Chiral phosphoric acid macrocyclic compound as well as preparation method and application thereof

Abstract

The invention discloses a chiral phosphoric acid macrocyclic compound as well as a preparation method and application thereof. The structural formula is shown as a formula I. The compound shown in the formula I serves as a catalyst to catalyze enantioselective fluorocyclization reaction to generate a chiral product. Cheap and easily available raw materials are selected, binaphthol and several cheap and easily available nucleophilic reagents are taken as starting materials, a chiral macroring derived from binaphthol can be prepared through a simple nucleophilic substitution reaction, then the chiral diphosphate macroring can be obtained through deprotection and phosphorylation, and the macroring has good catalytic performance as a catalyst. The reaction conditions are relatively mild, and the obtained fluorine-containing product has special properties and has good practicability and application prospects. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of organic chemistry, and relates to a class of chiral phosphate macrocyclic compounds and a preparation method and application thereof, and more specifically to a class of chiral phosphate macrocyclic compounds with a binaphthol skeleton and a study on the synthesis and catalytic performance thereof. Background Art

[0002] Supramolecular chemistry plays an important role in many fields, such as material technology, medicine, data storage, sensor technology, catalysis, etc. Supramolecular catalysis is the intersection of supramolecular chemistry and catalysis, and supramolecular catalysis mainly focuses on two ideas: one is to construct catalytic modules with the help of supramolecular chemical tools to provide a flexible, functional group-rich catalyst library; the other is to use non-covalent interactions to simulate enzyme catalysis, with the goal of achieving efficient and highly selective catalysis (PWNM van Leeuwen. Chem. Soc. Rev. 2014, 43, 1734-1787).

[0003] Supramolecular catalysis based on macrocyclic compounds as the main molecule is an important research field. Although there are few studies on supramolecular catalysis based on covalent organic macrocycles (Q.-Q. Wang. Supramolecular Catalysis Using Organic Macrocycles, Chapter in Handbook of Macrocyclic Supramolecular Assembly, Y. Liu, Y. Chen, H.-Y. Zhang, Eds. Springer, Singapore, 2019), but this type of compound has important application prospects (Q.-Q. Wang. Angew. Chem. Int. Ed. 2020, 59, 2623-2627; Q.-Q. Wang, Angew. Chem. Int. Ed. 2020, 59, 10894-10898), especially the macrocycle based on chiral phosphate (Magnus Rueping. Chem. Rev. 2014, 114, 9047-9153). Its advantages include easy synthesis, convenient modification and regulation, and multiple catalytic active sites. We believe that using this compound as the basic skeleton and introducing special groups can give it specific functions. Therefore, it is urgent to develop efficient methods to construct a series of chiral phosphate macrocyclic compounds with a binaphthol skeleton and develop their potential applications in recognition, catalysis and other fields. Summary of the invention

[0004] The invention provides a chiral phosphoric acid macrocyclic compound with a binaphthol skeleton, a synthesis method thereof and application thereof in the catalysis field.

[0005] The chiral phosphate macrocyclic compound having a binaphthol skeleton provided by the present invention has a structural formula as shown in Formula I:

[0006]

[0007] In Formula I, linker is selected from any one of the following groups:

[0008]

[0009] The present invention also provides a method for preparing the compound represented by the above formula I.

[0010] The method comprises the following steps:

[0011] In an inert atmosphere, the compound represented by formula II is dissolved in an organic solvent, phosphorus oxychloride is added, reacted, water is added, and the reaction is continued to obtain the compound represented by formula I;

[0012]

[0013] The definition of Linker in Formula II is the same as that of Linker in Formula I above.

[0014] In the above method, the organic solvent is pyridine;

[0015] The usage ratio of the compound represented by formula II, phosphorus oxychloride, organic solvent and water is 0.1-0.2 mmol: 1-2 mmol: 1.2-3 mL: 1.1-1.6 mL, respectively;

[0016] After adding phosphorus oxychloride, the reaction temperature can be 60-80°C, and the reaction time can be 16-24 hours, specifically 17 hours;

[0017] After the reaction with phosphorus oxychloride is complete, return to room temperature, add water dropwise, and then raise the temperature to 60-80°C and continue the reaction for 4-24 hours.

