tripotassium phosphate monohydrate or cesium carbonate, and the solvent is acetone or degassed acetone. The t The structure of BuFOXAP is shown below: 。 3. The method for preparing chiral α-amino acids according to claim 2, characterized in that, The molar ratio of N-(diphenylmethylene)glycine tert-butyl ester to alkyl halide is 1:2; the asymmetric coupling reaction temperature is 0℃~35℃, and the time is 24h~36h.

4. The method for preparing chiral α-amino acids according to claim 2, characterized in that, The molar ratio of N-(diphenylmethylene)glycine butyl ester to copper salt is 40:1; the molar ratio of N-(diphenylmethylene)glycine tert-butyl ester to ligand is 100:3; and the molar ratio of N-(diphenylmethylene)glycine butyl ester to base is 1:

2.

5. The method for preparing chiral α-amino acids according to claim 2, characterized in that, The molar volume ratio of N-(diphenylmethylene)glycine butyl ester to solvent is 0.2 mmol: 1.0 mL.

6. The method for synthesizing the natural product phalloidin according to claim 1, characterized in that, The molar ratio of compound 3w to compound 4 is 5.7:6; the molar ratio of compound 5 to compound 6 is 6:6.3; the molar ratio of compound 8 to compound 20 is 2.7:2.8; the molar ratio of compound 21 to I2 is 1.6:6.4; and the molar ratio of compound 24 to the condensing agent is 1:

2.

7. The method for synthesizing the natural product phalloidin according to claim 1, characterized in that, The preparation method of compound 20 includes the following steps: By protecting the amino, alcoholic hydroxyl, and carboxyl groups of cis-L-4-hydroxyproline, i.e., compound 9, compound 10 was obtained; The Fmoc group of compound 10 was removed to obtain compound 11; Using compound 11 and Fmoc-L-cysteine ​​(i.e., compound 12) as raw materials, amide condensation was carried out to obtain compound 13; Using compound 13 and Fmoc-D-threonine (i.e., compound 14) as raw materials, amide condensation was carried out to obtain compound 15; The Fmoc group of compound 15 was removed to obtain compound 16; Using compound 16 and Fmoc-L-alanine (compound 17) as raw materials, amide condensation was carried out to obtain compound 18; The hydroxyl group of compound 18 was protected to obtain compound 19; The carboxyl protecting group tert-butyl ester of compound 19 was removed to obtain the tetrapeptide, compound 20. The structures of compounds 9-11, 13, 15, 16, 18-20 are shown below: 。 8. The method for synthesizing the natural product phalloidin according to claim 7, characterized in that, The molar ratio of compound 11 to compound 12 is 17.4:18.3; the molar ratio of compound 13 to compound 14 is 12.5:13.2; and the molar ratio of compound 16 to compound 17 is 7.4:7.8.

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