Chiral peptide quaternary phosphonium salt catalyst as well as preparation method and application thereof

Abstract

The invention discloses a chiral peptide quaternary phosphonium salt catalyst as well as a preparation method and application thereof, and belongs to the technical field of catalysts. The catalyst is prepared by taking natural amino acid as a starting raw material, the synthesis route is simple, and the raw materials are cheap and easily available. The catalyst has the advantages of multiple modification sites, diversified and variable structures and extremely strong controllability. The catalyst has more hydrogen bond donor sites, and has strong chiral induction and catalysis capability; the coating is stable to water and air at room temperature and is easy to store; and the method has good water solubility, and has very strong practicability and industrial application value.

Description

Technical Field

[0001] The present invention relates to the technical field of catalysts, and in particular to a chiral peptide quaternary phosphonium salt catalyst, a preparation method and an application thereof. Background Art

[0002] In recent years, the application of quaternary phosphonium salt catalysts in organic chemistry has developed rapidly, but the application of chiral peptide monophosphine / polyphosphine quaternary phosphonium salt catalysts is relatively small. Chiral peptide monophosphine / polyphosphine quaternary phosphonium salt catalysts can enable reactions to proceed under mild conditions, accelerate reaction rates, significantly improve yields, and effectively control reaction enantioselectivity and diastereoselectivity. This technology has been widely used in laboratories and industry. Chiral peptide monophosphine / polyphosphine quaternary phosphonium salt catalysts have the advantages of high thermal stability, good catalytic efficiency, recyclability and low toxicity. They are widely used in the synthesis of many important bioactive molecules and drug molecules. Chiral peptide monophosphine / polyphosphine quaternary phosphonium salt catalysts are mainly divided into two types: carbon phosphine type and nitrogen phosphine type. Representative skeletons include binaphthyl skeleton and amino acid skeleton. Most of the quaternary phosphonium salts reported so far are monophosphine catalysts, and there are few examples of chiral peptide monophosphine / polyphosphine quaternary phosphonium salt catalysts containing flexible peptide chain skeletons. Summary of the Invention

[0003] In order to solve the above-mentioned deficiencies in the prior art, the purpose of the present invention is to provide a chiral peptide quaternary phosphonium salt catalyst and its preparation method and application. The present invention uses natural amino acids as starting materials to construct a class of flexible chiral peptide monophosphine / polyphosphine quaternary phosphonium salt catalysts.

[0004] The technical solution of the present invention to solve the above technical problems is as follows: a chiral peptide quaternary phosphonium salt catalyst is provided, comprising the following general structural formula and its corresponding enantiomers, diastereomers and racemates:

[0005] Chiral peptide monophosphine catalyst:

[0006]

[0007] Chiral peptide bisphosphine catalyst:

[0008]

[0009] Chiral peptide polyphosphine catalysts:

[0010]

[0011] Where R, R' are C 1-20 Alkyl, phenyl or substituted phenyl, heteroaromatic ring or substituted heteroaromatic ring (such as pyridyl or substituted pyridyl, pyranyl or substituted pyranyl, thienyl or substituted thienyl, etc.), benzyl or substituted benzyl, naphthyl or substituted naphthyl, polypeptide chain and its derivatives;

[0012] R 1 , R 2 ,R 3 ,R 5 ,R 6 ,R 7 ,R 8 ,R 9 All are hydrogen, C 1-20 alkyl, Phenyl or substituted phenyl, benzyl or substituted benzyl, heteroaromatic ring or substituted heteroaromatic ring (such as pyridyl or substituted pyridyl, pyranyl or substituted pyranyl, thienyl or substituted thienyl, etc.); R 11 H, TBS, TMS, TBDPS, TES, TPS, TIPS, Boc, Ac, Ts and their derivatives;

[0013] R 4 ,R 10 are Boc, Ts, acyl, urea, thiourea or substituted thiourea, carbonyl or substituted carbonyl and their derivatives, polypeptide chains and their derivatives;

[0014] R 21 ,R 22 ,R 23 ,R 24 are phenyl or substituted phenyl, naphthyl or substituted naphthyl, heteroaromatic ring or substituted heteroaromatic ring (such as pyridyl or substituted pyridyl, pyranyl or substituted pyranyl, thienyl or substituted thienyl, etc.), phenoxy or substituted phenoxy, naphthoxy or substituted naphthoxy, alkyl or alkoxy;

[0015] X is halogen, BF4 - ,OTf - ,OAc - , OBoc - , NO3 - , NO2 - , PO4 - , PF6 - , chiral phosphonate anion;

[0016] m=2, 3, 4, 5; n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10.

[0017] Furthermore, the structural formula of the chiral peptide monophosphine catalyst is as follows:

[0018]

[0019]

[0020]

[0021] Among them, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 are hydrogen, methyl, ethyl, propyl, butyl, benzyl, phenyl or R 11 For H, TBS, TMS, TBDPS, TES, TPS, TIPS, Boc, Ac, Ts;

[0022] R is methyl, ethyl, propyl, butyl, phenyl or substituted phenyl (such as phenyl substituted by at least one of halogen, trifluoromethyl, methyl, butyl, TMS, propyl, phenyl and methoxy), anthracenyl, pyridyl or substituted pyridyl, pyranyl or substituted pyranyl, thienyl or substituted thienyl;

[0023] R 12 is phenyl or substituted phenyl (such as phenyl substituted by at least one of methoxy, methyl, propyl, butyl, trifluoromethyl, nitro and halogen);

[0024] R 13 is methyl, ethyl, propyl, butyl, phenyl or substituted phenyl (such as phenyl substituted by at least one of halogen, methyl, methoxy, butyl, trifluoromethyl and nitro), naphthyl, pyridyl or substituted pyridyl, pyranyl or substituted pyranyl, thienyl or substituted thienyl;

[0025] R 14 is phenyl or substituted phenyl (e.g., phenyl substituted by at least one of halogen, methyl, methoxy, propyl, butyl, cyano, trifluoromethyl, and nitro), adamantyl, cyclopropyl, cyclopentyl, cyclohexyl, naphthyl, pyridyl or substituted pyridyl, pyranyl or substituted pyranyl, thienyl or substituted thienyl;

[0026] R 15 , R 16 are all phenyl or substituted phenyl (such as phenyl substituted with at least one of halogen, methoxy, propyl, butyl, trifluoromethyl, nitro and phenyl);

[0027] R 17 , R 18 are methyl, ethyl, propyl, butyl, phenyl or substituted phenyl (such as phenyl substituted with at least one of halogen, methyl, methoxy, butyl, trifluoromethyl and nitro), naphthyl, pyridyl or substituted pyridyl, pyranyl or substituted pyranyl, thienyl or substituted thienyl;

[0028] R 19 , R20 are phenyl or substituted phenyl (such as phenyl substituted with at least one of halogen, methyl, methoxy, propyl, butyl, cyano, trifluoromethyl and nitro), adamantyl, cyclopropyl, cyclopentyl, cyclohexyl, naphthyl, pyridyl or substituted pyridyl, pyranyl or substituted pyranyl, thienyl or substituted thienyl;

[0029] R 21 , R 22 are phenyl or substituted phenyl (e.g., phenyl substituted with at least one of halogen, methoxy, propyl, butyl, trifluoromethyl, and nitro), naphthyl, phenoxy, naphthyloxy, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, butyl, and butoxy;

[0030] X is halogen, BF4 - ,OTf - ,OAc - , OBoc - , NO3 - , NO2 - , PO4 - , PF6 - , chiral phosphonate anion; n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10.

[0031] Furthermore, the structural formula of the chiral peptide monophosphine catalyst is as follows:

[0032]

[0033]

[0034]

[0035]

[0036]

[0037]

[0038]

[0039]

[0040]

[0041] Furthermore, the structural formula of the chiral peptide bisphosphine catalyst is as follows:

[0042]

[0043]

[0044]

[0045] Among them, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 are hydrogen, methyl, ethyl, propyl, butyl, benzyl, phenyl or R 11 For H, TBS, TMS, TBDPS, TES, TPS, TIPS, Boc, Ac, Ts;

[0046] R, R' are methyl, ethyl, propyl, butyl, phenyl or phenyl substituted with at least one of halogen, trifluoromethyl, methyl, butyl, TMS, propyl, phenyl and methoxy, naphthyl, pyridyl or substituted pyridyl, pyranyl or substituted pyranyl, thienyl or substituted thienyl;

[0047] R 15 , R 16 are all phenyl or phenyl substituted with at least one of halogen, methoxy, propyl, butyl, trifluoromethyl, nitro and phenyl;

[0048] R 17 , R 18 are methyl, ethyl, propyl, butyl, phenyl or phenyl substituted with at least one of halogen, methyl, methoxy, butyl, trifluoromethyl and nitro, naphthyl, pyridyl or substituted pyridyl, pyranyl or substituted pyranyl, thienyl or substituted thienyl;

[0049] R 19 , R 20 are phenyl or phenyl substituted with at least one of halogen, methyl, methoxy, propyl, butyl, cyano, trifluoromethyl and nitro, adamantyl, cyclopropyl, cyclopentyl, cyclohexyl, naphthyl, pyridyl or substituted pyridyl, pyranyl or substituted pyranyl, thienyl or substituted thienyl;

[0050] R 21 , R 22 , R 23 , R 24 are phenyl or phenyl substituted with at least one of halogen, methoxy, propyl, butyl, trifluoromethyl and nitro, naphthyl, phenoxy, naphthyloxy, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, butyl and butoxy;

[0051] X is halogen, BF4 - ,OTf -,OAc - , OBoc - , NO3 - , NO2 - , PO4 - , PF6 - , chiral phosphonate anion;

[0052] n=0,1,2,3,4,5,6,7,8,9,10.