[0018] The compound represented by the above formula II is prepared by a method comprising the following steps: subjecting the compound represented by the formula III to a deprotection reaction with p-toluenesulfonic acid to obtain:

[0019]

[0020] The definition of Linker in Formula III is the same as that of Linker in Formula I above;

[0021] The reaction is carried out in an organic solvent, and the organic solvent can be a mixed solvent of dichloromethane and methanol in a volume ratio of 1:1;

[0022] The dosage of the compound represented by formula III, p-toluenesulfonic acid (monohydrate), and organic solvent are 0.22-0.4 mmol, 4.4-8 mmol, and 16-30 mL, respectively; the reaction temperature can be 24-40° C., and the reaction time can be 5-48 hours.

[0023] The compound represented by the above formula III is prepared by a method comprising the following steps: under alkaline conditions, allowing the compound represented by the formula IV to undergo a nucleophilic substitution reaction with X-Linker-X;

[0024]

[0025] In X-Linker-X, X represents a leaving group, which can be independently selected from at least one of -OTs and -Br; the definition of Linker is the same as that of Linker in the aforementioned formula I;

[0026] Specifically, X-Linker-X can be any one of the following compounds:

[0027] Type 1:

[0028] Type 2:

[0029] The formula III obtained by the reaction of type one linker is defined as formula III-A, and the formula III obtained by the reaction of type two linkers is defined as III-B;

[0030] The nucleophilic substitution reaction is carried out in an organic solvent.

[0031] In the step of constructing the structure of the compound represented by formula III-A, the organic solvent is N,N-dimethylformamide;

[0032] The alkaline condition is provided by an inorganic base, and the inorganic base can specifically be potassium carbonate;

[0033] The amount of the compound represented by formula IV, type 1 X-Linker-X, inorganic base potassium carbonate, and organic solvent used are 0.5-2.5 mmol, 0.5-2.5 mmol, 3-15 mmol, 50-300 mL, respectively;

[0034] In the reaction step, the temperature is 100-120° C., specifically 120° C., and the reaction time is 5-10 hours.

[0035] In the step of constructing the structure of the compound represented by formula III-B, the organic solvent is acetone or acetonitrile;

[0036] The alkaline condition is provided by potassium carbonate or cesium carbonate;

[0037] The dosage of the compound represented by formula IV, type II X-Linker-X, inorganic base potassium carbonate or cesium carbonate, and organic solvent are 0.5-2.5 mmol, 0.5-2.5 mmol, 3-15 mmol, 50-300 mL, respectively;

[0038] In the reaction step, the temperature is 60-80° C. and the reaction time is 24-48 hours.

[0039] In addition, the use of the compound represented by the above formula I in organic asymmetric catalysis also falls within the protection scope of the present invention.

[0040] The application includes but is not limited to being used as a catalyst to catalyze enantioselective fluorocyclization reaction to generate chiral products.

[0041] The present invention also provides a method for preparing a compound of formula A using a compound of formula I.

[0042]

[0043] In formula A, R 1 Can be: Bn;

[0044] R 2 Can be selected from: Ts, p-tBuPhSO 2 ;

[0045] R 3 Can be selected from: H, Br;

[0046] The method for preparing the compound of formula A provided by the present invention comprises the following steps: using the compound of formula B as a raw material, the compound of formula I as a catalyst, and a selective fluorine reagent as a fluorine source, and performing a fluorine cyclization reaction under alkaline conditions and inert gas protection to obtain the compound of formula A.

[0047]

[0048]

[0049] In formula B, R 1 Can be: Bn;

[0050] R 2 Can be selected from: Ts, p-tBuPhSO 2 ;

[0051] R 3 Can be selected from: H, Br.

[0052] The compound represented by formula I is 1-10 mol% of the compound represented by formula B, and specifically can be 2 mol%.

[0053] The invention uses cheap and readily available raw materials, starting from binaphthol and several cheap and readily available nucleophilic reagents, and can prepare a chiral macrocycle derived from binaphthol through a simple nucleophilic substitution reaction, and then obtain a chiral bisphosphonic acid macrocycle through deprotection and phosphorylation, and such macrocycle has good catalytic performance as a catalyst. The reaction conditions are relatively mild, and the obtained fluorine-containing product has special properties and has good practicality and application prospects. DETAILED DESCRIPTION

[0054] The present invention is further described in detail below in conjunction with specific embodiments, and the examples provided are only for illustrating the present invention, rather than for limiting the scope of the present invention. The examples provided below can be used as a guide for further improvements by those of ordinary skill in the art, and do not constitute a limitation of the present invention in any way.

