Method for asymmetric synthesis of organic catalytic chiral sulfur imine ester

Abstract

The method comprises the following steps: adding a sulfenamide compound, an alcohol compound, a catalyst and an alkaline regulator into an organic solvent, cooling the mixed solution to-40 DEG C, cooling for 5 minutes, then adding a regulation reagent, stirring for reaction at-40 DEG C, filtering, washing, and drying to obtain the chiral thioimine ester. And after the reaction is finished, purifying through a rapid chromatography to obtain the chiral (R)-thioimine ester or the chiral (S)-thioimine ester. The regulation reagent is a reagent A or a reagent B, the reagent A is selected from any one of N-chlorosuccinimide, N-bromosuccinimide, N-chlorophthalimide, N-bromophthalimide, 1, 3-dichloro-5, 5-dimethylhydantoin, 1, 3-dibromo-5, 5-dimethylhydantoin and bromochlorodimethylhydantoin, and the reagent B is selected from any one of N-chlorosuccinimide, N-bromophthalimide, N-bromophthalimide, 1, 3-dichloro-5, 5-dimethylhydantoin and bromochlorodimethylhydantoin; the reagent B is trichloroisocyanuric acid; according to the method disclosed by the invention, the chiral (R)-thioimino ester or the chiral (S)-thioimino ester can be selectively synthesized by selecting different regulation and control reagents (the reagent A or the reagent B), the reaction condition is mild, and the steps are simple.

Description

Technical Field

[0001] The present invention relates to the technical field of asymmetric synthesis of chiral compounds, in particular to a method for asymmetric synthesis of organocatalytic chiral sulfilimine esters. Background Art

[0002] Efficiently obtaining both enantiomers of chiral molecules is one of the most fundamental and challenging problems in asymmetric synthesis. Traditional methods for the construction of enantiomers require switching the configuration of chiral components such as chiral starting materials, auxiliaries, and chiral catalysts, but chiral components with inverted configurations are not always readily available. Catalytic synthesis of both enantiomers by adjusting the achiral parameters of the catalyst is an ideal approach. These parameters include the type of achiral metal center, achiral substitution of the catalyst or ligand, reagents, solvents, reaction time, and reaction temperature. While the construction of enantiomers of carbon stereocenters has been reported, few reports have been published on the use of achiral parameters to regulate the enantiomer synthesis of chiral sulfur compounds. This method is cumbersome, complex, and requires harsh reaction conditions. Furthermore, this method involves an intermediate nitrogen alkylation reaction, which makes subsequent catalyst modifications extremely inconvenient. Furthermore, imidazolium salts are difficult to store and are sensitive to air and water, which affects reaction efficiency.

[0003] The application of azasulfur stereogenic centers in drug discovery is gaining increasing attention. N-substitution of sulfur centers can provide additional modification sites, allowing for more hydrogen bonding and enhanced structural diversity, significantly improving the pharmacological parameters and physicochemical properties of certain drug candidates. For example, S(VI)-based pharmacophores and several sulfoximine-containing drug candidates, such as BAY 1143572, have entered clinical trials. Furthermore, sulfilimines have been discovered in several bioactive molecules, such as the collagen IV network,40 and have demonstrated the potential pharmaceutical potential of the S(IV) therein. These findings have further stimulated the study of sulfoximines, sulfilimines, and other aza-S(IV) and S(VI) stereogenic centers.

[0004] However, there are currently few reports on the asymmetric synthesis of sulfimidates. Kano et al. (Angew. Chem. Int. Ed. 2023, 62, e202300637) developed a method for preparing sulfimidates from enantiomerically enriched sulfinamides. However, this method requires enantiomerically enriched starting materials, which limits the practicality of the method itself. Therefore, the prior art still lacks a method for efficiently and simply synthesizing the two enantiomers of chiral sulfimidates. Summary of the Invention

[0005] In order to achieve efficient and simple synthesis of two enantiomers of chiral sulfilimine esters, the present invention provides a method for the asymmetric synthesis of chiral sulfilimine esters by organic catalysis.

[0006] The method of the present invention can selectively synthesize two chiral sulfilimine esters with R / S configurations by simple reagent regulation (changing the type of regulating reagent) without changing the types of main reaction raw materials and catalysts. Moreover, the synthesis method has mild reaction conditions, simple and efficient reaction steps, and does not require expensive metal catalysts.

[0007] The present invention provides a method for asymmetric synthesis of an organocatalytic chiral sulfilimidate. First, a sulfenamide compound, an alcohol compound, a catalyst, and an alkaline regulator are added to an organic solvent, the mixed solution is cooled to -40°C, a regulating reagent is added after cooling for 5 minutes, and the mixture is stirred and reacted at -40°C. After the reaction is completed, the mixture is purified by flash chromatography to obtain a chiral (R)-sulfilimidate or a chiral (S)-sulfilimidate.