[0053] Furthermore, the structural formula of the chiral peptide bisphosphine catalyst is as follows:

[0054]

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061] Furthermore, the structural formula of the chiral peptide polyphosphine catalyst is as follows:

[0062]

[0063]

[0064] Among them, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 are hydrogen, methyl, ethyl, propyl, butyl, benzyl, phenyl or R 11 For H, TBS, TMS, TBDPS, TES, TPS, TIPS, Boc, Ac, Ts;

[0065] R and R' are methyl, ethyl, propyl, butyl, phenyl or phenyl substituted with at least one of halogen, trifluoromethyl, methyl, butyl, TMS, propyl, phenyl and methoxy, naphthyl, pyridyl or substituted pyridyl, pyranyl or substituted pyranyl, thienyl or substituted thienyl;

[0066] R15 , R 16 are all phenyl or phenyl substituted with at least one of halogen, methoxy, propyl, butyl, trifluoromethyl, nitro and phenyl;

[0067] R 17 , R 18 are methyl, ethyl, propyl, butyl, phenyl or phenyl substituted with at least one of halogen, methyl, methoxy, butyl, trifluoromethyl and nitro, naphthyl, pyridyl or substituted pyridyl, pyranyl or substituted pyranyl, thienyl or substituted thienyl;

[0068] R 19 , R 20 are phenyl or phenyl substituted with at least one of halogen, methyl, methoxy, propyl, butyl, cyano, trifluoromethyl and nitro, adamantyl, cyclopropyl, cyclopentyl, cyclohexyl, naphthyl, pyridyl or substituted pyridyl, pyranyl or substituted pyranyl, thienyl or substituted thienyl;

[0069] R 21 , R 22 , R 23 , R 24 are phenyl or phenyl substituted with at least one of halogen, methoxy, propyl, butyl, trifluoromethyl and nitro, naphthyl, phenoxy, naphthyloxy, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, butyl and butoxy;

[0070] X is halogen, BF4 - ,OTf - ,OAc - , OBoc - , NO3 - , NO2 - , PO4 - , PF6 - , chiral phosphonate anion;

[0071] m=2, 3, 4, 5;

[0072] n=0,1,2,3,4,5,6,7,8,9,10.

[0073] Furthermore, the structural formula of the chiral peptide polyphosphine catalyst is as follows:

[0074]

[0075]

[0076]

[0077] The preparation method of the chiral peptide quaternary phosphonium salt catalyst is characterized in that when R1 To remove When there are groups other than , the reaction formula and specific reaction process are as follows:

[0078]

[0079] (1) The natural amino acid compound 1 is refluxed with a hydrochloric acid / methanol solution for 3-6 hours, the solvent is dried, and then TsCl and triethylamine are added and reacted at room temperature for 3-4 hours to obtain compound 2; wherein the molar ratio of the natural amino acid compound, TsCl and triethylamine is 1:1-2:2-3;

[0080] (2) Compound 2 was dissolved in an organic solvent, and then LiAlH4 was added to react at room temperature for 2-3 hours, filtered, and the filtered product was reacted with EsCl and triethylamine for 2-4 hours to obtain Compound 3; wherein the molar ratio of Compound 2, LiAlH4, EsCl and triethylamine was 1:2-3:1-2:2-3;

[0081] (3) Compound 3 was added to an alkaline solution and stirred at room temperature for 2-5 h to obtain compound 4;

[0082] (4) Compound 4 and KPR 21 R 22 Mix according to a molar ratio of 1:1-3, and then react at room temperature for 3-5 hours to obtain compound 5;

[0083] (5) Add concentrated sulfuric acid to compound 5, react at 75-85°C for 2-3 hours, then cool, wash with water, extract and concentrate to obtain compound 6;

[0084] (6) Substituting the hydrogen on the amino group of compound 6 to obtain compound 7;

[0085] (7) Compound 7 was hydrolyzed with trifluoroacetic acid for 1-2 h to obtain compound 8;

[0086] (8) Substituting the amino group of compound 8 to obtain compound 9, and repeating steps 6-8 to obtain compound 10;

[0087] (9) reacting compound 10 with a halogenated hydrocarbon to obtain compound 11, compound 12, or compound 13, namely, a monophosphine catalyst, a ring-opened diphosphine catalyst, and a ring-opened polyphosphine catalyst;

[0088] (10) Compounds 12 and 13 are reacted with halogenated hydrocarbons to obtain compound 14 or compound 15, i.e., a cyclic diphosphine catalyst and a cyclic polyphosphine catalyst;

[0089] In the above reaction process, RX 1，2，m and R'-X 2，mIt is a halogenated hydrocarbon, 1, 2, and m represent the number of the quaternary phosphonium salt that is ultimately substituted. For example, after the compound reacts with R-Br, a quaternary phosphonium salt is formed, the compound reacts with R-Br2 to obtain a diphosphine quaternary phosphonium salt, and the compound reacts with R-Br3 to obtain a triphosphine quaternary phosphonium salt.

[0090]

[0091] (1) The natural amino acid compound 16 was refluxed with a hydrochloric acid / methanol solution for 3-6 hours, the solvent was dried and then extracted and concentrated to obtain compound 17;

[0092] (2) Compound 17 was dissolved in an organic solvent, and then a Boc-protected amino acid was added. A condensation reaction was carried out using HOBT, EDCI, and DIPEA. The reaction was carried out at room temperature for 12-14 hours to obtain compound 18. The molar ratio of compound 27, HOBT, EDCI, and DIPEA was 1:1.5:1.5:2.

[0093] (3) Compound 18 is dissolved in an organic solvent, and then trifluoroacetic acid is added to carry out a deprotection reaction to obtain compound 19;

[0094] (4) Compound 19 was dissolved in an organic solvent, and then a Boc-protected amino acid was added. A condensation reaction was carried out using HOBT, EDCI, and DIPEA. The reaction was carried out at room temperature for 12-14 hours to obtain compound 20; wherein the molar ratio of compound 19, HOBT, EDCI, and DIPEA was 1:1.5:1.5:2; steps 2-4 were repeated to extend the peptide chain to obtain compound 21;

[0095] (5) Compound 21 was dissolved in an organic solvent, and then LiAlH4 was added for reduction reaction. The reaction was carried out at room temperature for 2-3 hours to obtain compound 22; wherein the molar ratio of compound 21 to LiAlH4 was 1:2;

[0096] (6) Compound 22 was dissolved in an organic solvent, and then NBS and PPh3 were added for bromination reaction to obtain compound 23; wherein the molar ratio of compound 27, NBS and PPh3 was 1:1.2:1.2;

[0097]

[0098] Compound 10 and compound 23 are subjected to reflux reaction in an organic solvent to prepare compound 24, i.e., a monophosphine catalyst;

[0099]

[0100] (1) Compound 10 and Compound 23 were hydrolyzed under the action of trifluoroacetic acid to obtain Compound 25 and Compound 26;

[0101] (2) Compound 25 and Compound 26 are subjected to a bonding reaction with a halogenated hydrocarbon or a carboxylic acid to obtain Compound 27;

[0102] (3) Compound 27 is subjected to reflux reaction in toluene to obtain compound 28, i.e., a cyclic chiral peptide monophosphine catalyst.

[0103] Furthermore, when R 1 for When the group, the reaction formula and specific reaction process are as follows:

[0104]

[0105] (1) Threonine was refluxed in a hydrochloric acid and methanol solution for 2 h, then concentrated and added with 1.5-2 equivalents of Boc2O under alkaline conditions, and reacted at room temperature for 2-3 h to obtain compound 30;

[0106] (2) Compound 30, DMP, and HCl were mixed in a molar ratio of 1:1-1.5:1-1.5 and reacted at room temperature for 5-6 h to obtain compound 31;

[0107] (3) Compound 31 was reacted with LiAlH4 for 2-3 h, and then EsCl and triethylamine were added and reacted at room temperature for 1-1.5 h to obtain compound 32; wherein the molar ratio of compound 31, LiAlH4, EsCl and triethylamine was 1:1.5-2:1.2-1.5:1.8-2.2;

[0108] (4) Compound 32 and KPR 21 R 22 The mixture was mixed at a molar ratio of 1:1-1.5, and then reacted at room temperature for 7-8 hours. After the reaction, 6M concentrated sulfuric acid was added and stirred at room temperature for 1 hour, and then directly filtered to obtain compound 33;

[0109] (5) Compound 33 and R 11 Cl was mixed in a molar ratio of 0.8-1.2:1.5-2.5, stirred at room temperature for 1.5-2.5h, and the solvent was dried to obtain a crude product; the crude product was stirred in 1M hydrochloric acid at room temperature for 20-40min, then dried, extracted, and concentrated to obtain an intermediate, and R was added continuously. 11 Cl was stirred at room temperature for 1-1.5 h to obtain compound 34;

[0110] (6) Compound 34 was hydrolyzed with trifluoroacetic acid for 1-2 hours to obtain compound 35. The process of preparing chiral peptide quaternary phosphonium salt catalyst from compound 35 was the same as that when R 1 for The subsequent steps are the same as when

[0111] Application of the chiral peptide quaternary phosphonium salt catalyst in asymmetric catalytic reactions.

[0112] The present invention has the following beneficial effects:

[0113] (1) The present invention uses natural amino acids as starting materials to construct a class of flexible chiral peptide monophosphine / polyphosphine quaternary phosphonium salt catalysts. The catalyst has multiple modification sites, diverse polypeptide chain structures, strong controllability, and multiple hydrogen bond binding sites, and has strong chiral induction ability.

[0114] (2) The chiral peptide monophosphine / polyphosphine quaternary phosphonium salt catalyst synthesized by the present invention is stable in air and water, easy to store and transport, not easily deactivated, and has good water solubility, is environmentally friendly, and has strong practicality.

[0115] (3) The chiral peptide monophosphine / polyphosphine quaternary phosphonium salt catalysts synthesized in the present invention exhibit excellent chiral control capabilities in various types of reactions, and can obtain the core skeletons of some important biologically active molecules and drugs with high reaction yields (yield), high enantioselectivity (ee) and high diastereoselectivity (dr). This type of chiral compound has important application value and potential in pharmaceutical applications.