[0055] The experimental methods in the following examples, unless otherwise specified, are all conventional methods, and are performed according to the techniques or conditions described in the literature in the field or according to the product instructions. The materials, reagents, etc. used in the following examples, unless otherwise specified, can all be obtained from commercial channels.

[0056] Example 1: Preparation of the compound represented by formula III-A1

[0057] The reaction formula is as follows:

[0058]

[0059] The specific preparation method is:

[0060] Add magnet, compound IV (279 mg, 0.5 mmol), K 2 CO 3 (415 mg, 3 mmol) and 30 mL of N,N-dimethylformamide. Under argon protection, (185 mg, 0.5 mmol) TsOCH 2 CH 2 OTs (0.025 mol / L in DMF) was dissolved in 20 mL DMF, and the solution was slowly added dropwise to a two-necked bottle over 20 min, and heated to 120°C for 5 h. The solvent was spin-dried, and column chromatography (silica gel 100-200 mesh, eluent: dichloromethane / methanol = 100:1) was performed to obtain 67 mg of the compound represented by formula III-A1, with a yield of 23%.

[0061] 1 HNMR (500MHz, CDCl 3)δ7.90(s,4H),7.86(d,J=8.2Hz,4H),7.68(d,J=8.7Hz,8H),7.39(ddd,J=8.1,6.1,1.8Hz,4H),7.28-7.23( m,8H),7.08(d,J=8.6Hz,8H),4.52-4.42(m,8H),4.40(d,J=5.8Hz,4H),4.31(d,J=5.8Hz,4H),2.32(s,12H);

[0062] 13 C NMR (125 MHz, CDCl 3 )δ158.1,151.5,135.0,133.4,132.1,130.8,130.7,130.0,127.8,126.5,126.4,126.1,125.1,115.6,98.4,67.4,55.8;

[0063] HRMS(ESI - )calc.for[MH] - (C 76 H 63 O 12 - )1167.4325,found:1167.4343.

[0064] It can be seen from the above that the structure of the above compound is correct, and it is the compound represented by formula III-A1.

[0065] Wherein, the preparation method of the compound represented by formula IV is as follows:

[0066]

[0067] Add sodium hydride (2.92g, 73mmol) to a two-necked flask, then add 150mL THF, and place in an ice bath pot to stir. Dissolve binaphthol (9.5g, 33.2mmol) in 50ml THF, and drip this solution into the above two-necked flask through a constant pressure dropping funnel. The dripping is completed in about 20 minutes. Continue to stir in an ice bath for 1h, then stir at room temperature for 15min, place in an ice bath pot again, slowly drip (chloromethyl) methyl ether, then remove the ice bath, and react at room temperature overnight. Stop the reaction, extract with dichloromethane, and the organic phase is washed with anhydrous Na 2 SO 4 After drying, the product was recrystallized from dichloromethane and n-hexane to obtain 11.45 g of a white solid compound with a yield of 93%.

[0068] Add the above white solid compound (5.6g, 15mmol) and 350mL of ether to a two-necked flask and stir at room temperature. Slowly add n-butyl lithium (1.6M, 28mL) to the above two-necked flask through a syringe, and the addition is completed in about 10 minutes. Continue stirring at room temperature for 3 hours, place the two-necked flask in a low-temperature bath at a temperature of -78°C, cool for 3 minutes, quickly add iodine particles (11.4g, 45mmol), then slowly warm to -30°C, and react at room temperature overnight. Stop the reaction, quench the reaction with saturated sodium thiosulfate, and extract with ethyl acetate. Spin dry the solvent, column chromatography (silica gel 100-200 mesh, eluent: petroleum ether / ethyl acetate = 15:1), and obtain 7.2g of yellow solid compound with a yield of 77%.

[0069] The yellow solid compound (1.92 g, 3 mmol), p-hydroxyphenylboronic acid (1.69 g, 12 mmol), Pd(PPh 3 ) 4 (355 mg, 0.307 mmol), argon replacement. 50 mL of deoxygenated DME solution and 8 mL of Na 2 CO 3 The solution (2M) was reacted at 85°C for 5 h. The reaction was stopped, extracted with ethyl acetate, filtered, the solvent was dried, and column chromatography (silica gel 100-200 mesh, eluent: petroleum ether / ethyl acetate = 3:1) was performed to obtain 1.4 g of a yellow solid compound of formula IV with a yield of 85%.

