A visible light-promoted method for α-alkylation modification of amino acids

Abstract

This invention pertains to the field of non-natural amino acids and discloses a visible light-promoted α-alkylation modification method for amino acids. The method involves adding an N-sulfonyl amino acid derivative, an alkane bromide, a base, a crown ether, a catalyst, and a photosensitizer to an organic solvent under a protective gas atmosphere, followed by a selective coupling reaction under visible light irradiation to obtain the α-alkyl amino acid derivative. This invention utilizes photocatalysis, employing readily available sulfonyl-protected amino acid derivatives as raw materials and readily available alkane bromides as alkylating agents to achieve the α-C-H alkylation reaction of amino acid derivatives. This effectively solves the technical problems of inconvenient substrate synthesis and limited applicability in the preparation of existing α-alkyl amino acid derivatives.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of unnatural amino acids, and more particularly relates to a method for visible light-promoted amino acid alpha-position alkylation modification. BACKGROUND

[0002] In the field of medicine, polypeptide drugs have become one of the hotspots of drug research and development, and selective modification of the residues of polypeptide compounds is an important means for the development of polypeptide drugs. Taking glycine as an example, as one of the basic constituent units of polypeptide compounds, the alkylation of the alpha-position C-H bond of glycine is the basis for the post-modification of polypeptide compounds.

[0003] At present, the substrates used to realize the alpha-C alkylation reaction of amino acid compounds are usually limited to aryl-protected amino acid esters or imine ester compounds, which often have defects such as inconvenient synthesis of raw materials and limited scope of substrate application. SUMMARY

[0004] In view of the above defects or improvement needs of the prior art, the purpose of the present application is to provide a method for visible light-promoted amino acid alpha-position alkylation modification, which uses easily prepared sulfuryl-protected amino acid derivatives as raw materials and simple and readily available alkane bromides as alkylation reagents to realize the alpha-position C-H alkylation reaction of amino acid derivatives, which can effectively solve the technical problems of inconvenient synthesis of substrates and limited scope of application in the preparation of existing alpha-alkyl amino acid derivatives. The raw materials used in the present application are simple and readily available, chemically stable, the reaction conditions are mild, the substrate range is wide, the product structure type is rich, and the product application range is wide. Moreover, the alpha-alkyl amino acid derivatives obtained by the present application can be further used to prepare N-tert-butoxycarbonyl amino acid derivatives, so that from the material of the low-cost sulfuryl protecting group, through the convenient processing of the present application, the material of the tert-butoxycarbonyl (Boc) protecting group which is more suitable for actual processing and has high added value can be finally obtained, compared with the prior art, the product protecting group is easy to convert.

[0005] To achieve the above-mentioned purpose, according to one aspect of the present application, a method for preparing alpha-alkyl amino acid derivatives promoted by visible light is provided, characterized in that the method is to add N-sulfuryl amino acid derivatives, alkane bromides, bases, crown ethers, catalysts and photosensitizers into an organic solvent under a protective gas atmosphere, and to obtain alpha-alkyl amino acid derivatives by selective coupling reaction under visible light irradiation conditions.

[0006] Among them, the N-sulfuryl amino acid derivative is specifically shown in the structure of formula I, the alkane bromide is specifically shown in the structure of formula II, and the alpha-alkyl amino acid derivative is specifically shown in the structure of formula III.

[0007]

[0008] In the formula, R 1 Selected from OR 5 NR 6 R 7 substituted or unsubstituted aryl or polypeptide residues, wherein R 5 R 6 and R 7 C1-C20 alkanes; R 2 Selected from C1-C20 alkanes, alkenes, substituted or unsubstituted aromatics; R 3 Selected from H, C1-C20 alkanes, cycloalkanes, or C1-C20 alkane groups containing nitrogen and / or oxygen atoms; R 4 Selected from C1-C20 alkanes, cycloalkanes, or C1-C20 alkane groups containing nitrogen and / or oxygen atoms.

[0009] As a further preferred embodiment of the present invention, the N-sulfonyl amino acid derivative is selected from: N-sulfonyl amino acid esters, N-sulfonyl amino ketones, and N-terminal sulfonyl-protected polypeptides.

[0010] As a further preferred embodiment of the present invention, the alkali includes at least one selected from potassium carbonate, cesium carbonate, tripotassium phosphate, potassium fluoride, and cesium fluoride.

[0011] As a further preferred embodiment of the present invention, the catalyst is a transition metal salt, which is represented by the following formula IV:

[0012]

[0013]

[0014] Wherein Ar is an aromatic ring that is mono- or poly-substituted by an alkane, alkoxy group, amino group, halogen or haloalkane; preferably, the transition metal salt is Pd(PPh3)4;

[0015] Alternatively, the catalyst may simultaneously comprise a transition metal salt and a ligand, wherein the transition metal salt comprises one of Pd(OAc)₂, Pd(dba)₂, NiBr₂, Ni(OAc)₂·4H₂O, and NiCl₂·glyme; and the ligand comprises one of triphenylphosphine, tris(4-methoxyphenyl)phosphine, tris(3,5-dimethylphenyl)phosphine, tris(o-methylphenyl)phosphine, tris(4-fluorophenyl)phosphine, tris(3-fluorophenyl)phosphine, tris(2-fluorophenyl)phosphine, tris(4-trifluorotolyl)phosphine, tris(pentafluorophenyl)phosphine, 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene, 1,1'-binaphthyl-2,2'-bis(diphenylphosphine), bipyridine, and 4,4'-dimethoxy-2,2'-dipyridine.

[0016] The photosensitizers include [Ir(dF(CF3)ppy)2(bpy)]PF6, [Ir(dF(CF3)ppy)2(dtbbpy)]PF6, 4-CzIPN, and Mes-Acr. + One of EosinY.

[0017] As a further preferred embodiment of the present invention, the molar ratio of the N-sulfonyl amino acid derivative, alkane bromide, base, crown ether, catalyst and photosensitizer is 1:(1.0-5.0):(1.0-5.0):(1.0-5.0):(0.001-0.1):(0.0001-0.1).

[0018] As a further preferred embodiment of the present invention, the organic solvent is one or more selected from trifluorotoluene, toluene, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, and acetonitrile.

[0019] As a further preferred embodiment of the present invention, the protective gas is nitrogen or an inert gas; preferably, the inert gas is argon.

[0020] As a further preferred embodiment of the present invention, the illumination is a visible light source with a wavelength of 400-500nm;

[0021] The selective coupling reaction is carried out at a temperature of 0-40℃ and for a time of 1-24h.

[0022] According to another aspect of the present invention, the present invention provides a method for preparing N-tert-butoxycarbonyl amino acid derivatives, characterized in that the method first prepares an α-alkyl amino acid derivative according to the above preparation method, then introduces a tert-butoxycarbonyl group onto the N atom of the α-alkyl amino acid derivative using ditert-butyl dicarbonate under the action of triethylamine and DMAP, and then removes the p-toluenesulfonyl group using elemental Mg in MeOH to obtain the N-tert-butoxycarbonyl amino acid derivative;

[0023] The process of introducing a tert-butyloxycarbonyl group onto the N atom of the α-position alkyl amino acid derivative using ditert-butyl dicarbonate under the action of triethylamine and DMAP is carried out at a temperature of 30-35°C.

[0024] The removal of the p-toluenesulfonyl group using elemental Mg in MeOH was carried out at a temperature of 0-35°C.

[0025] Compared with the prior art, the amino acid α-alkylation modification method of the present invention uses N-sulfonyl amino acid derivatives (such as N-sulfonyl glycine derivatives) as substrates and alkane bromides as alkylation subjects. Under the action of catalysts and photosensitizers, and under visible light irradiation (such as visible light with wavelengths of 400nm to 500nm; blue light with a wavelength of 450nm is used in the following examples), the amino acid derivatives are directly converted into α-alkyl amino acid derivatives.

[0026] Specifically, the present invention can achieve the following beneficial effects:

[0027] (1) The sulfonyl-protected amino acid derivatives (i.e., N-sulfonyl amino acid derivatives) used in the preparation process of this invention can be obtained from various amino acid esters containing amino residues through a one-step acylation reaction according to existing technology. Compared with aryl-protected amino acid derivatives and imine esters, it is more convenient to synthesize and the raw materials are more stable. In addition, the alkane bromides used are also widely available and easy to obtain.