[0116] (4) The chiral peptide monophosphine / polyphosphine quaternary phosphonium salt catalyst provided by the present invention has a simple synthesis route and is easy to operate. It can obtain a high yield without the need for harsh anhydrous and anaerobic conditions. It uses natural amino acids as raw materials, has low cost, and is suitable for large-scale industrial production. DETAILED DESCRIPTION

[0117] The following examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. In the examples, where specific conditions are not specified, the experiments were performed under conventional conditions or those recommended by the manufacturer. Reagents or instruments used, where the manufacturer is not specified, are commercially available conventional products.

[0118] Example 1:

[0119] ((R)-2-((S)-2-((tert-Butoxycarbonyl)amino)-3-methylbutanamide)-3-methylbutyl)(3-((((S)-2-((tert-Butoxycarbonyl)amino)-3-methylbutyl)diphenylphosphonyl)methyl)benzenelammonium bromide, the structural formula is:

[0120]

[0121] The reaction formula and specific preparation process are as follows:

[0122]

[0123] (1) Valine was refluxed in a hydrochloric acid / methanol solution for 5 h, the solvent was dried, and then TsCl and triethylamine were added and reacted at room temperature for 3 h. Compound 37 was prepared by extraction and concentration; wherein the molar ratio of valine, TsCl, and triethylamine was 1:1.2:2;

[0124] (2) Compound 37 was dissolved in an organic solvent, and then LiAlH4 was added and reacted at room temperature for 3 h. The mixture was filtered, and the filtered product was reacted with EsCl and triethylamine for 3 h to obtain compound 38; wherein the molar ratio of compound 37, LiAlH4, EsCl and triethylamine was 1:2:1.2:2;

[0125] (3) Compound 38 was added to a NaOH aqueous solution, stirred at room temperature for 3 h, and extracted and concentrated to obtain compound 39;

[0126] (4) Compound 39 was mixed with KPPh2 at a molar ratio of 1:1, reacted in DCM at room temperature for 4 h, and filtered directly to obtain compound 40;

[0127] (5) Concentrated sulfuric acid was added to compound 40, and the mixture was reacted at 80°C for 2 h. The mixture was then cooled, washed with water, extracted and concentrated to obtain compound 41.

[0128] (6) Substituting the hydrogen on the amino group of compound 41 to obtain compound 42, namely tert-butyl ((S)-1-((S)-1-(diphenylphosphino)-3-methylbutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate;

[0129] (7) 7941.2 mg (2 mmol) of tert-butyl ((S)-1-((S)-1-(diphenylphosphino)-3-methylbutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate and 264.0 mg (1 mmol) of 1,3-bis(bromomethyl)benzene were dissolved in 20 mL of toluene and refluxed at 130°C for 2-6 h to obtain 922.6 mg of the catalyst with a yield of 90%.

[0130] NMR and mass spectrometry data: 1H NMR (400MHz, CDCl3) δ8.64 (d, J = 9.3Hz, 2H), 7.94-7.81 (m, 4H), 7.81-7.43 (m, 18H), 6.52(t,J=7.7Hz,1H),6.15(dd,J=38.8,8.7Hz,4H),5.18(s,1H),4.11-3.56(m,8H), 3.43(t,J=14.9Hz,2H),2.89(s,1H),2.23-1.96(m,2H),1.85(dt,J=13.6,7.2Hz,2H) ,1.16(s,18H),0.81(d,J=6.6Hz,6H),0.75(d,J=6.7Hz,6H),0.67(t,J=8.1Hz,12H); 13 C NMR (100MHz, CDCl3) δ172.10, 155.93, 134.90 (d, J = 11.3Hz), 133.90 (d, J = 9.1Hz), 1 33.54(d,J=9.5Hz),132.10,130.20(d,J=11.8Hz),129.98(d,J=11.9Hz),128.96,1 28.68,118.06(d,J=83.9Hz),115.88(d,J=82.6Hz),78.87,77.55,61.32,49.36,34 .22(d,J=12.1Hz),30.79,28.20,23.98(d,J=47.9Hz),19.58,18.93,18.70,18.02; 31 P NMR (162MHz, CDCl3) δ28.24; HRMS (ESI) m / z calcd for C 62 H 86 BrN4O6P2[M-Br] + =1123.5200,found=1123.5198. According to the NMR and mass spectrometry data, the product structure is correct.

[0131] Example 2:

[0132] (1,3-phenylbismethylene)bis(((R)-2-((S)-2-((tert-butyloxycarbonyl)amino)-3-methylbutanamide)-3-methylbutyl)diphenylphosphonium bromide), the structural formula is:

[0133]

[0134] According to the preparation method of Example 1, the starting material is also valine. During the reaction, the substitution group is replaced according to the above structure to finally prepare (3-(bromomethyl)benzyl)((R)-2-((S)-2-((tert-butoxycarbonyl)amino)-3-methylbutyryl)diphenylphosphonium bromide. 941.2 mg (2 mmol) of (3-(bromomethyl)benzyl)((R)-2-((S)-2-((tert-butoxycarbonyl)amino)-3-methylbutyryl)diphenylphosphonium bromide and 264.0 mg (1.0 mmol) of 1,3-bis(bromomethyl)benzene are dissolved in 20 mL of toluene and refluxed at 130° C. for 2-6 h to obtain 943.1 mg of the catalyst with a yield of 92%.

[0135] NMR and mass spectrometry data: 1 H NMR(400MHz, CDCl3)δ8.91(s,2H),7.89(s,2H),7.82-7.48(m,16H),7.44(s ,4H),6.83(s,1H),6.69(s,1H),6.11(s,1H),5.17(d,J=14.4Hz,1H),4.94(s ,2H),4.36(s,2H),4.08(s,4H),3.76(s,2H),2.91(s,2H),2.16(s,2H),1.75 (s,2H),1.34(s,18H),0.91(d,J=7.1Hz,6H),0.74(dt,J=22.9,7.5Hz,18H); 13 C NMR (100MHz, CDCl3) δ171.52, 156.01, 135.38 (d, J = 118.9Hz), 133.54 (d, J = 9.8Hz), 133.29(d,J=8.6Hz),131.81,130.37(d,J=12.2Hz),129.92(d,J=12.8Hz),128.94, 128.70,117.65(d,J=83.9Hz),115.24(d,J=82.7Hz),78.85,77.44,59.11,48.94,3 4.42(d,J=13.2Hz),31.09,28.35,25.64(d,J=48.1Hz),19.68,18.63,18.47,17.00; 31 P NMR (162MHz, CDCl3) δ27.88; HRMS (ESI) m / z calcd for C 62 H 86 BrN4O6P2[M-Br] +=1123.5200,found=1123.5195. According to the NMR and mass spectrometry data, the product structure is correct.

[0136] Example 3:

[0137] (1,3-phenylbismethylene)bis((S)-2-((R)-2-((tert-butyloxycarbonyl)amino)-3-methylbutanamide)-3-methylbutyl)diphenylphosphonium bromide, the structural formula is:

[0138]

[0139] The specific preparation process is as follows:

[0140] According to the preparation method of Example 1, the starting material is also threonine. During the reaction, the substituent group is replaced according to the above structure to finally prepare (3-(bromomethyl)benzyl)((S)-2-((R)-2-((tert-butoxycarbonyl)amino)-3-methylbutyryl)diphenylphosphonium bromide. 941.2 mg (2.0 mmol) of (3-(bromomethyl)benzyl)((S)-2-((R)-2-((tert-butoxycarbonyl)amino)-3-methylbutyryl)diphenylphosphonium bromide, 264.0 mg (1.0 mmol) of 1,3-bis(bromomethyl)benzene and 20 ml of toluene were added to a reaction flask, and the reaction was refluxed for 8 hours to obtain 912.0 mg of the product with a yield of 89%.

[0141] NMR and mass spectrometry data: 1 H NMR(400MHz, CDCl3)δ8.91(s,2H),7.89(s,2H),7.82-7.48(m,16H),7.44(s ,4H),6.83(s,1H),6.69(s,1H),6.11(s,1H),5.17(d,J=14.4Hz,1H),4.94(s ,2H),4.36(s,2H),4.08(s,4H),3.76(s,2H),2.91(s,2H),2.16(s,2H),1.75 (s,2H),1.34(s,18H),0.91(d,J=7.1Hz,6H),0.74(dt,J=22.9,7.5Hz,18H); 13C NMR (101MHz, CDCl3) δ171.50, 155.96, 135.34 (d, J = 109.3Hz), 133.53 (d, J = 9.7Hz), 133.27(d,J=8.3Hz),131.80,130.30(d,J=12.4Hz),129.90(d,J=12.8Hz),128.94, 128.69,117.63(d,J=84.0Hz),115.26(d,J=82.4Hz),78.83,77.52,59.06,48.90,3 4.39(d,J=12.8Hz),31.07,28.32,25.56(d,J=48.3Hz),19.66,18.62,18.42,16.97; 31 P NMR (162MHz, CDCl3) δ27.88; HRMS (ESI) m / z calcd for C 62 H 86 BrN4O6P2[M-Br] + =1123.5200,found=1123.5203. According to the NMR and mass spectrometry data, the product structure is correct.

[0142] Example 4:

[0143] (1,3-phenylbis(methylene)bis(((R)-2-((tert-butyloxycarbonyl)amino)-3-methylbutanamide)-3-methylbutyl)diphenylphosphonium bromide), the structural formula is:

[0144]

[0145] According to the preparation method of Example 1, the starting material is also threonine. During the reaction, the substitution group is replaced according to the above structure to obtain the target product (3-(bromomethyl)benzyl)((R)-2-((R)-2-((tert-butoxycarbonyl)amino)-3-methylbutyryl)diphenylphosphonium bromide. 941.2 mg (2.0 mmol) of (3-(bromomethyl)benzyl)((R)-2-((R)-2-((tert-butoxycarbonyl)amino)-3-methylbutyryl)diphenylphosphonium bromide, 264.0 mg (1.0 mmol) of 1,3-bis(bromomethyl)benzene and 20 ml of toluene are added to a reaction flask, and the reaction is refluxed for 8 hours to obtain 917.5 mg of the product with a yield of 90%.