[0070] 1 H NMR (500MHz, DMSO) δ9.58(s,2H),8.01(s,2H),8.00(d,J=8.6Hz,2H),7.54(d,J=8.6Hz,4H),7.44(t,J=7.5Hz,2H),7.29( t,J=7.0Hz,2H),7.09(d,J=8.5Hz,2H),6.90(d,J=8.6Hz,4H),4.36(d,J=5.4Hz,2H),4.26(d,J=5.4Hz,2H),2.30(s,6H);

[0071] 13 C NMR (125MHz, DMSO) δ156.8,150.5,134.8,132.5,130.4,130.2,129.6,128.8,127.8,126.0,125.8,125.5,124.9,115.2,97.3,55.1.

[0072] Example 2: Preparation of the hydroxy macrocycle represented by structural formula II (compound represented by formula II-A1)

[0073] The reaction formula is as follows:

[0074]

[0075] The specific preparation method is:

[0076] Add a magnetic particle, the compound represented by formula III-A1 (340 mg, 0.29 mmol), p-toluenesulfonic acid monohydrate (1.1 g, 5.8 mmol), 11 mL of dichloromethane and 11 mL of methanol to a clean single-mouth bottle. After reacting at room temperature for 5 hours, the solvent was dried and column chromatography (silica gel 100-200 mesh, eluent: dichloromethane / methanol = 200:1) was performed to obtain 182 mg of the compound represented by formula II-A1, with a yield of 63%.

[0077] 1 HNMR (500MHz, CDCl 3 )δ7.96(s,4H),7.88(d,J=8.1Hz,4H),7.59(d,J=7.2Hz,8H),7.36(t,J=7.4Hz,4H),7.27 (t,J=8.0Hz,4H),7.17(d,J=8.5Hz,4H),7.02(d,J=7.4Hz,8H),5.27(s,4H),4.46(s,8H);

[0078] 13 C NMR (125 MHz, CDCl 3 )δ157.9,150.0,133.1,130.8,130.7,130.3,130.1,129.4,128.3,127.0,124.5,124.2,115.5,112.4,66.5.

[0079] HRMS(ESI - )calc.for[MH] - (C 68 H 47 O 8 - )991.3276,found:991.3270.

[0080] From the above, it can be seen that the structure of the above compound is correct, and it is the compound represented by formula II-A1.

[0081] The preparation method of the compound represented by formula III-A1 is detailed in Example 1.

[0082] Example 3: Preparation of the Phosphate Macrocycle of Formula I (Compound of Formula I-A1)

[0083] The reaction formula is as follows:

[0084]

[0085] The specific preparation method is:

[0086] Add a magnet and the compound of formula II-A1 (149 mg, 0.15 mmol) to a clean Schlenk tube. Add 1.2 mL of pyridine under argon protection and stir at room temperature for 15 min. Slowly add POCl 3 (140 μL, 1.5 mmol), react at 70°C for 17 h, return to room temperature, slowly add 1.15 mL of water, and then heat to 70°C for 4 h. Stop the reaction, spin dry the solvent, wash with 6M hydrochloric acid solution, extract with dichloromethane, filter, column chromatography (silica gel 100-200 mesh, eluent: dichloromethane / methanol = 30:1), and obtain 151 mg of the compound represented by formula I-A1, with a yield of 90%.

[0087] 1 H NMR (400MHz, DMSO) δ8.14(s,4H),8.10(d,J=8.2Hz,4H),7.63(d,J=8.3Hz,8H),7.51(t,J=7 .5Hz,4H),7.34(t,J=7.7Hz,4H),7.20(d,J=8.6Hz,4H),7.10(d,J=8.5Hz,8H),4.48(s,8H);

[0088] 13 C NMR (125MHz, DMSO) δ157.1,145.6,133.6,131.1,131.0,130.7,130.0,129.7,128.5,126.3,125.9,125.4,122.2,114.1,65.3;

[0089] 31 P NMR (162 MHz, DMSO) δ 0.77.

[0090] HRMS(ESI - )calc.for[MH] - (C 68 H 45 O 12 P 2 - )1115.2392,found:1115.2388.

[0091] It can be seen from the above that the structure of the above compound is correct, and it is the compound shown in formula I-A1.

[0092] The preparation method of the compound represented by formula II-A1 is detailed in Example 2.