[0028] (2) This invention achieves the activation of sulfonyl amino acid derivatives through a proton-coupled electron transfer process, which requires the participation of a base. However, for sulfonyl-protected amino acid derivatives, under alkaline conditions, the brominated derivatives will be activated via S... N The reaction proceeds in step 2, generating nitrogen-alkylated byproducts. This invention, through the addition of crown ethers, rationally controls the basicity of the reaction, ensuring both high activation efficiency of the amino acid derivatives and significantly inhibiting S... N 2. The occurrence of side reactions. In particular, this invention can use potassium carbonate, cesium carbonate, tripotassium phosphate, potassium fluoride, and cesium fluoride as bases to participate in the reaction, and in conjunction with other reaction participants such as crown ethers, it is more conducive to the progress of the target reaction.

[0029] (3) Based on the α-alkyl amino acid derivatives obtained by the method of this invention, N-tert-butoxycarbonyl amino acid derivatives can be further prepared (that is, N-sulfonyl amino acid derivatives can be used as the starting material to ultimately prepare N-tert-butoxycarbonyl amino acid derivatives). Compared with sulfonyl protecting groups, tert-butoxycarbonyl can be easily removed under acidic conditions, and the reaction products do not bring about other side reactions, which is more conducive to actual processing and has high added value. Detailed Implementation

[0030] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention. Furthermore, the technical features involved in the various embodiments of this invention described below can be combined with each other as long as they do not conflict with each other.

[0031] The method for preparing the α-alkyl amino acid derivative in this invention can be as follows: under protective gas conditions (such as nitrogen or inert gases such as argon), N-sulfonyl amino acid derivatives and alkane bromides are added to an organic solvent, and then a catalyst and a photoinitiator (i.e., photosensitizer) are added to undergo a selective coupling reaction to obtain the α-alkyl amino acid derivative.

[0032] Taking a transition metal salt and ligand as examples, the synthetic route of the present invention can be exemplarily described as follows:

[0033]

[0034] In the formula, R 1 Selected from OR 5 NR 6 R 7 substituted or unsubstituted aryl or polypeptide residues, wherein R 5 R 6 and R 7 C1-C20 alkanes; R 2 Selected from C1-C20 alkanes, alkenes, substituted or unsubstituted aromatics; R 3 Selected from H, C1-C20 alkanes, cycloalkanes, or C1-C20 alkane groups containing nitrogen and / or oxygen atoms; R 4 Selected from C1-C20 alkanes, cycloalkanes, or C1-C20 alkane groups containing nitrogen and / or oxygen atoms.

[0035] Furthermore, the α-alkyl amino acid derivative obtained by the above preparation method, as shown in Formula III, can be used to prepare N-tert-butoxycarbonyl amino acid derivatives. Specifically, in the presence of triethylamine and DMAP, ditert-tert-butyl dicarbonate can be used to introduce the tert-butoxycarbonyl group onto the N atom of the α-alkyl amino acid derivative product. Subsequently, the p-toluenesulfonyl group is successfully removed using elemental Mg (such as Mg scrap) in MeOH to obtain the N-tert-butoxycarbonyl amino acid derivative. The reaction formula can be as follows:

[0036]

[0037] The following are specific examples:

[0038] Example 1

[0039] In a nitrogen atmosphere, photosensitizers [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (0.001 mmol, 1.0 mg), Pd(PPh3)4 (0.001 mmol, 1.2 mg), N-(p-toluenesulfonyl)glycine ethyl ester (0.1 mmol, 25.7 mg), 18-crown-6 (0.2 mmol, 52 mg), KF (0.3 mmol, 17.4 mg), acetonitrile (2.0 mL), and 1-bromo-2-methylpropane (0.2 mmol, 22 μL) were added to a reaction tube containing a magnetic stirrer. The reaction tube was stirred for 12 h at 5 °C under irradiation with a 6 W blue LED (450 nm). After the reaction was completed, the reaction was quenched with saturated NH4Cl aqueous solution. The aqueous phase was extracted with EtOAc (2 mL × 3), dried over anhydrous sodium sulfate, and then evaporated to dryness. The crude product was purified by rapid column chromatography to obtain product 1 in 24% yield (the specific structural formula of product 1 is shown below; the same applies below). The NMR data of the product are as follows:

[0040] 1 H NMR (400MHz, CDCl3) δ7.75–7.68(m,2H),7.31–7.24(m,2H),5.01(d,J=10.1Hz,1H),3.95–3.81(m, 3H),2.40(s,3H),1.88–1.73(m,1H),1.53–1.40(m,2H),1.07(t,J=7.1Hz,3H),0.93–0.86(m,6H); 13 C NMR (100MHz, CDCl3) δ172.30,143.58,136.69,129.54,127.35,61.45,54.39,42.44,24.27,22.74,21.48,21.40,13.85.

[0041] Example 2

[0042] The method was the same as in Example 1, using N-(p-toluenesulfonyl)glycine ethyl ester and 1-bromo-2,2-dimethylpropane (that is, only the 0.2 mmol of 1-bromo-2-methylpropane in Example 1 was replaced with 0.2 mmol of 1-bromo-2,2-dimethylpropane, while all other reaction parameters and conditions remained unchanged), yielding product 2 in 29% yield. The NMR data of the product are as follows:

[0043] 1H NMR (400MHz, CDCl3) δ7.74–7.67(m,2H),7.30–7.24(m,2H),4.94(d,J=10.8Hz,1H),3.96(ddd,J=10.8,8. 6,4.1Hz,1H),3.78(q,J=7.1Hz,2H),2.40(s,3H),1.56–1.39(m,2H),1.04(t,J=7.1Hz,3H),0.96(s,9H); 13 C10 NMR (100MHz, CDCl3) δ 172.6, 143.6, 136.6, 129.5, 127.4, 61.4, 53.8, 46.8, 30.8, 29.6, 21.5, 13.7; High-resolution mass spectrometry [ESI]: Calculated values ​​are C10, 143.6, 136.6, 129.5, 127.4, 61.4, 53.8, 46.8, 30.8, 29.6, 21.5, 13.7; 16 H 26 NO4S + [M+H] + 328.1577, the actual measured value is 328.1574.

[0044] Example 3

[0045] The method was the same as in Example 1, using N-(p-toluenesulfonyl)glycine ethyl ester and bromomethylcyclopropane (that is, only the 0.2 mmol of 1-bromo-2-methylpropane in Example 1 was replaced with 0.2 mmol of bromomethylcyclopropane, while all other reaction parameters and conditions remained unchanged), yielding product 3 in 28% yield. The NMR data of the product are as follows:

[0046] 1 H NMR (400MHz, CDCl3)7.71(d,J=8.2Hz,2H),7.28(d,J=8.2Hz,2H),5.73(ddt,J=16.9,10.2,6.6Hz,1H),5.15(d,J=9.3H z,1H),5.04–4.97(m,2H),3.97–3.84(m,3H),2.41(s,3H),2.18–2.08(m,2H),1.88–1.62(m,2H),1.09(t,J=7.2Hz,3H); 13 C10 NMR (100MHz, CDCl3) δ 171.7, 143.6, 136.6, 129.6, 127.3, 116.0, 61.7, 55.2, 32.7, 29.0, 21.5, 13.9 High-resolution mass spectrometry [ESI]: Calculated values ​​are C10 NMR. 15 H 22 NO4S + [M+H] + 312.1264, the actual measured value is 312.1261.

[0047] Example 4

[0048] The method was the same as in Example 1, using N-(p-toluenesulfonyl)glycine ethyl ester and bromomethylcyclohexane (that is, only the 0.2 mmol of 1-bromo-2-methylpropane in Example 1 was replaced with 0.2 mmol of bromomethylcyclohexane, while all other reaction parameters and conditions remained unchanged), yielding product 4 in 30% yield. The NMR data of the product are as follows:

[0049] 1 H NMR (400MHz, CDCl3) δ7.72(d,J=8.0Hz,2H),7.28(d,J=7.9Hz,2H),4.99(d,J=10.0Hz,1H),3.97–3. 83(m,3H),2.41(s,3H),1.69–1.56(m,6H),1.47–1.39(m,3H),1.27–1.03(m,6H),0.96–0.73(m,2H); 13 C10 NMR (100MHz, CDCl3) δ 172.4, 143.6, 136.7, 129.5, 127.4, 61.4, 53.7, 41.0, 33.44, 33.40, 32.1, 26.3, 26.1, 25.9, 21.5, 13.9; High-resolution mass spectrometry [ESI]: Calculated values ​​are C10 NMR (100MHz, CDCl3) δ 172.4, 143.6, 136.7, 129.5, 127.4, 61.4, 53.7, 41.0, 33.44, 33.40, 32.1, 26.3, 26.1, 25.9, 21.5, 13. 18 H 28 NO4S + [M+H] + 354.1734, the actual measured value is 354.1730.