[0146] NMR and mass spectrometry data: 1H NMR(400MHz, CDCl3) δ8.68(d,J=9.3Hz,2H),7.90(s,4H),7.63(dt,J=42.9,7.4Hz,18H),6.5 5(t,J=7.8Hz,1H),6.18(dd,J=45.6,8.9Hz,4H),5.30-5.18(m,1H),3.89(dq,J=32.9,10.6,8 .1Hz,8H),3.47(t,J=15.0Hz,2H),3.05-2.69(m,1H),2.15(d,J=7.1Hz,2H),1.97-1.77(m,2H ),1.20(s,18H),0.85(d,J=6.7Hz,6H),0.79(d,J=6.7Hz,6H),0.71(dd,J=11.5,6.7Hz,12H). 13 C NMR (101MHz, CDCl3) δ172.15, 155.98, 134.92 (d, J = 9.7Hz), 133.95 (d, J = 9.4Hz), 1 33.57(d,J=9.3Hz),132.18,130.23(d,J=11.8Hz),130.02(d,J=11.6Hz),128.97,1 28.74,118.13(d,J=84.1Hz),115.93(d,J=82.4Hz),78.92,77.47,61.36,49.39,34 .27(d,J=12.3Hz),30.81,28.23,24.00(d,J=47.7Hz),19.60,18.94,18.74,18.04; 31 P NMR(162MHz,CDCl3)δ28.31.HRMS(ESI)m / z calcdfor C 62 H 86 BrN4O6P2[M-Br] + =1123.5200,found=1123.5200. According to the NMR and mass spectrometry data, the product structure is correct.

[0147] Example 5:

[0148] The structural formula of (1,2-phenylenebis(methylene)bis(((S)-2-((tert-butyloxycarbonyl)amino)-3-methylbutyramido)-3-methylbutyl)diphenylphosphonium) bromide is:

[0149]

[0150] According to the preparation method of Example 1, the starting material is also threonine. During the reaction, the substitution group is replaced according to the above structure to obtain the target product (S)-1-(((S)-1-[diphenylphosphino]-3-methylbutan-2-yl]amino)-3-methyl-1-oxobutan-2-yl)carbamate. 941.2 mg (2.0 mmol) of tert-butyl (S)-1-(((S)-1-[diphenylphosphino]-3-methylbutan-2-yl]amino)-3-methyl-1-oxobutan-2-yl)carbamate, 264.0 mg (1.0 mmol) of 1,2-bis(bromomethyl)benzene and 20 ml of toluene were added to the reaction flask, and the reaction was refluxed for 8 hours to obtain 998.0 mg of the product with a yield of 83%.

[0151] NMR and mass spectrometry data: 1 H NMR(400MHz, CDCl3)δ8.80(d,J=9.4Hz,1H),8.10-7.96(m,5H),7.89-7.60(m,18H),6.65(t,J=7.7Hz ,1H),6.37(d,J=10.1Hz,1H),6.22(d,J=7.4Hz,2H),5.35(s,1H),4.14-4.02(m,2H),3.95(q,J=11.6, 8.6Hz,6H),3.59(t,J=14.9Hz,1H),2.97(s,1H),2.87(s,1H),2.26(q,J=6.8Hz,2H),1.99(q,J=8.1,7 .3Hz,2H),1.31(s,18H),0.96(d,J=6.7Hz,6H),0.90(d,J=6.7Hz,6H),0.82(dd,J=12.0,6.7Hz,12H). 13 C NMR (100MHz, CDCl3) δ172.13, 162.49, 155.98, 134.91 (d, J = 10.7Hz), 133.96 (d, J = 9.4Hz), 13 3.58(d,J=9.5Hz),132.19,130.22(d,J=12.0Hz),130.01(d,J=12.3Hz),128.95,128.74(d,J= 7.4Hz),118.16(d,J=83.8Hz),115.94(d,J=82.3Hz),78.88,77.47,61.41,49.41(d,J=4.4Hz) ,36.47,34.27(d,J=12.2Hz),30.84,28.23,23.98(d,J=47.6Hz),19.60,18.96,18.75,18.07; 31P NMR(162MHz,CDCl3)δ28.32.HRMS(ESI)m / zcalcd for C 62 H 86 BrN4O6P2[M-Br] + =1123.5200,found=1123.5200. According to the NMR and mass spectrometry data, the product structure is correct.

[0152] Example 6:

[0153] The structural formula of (1,2-phenylenebis(methylene)bis((((S)-2-((tert-butyloxycarbonyl)amino)-3,3-dimethylbutyramido)-3-methylbutyl)diphenylphosphonium) bromide is:

[0154]

[0155] According to the preparation method of Example 1, the starting material is also threonine. During the reaction, the substitution group is replaced according to the above structure to obtain the target product (S)-1-(((S)-1-[diphenylphosphino]-3-methylbutan-2-yl]amino)-3,3-dimethyl-1-oxobutan-2-yl)carbamate. 969.2 mg (2.0 mmol) of tert-butyl (S)-1-(((S)-1-[diphenylphosphino]-3-methylbutan-2-yl]amino)-3,3-dimethyl-1-oxobutan-2-yl)carbamate, 264.0 mg (1.0 mmol) of 1,2-bis(bromomethyl)benzene and 20 ml of toluene were added to the reaction flask, and the reaction was refluxed for 8 h to obtain 1.2 g of the product with a yield of 97%.

[0156] NMR and mass spectrometry data: 1 H NMR(400MHz, CDCl3)δ8.65(s,1H),7.90(s,4H),7.74-7.53(m,19H),6.59(s,3H),6.42(s,1H),5.61(s,1H),4.19(s,1H),3.98(dt ,J=15.9,8.2Hz,5H),3.44(s,1H),1.99-1.93(m,1H),1.67(s,2H),1.32(s,3H),1.18(s,18H),0.93(s,18H),0.84-0.65(m,12H). 13C NMR (100MHz, CDCl3) δ170.78, 155.95, 134.90, 133.75 (d, J = 7.4Hz), 133.25 (d, J = 9.7Hz ),131.36,130.27(d,J=11.7Hz),130.03(d,J=11.9Hz),129.23,128.90,118.18(d,J=8 3.3Hz),115.53(d,J=82.8Hz),79.60,78.57,64.51,60.19,53.56,48.56,34.23,30.80 (d,J=46.1Hz),28.22,27.11,24.33(d,J=47.6Hz),20.93,18.34(d,J=37.1Hz),14.08. 31 P NMR(162MHz,CDCl3)δ28.8.HRMS(ESI)m / z calcdfor C 64 H 90 BrN4O6P2

[0157] [M-Br] + =1151.5519,found=1151.5511. According to the NMR and mass spectrometry data, the product structure is correct.

[0158] Example 7:

[0159] The structural formula of (1,2-phenylenebis(methylene)bis((((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutyramido)-3,3-dimethylbutyl)diphenylphosphonium) bromide is:

[0160]

[0161] According to the preparation method of Example 1, the starting material is tert-leucine, and the substitution group is replaced according to the above structure during the reaction to obtain the target product (S)-1-(((S)-1-[diphenylphosphino]-3,3-dimethylbutan-2-yl]amino)-3,3-dimethyl-1-oxobutan-2-yl)carbamate. 997.3 mg (2.0 mmol) of tert-butyl (S)-1-(((S)-1-[diphenylphosphino]-3,3-dimethylbutan-2-yl]amino)-3,3-dimethyl-1-oxobutan-2-yl)carbamate, 264.0 mg (1.0 mmol) of 1,2-bis(bromomethyl)benzene and 20 ml of toluene were added to the reaction flask, and the reaction was refluxed for 8 hours to obtain 1.1 g of the product with a yield of 89%.

[0162] NMR and mass spectrometry data: 1H NMR (400MHz, CDCl3) δ8.38-8.33(m,3H),8.30-8.20(m,1H),7.94(d,J=9.7Hz,2H),7.84-7.72(m,8H),7 .61-7.56(m,6H),7.47(d,J=4.7Hz,4H),7.29-7.12(m,1H),6.80-6.68(m,2H),6.51(s,1H),6.21(d,J= 10.8Hz,1H),5.44(t,J=15.2Hz,2H),4.86(t,J=15.4Hz,1H),4.48-4.41(m,1H),3.87(dt,J=19.0,9.0H z,2H),3.76(d,J=10.8Hz,1H),3.64(t,J=15.2Hz,2H),3.13(s,2H),1.43(s,18H),0.90-0.74(m,36H). 13 CNMR(100MHz, CDCl3)δ170.46,156.00,134.95(d,J=12.9Hz),134.51,133.73(d,J=9.6Hz),131 .45,129.94(d,J=12.5Hz), 129.63(d,J=12.6Hz), 128.57(d,J=81.1Hz), 128.39(d,J=83.1Hz), 126.46,125.24,117.39(d,J=82.3Hz),115.12(d,J=83.3Hz),79.91,79.23,63.52,51.31,37.1 2(d,J=10.8Hz),34.29,30.19(d,J=47.0Hz),28.45,26.66,26.09,25.24(d,J=46.8Hz),21.42. 31 P NMR(162MHz,CDCl3)δ32.65.HRMS(ESI)m / z calcd forC 66 H 94 BrN4O6P2[M-Br] + =1179.5832,found=1179.5819. According to the NMR and mass spectrometry data, the product structure is correct.