[0093] Example 5: Preparation of the Phosphate Macrocycle of Formula I (Compound of Formula I-A2)

[0094] The reaction formula is as follows:

[0095]

[0096] The specific preparation method is:

[0097] Add a magnet and the compound of formula II-A2 (200 mg, 0.19 mmol) to a clean Schlenk tube. Add 2.3 mL of pyridine under argon protection and stir at room temperature for 15 min. Slowly drop POCl 3 (177 μL, 1.9 mmol), react at 70°C for 16 h, return to room temperature, slowly add 1.15 mL of water, and then heat to 70°C for 22 h. Stop the reaction, spin dry the solvent, wash with 6M hydrochloric acid solution, extract with dichloromethane, filter, column chromatography (silica gel 100-200 mesh, eluent: dichloromethane / methanol = 30:1), and obtain 210 mg of the compound represented by formula I-A2, with a yield of 93%.

[0098] 1 H NMR (500MHz, DMSO) δ8.15(s,4H),8.10(d,J=8.3Hz,4H),7.65(d,J=8.3Hz,8H),7.51(t,J=7.8Hz,4H),7. 34(t,J=7.7Hz,4H),7.18(d,J=8.6Hz,4H),7.07(d,J=8.9Hz,8H),4.28-4.16(m,8H),2.30-2.22(m,4H);

[0099] 13 C NMR (125MHz, DMSO) δ158.0, 145.5 (d, J = 9.2Hz), 133.5, 131.1, 130.8, 130.7, 130.1, 129.4, 128.4, 126.3, 125.9, 125.4, 122.2, 113.9, 63.4, 28.5;

[0100] 31 P NMR (162 MHz, DMSO) δ 1.20.

[0101] HRMS(ESI - )calc.for[MH] - (C 70 H 49 O12 P 2 - )1143.2705,found:1143.2684.

[0102] It can be seen from the above that the structure of the above compound is correct, and it is the compound shown in formula I-A2.

[0103] Wherein, the preparation method of the compound represented by formula II-A2 refers to Example 2.

[0104] Example 6: Preparation of the Phosphate Macrocycle of Structural Formula I (Compound of Formula I-A3)

[0105] The reaction formula is as follows:

[0106]

[0107] The specific preparation method is:

[0108] Add a magnet and the compound of formula II-A3 (105 mg, 0.1 mmol) to a clean Schlenk tube. Add 1.2 mL of pyridine under argon protection and stir at room temperature for 15 min. Slowly add POCl 3 (93 μL, 1 mmol), react at 70°C for 16 h, return to room temperature, slowly add 1.15 mL of water, and then heat to 70°C for 4 h. Stop the reaction, spin dry the solvent, wash with 6M hydrochloric acid solution, extract with dichloromethane, filter, column chromatography (silica gel 100-200 mesh, eluent: dichloromethane / methanol = 30:1), and obtain 108 mg of the compound represented by formula I-A3, with a yield of 92%.

[0109] 1 H NMR (500MHz, DMSO) δ8.14(s,4H),8.09(d,J=8.2Hz,4H),7.75(d,J=8.2Hz,8H),7.50(t,J=7.5Hz,4H),7. 32(t,J=8.0Hz,4H),7.12(d,J=8.6Hz,4H),7.08(d,J=8.8Hz,8H),4.21-4.11(m,8H),2.03-1.94(m,8H);

[0110] 13 C NMR (125MHz, DMSO) δ158.2, 145.3 (d, J = 9.7Hz), 133.4, 131.2, 131.0, 130.8, 130.6, 129.2, 128.5, 126.5, 126.0, 125.6, 122.2, 114.2, 66.6, 24.9;

[0111] 31 P NMR (162 MHz, DMSO) δ 1.23.

[0112] HRMS(ESI - )calc.for[MH] - (C 72 H 53 O 12 P 2 - )1171.3018,found:1171.3015.

[0113] It can be seen from the above that the structure of the above compound is correct, and it is the compound shown in formula I-A3.

[0114] Wherein, the preparation method of the compound represented by formula II-A3 refers to Example 2.

[0115] Example 7: Preparation of the compound represented by formula III-B1

[0116] The reaction formula is as follows:

[0117]

[0118] The specific preparation method is:

[0119] Add magnet, compound IV (279 mg, 0.5 mmol), Cs 2 CO 3 (977mg, 3mmol) and 30mL of acetone. Under argon protection, (132mg, 0.5mmol) 1,2-di(bromomethyl)benzene (0.025mol / L inacetone) was dissolved in 20mL of acetone, and the above solution was slowly added dropwise to a two-necked bottle, and the addition was completed in 20 minutes. After heating to 60°C and reacting for 48 hours, the solvent was spin-dried and column chromatography (silica gel 100-200 mesh, eluent: dichloromethane / methanol = 100:1) was performed to obtain 69mg of the compound shown in formula III-B1, with a yield of 20%.