[0050] Example 5

[0051] In a nitrogen atmosphere, photosensitizers [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (0.001 mmol, 1.0 mg), Pd(PPh3)4 (0.001 mmol, 1.2 mg), N-(p-toluenesulfonyl)glycine ethyl ester (0.1 mmol, 25.7 mg), 18-crown-6 (0.2 mmol, 52 mg), K2CO3 (0.1 mmol, 13.8 mg), and KF (0.2 mmol, 11.6 mg), along with acetonitrile (2.0 mL) and 2-bromopropane (0.2 mmol, 18.7 μL), were added to a reaction tube containing a magnetic stirrer. The reaction tube was stirred for 5 hours at room temperature under irradiation with a 6W blue LED (450 nm). After the reaction was complete, the reaction was quenched with saturated NH4Cl aqueous solution. The aqueous phase was extracted with EtOAc (2 mL × 3), dried over anhydrous sodium sulfate, and then evaporated to dryness. The crude product was purified by rapid column chromatography to obtain product 5. The yield was 31%. The NMR data of the product are as follows:

[0052] 1 H NMR (400MHz, CDCl3) δ7.74–7.67(m,2H),7.30–7.26(m,2H),5.09(d,J=10.1Hz,1H),3.94–3.82(m,2H),3.70(dd,J=1 0.1,5.0Hz,1H),2.40(s,3H),2.09–1.96(m,1H),1.06(t,J=7.1Hz,3H),0.96(d,J=6.9Hz,3H),0.86(d,J=6.9Hz,3H); 13 C NMR (100MHz, CDCl3) δ171.28,143.53,136.68,129.52,127.33,61.37,60.99,31.66,21.47,18.93,17.34,13.91.

[0053] Example 6

[0054] The method was the same as in Example 5, using N-(p-toluenesulfonyl)glycine ethyl ester and 2-bromobutane (that is, only the 0.2 mmol of 2-bromopropane in Example 5 was replaced with 0.2 mmol of 2-bromobutane, while all other reaction parameters and conditions remained unchanged), yielding product 6 in 32% yield. The NMR data of the product are as follows:

[0055] 1¹H NMR (400MHz, CDCl₃) δ 7.74–7.67 (m, 2H), 7.30–7.24 (m, 2H), 5.12 (d, J = 10.0 Hz, 1H, isomer 1), 5.07 (d, J = 10.3 Hz, 1H, isomer 2), 3.93–3.71 (m, 3H), 2.40 (s, 3H), 1.82–1.70 (m, 1H), 1.55–1.34 (m, 2H), 1.32–1.09 (m, 1H), 1.11–0.99 (m, 3H), 0.94–0.77 (m, 6H); High-resolution mass spectrometry [ESI]: calculated value C 15 H 24 NO4S + [M+H] + 314.1421, the actual measured value is 314.1419.

[0056] Example 7

[0057] The method was the same as in Example 5, using N-(p-toluenesulfonyl)glycine ethyl ester and 2-bromopentane (that is, only the 0.2 mmol of 2-bromopropane in Example 5 was replaced with 0.2 mmol of 2-bromopentane, while all other reaction parameters and conditions remained unchanged), yielding product 7 in 32% yield. The NMR data of the product are as follows:

[0058] 1 H NMR (400MHz, CDCl3) δ7.71(d,J=8.2Hz,2H),7.27(d,J=8.2Hz,2H),5.03(d,J=10.1Hz,1H),3.96–3.82(m,3H),2.40(s,3H),1 .57–1.47(m,1H),1.41–1.31(m,2H),1.31–1.18(m,2H),1.06(t,J=7.1Hz,3H),0.90(t,J=7.3Hz,3H),0.85(t,J=7.3Hz,3H); 13 C10 NMR (100MHz, CDCl3) δ 171.8, 143.5, 136.7, 129.5, 127.4, 61.4, 57.4, 45.1, 22.2, 21.7, 21.5, 13.9, 11.4, 11.3; High-resolution mass spectrometry [ESI]: Calculated values ​​are C10, 143.5, 136.7, 129.5, 127.4, 61.4, 57.4, 45.1, 22.2, 21.7, 21.5, 13.9, 11.4, 11.3; 16 H 26 NO4S + [M+H] + 328.1577, the actual measured value is 328.1574.

[0059] Example 8

[0060] The method was the same as in Example 5, using N-(p-toluenesulfonyl)glycine ethyl ester and (3-bromobutyl)benzene (that is, only the 0.2 mmol of 2-bromopropane in Example 5 was replaced with 0.1 mmol of (3-bromobutyl)benzene, while all other reaction parameters and conditions remained unchanged), yielding product 8 in 42% yield. The NMR data of the product are as follows:

[0061] 1 H NMR (400MHz, CDCl3) δ7.79–7.68(m,2H),7.33–7.25(m,4H),7.22–7.17(m,2H),7.16–7.10(m,1H),5.22(d,J=6.2Hz,1H,isomer 1),5.19(d,J=6.2Hz,1H,isomer 2),4.01–3.78(m,3H),2.77–2.47(m,2H),2.02–1.41(m,3H),1.07(t,J=7.1Hz,3H,isomer 1),1.05(t,J=7.2Hz,3H,isomer 2),1.01(d,J=6.8Hz,3H,isomer 1),0.87(d,J=6.9Hz,3H,isomer 2); 13 C NMR (100MHz, CDCl3) δ171.3(isomer 1), 171.0(isomer 2), 143.55(isomer1), 143.51(isomer 2), 141.8(isomer 1), 141.6(isomer 2), 136.62(isomer 1), 136.59(isomer 2),129.5,128.4(isomer 1),128.3(isomer 2),128.3,127.30(isomer 1),127.27(isomer 2),125.8(isomer 1),125.7(isomer 2),61.5(isomer 1),61.4(isomer2),60.3(isomer 1),58.8(isomer 2),36.0(isomer 1),35.8(isomer 2), 34.9 (isomer 1), 33.4 (isomer 2), 33.0 (isomer 1), 32.8 (isomer 2), 21.4, 15.8, 14.5, 13.9 (isomer 1), 13.8 (isomer 2); High-resolution mass spectrometry [ESI]: calculated value C 21 H 28 NO4S +[M+H] + 390.1734, the actual measured value is 390.1730.

[0062] Example 9

[0063] The method was the same as in Example 5, using N-(p-toluenesulfonyl)glycine ethyl ester and bromocyclobutane (that is, only the 0.2 mmol of 2-bromopropane in Example 5 was replaced with 0.2 mmol of bromocyclobutane, while all other reaction parameters and conditions remained unchanged), yielding product 9 in 25% yield. The NMR data of the product are as follows:

[0064] 1 H NMR (400MHz, CDCl3) δ7.74–7.68(m,2H),7.31–7.24(m,2H),5.08(d,J=10.0Hz,1H),3.91–3.82(m,2H),3.78(dd, J=10.0,7.6Hz,1H),2.60–2.46(m,1H),2.40(s,3H),2.05–1.88(m,3H),1.88–1.75(m,3H),1.05(t,J=7.1Hz,3H); 13 C10 NMR (100MHz, CDCl3) δ 171.0, 143.6, 136.8, 129.5, 127.3, 61.3, 59.3, 38.0, 24.4, 21.5, 17.7, 13.9; High-resolution mass spectrometry [ESI]: Calculated values ​​are C10 NMR values. 15 H 22 NO4S + [M+H] + 312.1264, the actual measured value is 312.1261.