[0163] Example 8:

[0164] The structural formula of ((4-fluoro-1,2-phenylene)bis(methylene))bis((((S)-2-((tert-butyloxycarbonyl)amino)-3,3-dimethylbutyramido)-3-methylbutyl)diphenylphosphonium) bromide is:

[0165]

[0166] According to the preparation method of Example 1, the starting material is also threonine. During the reaction, the substitution group is replaced according to the above structure to obtain the target product (S)-1-(((S)-1-[diphenylphosphino]-3-methylbutan-2-yl]amino)-3,3-dimethyl-1-oxobutan-2-yl)carbamate. 969.2 mg (2.0 mmol) of tert-butyl (S)-1-(((S)-1-[diphenylphosphino]-3-methylbutan-2-yl]amino)-3,3-dimethyl-1-oxobutan-2-yl)carbamate, 282.0 mg (1.0 mmol) of 1,2-bis(bromomethyl)-4-fluorobenzene and 20 ml of toluene were added to the reaction flask, and the reaction was refluxed for 8 h to obtain 1.2 g of the product with a yield of 96%.

[0167] NMR and mass spectrometry data: 1 H NMR (400MHz, CDCl3) δ8.28-8.22(m,4H),7.93(d,J=8.5Hz,1H),7.80-7.72(m,3H),7.71-7.61(m,7H),7.58-7.5 4(m,3H),7.50-7.42(m,4H),6.50-6.37(m,2H),6.16(d,J=8.7Hz,1H),5.97(d,J=10.4Hz,1H),5.75-5.57(m,3H ),5.02(t,J=15.4Hz,1H),4.70(t,J=15.1Hz,1H),4.36-4.17(m,2H),4.00-3.85(m,2H),3.70(d,J=10.3Hz,1H) ,3.66-3.52(m,3H),1.80-1.69(m,2H),1.38(s,9H),1.36(s,9H),0.85(s,9H),0.82(s,9H),0.80-0.68(m,12H); 13C NMR (100MHz, CDCl3) δ170.73, 170.68, 161.29 (d, J = 251.3Hz) 155.79 (d, J = 10.8Hz), 135.17 (d, J = 10.7Hz), 134.78 (d, J = 10.5Hz), 134.6 8(d,J=9.4Hz),133.83(d,J=5.4Hz),133.74(d,J=5.7Hz),133.46(t,J=6.5Hz),131.52(dd,J=14.4,7.2Hz),130.20(d,J=8.3Hz),130.0 9(d,J=7.6Hz),129.92(d,J=12.4Hz),124.87,117.95(dd,J=71.8,26.7Hz),116.78(d,J=27.0Hz),115.95(d,J=25.5Hz),115.30(dd,J= 38.2, 20.8Hz), 79.22 (d, J = 9.3Hz), 63.39 (d, J = 42.3Hz), 48.88 (d, J = 31.6Hz), 34.42, 34.22, 28.48, 28.43, 26.89, 26.83, 18.41, 18.02; 31 P NMR (162MHz, CDCl3) δ31.20, 30.97; 19 FNMR(376MHz, CDCl3)δ-111.85; HRMS(ESI)m / z calcd for C 64 H 89 BrFN4O6P2[M-Br] + =1169.5425,found=1169.5413. According to the NMR and mass spectrometry data, the product structure is correct.

[0168] Example 9:

[0169] The structural formula of ((4-fluoro-1,2-phenylene)bis(methylene))bis((((R)-2-((tert-butyloxycarbonyl)amino)-3,3-dimethylbutyramido)-3-methylbutyl)diphenylphosphonium) bromide is:

[0170]

[0171] According to the preparation method of Example 1, the starting material is also threonine. During the reaction, the substitution group is replaced according to the above structure to obtain the target product (R)-1-(((R)-1-[diphenylphosphino]-3-methylbutan-2-yl]amino)-3,3-dimethyl-1-oxobutan-2-yl)carbamate. 969.2 mg (2.0 mmol) of tert-butyl (R)-1-(((R)-1-[diphenylphosphino]-3-methylbutan-2-yl]amino)-3,3-dimethyl-1-oxobutan-2-yl)carbamate, 282.0 mg (1.0 mmol) of 1,2-bis(bromomethyl)-4-fluorobenzene and 20 ml of toluene were added to the reaction flask, and the reaction was refluxed for 8 h to obtain 1.2 g of the product with a yield of 96%.

[0172] NMR and mass spectrometry data: 1 H NMR (400MHz, CDCl3) δ8.30-8.18(m,4H),7.92(d,J=8.4Hz,1H),7.79-7.73(m,3H),7.71-7.61(m,7H),7.60-7.5 0(m,3H),7.50-7.42(m,4H),6.50-7.36(m,2H),6.16(d,J=8.5Hz,1H),5.96(d,J=10.4Hz,1H),5.75-5.55(m,3H ),5.02(t,J=15.3Hz,1H),4.69(t,J=14.8Hz,1H),4.39-4.10(m,2H),4.00-3.85(m,2H),3.69(d,J=10.1Hz,1H) ,3.64-3.52(m,3H),1.78-1.68(m,2H),1.38(s,9H),1.35(s,9H),0.85(s,9H),0.82(s,9H),0.78-0.70(m,12H); 13C NMR (100MHz, CDCl3) δ170.71, 170.66, 161.27 (d, J = 250.8Hz), 155.77 (d, J = 10.2Hz), 135.16 (d, J = 8.5Hz), 134.77 (d, J = 10.2Hz), 134.67 ( d,J=9.4Hz),133.81(d,J=6.2Hz),133.72(d,J=5.4Hz),133.42(dd,J=9.5,4.6Hz),131.50(dd,J=14.4,7.3Hz),130.19(d,J=7.9Hz),130 .07(d,J=8.0Hz),129.91(d,J=12.4Hz),124.82,117.92(dd,J=70.9,25.4Hz),116.76(d,J=25.0Hz),115.93(d,J=24.5Hz),115.29(dd,J =39.3,19.4Hz),79.20(d,J=9.6Hz),63.38(d,J=41.8Hz),48.89(d,J=27.1Hz),34.41,34.20,28.47,28.42,26.88,26.82,18.40,18.00; 31 P NMR (162MHz, CDCl3) δ31.19,30.95; 19 F NMR(376MHz, CDCl3)δ-111.86; HRMS(ESI)m / z calcd forC 64 H 89 BrFN4O6P2[-Br] + =1169.5425,found=1169.5411. According to the NMR and mass spectrometry data, the product structure is correct.

[0173] Example 10:

[0174] The structural formula of ((4-fluoro-1,2-phenylene)bis(methylene))bis((((S)-2-((tert-butoxycarbonyl)amino)-N,3,3-trimethylbutyramido)-3-methylbutyl)diphenylphosphonium) bromide is:

[0175]

[0176] According to the preparation method of Example 1, the starting material is also threonine. During the reaction, the substitution group is replaced according to the above structure to obtain the target product (S)-1-(((S)-1-[diphenylphosphino]-3-methylbutan-2-yl](methyl)amino)-3,3-dimethyl-1-oxobutan-2-yl)carbamate. To the reaction flask were added 997.3 mg (2.0 mmol) of tert-butyl (S)-1-(((S)-1-[diphenylphosphino]-3-methylbutan-2-yl](methyl)amino)-3,3-dimethyl-1-oxobutan-2-yl)carbamate, 282.0 mg (1.0 mmol) of 1,2-bis(bromomethyl)-4-fluorobenzene and 20 ml of toluene. The reaction was refluxed for 8 h to obtain 846 mg of the product with a yield of 66%.

[0177] NMR and mass spectrometry data: 1 H NMR (400MHz, CDCl3) δ8.16-8.09(m,4H),7.61(t,J=7.2Hz,2H),7.57-7.51(m,4H),7.48(d,J=7.1Hz,2H),7.43-7.37( m,4H),7.26-7.21(m,4H),6.47-6.40(m,1H),6.25(t,J=7.8Hz,1H),6.04(d,J=9.2Hz,1H),4.71(d,J=10.2Hz,2H),4. 69-4.54(m,4H),4.42(t,J=14.1Hz,1H),4.29(t,J=14.9Hz,1H),4.12-3.99(m,4H),3.12(d,J=15.4Hz,1H),3.04(d,J =18.0Hz,1H),2.98(s,6H),1.64(dt,J=15.2,6.4Hz,2H),1.07(s,18H),0.43(s,9H),0.42(s,9H),0.41-0.31(m,12H); 13C NMR (100MHz, CDCl3) δ173.81,173.78,162.10,159.61,155.02,134.86,134.77,133.40 (d,J=8.1Hz),13 3.32(d,J=8.0Hz),132.66(d,J=10.7Hz),131.17(dd,J=14.1,7.6Hz),129.71(d,J=12.1Hz),129.43(d,J =12.0Hz),124.70,117.83,117.61,115.64,115.50,115.01,114.82,114.68,114.50,113.83,113.68,7 9.01,56.09,53.80,33.85,31.90(d,J=3.6Hz),31.77(d,J=11.9Hz),27.76,25.86,19.68,19.64,18.18; 31 P NMR (162MHz, CDCl3) δ32.17,32.06; 19 F NMR(376MHz, CDCl3)δ-111.71; HRMS(ESI)m / z calcd for C 66 H 93 BrFN4O6P2[M-Br] + =1197.5738,found=1197.5735. According to the NMR and mass spectrometry data, the product structure is correct.