[0120] 1 HNMR (400MHz, CDCl 3)δ7.87(s,4H),7.82(d,J=8.2Hz,4H),7.69(d,J=8.2Hz,8H),7.60(dd,J=5.6,3.5Hz,4H),7.44(dd,J=5.6,3.4Hz,4H),7.40-7.3 3(m,4H),7.22(d,J=3.9Hz,8H),7.10(d,J=8.2Hz,8H),5.23(s,8H),4.35(d,J=5.8Hz,4H),4.28(d,J=5.8Hz,4H),2.21(s,12H);

[0121] 13 C NMR (101 MHz, CDCl 3 )δ158.1,151.4,135.2,134.9,133.4,131.9,130.8,130.1,129.3,128.6,127.7,126.5,126.4,126.1,125.0,114.6,98.3,68.3,55.7.

[0122] HRMS(ESI + )calc.for[M+Na] + (C 88 H 72 O 12 Na + )1343.4916,found:1343.4903.

[0123] From the above, it can be seen that the structure of the above compound is correct, and it is the compound shown in formula III-B1.

[0124] Example 8: Preparation of the hydroxy macrocycle represented by structural formula II (compound represented by formula II-B1)

[0125]

[0126] The reaction formula is as follows:

[0127] The specific preparation method is:

[0128] Add a magnetic particle, the compound shown in formula III-B1 (383 mg, 0.29 mmol), p-toluenesulfonic acid monohydrate (1.1 g, 5.8 mmol), 11 mL of dichloromethane and 11 mL of methanol to a clean single-mouth bottle. After reacting at room temperature for 10 hours, spin dry the solvent, and perform column chromatography (silica gel 100-200 mesh, eluent: dichloromethane / methanol = 200:1) to obtain 284 mg of the compound shown in formula II-B1, with a yield of 85%.

[0129] 1HNMR (400MHz, CDCl 3 )δ7.96(s,4H),7.87(d,J=8.0Hz,4H),7.65(d,J=8.7Hz,8H),7.61(dd,J=5.6,3.4Hz,4H),7.43(dd,J=5.6,3.4Hz,4H),7.34(t,J =8.1Hz,4H),7.26(t,J=8.4Hz,4H),7.16(d,J=8.4Hz,4H),7.10(d,J=8.7Hz,8H),5.28(s,4H),5.20(dd,J=14.3Hz,11.5Hz,8H);

[0130] 13 C NMR (125 MHz, CDCl 3 )δ158.4,150.2,135.1,132.8,131.0,130.9,130.2,130.1,129.5,129.1,128.6,128.3,127.1,124.2,114.8,112.2,68.1.

[0131] HRMS(ESI - )calc.for[MH] - (C 80 H 55 O 8 - )1143.3902,found:1143.3873.

[0132] From the above, it can be seen that the structure of the above compound is correct, and it is the compound shown in formula II-B1.

[0133] Example 9: Preparation of the molecular cage represented by structural formula I (compound represented by formula I-B1)

[0134] The reaction formula is as follows:

[0135]

[0136] The specific preparation method is:

[0137] Add a magnet and the compound of formula II-B1 (172 mg, 0.15 mmol) to a clean Schlenk tube. Add 1.8 mL of pyridine under argon protection and stir at room temperature for 15 min. Slowly drop POCl 3(140 μL, 1.5 mmol), react at 70°C for 24 h, return to room temperature, slowly add 1.6 mL of water, and then heat to 70°C for 14 h. Stop the reaction, spin dry the solvent, wash with 6M hydrochloric acid solution, extract with dichloromethane, filter, column chromatography (silica gel 100-200 mesh, eluent: dichloromethane / methanol = 30:1), and obtain 171 mg of the compound shown in formula I-B1, with a yield of 90%.