[0065] Example 10

[0066] The method was the same as in Example 5, using N-(p-toluenesulfonyl)glycine ethyl ester and bromocyclopentane (that is, only the 0.2 mmol of 2-bromopropane in Example 5 was replaced with 0.5 mmol of bromocyclopentane, while all other reaction parameters and conditions remained unchanged), yielding product 10 in 71% yield. The NMR data of the product are as follows:

[0067] 1H NMR (400MHz, CDCl3) δ7.73–7.67(m,2H),7.30–7.26(m,2H),5.11(d,J=10.2Hz,1H),3.91–3.78(m,2H),3.74(dd,J =10.2,6.9Hz,1H),2.40(s,3H),2.18–2.06(m,1H),1.69–1.55(m,4H),1.56–1.23(m,4H),1.05(t,J=7.1Hz,3H).; 13 C NMR(100MHz, CDCl3)δ171.7,143.5,136.7,129.5,127.4,61.3,59.0,42.8,28.7,28.3,25.3,25.0,21.5,13.9; HRMS(ESI,m / z):calcd for C 15 H 22 NO4S + [M+H] + 312.1264, found 312.1261; High-resolution mass spectrometry [ESI]: calculated value is C 16 H 24 NO4S + [M+H] + 326.1421, actual measured value is 326.1419.

[0068] Example 11

[0069] The method was the same as in Example 5, using N-(p-toluenesulfonyl)glycine ethyl ester and bromocyclohexane (that is, only the 0.2 mmol of 2-bromopropane in Example 5 was replaced with 0.2 mmol of bromocyclohexane, while all other reaction parameters and conditions remained unchanged), yielding product 11 in 40% yield. The NMR data of the product are as follows:

[0070] 1 H NMR (400MHz, CDCl3) δ7.69(d,J=8.2Hz,2H),7.26(d,J=8.2Hz,2H),5.09(d,J=10.1Hz,1H),3.86(q,J=7.2H z,2H),3.68(dd,J=10.1,5.3Hz,1H),2.40(s,3H),1.78–1.52(m,6H),1.26–1.10(m,4H),1.09–0.94(m,4H); 13C10 NMR (100MHz, CDCl3) δ 171.2, 143.5, 136.7, 129.5, 127.3, 61.3, 60.7, 41.1, 29.3, 27.9, 25.8, 25.8, 25.8, 21.5, 13.9; High-resolution mass spectrometry [ESI]: Calculated values ​​are C10 NMR, 143.5, 136.7, 129.5, 127.3, 61.3, 60.7, 41.1, 29.3, 27.9, 25.8, 25.8, 25.8, 21.5, 13.9; 17 H 26 NO4S + [M+H] + 340.1577, the actual measured value is 340.1577.

[0071] Example 12

[0072] The method was the same as in Example 5, using N-(p-toluenesulfonyl)glycine ethyl ester and bromocycloheptane (that is, only the 0.2 mmol of 2-bromopropane in Example 5 was replaced with 0.2 mmol of bromocycloheptane, while all other reaction parameters and conditions remained unchanged), yielding product 12 in 62% yield. The NMR data of the product are as follows:

[0073] 1 H NMR (400MHz, CDCl3) δ7.69(d,J=8.0Hz,2H),7.26(d,J=8.2Hz,2H),5.16–5.08(m,1H),3.85(q,J=7.1Hz,2H),3.74(d d,J=10.1,4.9Hz,1H),2.40(s,3H),1.88–1.78(m,1H),1.73–1.60(m,3H),1.59–1.19(m,9H),1.05(t,J=7.1Hz,3H); 13 C10 NMR (100MHz, CDCl3) δ 171.3, 143.5, 136.7, 129.5, 127.3, 61.3, 42.7, 31.1, 29.0, 28.1, 27.7, 26.3, 26.3, 21.5, 13.9; High-resolution mass spectrometry [ESI]: Calculated values ​​are C10 NMR (100MHz, CDCl3) δ 171.3, 143.5, 136.7, 129.5, 127.3, 61.3, 42.7, 31.1, 29.0, 28.1, 27.7, 26.3, 26.3, 21.5, 13.9; High-resolution mass spectrometry [ESI]: Calc 18 H 28 NO4S + [M+H] + 354.1734, the actual measured value is 354.1731.

[0074] Example 13

[0075] The method was the same as in Example 5, using N-(p-toluenesulfonyl)glycine ethyl ester and (1S,2R,4R)-2-bromo-1-isopropyl-4-methylcyclohexane (that is, only the 0.2 mmol of 2-bromopropane in Example 5 was replaced with 0.2 mmol of (1S,2R,4R)-2-bromo-1-isopropyl-4-methylcyclohexane, while all other reaction parameters and conditions remained unchanged), yielding product 13 in 45% yield. The NMR data of the product are as follows:

[0076] 1 H NMR (400MHz, CDCl3) δ7.74–7.68(m,2H),7.30–7.25(m,2H),5.34(d,J=8.6Hz,1H,isomer 1),4.94(d,J=10.6Hz,1H,isomer 2),4.20–4.06(m,1H),4.01–3.73(m,2H),2.40(d,J=1.8Hz,3H),2.09–1.94(m,1H),1.74–1.64(m,2H),1.33–0.68(m,19H).

[0077] Example 14

[0078] The method was the same as in Example 5, with the starting materials being N-(p-toluenesulfonyl)glycine ethyl ester and 4-bromotetrahydrofuran (that is, only the 0.2 mmol of 2-bromopropane in Example 5 was replaced with 0.2 mmol of 4-bromotetrahydrofuran, while the other reaction parameters and conditions remained unchanged), yielding the corresponding product 14 in a yield of 35%.

[0079] Example 15

[0080] The method was the same as in Example 5, with N-(p-toluenesulfonyl)glycine ethyl ester and tert-butyl 4-bromopiperidine-1-carboxylate as the starting materials (that is, only the 0.2 mmol of 2-bromopropane in Example 5 was replaced with 0.2 mmol of tert-butyl 4-bromopiperidine-1-carboxylate, while other reaction parameters and conditions remained unchanged), yielding the corresponding product 15 in 40% yield.

[0081] Example 16

[0082] The method was the same as in Example 5, using N-(p-toluenesulfonyl)glycine ethyl ester and tert-butane bromide (that is, only the 0.2 mmol of 2-bromopropane in Example 5 was replaced with 0.2 mmol of tert-butane bromide, while all other reaction parameters and conditions remained unchanged), yielding product 16 in 60% yield. The NMR data of the product are as follows:

[0083] 1H NMR (400MHz, CDCl3) δ7.72–7.66(m,2H),7.29–7.23(m,2H),5.16(d,J=10.7Hz,1H),3.8 5–3.65(m,2H),3.52(d,J=10.7Hz,1H),2.39(s,3H),1.02(t,J=7.2Hz,3H),0.94(s,9H).

[0084] Example 17

[0085] The method was the same as in Example 5, using N-(p-toluenesulfonyl)glycine ethyl ester and 2-bromo-2,5-dimethylhexane (that is, only the 0.2 mmol of 2-bromopropane in Example 5 was replaced with 0.2 mmol of 2-bromo-2,5-dimethylhexane, while all other reaction parameters and conditions remained unchanged), yielding product 17 in 63% yield. The NMR data of the product are as follows:

[0086] 1 H NMR (400MHz, CDCl3) δ7.70(d,J=8.1Hz,2H),7.27(d,J=8.1Hz,2H),5.07(d,J=10.9Hz,1H),3.85–3.65(m,2H),3.62(d,J=10.9Hz,1 H),2.40(s,3H),1.48–1.34(m,1H),1.34–1.18(m,2H),1.18–1.09(m,2H),1.04(t,J=7.1Hz,3H),0.91(s,3H),0.87–0.82(m,9H).; 13 C10 NMR (100MHz, CDCl3) δ 171.0, 143.5, 136.5, 129.5, 127.5, 62.8, 61.0, 37.1, 36.8, 32.3, 28.6, 23.5, 23.4, 22.6, 22.6, 21.5, 13.8; High-resolution mass spectrometry [ESI]: Calculated values ​​are C10 NMR (100MHz, CDCl3) δ 171.0, 143.5, 136.5, 129.5, 127.5, 62.8, 61.0, 37.1, 36.8, 32.3, 28.6, 23.5, 23.4, 22.6, 22.6, 2 19 H 32 NO4S + [M+H] + 370.2047, the actual measured value is 370.2045.