[0178] Example 11:

[0179] The structural formula of (((4-fluoro-1,2-phenylene)bis(methylene))bis(((((S)-2-((tert-butoxycarbonyl)(methyl)amino)-3,3-dimethylbutyramido)-3-methylbutyl)diphenylphosphonium) bromide is:

[0180]

[0181] According to the preparation method of Example 1, the starting material is also threonine. During the reaction, the substituent group is replaced according to the above structure to obtain the target product ((4-fluoro-1,2-phenylene)bis(methylene))bis((((S)-2-((tert-butoxycarbonyl)(methyl)amino)-3,3-dimethylbutyramido)-3-methylbutyl)diphenylphosphonium) bromide. 997.3 mg (2.0 mmol) of ((4-fluoro-1,2-phenylene)bis(methylene))bis((((S)-2-((tert-butoxycarbonyl)(methyl)amino)-3,3-dimethylbutyramido)-3-methylbutyl)diphenylphosphonium) bromide, 282.0 mg (1.0 mmol) of 1,2-bis(bromomethyl)-4-fluorobenzene and 20 ml of toluene were added to a reaction flask, and the reaction was refluxed for 8 hours to obtain 786.0 mg of the product with a yield of 61%.

[0182] NMR and mass spectrometry data: 1 H NMR (400MHz, CDCl3) δ8.29 (d, J = 7.9Hz, 1H), 8.20-8.05 (m, 1H), 7.68-7.36 (m, 20H), 6.54-6.22 (m, 2H), 6.1 9(d,J=8.9Hz,1H),5.71(dd,J=29.9,12.6Hz,1H),4.95(dd,J=30.4,15.1Hz,1H),4.89-4.62(m,2H),4.41- 4.24(m,2H),4.16-3.95(m,2H),2.89(d,J=12.0Hz,1H),2.81(d,J=9.4Hz,1H),2.71(d,J=9.6Hz,1H),2.55 -2.45(m,1H),1.85-1.75(m,2H),1.47(s,9H),1.38-1.30(m,12H),0.99-0.90(m,9H),0.88-0.76(m,21H); 13C NMR (100MHz, CDCl3) δ170.45 (d, J = 11.8Hz), 170.04 (d, J = 27.7Hz), 168.29, 161.16 (d, J = 23 5.9Hz),157.04(d,J=11.9Hz),156.66(d,J=21.9Hz),155.73(d,J=5.4Hz),135.55,135.30 (d, J=11.3Hz), 134.56 (dd, J=37.9, 10.8Hz), 133.67 (dd, J=25.1, 15.3Hz), 133.36 (d, J=8. 0Hz),133.11(dd,J=21.3,5.5Hz),130.22,130.11,130.01,129.88,129.41,129.29,124.7 9,118.13(d,J=17.4Hz),115.22(dd,J=54.7,26.9Hz),80.24,79.51,65.05(d,J=19.0Hz), 64.27(d,J=38.4Hz),63.61,48.82(d,J=50.2Hz),36.42(d,J=14.5Hz),35.27(d,J=25.5Hz ),34.81(d,J=13.0Hz),33.95(d,J=19.5Hz),33.41,33.16(d,J=12.8Hz),31.93,28.68,28 .50,28.27,27.71,18.72(d,J=23.8Hz),18.45(d,J=12.9Hz),17.96(d,J=25.3Hz),16.60; 31 P NMR (162MHz, CDCl3) δ31.49,31.29,29.85,29.70,28.90,28.37; 19 F NMR(376MHz, CDCl3)δ-111.45,-111.83; HRMS(ESI)m / z calcd for C 66 H 93 BrFN4O6P2[M-Br] + =1197.5738,found=1197.5740. According to the NMR and mass spectrometry data, the product structure is correct.

[0183] Example 12:

[0184] The structural formula of (4S,4'S,7R,7'R,8R,8'R)-1,1'-(5-(tert-butyl)-2-methoxy-1,3-phenylene)bis(7-((tert-butyloxycarbonyl)amino)-4-(tert-butyl)-8,10,11,11-pentamethyl-6-oxo-2,2-diphenyl-9-oxo-5-aza-2-phospho-10-dodecadienoic acid-2-ium) is:

[0185]

[0186] According to the preparation method of Example 1, the starting material is tert-leucine, and the substitution group is replaced according to the above structure during the reaction to obtain the target product (2R, 3R)-3-((tert-butyldimethylsilyl)oxy)-1-(((S)-1-(diphenylphosphino)-3,3-dimethylbutan-2-yl)amino)-1-oxobutan-2-ylcarbamic acid tert-butyl ester, and (2R, 3R)-3-((tert-butyldimethylsilyl)oxy)-1-(((S)-1-(diphenylphosphino)-3,3-dimethylbutan-2-yl)amino)-1-oxobutan-2-ylcarbamate is added to the reaction flask. 1.2 g (2.0 mmol) of tert-butyl 1-(((S)-1-(diphenylphosphino)-3,3-dimethylbutan-2-yl)amino)-1-oxobutan-2-ylcarbamate, 350.0 mg (1.0 mmol) of 1,3-bis(bromomethyl)-5-(tert-butyl)-2-methoxybenzene and 20 ml of toluene were refluxed for 8 h to obtain 1.5 g of the product with a yield of 97%.

[0187] NMR and mass spectrometry data: 1 H NMR (400MHz, CDCl3) δ8.39(d,J=9.4Hz,1H),7.84(dd,J=12.6,7.7Hz,2H),7.65(d,J=7.5Hz,1H),7.58-7.48(m,4H) ,7.35(td,J=7.8,3.2Hz,2H),6.62(s,1H),5.36(d,J=7.1Hz,1H),4.74(dt,J=36.0,14.5Hz,2H),4.52(t,J=14.9Hz, 1H),4.09(dq,J=11.8,6.8Hz,1H),3.95(d,J=7.1Hz,2H),3.59(s,2H),2.87(s,2H),2.64(t,J=14.7Hz,1H),1.36(s ,10H),1.28(d,J=6.5Hz,3H),1.22-1.14(m,1H),0.78(s,13H),0.75(s,11H),0.60(s,5H),-0.02(d,J=10.4Hz,7H). 13C NMR (101MHz, CDCl3) δ168.38, 155.05, 134.63 (d, J = 15.0Hz), 134.19 (d, J = 9 .8Hz),133.69(d,J=8.9Hz),129.74(d,J=12.8Hz),129.56(d,J=12.2Hz),12 9.32,117.79,116.95,116.13,79.01,69.28,62.90,59.47,51.79,36.75(d, J=12.0Hz),33.85,30.63,28.39,26.18,25.61,20.79,17.82,-4.78,-4.91. 31 PNMR(162MHz,CDCl3)δ29.74.HRMS(ESI)m / z calcd for C 79 H 124 BrN4O9P2Si2[M-Br] + =1469.7560,found=1469.7559. According to the NMR and mass spectrometry data, the product structure is correct.

[0188] The chiral peptide monophosphine / polyphosphine quaternary phosphonium salt catalyst prepared by the present invention has the advantages of diverse structures and adjustable sites. The flexible and adjustable structural characteristics of its polypeptide chain show strong chiral induction ability in many reactions, as shown in the following test examples: Test Example 1

[0189] The catalysts prepared in Example 1 and Example 8 were used to detect the chiral induction ability in asymmetric catalytic synthesis, and were applied to the desymmetric reaction of molecular cages to efficiently construct chiral molecular cage derivatives in one step, achieving excellent yields and good enantioselectivity.

[0190]

[0191] The specific reaction process is as follows:

[0192] (1) Molecular cage 36 (0.05 mmol), 2-naphthol 37 (0.06 mmol), PTC catalyst (10 mol%), and CsOH (0.15 mmol) were added to a 20 mL reaction tube;

[0193] (2) 10 mL of mesitylene cooled in a -15°C low-temperature bath was added to the system, and the reaction system was then placed in a -15°C low-temperature bath for 10 hours;

[0194] (3) The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was transferred to room temperature and diluted with dichloromethane. The target product 38 was obtained by purification by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1 (v:v) or dichloromethane).

[0195] The NMR data of target product 38 are as follows:

[0196] 1 H NMR (400MHz, CDCl3) δ7.93(d,J=9.0Hz,1H),7.89-7.82(m,2H),7.71(d,J=2.2Hz,1H),7.55-7.46(m,2H),7.39(dd,J=9.0,2.2 Hz,1H),6.60(t,J=2.0Hz,1H),6.58(t,J=2.0Hz,1H),6.55(t,J=2.0Hz,1H),3.69(dt,J=12.9,6.6Hz,4H),2.09-1.94(m,4H); 13 C NMR (100MHz, CDCl3) δ175.31,175.05,173.98,172.94,171.77,171.72,170.59, 169.43,165.68,153.89,153.02,152.46,149.07,148.31,147.43,146.84,133.8 6,131.91,130.05,127.98,127.91,126.95,126.28,120.74,118.52,116.00,115 .30,114.10,112.98,112.21,110.88,47.28,47.25,25.24,25.22; HRMS(ESI)m / z calcd for C 35 H 18 Br3ClN 10 O7[M+H] + =962.8677,found=962.8684.

[0197] Using molecular cage 36 and 2-naphthol 37 as template reaction substrates, this flexible chiral peptide monophosphine / polyphosphine quaternary phosphonium salt catalyst, cesium hydroxide as a base, toluene as a solvent, and a reaction temperature of -15°C for 10 hours, an asymmetric nucleophilic addition reaction occurred, affording a chiral molecular cage derivative in a 77% yield and 94% ee. Conventional chiral quaternary ammonium salts, chiral tertiary amines, and chiral phosphates were unable to achieve this reaction with high enantioselectivity, highlighting the unique advantages and potential of this chiral peptide monophosphine / polyphosphine quaternary phosphonium salt catalyst for the catalytic synthesis of chiral macromolecules.

[0198] Test Example 2

[0199] The catalyst prepared in Example 1 was used to detect the chiral induction ability in asymmetric catalytic synthesis and applied to the dynamic kinetic resolution reaction of aromatic alkenyl compounds to efficiently construct chiral alkenyl axial chiral derivatives in one step, achieving excellent yield and good enantioselectivity.