[0138] 1 H NMR (400MHz, DMSO) δ8.16(s,4H),8.09(d,J=8.2Hz,4H),7.82(d,J=8.3Hz,8H),7.64(dd,J=5.6,3.5Hz,4H),7.50(t,J=7.6Hz,4H), 7.45(dd,J=5.7,3.4Hz,4H),7.32(t,J=7.8Hz,4H),7.22(d,J=8.4Hz,8H),7.12(d,J=8.6Hz,4H),5.33(dd,J=15.7Hz,12.0Hz,8H);

[0139] 13 C NMR(125MHz,DMSO)δ157.9,145.3(d,J=9.5Hz),135.1,133.2,131.1,131.0, 130.7,130.5,129.6,128.4,128.1,126.4,125.9,125.5,122.1,114.4,67.1;

[0140] 31 P NMR (162 MHz, DMSO) δ 1.13.

[0141] HRMS(ESI - )calc.for[MH] - (C 80 H 53 O 12 P 2 - )1267.3018,found:1267.3027.

[0142] It can be seen from the above that the structure of the above compound is correct, and it is the compound shown in formula I-B1.

[0143] Example 10: Preparation of the molecular cage represented by structural formula I (compound represented by formula I-B2)

[0144] The reaction formula is as follows:

[0145]

[0146] The specific preparation method is:

[0147] Add a magnet and the compound of formula II-B2 (172 mg, 0.15 mmol) to a clean Schlenk tube. Add 1.8 mL of pyridine under argon protection and stir at room temperature for 15 min. Slowly add POCl 3 (140 μL, 1.5 mmol), react at 70°C for 24 h, return to room temperature, slowly add 1.6 mL of water, and heat to 70°C for 24 h. Stop the reaction, spin dry the solvent, wash with 6M hydrochloric acid solution, extract with dichloromethane, filter, column chromatography (silica gel 100-200 mesh, eluent: dichloromethane / methanol = 30:1), and obtain 171 mg of the compound shown in formula I-B2, with a yield of 90%.

[0148] 1 H NMR (400MHz, DMSO) δ8.16(s,4H),8.10(d,J=8.3Hz,4H),7.78(d,J=8.3Hz,8H),7.72(s,2H),7.50(t,J=7 .5Hz,4H),7.47(s,6H),7.32(t,J=7.7Hz,4H),7.15(d,J=8.3Hz,8H),7.13(d,J=8.2Hz,4H),5.21(s,8H);

[0149] 13 C NMR(125MHz,DMSO)δ157.9,145.3(d,J=9.6Hz),137.4,133.2,131.1,131.0,130 .7,130.4,129.5,128.4,127.1,127.0,126.4,125.9,125.4,122.1,114.4,69.1;

[0150] 31 P NMR (162 MHz, DMSO) δ 1.19.

[0151] HRMS(ESI - )calc.for[MH] - (C 80 H 53 O 12 P 2 - )1267.3018,found:1267.3004.

[0152] From the above, it can be seen that the structure of the above compound is correct, and it is the compound shown in formula I-B2.

[0153] Among them, the preparation method of the compound represented by formula II-B2 refers to the preparation method of the compound represented by formula II-B1 in Example 8.

[0154] Example 11: Preparation of the molecular cage represented by structural formula I (compound represented by formula I-B3)

[0155] The reaction formula is as follows:

[0156]

[0157] The specific preparation method is:

[0158] Add a magnet and the compound of formula II-B3 (172 mg, 0.15 mmol) to a clean Schlenk tube. Add 1.8 mL of pyridine under argon protection and stir at room temperature for 15 min. Slowly add POCl 3 (140 μL, 1.5 mmol), react at 70°C for 24 h, return to room temperature, slowly add 1.6 mL of water, and heat to 70°C for 24 h. Stop the reaction, spin dry the solvent, wash with 6M hydrochloric acid solution, extract with dichloromethane, filter, column chromatography (silica gel 100-200 mesh, eluent: dichloromethane / methanol = 30:1), and obtain 171 mg of the compound shown in formula I-B3, with a yield of 90%.

[0159] 1 H NMR (500MHz, DMSO) δ8.13(s,4H),8.09(d,J=8.2Hz,4H),7.72(d,J=8.6Hz,8H),7.53(s,8H),7.50( t,J=7.4Hz,4H),7.32(t,J=8.0Hz,4H),7.13(d,J=8.6Hz,4H),7.08(d,J=8.8Hz,8H),5.23(s,8H);

[0160] 13 C NMR(125MHz,DMSO)δ157.6,145.3(d,J=9.1Hz),136.8,133.3,131.1,130.9, 130.7,130.5,129.5,128.4,127.7,126.4,125.9,125.5,122.1,114.4,68.5;

[0161] 31 P NMR (162 MHz, DMSO) δ 0.88.