[0087] Example 18

[0088] The method was the same as in Example 5, using N-(p-toluenesulfonyl)glycine ethyl ester and (3-bromo-3-methylbutyl)cyclohexane (that is, only the 0.2 mmol of 2-bromopropane in Example 5 was replaced with 0.2 mmol of (3-bromo-3-methylbutyl)cyclohexane, while all other reaction parameters and conditions remained unchanged), yielding product 18 in 63% yield. The NMR data of the product are as follows:

[0089] 1 H NMR (400MHz, CDCl3) δ7.70(d,J=8.2Hz,2H),7.27(d,J=8.2Hz,2H),5.09(d,J=10.9Hz,1H),3. 85–3.65(m,2H),3.62(d,J=10.9Hz,1H),2.40(s,3H),1.34–0.99(m,15H),0.92–0.78(m,9H); 13 C10 NMR (100MHz, CDCl3) δ 171.0, 143.5, 136.5, 129.5, 127.5, 62.8, 61.0, 38.3, 37.1, 36.3, 33.4, 30.9, 26.6, 26.4, 23.5, 23.3, 21.4, 13.8; High-resolution mass spectrometry [ESI]: Calculated values ​​are C10 NMR (100MHz, CDCl3) δ 171.0, 143.5, 136.5, 129.5, 127.5, 62.8, 61.0, 38.3, 37.1, 36.3, 33.4, 30.9, 26.6, 26.4, 2 22 H 36 NO4S + [M+H] + 410.2360, the actual measured value is 410.2360.

[0090] Example 19

[0091] The method was the same as in Example 5, using N-(p-toluenesulfonyl)glycine ethyl ester and (3-bromo-3-methylbutyl)benzene (that is, only the 0.2 mmol of 2-bromopropane in Example 5 was replaced with 0.2 mmol of (3-bromo-3-methylbutyl)benzene, while all other reaction parameters and conditions remained unchanged), yielding product 19 in 62% yield. The NMR data of the product are as follows:

[0092] 1H NMR(400MHz, CDCl3)δ7.71(d,J=8.0Hz,2H),7.30–7.22(m,4H),7.20–7.13(m,3H),5.19–5.11(m,1H),3.86–3.66(m,3H),2.70–2.5 0(m,2H),2.40(s,3H),1.68(td,J=13.1,5.1Hz,1H),1.52(td,J=13.1,5.1Hz,1H),1.03(t,J=7.2Hz,3H),0.99(s,3H),0.97(s,3H); 13 C10 NMR (100MHz, CDCl3) δ 170.8, 143.6, 142.3, 136.4, 129.5, 128.3, 128.3, 127.5, 125.7, 62.4, 61.1, 41.4, 37.3, 30.0, 23.7, 23.5, 21.5, 13.8; High-resolution mass spectrometry [ESI]: Calculated values ​​are C10 and C20. 22 H 30 NO4S + [M+H] + 404.1890, the actual measured value is 404.1886.

[0093] Example 20

[0094] The method was the same as in Example 5, using N-(p-toluenesulfonyl)glycine ethyl ester and 3-bromo-3-methylbutyl4-methylbenzenesulfonate as the starting materials (i.e., only the 0.2 mmol of 2-bromopropane in Example 5 was replaced with 0.2 mmol of 3-bromo-3-methylbutyl4-methylbenzenesulfonate, while all other reaction parameters and conditions remained unchanged), yielding product 20 in 63% yield. The NMR data of the product are as follows:

[0095] 1 H NMR (400MHz, CDCl3) δ7.74(d,J=8.1Hz,2H),7.30(d,J=8.1Hz,2H),4.15(p,J=7.0Hz,2H),3.83(s,1H),3.60–3. 52(m,1H),3.37–3.26(m,1H),2.42(s,3H),1.59–1.49(m,2H),1.26(t,J=7.1Hz,3H),0.98(s,3H),0.82(s,3H); 13C10 NMR (100MHz, CDCl3) δ 171.1, 143.4, 135.3, 129.5, 127.3, 69.9, 61.0, 46.4, 42.7, 38.0, 27.1, 23.3, 21.5, 14.2; High-resolution mass spectrometry [ESI]: Calculated values ​​are C10 NMR (100MHz, CDCl3) δ 171.1, 143.4, 135.3, 129.5, 127.3, 69.9, 61.0, 46.4, 42.7, 38.0, 27.1, 23.3, 21.5, 14.2; 16 H 24 NO4S + [M+H] + 326.1421, the actual measured value is 326.1419.

[0096] Example 21

[0097] The method was the same as in Example 5, using N-(p-toluenesulfonyl)cyclopropylglycine methyl ester and tert-butane bromide (that is, only the 0.1 mmol of N-(p-toluenesulfonyl)glycine ethyl ester in Example 5 was replaced with 0.1 mmol of N-(p-toluenesulfonyl)cyclopropylglycine methyl ester, and the 0.2 mmol of 2-bromopropane was replaced with 0.2 mmol of tert-butane bromide, while other reaction parameters and conditions remained unchanged), yielding product 21 in 31% yield. The NMR data of the product are as follows:

[0098] 1 H NMR (400MHz, CDCl3) δ7.78(d,J=8.0Hz,2H),7.25(d,J=8.2Hz,2H),5.33(s,1H),3.62(s,3H),2.55–2.45(m,1H),2.40(s ,3H),1.80–1.69(m,1H),1.65–1.32(m,6H),1.30–1.18(m,1H),0.71–0.60(m,1H),0.45–0.34(m,1H),0.23–0.04(m,2H); 13 C10 NMR (100MHz, CDCl3) δ 171.9, 142.8, 140.0, 129.1, 127.1, 68.8, 52.2, 48.0, 27.5, 27.2, 25.32, 25.28, 21.5, 15.2, 4.1, 3.3; High-resolution mass spectrometry [ESI]: Calculated values ​​are C10 NMR (100MHz, CDCl3) δ 171.9, 142.8, 140.0, 129.1, 127.1, 68.8, 52.2, 48.0, 27.5, 27.2, 25.32, 25.28, 21.5, 15.2, 4.1, 3.3; High- 19 H 28 NO4S + [M+H] + 366.1734, the actual measured value is 366.1734.

[0099] Example 22

[0100] The method was the same as in Example 5, using N-(p-toluenesulfonyl)alanine methyl ester and tert-butane bromide (that is, only the 0.1 mmol of N-(p-toluenesulfonyl)glycine ethyl ester in Example 5 was replaced with 0.1 mmol of N-(p-toluenesulfonyl)alanine methyl ester, and the 0.2 mmol of 2-bromopropane was replaced with 0.2 mmol of tert-butane bromide, while other reaction parameters and conditions remained unchanged), yielding product 22 in 45% yield. The NMR data of the product are as follows:

[0101] 1 H NMR (400MHz, CDCl3) δ7.73(d,J=7.8Hz,2H),7.27(d,J=7.8Hz,2H),5.27(s,1H),3.60(s,3H),2.41(s,3H),1.34(s,3H),0.94(s,9H). 13 C NMR (100MHz, CDCl3) δ173.37,143.21,138.99,129.42,127.25,66.97,52.14,37.88,25.16,21.47,15.91.

[0102] Example 23

[0103] The method was the same as in Example 5, with the starting materials being methyl O-(tert-butyldimethylsilyl)-N-tosylserinate and tert-butane bromide (that is, only the 0.1 mmol N-(p-toluenesulfonyl)glycine ethyl ester in Example 5 was replaced with 0.1 mmol methyl O-(tert-butyldimethylsilyl)-N-tosylserinate, and the 0.2 mmol 2-bromopropane was replaced with 0.2 mmol tert-butane bromide, while other reaction parameters and conditions remained unchanged), yielding the corresponding product 23 in 41% yield. The NMR data of the product are as follows:

[0104] 1 H NMR (400MHz, CDCl3) δ7.80–7.73(m,2H),7.29–7.22(m,2H),5.18(s,1H),4.23(dd,J= 73.1,10.6Hz,2H),3.56(s,3H),2.40(s,3H),1.03(s,9H),0.86(s,9H),0.02(s,6H); 13C NMR (100MHz, CDCl3) δ170.95,142.15,140.92,128.98,126.14,72.79,62.33,51.64,38.20,26.73,25.88,21.42,18.30,-5.67,-5.80.

[0105] Example 24

[0106] The method was the same as in Example 5, with the starting materials being N-(p-toluenesulfonyl)isopropylglycine methyl ester and tert-butane bromide (that is, only the 0.1 mmol of N-(p-toluenesulfonyl)glycine ethyl ester in Example 5 was replaced with 0.1 mmol of N-(p-toluenesulfonyl)isopropylglycine methyl ester, and the 0.2 mmol of 2-bromopropane was replaced with 0.2 mmol of tert-butane bromide, while other reaction parameters and conditions remained unchanged), yielding the corresponding product 24 in 43% yield.