[0200]

[0201] The specific reaction process is as follows:

[0202] (1) The racemic reaction substrate 39 (0.01 mmol), diphenylphosphine oxide 40 (0.11 mmol), PTC catalyst (20 mol%), and Cs2CO3 (0.2 mmol) were added to a 3 mL reaction tube;

[0203] (2) 2 mL of a CCl4 / toluene mixed solvent (CCl4 / toluene = 1 / 10, v / v) cooled in a -10°C low-temperature bath was added to the system, and the reaction system was placed in a -10°C low-temperature bath for 48 hours;

[0204] (3) The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was transferred to room temperature and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, v:v) to obtain the target product 41.

[0205] The NMR data of the target product 41 are as follows:

[0206] 1 H NMR(400MHz, CDCl3)δ7.98(d,J=9.0Hz,1H),7.87(dd,J=6.8,2.5Hz,1H),7.59-7.51(m,1H),7.42-7.36(m,2H),7.36-7.27(m,5H),7.25-7.1 9(m,2H),7.19-7.07(m,5H),7.04(td,J=7.4,1.1Hz,1H),6.91(td,J=7.6,0.9Hz,1H),6.49(d,J=7.0Hz,1H),3.78(s,3H),3.05-2.88(m,4H); 13C NMR (100MHz, CDCl3) δ155.03,148.31(d,J=8.1Hz),135.34,133.48,133.09,132.11,132.06(d, J=2.8Hz),131.99,131.96,131.68(d,J=139.7Hz),131.63(d,J=10.6Hz),131.57,131.46,130.7 4,129.56,129.27,128.37(d,J=6.3Hz),128.26,128.20,128.01,127.14,126.70,126.63,126. 18,125.75,124.89,123.78,118.33,117.68,117.60,113.72,56.57,28.87,28.21(d,J=2.8Hz); 31 P NMR (162MHz, CDCl3) δ28.01; HRMS (ESI) m / z calcd for C 33 H 27 O3P[M+Na] + =525.1596,found=525.1587.

[0207] Using racemic compound 1 and diphenylphosphine oxide as template reaction substrates, this flexible chiral peptide monophosphine / polyphosphine quaternary phosphonium salt catalyst, cesium hydroxide as the base, CCl4 / toluene = 1:1 (V:V) as the solvent, and reacting at -10°C for 48 hours, an asymmetric AT reaction occurred, affording axially chiral aromatic and alkenyl derivatives with a yield of 91% and 92% ee. Currently available catalysts struggle to achieve this catalytic effect, demonstrating the potential of this chiral peptide monophosphine / polyphosphine quaternary phosphonium salt catalyst for the catalytic synthesis of axially chiral compounds.

[0208] Test Example 3

[0209]

[0210] The specific preparation process is as follows:

[0211] (1) Compound 42 (0.1 mmol), PPh3AuCl (5 mol%), and AgPF6 (4 mol%) were added to a 3 ml reaction tube in a nitrogen-protected glove box. 2 ml of toluene was added and the mixture was reacted at room temperature for 20 min.

[0212] (2) After reacting for 20 min, compound 43 (0.12 mmol), PTC (2.5 mol%), and Cs2CO3 (0.4 mmol) were added to the system, and then reacted in air at room temperature for 8 h;

[0213] (3) The reaction system was monitored using TLC. After the reaction was completed, the reaction mixture was transferred to room temperature and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1, v:v) to obtain the target product 44.

[0214] The NMR data of target product 44 are as follows:

[0215] 1 H NMR(400MHz,CHCl3)δ7.82(d,J=8.1Hz,2H),7.66-7.55(m,2H),7.45-7.20(m, 11H), 6.24 (dd, J=12.8, 7.6Hz, 1H), 6.17 (dd, J=6.8, 4.6Hz, 1H), 5.93 (dd, J=6. 8,3.3Hz,1H),4.35-4.20(m,4H),4.09(dp,J=9.9,7.2Hz,1H),3.68(tq,J=9.9 ,7.0Hz,1H),2.50(s,3H),1.39(dt,J=12.7,7.1Hz,6H),1.15(t,J=7.1Hz,3H). 13 C NMR(101MHz,CHCl3)δ167.07(d,J=7.7Hz),150.48,144.05,141.52(d,J=16.4Hz),137.34(d, J=2.2Hz),136.31,130.19,129.87(d,J=13.5Hz),129.60,128.51,128.18(d,J=3.0Hz),128.0 6,127.85,127.56,125.10(d,J=11.7Hz),123.81,114.08(d,J=6.9Hz),109.49(d,J=3.6Hz), 77.30,64.10,64.04,63.97,62.60,58.86,55.14(d,J=130.3Hz),21.64,16.48,16.35,13.95. 31 P NMR(162MHz,CHCl3)δ18.81.HRMS(ESI)m / z calcd for C 34 H 37 NO8P S [M+H] + =650.1972,found=650.1972.

[0216] Under the action of this type of flexible chiral peptide monophosphine / polyphosphine quaternary phosphonium salt catalyst, the aza-cope rearrangement reaction was successfully achieved with an 84% yield and 97% ee. The above reaction effect is difficult to achieve using quaternary ammonium salt phase transfer catalysts, which demonstrates the application potential of this type of chiral peptide monophosphine / polyphosphine quaternary phosphonium salt catalyst in catalyzing such reactions.

[0217] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A chiral peptide quaternary phosphonium salt catalyst, characterized in that: It includes the following general structural formula and its corresponding enantiomers, diastereomers and racemates: Chiral peptide monophosphine catalyst: Chiral peptide bisphosphine catalyst: Chiral peptide polyphosphine catalysts: Where R, R' are C 1-20 Alkyl, phenyl or substituted phenyl, heteroaromatic ring or substituted heteroaromatic ring, benzyl or substituted benzyl, naphthyl or substituted naphthyl, polypeptide chain and its derivatives; R 1 , R 2 ,R 3 ,R 5 ,R 6 ,R 7 ,R 8 ,R 9 All are hydrogen, C 1-20 alkyl, Phenyl or substituted phenyl, benzyl or substituted benzyl, heteroaromatic ring or substituted heteroaromatic ring; R 11 H, TBS, TMS, TBDPS, TES, TPS, TIPS, Boc, Ac, Ts and their derivatives; R 4 ,R 10 are Boc, Ts, acyl, urea, thiourea or substituted thiourea, carbonyl or substituted carbonyl and their derivatives, polypeptide chains and their derivatives; R 21 ,R 22 ,R 23 ,R 24 are phenyl or substituted phenyl, naphthyl or substituted naphthyl, heteroaromatic or substituted heteroaromatic, phenoxy or substituted phenoxy, naphthoxy or substituted naphthoxy, alkyl or alkoxy; X is halogen, BF4 - ,OTf - ,OAc - , OBoc - , NO3 - , NO2 - , PO4 - , PF6 - , chiral phosphonate anion; m=2, 3, 4, 5; n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10.

2. The chiral peptide quaternary phosphonium salt catalyst according to claim 1, characterized in that Its structural formula is as follows: Among them, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 are hydrogen, methyl, ethyl, propyl, butyl, benzyl, phenyl or R 11 For H, TBS, TMS, TBDPS, TES, TPS, TIPS, Boc, Ac, Ts; R is methyl, ethyl, propyl, butyl, phenyl or phenyl substituted with at least one of halogen, trifluoromethyl, methyl, butyl, TMS, propyl, phenyl and methoxy, anthracenyl, pyridyl or substituted pyridyl, pyranyl or substituted pyranyl, thienyl or substituted thienyl; R 12 Phenyl or phenyl substituted by at least one of methoxy, methyl, propyl, butyl, trifluoromethyl, nitro and halogen; R 13 Methyl, ethyl, propyl, butyl, phenyl or phenyl substituted with at least one of halogen, methyl, methoxy, butyl, trifluoromethyl and nitro, naphthyl, pyridyl or substituted pyridyl, pyranyl or substituted pyranyl, thienyl or substituted thienyl; R 14 Phenyl or phenyl substituted with at least one of halogen, methyl, methoxy, propyl, butyl, cyano, trifluoromethyl and nitro, adamantyl, cyclopropyl, cyclopentyl, cyclohexyl, naphthyl, pyridyl or substituted pyridyl, pyranyl or substituted pyranyl, thienyl or substituted thienyl; R 15 , R 16 are all phenyl or phenyl substituted with at least one of halogen, methoxy, propyl, butyl, trifluoromethyl, nitro and phenyl; R 17 , R 18 are methyl, ethyl, propyl, butyl, phenyl or phenyl substituted with at least one of halogen, methyl, methoxy, butyl, trifluoromethyl and nitro, naphthyl, pyridyl or substituted pyridyl, pyranyl or substituted pyranyl, thienyl or substituted thienyl; R 19 , R 20 are phenyl or phenyl substituted with at least one of halogen, methyl, methoxy, propyl, butyl, cyano, trifluoromethyl and nitro, adamantyl, cyclopropyl, cyclopentyl, cyclohexyl, naphthyl, pyridyl or substituted pyridyl, pyranyl or substituted pyranyl, thienyl or substituted thienyl; R 21 , R 22 are phenyl or phenyl substituted with at least one of halogen, methoxy, propyl, butyl, trifluoromethyl and nitro, naphthyl, phenoxy, naphthyloxy, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, butyl and butoxy; X is halogen, BF4 - ,OTf - ,OAc - , OBoc - , NO3 - , NO2 - , PO4 - , PF6 - , chiral phosphonate anion; n＝0，1，2，3，4，5，6，7，8，9，10。 3. The chiral peptide quaternary phosphonium salt catalyst according to claim 2, characterized in that Its structural formula is as follows:

4. The chiral peptide quaternary phosphonium salt catalyst according to claim 1, characterized in that Its structural formula is as follows: Among them, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 are hydrogen, methyl, ethyl, propyl, butyl, benzyl, phenyl or R 11 For H, TBS, TMS, TBDPS, TES, TPS, TIPS, Boc, Ac, Ts; R, R' are methyl, ethyl, propyl, butyl, phenyl or phenyl substituted with at least one of halogen, trifluoromethyl, methyl, butyl, TMS, propyl, phenyl and methoxy, naphthyl, pyridyl or substituted pyridyl, pyranyl or substituted pyranyl, thienyl or substituted thienyl; R 15 , R 16 are all phenyl or phenyl substituted with at least one of halogen, methoxy, propyl, butyl, trifluoromethyl, nitro and phenyl; R 17 , R 18 are methyl, ethyl, propyl, butyl, phenyl or phenyl substituted with at least one of halogen, methyl, methoxy, butyl, trifluoromethyl and nitro, naphthyl, pyridyl or substituted pyridyl, pyranyl or substituted pyranyl, thienyl or substituted thienyl; R 19 , R 20 are phenyl or phenyl substituted with at least one of halogen, methyl, methoxy, propyl, butyl, cyano, trifluoromethyl and nitro, adamantyl, cyclopropyl, cyclopentyl, cyclohexyl, naphthyl, pyridyl or substituted pyridyl, pyranyl or substituted pyranyl, thienyl or substituted thienyl; R 21 , R 22 , R 23 , R 24 are phenyl or phenyl substituted with at least one of halogen, methoxy, propyl, butyl, trifluoromethyl and nitro, naphthyl, phenoxy, naphthyloxy, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, butyl and butoxy; X is halogen, BF4 - ,OTf - ,OAc - , OBoc - , NO3 - , NO2 - , PO4 - , PF6 - , chiral phosphonate anion; n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10.

5. The chiral peptide quaternary phosphonium salt catalyst according to claim 4, characterized in that Its structural formula is as follows:

6. The chiral peptide quaternary phosphonium salt catalyst according to claim 1, characterized in that Its structural formula is as follows: Among them, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 are hydrogen, methyl, ethyl, propyl, butyl, benzyl, phenyl or R 11 For H, TBS, TMS, TBDPS, TES, TPS, TIPS, Boc, Ac, Ts; R and R' are methyl, ethyl, propyl, butyl, phenyl or phenyl substituted with at least one of halogen, trifluoromethyl, methyl, butyl, TMS, propyl, phenyl and methoxy, naphthyl, pyridyl or substituted pyridyl, pyranyl or substituted pyranyl, thienyl or substituted thienyl; R 15 , R 16 are all phenyl or phenyl substituted with at least one of halogen, methoxy, propyl, butyl, trifluoromethyl, nitro and phenyl; R 17 , R 18 are methyl, ethyl, propyl, butyl, phenyl or phenyl substituted with at least one of halogen, methyl, methoxy, butyl, trifluoromethyl and nitro, naphthyl, pyridyl or substituted pyridyl, pyranyl or substituted pyranyl, thienyl or substituted thienyl; R 19 , R 20 are phenyl or phenyl substituted with at least one of halogen, methyl, methoxy, propyl, butyl, cyano, trifluoromethyl and nitro, adamantyl, cyclopropyl, cyclopentyl, cyclohexyl, naphthyl, pyridyl or substituted pyridyl, pyranyl or substituted pyranyl, thienyl or substituted thienyl; R 21 , R 22 , R 23 , R 24 are phenyl or phenyl substituted with at least one of halogen, methoxy, propyl, butyl, trifluoromethyl and nitro, naphthyl, phenoxy, naphthyloxy, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, butyl and butoxy; X is halogen, BF4 - ,OTf - ,OAc - , OBoc - , NO3 - , NO2 - , PO4 - , PF6 - , chiral phosphonate anion; m＝2，3，4，5； n＝0，1，2，3，4，5，6，7，8，9，10。 7. The chiral peptide quaternary phosphonium salt catalyst according to claim 6, characterized in that Its structural formula is as follows:

8. The method for preparing the chiral peptide quaternary phosphonium salt catalyst according to any one of claims 1 to 7, characterized in that: When R 1 To remove When there are groups other than , the reaction formula and specific reaction process are as follows: (1) The natural amino acid compound 1 is refluxed with a hydrochloric acid / methanol solution for 3-6 hours, the solvent is dried, and then TsCl and triethylamine are added and reacted at room temperature for 3-4 hours to obtain compound 2; wherein the molar ratio of the natural amino acid compound, TsCl and triethylamine is 1:1-2:2-3; (2) Compound 2 was dissolved in an organic solvent, and then LiAlH4 was added to react at room temperature for 2-3 hours, filtered, and the filtered product was reacted with EsCl and triethylamine for 2-4 hours to obtain Compound 3; wherein the molar ratio of Compound 2, LiAlH4, EsCl and triethylamine was 1:2-3:1-2:2-3; (3) Compound 3 was added to an alkaline solution and stirred at room temperature for 2-5 hours to obtain compound 4; (4) Compound 4 and KPR 21 R 22 Mix according to a molar ratio of 1:1-3, and then react at room temperature for 3-5 hours to obtain compound 5; (5) Add concentrated sulfuric acid to compound 5, react at 75-85°C for 2-3 hours, then cool, wash with water, extract and concentrate to obtain compound 6; (6) Substituting the hydrogen on the amino group of compound 6 to obtain compound 7; (7) Compound 7 was hydrolyzed with trifluoroacetic acid for 1-2 h to obtain compound 8; (8) Substituting the amino group of compound 8 to obtain compound 9, and repeating steps 6-8 to obtain compound 10; (9) reacting compound 10 with a halogenated hydrocarbon to obtain compound 11, compound 12, or compound 13, namely, a monophosphine catalyst, a ring-opened diphosphine catalyst, and a ring-opened polyphosphine catalyst; (10) Compounds 12 and 13 are reacted with halogenated hydrocarbons to obtain compound 14 or compound 15, i.e., a cyclic diphosphine catalyst and a cyclic polyphosphine catalyst; (1) The natural amino acid compound 16 was refluxed with a hydrochloric acid / methanol solution for 3-6 hours, the solvent was dried and then extracted and concentrated to obtain compound 17; (2) Compound 17 was dissolved in an organic solvent, and then a Boc-protected amino acid was added. A condensation reaction was carried out using HOBT, EDCI, and DIPEA. The reaction was carried out at room temperature for 12-14 hours to obtain compound 18. The molar ratio of compound 27, HOBT, EDCI, and DIPEA was 1:1.5:1.5:

2. (3) Compound 18 is dissolved in an organic solvent, and then trifluoroacetic acid is added to carry out a deprotection reaction to obtain compound 19; (4) Compound 19 was dissolved in an organic solvent, and then a Boc-protected amino acid was added. A condensation reaction was carried out using HOBT, EDCI, and DIPEA. The reaction was carried out at room temperature for 12-14 hours to obtain compound 20; wherein the molar ratio of compound 19, HOBT, EDCI, and DIPEA was 1:1.5:1.5:2; steps 2-4 were repeated to extend the peptide chain to obtain compound 21; (5) Compound 21 was dissolved in an organic solvent, and then LiAlH4 was added for reduction reaction. The reaction was carried out at room temperature for 2-3 hours to obtain compound 22; wherein the molar ratio of compound 21 to LiAlH4 was 1:2; (6) Compound 22 was dissolved in an organic solvent, and then NBS and PPh3 were added for bromination reaction to obtain compound 23; wherein the molar ratio of compound 27, NBS and PPh3 was 1:1.2:1.2; Compound 10 and compound 23 are subjected to reflux reaction in an organic solvent to prepare compound 24, i.e., a monophosphine catalyst; (1) Compound 10 and Compound 23 were hydrolyzed under the action of trifluoroacetic acid to obtain Compound 25 and Compound 26; (2) Compound 25 and Compound 26 are subjected to a bonding reaction with a halogenated hydrocarbon or a carboxylic acid to obtain Compound 27; (3) Compound 27 is subjected to reflux reaction in toluene to obtain compound 28, i.e., a cyclic chiral peptide monophosphine catalyst.

9. The method for preparing the chiral peptide quaternary phosphonium salt catalyst according to any one of claims 1 to 7, characterized in that: When R 1 for When the group, the reaction formula and specific reaction process are as follows: (1) Threonine was refluxed in a hydrochloric acid and methanol solution for 2 h, then concentrated and added with 1.5-2 equivalents of Boc2O under alkaline conditions, and reacted at room temperature for 2-3 h to obtain compound 30; (2) Compound 30, DMP, and HCl were mixed in a molar ratio of 1:1-1.5:1-1.5 and reacted at room temperature for 5-6 h to obtain compound 31; (3) Compound 31 was reacted with LiAlH4 for 2-3 h, and then EsCl and triethylamine were added and reacted at room temperature for 1-1.5 h to obtain compound 32; wherein the molar ratio of compound 31, LiAlH4, EsCl and triethylamine was 1:1.5-2:1.2-1.5:1.8-2.2; (4) Compound 32 and KPR 21 R 22 The mixture was mixed at a molar ratio of 1:1-1.5, and then reacted at room temperature for 7-8 hours. After the reaction, 6M concentrated sulfuric acid was added and stirred at room temperature for 1 hour, and then directly filtered to obtain compound 33; (5) Compound 33 and R 11 Cl was mixed in a molar ratio of 0.8-1.2:1.5-2.5, stirred at room temperature for 1.5-2.5h, and the solvent was dried to obtain a crude product; the crude product was stirred in 1M hydrochloric acid at room temperature for 20-40min, then dried, extracted, and concentrated to obtain an intermediate, and R was added continuously. 11 Cl was stirred at room temperature for 1-1.5 h to obtain compound 34; (6) Compound 34 was hydrolyzed with trifluoroacetic acid for 1-2 hours to obtain compound 35. The process of preparing chiral peptide quaternary phosphonium salt catalyst from compound 35 was the same as that when R 1 for The subsequent steps are the same as when 10. Use of the chiral peptide quaternary phosphonium salt catalyst according to any one of claims 1 to 7 in an asymmetric catalytic reaction.

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