[0162] HRMS(ESI - )calc.for[MH] - (C 80 H53 O 12 P 2 - )1267.3018,found:1267.2993.

[0163] From the above, it can be seen that the structure of the above compound is correct, and it is the compound shown in formula I-B3.

[0164] Among them, the preparation method of the compound represented by formula II-B3 refers to the preparation method of the compound represented by formula II-B1 in Example 8.

[0165] Example 12: Asymmetric catalysis experiment

[0166] The chiral phosphate macrocycles substituted with different groups prepared by the present invention are used as catalysts to catalyze enantioselective fluorocyclization reactions:

[0167] We applied this series of chiral phosphate macrocycles to the fluorocyclization reaction of tryptamine derivatives, realizing the first organic asymmetric catalysis based on the activation of chiral phosphate macrocycles, which can obtain 61% yield and 91% ee. This type of catalytic reaction has the characteristics of mild reaction conditions, low catalyst dosage, wide substrate universality, and green economy.

[0168] The reaction formula is as follows:

[0169]

[0170]

[0171] The specific preparation method is:

[0172] The macrocycle (0.002 mmol) of formula I, the selective fluorine reagent (0.12 mmol), and sodium carbonate (0.12 mmol) were added to a 10 mL Schlenk reaction tube equipped with a magnet, and the air was excluded. A chloroform solution (1 mL) of a tryptamine derivative was added under argon protection, and the mixture was stirred and dissolved at 0°C. The reaction was continued at 0°C until the raw tryptamine reacted completely as detected by TLC, and the product was obtained by silica gel flash column chromatography (petroleum ether: ethyl acetate = 5:1 as eluent), where * represents chirality, which is 3aR8aS or 3aS8aR.

[0173] The present invention has been described in detail above. For those skilled in the art, without departing from the purpose and scope of the present invention, and without the need to carry out unnecessary experimental conditions, the present invention can be implemented in a wide range under equivalent parameters, concentrations and conditions. Although the present invention provides specific embodiments, it should be understood that the present invention can be further improved. In a word, according to the principles of the present invention, the application is intended to include any changes, uses or improvements to the present invention, including departure from the disclosed scope in the application, and changes made with conventional techniques known in the art.

Claims

1. A chiral phosphoric acid macrocyclic compound having a binaphthol skeleton as shown in formula I: In Formula I, linker is selected from any one of the following groups:

2. A method for preparing the compound of formula I in claim 1, comprising the steps of: dissolving the compound of formula II in an organic solvent in an inert atmosphere, adding phosphorus oxychloride, reacting, adding water, and continuing the reaction to obtain the compound of formula I; The definition of Linker in Formula II is the same as the definition of Linker in Formula I in Claim 1.

3. The method according to claim 2, It is characterized in that In the method, the organic solvent is pyridine; The usage ratio of the compound represented by formula II, phosphorus oxychloride, organic solvent and water is 0.1-0.2 mmol: 1-2 mmol: 1.2-3 mL: 1.1-1.6 mL, respectively; After adding phosphorus oxychloride, the reaction temperature is 60-80°C and the reaction time is 16-24 hours; After the reaction with phosphorus oxychloride is complete, return to room temperature, add water dropwise, and then raise the temperature to 60-80°C and continue the reaction for 4-24 hours.

4. The compound represented by formula II according to claim 2.

5. A method for preparing the compound of formula II in claim 2, comprising the steps of: subjecting the compound of formula III to a deprotection reaction with p-toluenesulfonic acid to obtain: The definition of Linker in Formula III is the same as the definition of Linker in Formula I of Claim 1.

6. The compound represented by formula III according to claim 5.

7. Use of the compound represented by formula I in organic asymmetric catalysis.

8. The use according to claim 7, Features: The compound shown in formula I is used as a catalyst to catalyze an enantioselective fluorocyclization reaction to generate a chiral product.

9. A method for preparing a compound of formula A, In formula A, R 1 For: Bn; R 2 Selected from: Ts, p-tBuPhSO 2 ; R 3 Selected from: H, Br; The method comprises the following steps: using the compound shown in formula B as a raw material, the compound shown in formula I in claim 1 as a catalyst, and a selective fluorine reagent as a fluorine source, and performing a fluorine cyclization reaction under alkaline conditions and inert gas protection to obtain a compound shown in formula A. In formula B, R 1 For: Bn; R 2 Selected from: Ts, p-tBuPhSO 2 ; R 3 Selected from: H, Br.

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