[0107] Example 25

[0108] The method is the same as in Example 5, and the raw material is methyl N. 6 -(tert-butoxycarbonyl)-N 2 -tosyllysinate and tert-butane bromide (that is, simply replacing 0.1 mmol of N-(p-toluenesulfonyl)glycine ethyl ester in Example 5 with 0.1 mmol of methyl N- 6 -(tert-butoxycarbonyl)-N 2 -tosyllysinate, replacing 0.2 mmol of 2-bromopropane with 0.2 mmol of tert-butane bromide, while keeping other reaction parameters and conditions unchanged, yielded the corresponding product 25 in 11% yield.

[0109] Example 26

[0110] The method was the same as in Example 5, using N-(p-toluenesulfonyl)glycylglycine ethyl ester and tert-butane bromide (that is, only the 0.1 mmol of N-(p-toluenesulfonyl)glycine ethyl ester in Example 5 was replaced with 0.1 mmol of N-(p-toluenesulfonyl)glycylglycine ethyl ester, and the 0.2 mmol of 2-bromopropane was replaced with 0.2 mmol of tert-butane bromide, while other reaction parameters and conditions remained unchanged), yielding product 26 in 50% yield. The NMR data of the product are as follows:

[0111] 1H NMR (400MHz, CDCl3) δ7.69(d,J=8.0Hz,2H),7.24(d,J=8.0Hz,2H),5.93–5.88(m,1H),5.39(d,J=8.8Hz,1H),4.19(q,J=7.1Hz,2H ),3.81(dd,J=18.4,5.2Hz,1H),3.49(dd,J=18.4,4.7Hz,1H),3.37–3.30(m,1H),2.38(s,3H),1.27(t,J=7.2Hz,3H),0.96(s,9H); 13 C10 NMR (100MHz, CDCl3) δ 169.6, 169.2, 143.4, 136.5, 129.7, 127.5, 65.1, 61.7, 41.2, 34.5, 26.4, 21.5, 14.1; High-resolution mass spectrometry [ESI]: Calculated values ​​are C10 NMR. 17 H 27 N2O5S + [M+H] + 371.1635, the actual measured value is 371.1633.

[0112] Example 27

[0113] The method was the same as in Example 5, using N-(p-toluenesulfonyl)glycylphenylalanine methyl ester and tert-butane bromide (that is, only the 0.1 mmol of N-(p-toluenesulfonyl)glycine ethyl ester in Example 5 was replaced with 0.1 mmol of N-(p-toluenesulfonyl)glycylphenylalanine methyl ester, and the 0.2 mmol of 2-bromopropane was replaced with 0.2 mmol of tert-butane bromide, while other reaction parameters and conditions remained unchanged), yielding product 27 in 49% yield. The NMR data of the product are as follows:

[0114] 1H NMR(400MHz,CDCl3)δ7.73(d,J=8.1Hz,2H,isomer 1),7.67(d,J=8.0Hz,2H,isomer 2),7.32–7.18(m,5H),7.08–7.02(m,2H,isomer 1),6.94–6.89(m,2H,isomer 2),6.08(dd,J=7.7,3.7Hz,1H,isomer 1),5.93(dt,J=9.6,4.7Hz,1H,isomer 2),5.68–5.51(m,1H,isomer 1),5.51–5.34(m,1H,isomer 2),4.63–4.54(m,1H,isomer 1),4.50–4.40(m,1H,isomer 2),3.69(s,3H,isomer 1),3.62(s,3H,isomer 2),3.34(ddd,J=8.9,3.6,1.5Hz,2H,isomer 1),2.98(d,J=6.2Hz,2H,isomer 2),2.87(dd,J=13.8,5.1Hz,1H,isomer 1),2.63(dd,J=13.8,6.5Hz,1H,isomer 2),2.36(s,3H,isomer 1),2.32(s,3H,isomer 2),0.92(s,9H,isomer 1),0.85(s,9H,isomer 2); 13C NMR (100MHz, CDCl3) δ171.4(isomer 1),171.3(isomer 2),169.1,143.6(isomer 1),143.3(isomer 2),137.0(isomer1),136.6(isomer 2),135.5(isomer 1),135.3(isomer 2),129.5(isomer 1),129.4(isomer 2),129.1(isomer 1),129.0(isomer2),128.7(isomer 1),128.5(isomer 2),127.4(isomer 1),127.39(isomer 2),127.32(isomer 1),127.27(isomer 2),65.2(isomer 1),64.8(isomer 2),53.2(isomer 1), 53.1 (isomer 2), 52.22 (isomer 1), 52.19 (isomer 2), 38.4 (isomer 1), 37.9 (isomer 2), 34.7 (isomer 1), 34.4 (isomer 2), 26.42 (isomer 1), 26.39 (isomer 2), 21.4; High-resolution mass spectrometry [ESI]: Calculated value C 23 H 31 N2O5S + [M+H] + 447.1948, the actual measured value is 447.1943.

[0115] Example 28

[0116] The method was the same as in Example 5, using N-(p-toluenesulfonyl)glycine methyl ester and tert-butane bromide (that is, only the 0.1 mmol of N-(p-toluenesulfonyl)glycine ethyl ester in Example 5 was replaced with 0.1 mmol of N-(p-toluenesulfonyl)glycine methyl ester, and the 0.2 mmol of 2-bromopropane was replaced with 0.2 mmol of tert-butane bromide, while other reaction parameters and conditions remained unchanged), yielding product 28 in 28% yield. The NMR data of the product are as follows:

[0117] 1H NMR(400MHz, CDCl3) δ7.73(d,J=8.0Hz,1H),7.66(d,J=8.0Hz,1H),7.29–7.23(m,1H),7.1 6(d,J=7.9Hz,1H),6.96(d,J=8.7Hz,1H),6.79–6.71(m,3H),6.14(d,J=6.6Hz,1H,isomer 1),5.87(d,J=11.1Hz,1H,isomer 2),5.59–5.47(m,1H),4.61-4.52(m,1H,isomer 1),4.51–4.41(m,1H,isomer 2),3.71(s,3H),3.64(s,3H),3.32(dd,J=8.9,2.5Hz,1H),2.95(qd,J=14.2,5.7Hz,1H),2.83(dd,J=13.9,5.0Hz,1H,isomer 1),2.57(dd,J=13.9,6.1Hz,1H,isomer 2),2.36(s,3H),2.33(s,3H),0.91(s,9H,isomer 1),0.85(s,9H,isomer 2); 13 C NMR (100MHz, CDCl3) δ 171.5, 169.2, 155.2, 143.7 (isomer 1), 143.5 (isomer 2), 136.9, 130.4 (isomer 1), 130.2 (isomer 2), 129.6 (isomer 1), 129.5 (isomer 2), 127.4 (isomer 1),127.3(isomer 2),127.0,115.58(isomer 1),115.63(isomer 2),65.4(isomer 1),64.9(isomer 2),53.2,52.3,37.6(isomer 1),37.1(isomer 2),34.8(isomer 1),34.4(isomer 2), 26.4, 21.5; High-resolution mass spectrometry [ESI]: calculated value is C 23 H 31 N2O6S + [M+H] + 463.1897, the actual measured value is 463.1894.

[0118] Example 29

[0119] The method was the same as in Example 5, using N-(p-toluenesulfonyl)glycine methyl ester and tert-butane bromide (that is, only the 0.1 mmol of N-(p-toluenesulfonyl)glycine ethyl ester in Example 5 was replaced with 0.1 mmol of N-(p-toluenesulfonyl)glycine methyl ester, and the 0.2 mmol of 2-bromopropane was replaced with 0.2 mmol of tert-butane bromide, while other reaction parameters and conditions remained unchanged), yielding product 29 in 24% yield. The NMR data of the product are as follows:

[0120] 1 H NMR(400MHz, CDCl3)δ8.32(s,1H,major),8.23(s,1H,minor),7.74–7.63(m,2H),7.52–7.41(m,2H),7.40–7.29(m,2H),7.24–7.06(m,4H+1H,isomer 1),6.94–6.89(m,1H,isomer 2),6.33–6.22(m,1H,major),6.00–5.91(m,1H,minor),5.61–5.49(m,1H),4.63–4. 55(m,1H),3.61(s,3H,major),3.58(s,3H,minor),3.36–3.25(m,1H+1H,minor),3.1 4(ddd,J=14.7,11.7,5.5Hz,1H,major+1H,major),2.87(dd,J=14.7,5.8Hz,1H,mino r),2.32(s,3H,major),2.29(s,3H,minor),0.89(s,9H,major),0.83(s,9H,minor); 13CNMR(100MHz, CDCl3)δ171.9(major),171.8(minor),169.23(isomer 1),169.16(isomer2),143.68(isomer 1),143.53(isomer 2),137.0,136.2,129.6,127.36,127.33,123.2(isomer 1),123.0(isomer 2),122.5(isomer 1),122.2(isomer2),119.9(isomer 1),119.6(isomer 2),118.5(major),118.3(minor),111.5(isomer 1),111.3(isomer 2),109.5,65.5(isomer 1),65.0(isomer 2), 52.7 (isomer 1), 52.5 (isomer 2), 52.3, 34.8 (isomer 1), 34.4 (isomer 2), 28.1 (major), 27.5 (minor), 26.47 (major), 26.43 (minor), 21.5; High-resolution mass spectrometry [ESI]: calculated value C 25 H 32 N3O5S + [M+H] + 486.2057, the actual measured value is 486.2054.

[0121] Example 30

[0122] The method was the same as in Example 5, with the starting materials being N-(p-toluenesulfonyl)glycylglutamic acid methyl ester and tert-butane bromide (that is, only the 0.1 mmol of N-(p-toluenesulfonyl)glycine ethyl ester in Example 5 was replaced with 0.1 mmol of N-(p-toluenesulfonyl)glycylglutamic acid methyl ester, and the 0.2 mmol of 2-bromopropane was replaced with 0.2 mmol of tert-butane bromide, while other reaction parameters and conditions remained unchanged), yielding the corresponding product 30 in a yield of 34%.

[0123] Example 31

[0124] The method was the same as in Example 5, using N-(p-toluenesulfonyl)glycine ethyl ester and (3R,8R,9S,10S,13R,14S,17R)-17-((R)-5-bromo-5-methylhexan-2-yl)-10,13-dim ethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate (that is, only the 0.2 mmol of 2-bromopropane in Example 5 was replaced with 0.2 mmol of (3R,8R,9S,10S,13R,14S,17R)-17-((R)-5-bromo-5-methylhexan-2-yl)-10,13-dim ethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate, while other reaction parameters and conditions remained unchanged), yielding the corresponding product 31 in 42% yield. The NMR data of the product are as follows:

[0125] 1 H NMR (400MHz, CDCl3) δ7.69 (d, J = 7.9 Hz, 2H), 7.26 (d, J = 8.3 Hz, 2H), 5.10 (dd, J = 10. 8,2.9Hz,1H),4.77–4.64(m,1H),3.81–3.57(m,3H),2.39(s,3H),2.02(s,3H),1.9 8–1.91(m,1H),1.89–1.76(m,4H),1.71–1.63(m,1H),1.60–1.49(m,2H),1.45–1.2 9(m,9H),1.27–1.19(m,4H),1.19–0.94(m,10H),0.93–0.73(m,13H),0.62(s,3H).; 13C NMR (100MHz, CDCl3) δ170.9,170.6,143.5,136.6,129.4,127.5,74.4,63.1(isomer 1),62.9(isomer2),60.9,56.49(isomer 1),56.46(isomer 1),56.1(isomer 1),56.0(isomer 2),42.6,41.9,40.4,40.12(isomer 1),40.09(isomer 2),37.2(isomer 1),37.1(isomer 2),36.2(isomer 1),36.1(isomer 2),35.8,35.30(isomer 1),35.21(isomer 2), 35.0, 34.5, 32.2, 29.13 (isomer 1), 29.08 (isomer 2), 28.20 (isomer 1), 28.16 (isomer 2), 27.0, 26.6, 26.3, 24.2, 23.5, 23.40 (isomer 1), 23.35 (isomer 1), 23.3, 21.4, 20.8, 18.64 (isomer 1), 18.62 (isomer 2), 13.8, 13.8, 12.0; High-resolution mass spectrometry [ESI]: calculated value C 39 H 62 NO6S + [M+H] + 672.4292, the actual measured value is 672.4290.

[0126] Example 32

[0127] The method was the same as in Example 5, using N-(p-toluenesulfonyl)glycine ethyl ester and (3aR,5R,6aS)-6-bromo-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole (that is, only the 0.2 mmol of 2-bromopropane in Example 5 was replaced with 0.2 mmol of (3aR,5R,6aS)-6-bromo-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole, while other reaction parameters and conditions remained unchanged), yielding the corresponding product 32 in 35% yield.

[0128] Example 33

[0129] The method was the same as in Example 5, using N-(p-toluenesulfonyl)glycine ethyl ester and (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-bromotetrahydro-2H-pyran-3,4,5-triyltriacetate as the starting materials (that is, only the 0.2 mmol of 2-bromopropane in Example 5 was replaced with 0.2 mmol of (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-bromotetrahydro-2H-pyran-3,4,5-triyltriacetate, while all other reaction parameters and conditions remained unchanged), yielding the corresponding product 33 in 63% yield.

[0130] Example 34

[0131] The method was the same as in Example 5, using N-(p-toluenesulfonyl)glycine ethyl ester and (3aS,6R,6aS)-4-bromo-6-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole (that is, only the 0.2 mmol of 2-bromopropane in Example 5 was replaced with 0.2 mmol of (3aS,6R,6aS)-4-bromo-6-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole, while other reaction parameters and conditions remained unchanged), yielding the corresponding product 34 in 61% yield.

[0132] Example 35

[0133] The method is the same as in Example 5, but the raw materials are N-(p-toluenesulfonyl)glycine methyl ester and (3aS,6R,6aS)-4-bromo-6-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole (that is, only the 0.1 mmol N-(p-toluenesulfonyl)glycine ethyl ester in Example 5 is changed to 0.1 mmol). N-(p-toluenesulfonyl)glycylphenylalanine methyl ester was reacted with 0.2 mmol of 2-bromopropane instead of (3aS,6R,6aS)-4-bromo-6-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole (while keeping other reaction parameters and conditions unchanged), yielding product 35 in 38% yield. The NMR data of the product are as follows:

[0134] 1 H NMR(400MHz, CDCl3)δ8.32(s,1H,major),8.23(s,1H,minor),7.74–7.63(m,2H),7.52–7.41(m,2H),7.40–7.29(m,2H),7.24–7.06(m,4H+1H,isomer 1),6.94–6.89(m,1H,isomer 2),6.33–6.22(m,1H,major),6.00–5.91(m,1H,minor),5.61–5.49(m,1H),4.63–4. 55(m,1H),3.61(s,3H,major),3.58(s,3H,minor),3.36–3.25(m,1H+1H,minor),3.1 4(ddd,J=14.7,11.7,5.5Hz,1H,major+1H,major),2.87(dd,J=14.7,5.8Hz,1H,mino r),2.32(s,3H,major),2.29(s,3H,minor),0.89(s,9H,major),0.83(s,9H,minor); 13CNMR(100MHz, CDCl3)δ171.9(major),171.8(minor),169.23(isomer 1),169.16(isomer2),143.68(isomer 1),143.53(isomer 2),137.0,136.2,129.6,127.36,127.33,123.2(isomer 1),123.0(isomer 2),122.5(isomer 1),122.2(isomer2),119.9(isomer 1),119.6(isomer 2),118.5(major),118.3(minor),111.5(isomer 1),111.3(isomer 2),109.5,65.5(isomer 1),65.0(isomer 2),52.7(isomer 1),52.5(isomer 2),52.3,34.8(isomer 1),34.4(isomer 2),28.1(major),27.5(minor),26.47(major),26.43(minor),21.5; HRMS(ESI,m / z):calcd for C 25 H 32 N3O5S + [M+H] + 486.2057, found 486.2054.

[0135] Example 36

[0136] The method was the same as in Example 5, with the starting materials being N-(p-toluenesulfonyl)glycylalanylphenylalanine methyl ester and tert-butane bromide (that is, only the 0.1 mmol of N-(p-toluenesulfonyl)glycine ethyl ester in Example 5 was replaced with 0.1 mmol of N-(p-toluenesulfonyl)glycylalanylphenylalanine methyl ester, and the 0.2 mmol of 2-bromopropane was replaced with 0.2 mmol of tert-butane bromide, while other reaction parameters and conditions remained unchanged), yielding the corresponding product 36 in 41% yield.

[0137] It is easy to see from the above embodiments that the substrate range of the present invention is broad (of course, the present invention is more applicable to secondary and tertiary halides than to primary halides).

[0138] Example 37

[0139] Under air conditions, product 17 (0.2 mmol, 73.9 mg), DMAP (0.12 mmol, 14.6 mg), and dry CH2Cl2 (3 mL) were added to a reaction tube equipped with a stir bar. Boc2O (0.4 mmol, 87.2 mg) and Et3N (0.6 mmol, 1.46 mL) were added at 0 °C. After stirring overnight at room temperature, the mixture was concentrated to dryness using a rotary evaporator and purified by rapid column chromatography to obtain the corresponding N-Boc product. This product was then dissolved in MeOH (6 mL), and Mg scrap (5 mmol, 120 mg) was added at 0 °C. The reaction was vigorously stirred until the reactants were consumed. The mixture was quenched with saturated NH4Cl aqueous solution, and the organic phase was extracted three times with CH2Cl2. After drying with anhydrous sodium sulfate, the product was purified by rapid column chromatography to obtain the target product 37 in 51% of the total yield. The NMR data of the product are as follows:

[0140] 1 H NMR (400MHz, CDCl3) δ5.08 (d, J = 9.9 Hz, 1H), 4.21–4.10 (m, 3H), 1.46–1.41 (m, 11H), 1.31–1.23 (m, 6H), 0.91 (s, 3H), 0.90 (s, 3H), 0.89–0.83 (m, 6H); 13 C10 NMR (100MHz, CDCl3) δ 172.2, 155.5, 79.7, 60.8, 60.1, 37.2, 37.1, 32.5, 28.7, 28.3, 23.8, 23.7, 22.7, 22.6, 14.2; High-resolution mass spectrometry [ESI]: calculated values ​​are C10 NMR, 155.5, 79.7, 60.8, 60.1, 37.2, 37.1, 32.5, 28.7, 28.3, 23.8, 23.7, 22.7, 22.6, 14.2; 17 H 34 NO4 + [M+H] + 316.2482, the actual measured value is 316.2481.

[0141] Comparative Example 1

[0142] In a nitrogen atmosphere, the following were added to a reaction tube containing a magnetic stirrer: photosensitizer [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (0.001 mmol, 1.0 mg), N-(p-toluenesulfonyl)glycine ethyl ester (0.1 mmol, 25.7 mg), 18-crown-6 (0.2 mmol, 52 mg), K2CO3 (0.1 mmol, 13.8 mg), KF (0.2 mmol, 11.6 mg), acetonitrile (2.0 mL), and bromocyclopentane (0.2 mmol, 21.4 μL). The reaction tube was stirred for 5 h at room temperature under irradiation with a 6W blue LED (450 nm). The experimental results show that the target product could not be obtained without the metal salt to activate the brominated product.

[0143] Comparative Example 2

[0144] In an air atmosphere, photosensitizer [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (0.001 mmol, 1.0 mg), Pd(PPh3)4 (0.001 mmol, 1.2 mg), N-(p-toluenesulfonyl)glycine ethyl ester (0.1 mmol, 25.7 mg), 18-crown-6 (0.2 mmol, 52 mg), K2CO3 (0.1 mmol, 13.8 mg), KF (0.2 mmol, 11.6 mg), acetonitrile (2.0 mL), and bromocyclopentane (0.2 mmol, 21.4 μL) were added to a reaction tube containing a magnetic stirrer. The reaction tube was stirred for 5 hours at room temperature under irradiation with a 6W blue LED (450 nm). The experimental results showed that the starting material N-(p-toluenesulfonyl)glycine ethyl ester reacted completely, yielding only p-toluenesulfonamide as a byproduct. The analysis shows that the raw material is oxidized into imine, and then hydrolyzed to obtain this byproduct.

[0145] Comparative Example 3

[0146] In a nitrogen atmosphere, photosensitizer [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (0.001 mmol, 1.0 mg), N-(p-toluenesulfonyl)glycine ethyl ester (0.1 mmol, 25.7 mg), Pd(PPh3)4 (0.001 mmol, 1.2 mg), K2CO3 (0.1 mmol, 13.8 mg), KF (0.2 mmol, 11.6 mg), acetonitrile (2.0 mL), and bromocyclopentane (0.2 mmol, 21.4 μL) were added to a reaction tube containing a magnetic stirrer. The reaction tube was stirred for 5 h at room temperature under irradiation with a 6W blue LED (450 nm). The experimental results showed a significant decrease in reaction yield to approximately 10%. Analysis suggests that the lack of crown ether resulted in insufficient basicity of the reaction system, leading to a reduced activation efficiency of the glycine ester. Furthermore, the solubility of the base was also reduced, decreasing the light absorption efficiency of the reaction and consequently lowering the reaction yield.

[0147] The structural formulas of products 1 to 37 obtained in the above embodiments are shown below:

[0148]

[0149]

[0150] The above embodiments are merely examples. For instance, in addition to [Ir(dF(CF3)ppy)2(dtbbpy)]PF6, other photoinitiators such as [Ir(dF(CF3)ppy)2(bpy)]PF6, 4-CzIPN, and Mes-Acr can also be used. + The photoinitiators used are commonly known in the prior art, such as Eosin Y. Furthermore, all the raw materials used in the above embodiments were commercially available.

[0151] Those skilled in the art will readily understand that the above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for the preparation of a visible light-promoted α-alkyl amino acid derivative, characterized by, The method is to add a sulfonyl amino acid derivative, an alkane bromide, a base, a crown ether, a catalyst and a photosensitizer into an organic solvent to occur selective coupling reaction under visible light illumination to obtain an α-alkyl amino acid derivative. N- The method is to add a sulfonyl amino acid derivative, an alkane bromide, a base, a crown ether, a catalyst and a photosensitizer into an organic solvent to occur selective coupling reaction under visible light illumination to obtain an α-alkyl amino acid derivative. The catalyst is a transition metal salt, and the transition metal salt is Pd(PPh3)4; the photosensitizer comprises one of [Ir(dF(CF3)ppy)2(bpy)]PF6, [Ir(dF(CF3)ppy)2(dtbbpy)]PF6, 4-CzIPN, Mes-Acr + , and Eosin Y. The N- The sulfonamide acid derivative has the structure of formula I, the alkyl bromide has the structure of formula II, and the alpha alkyl amino acid derivative has the structure of formula III. wherein R 1 is selected from the group consisting of OR 5 , NR 6 , R 7 , substituted or unsubstituted aryl, polypeptide residue, wherein R 5 , R 6 and R 7 are C1-C20 alkane; R 2 is selected from the group consisting of C1-C20 alkane, alkene, substituted or unsubstituted arene; R 3 is selected from the group consisting of H, C1-C20 alkane, cycloalkane or C1-C20 alkyl group containing nitrogen and / or oxygen atoms; R 4 is selected from the group consisting of C1-C20 alkane, cycloalkane or C1-C20 alkyl group containing nitrogen and / or oxygen atoms; And, the formula III is specifically any one of compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 9, compound 10, compound 11, compound 12, compound 14, compound 15, compound 16, compound 20: 。 2. The preparation method according to claim 1, characterized in that, The base includes at least one of potassium carbonate, cesium carbonate, tri-potassium phosphate, potassium fluoride, cesium fluoride.

3. The preparation method according to claim 1, characterized in that, The N- The molar ratio of the sulfonyl amino acid derivative, alkane bromide, base, crown ether, catalyst and photosensitizer is 1 : (1.0-5.0) : (1.0-5.0) : (1.0-5.0) : (0.001-0.1) : (0.0001-0.1).

4. The preparation method according to claim 1, characterized in that, The organic solvent is one or more of trifluorotoluene, toluene, ethyl acetate, tetrahydrofuran, N , N dimethylformamide, N , N dimethylacetamide and acetonitrile.

5. The method of claim 1, wherein the step of forming the first and second layers is performed by a method selected from the group consisting of: sputtering, evaporation, and chemical vapor deposition. The protective gas is nitrogen or an inert gas.

6. The preparation method according to claim 5, characterized in that, The inert gas is argon.

7. The preparation method according to claim 1, characterized in that, The light is a visible light source with a wavelength of 400-500 nm; The reaction temperature of the selective coupling reaction is 0-40 DEG C, and the reaction time is 1-24 h.

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