[0008] The structural formula of the sulfenamide compound is as follows:

[0009]

[0010] Where R 1 is alkyl, aryl, or heteroaryl; R 2 For acyl.

[0011] The structural formula of the alcohol compound is R 3- OH, R 3 is an alkyl group or a benzyl group.

[0012] The catalyst is a 3,5-ditrifluoromethylbenzyl bromide substituted pentazoguanidine salt skeleton catalyst, and the molecular structure is as follows:

[0013]

[0014] Wherein, R is 3,5-(CF3)2PhCH2-.

[0015] The regulating reagent is reagent A or reagent B, wherein reagent A is selected from any one of N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-chlorophthalimide (NCP), N-bromophthalimide (NBP), 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), 1,3-dibromo-5,5-dimethylhydantoin (DBDMH), and bromochlorodimethylhydantoin (BCDMH). Reagent B is trichloroisocyanuric acid (TCCA).

[0016] By selecting different types of regulating reagents, chiral (R)-sulfilimine esters or chiral (S)-sulfilimine esters can be selectively synthesized. When the regulating reagent is selected as reagent A, the synthesized product is a chiral (R)-sulfilimine ester. When the regulating reagent is selected as reagent B, the synthesized product is a chiral (S)-sulfilimine ester. When using reagent A, NCP is preferred, which can achieve the highest product yield and the best enantioselectivity.

[0017] The alkaline compound is one of cesium carbonate, potassium carbonate, cesium hydroxide, sodium hydroxide, potassium hydroxide, potassium phosphate, and sodium phosphate. When used, the alkaline compound is prepared as an aqueous solution. Preferably, a 50% by mass concentration of cesium carbonate aqueous solution can obtain the optimal enantioselectivity and yield of the sulfinamide product.

[0018] The organic solvent is one of ethyl acetate, dichloromethane, tetrahydrofuran, a benzene reagent, and an ether. The ether reagent can be one of diethyl ether (Et2O), cyclopentyl methyl ether (CPME), and methyl tert-butyl ether (MTBE). Furthermore, when synthesizing chiral (R)-sulfimidates, the organic solvent is preferably diethyl ether. When synthesizing chiral (S)-sulfimidates, the organic solvent is preferably diethyl ether or cyclopentyl methyl ether.

[0019] When the regulating reagent is reagent A, the reaction conditions are: stirring at -40°C for 12-24 hours, and the synthesized product is a chiral (R)-sulfilimine ester. Preferably, the amount of reagent A is 1.2 times the molar amount of the sulfenamide compound.

[0020] When the regulating reagent is reagent B, the reaction conditions are: stirring and reacting for several minutes at -40°C, and the synthesized product is a chiral (S)-sulfilimine ester. Preferably, the amount of reagent B is 1.75 times the molar amount of the sulfenamide compound.

[0021] Preferably, the molar ratio of the sulfenamide compound to the alcohol compound is 1:1.5.

[0022] The reaction principle of the organocatalytic chiral sulfilimine ester asymmetric synthesis of the present invention is as follows:

[0023]

[0024] Compared with the prior art, the present invention is beneficial in that:

[0025] (1) The present invention proposes for the first time that by regulating the reagent, that is, simply changing the type of regulating reagent, two chiral sulfilimine esters with R / S configurations can be efficiently synthesized under the same reaction raw materials and the same catalyst conditions.

[0026] (2) Compared with existing synthetic methods, the synthetic method of the present invention has mild reaction conditions, does not require expensive metal catalysis, and has simple reaction steps. For S-configured sulfilimine esters, the synthetic reaction conditions only require 5 minutes to obtain the target product with high enantioselectivity and high yield. Furthermore, the method is suitable for gram-scale experiments, and high-yield and high-enantioselective products can still be obtained in 5 minutes at gram-scale. The method also has a wide substrate range, and the resulting sulfilimine esters are easily converted to different aza-S(IV) and S(VI) stereocenters.

[0027] Other advantages, objectives and features of the present invention will be reflected in part through the following description, and in part will be understood by those skilled in the art through study and practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 The NMR of the catalyst cat prepared in Example 1 is 1 H NMR spectrum.

[0029] Figure 2 The NMR of the catalyst cat prepared in Example 1 is 13 C NMR spectrum.

[0030] Figure 3 The NMR of the catalyst cat prepared in Example 1 is 19 F NMR spectrum.

[0031] Figure 4 It is a diagram of the molecular structures of 17 quinine catalysts (QN1-17).

[0032] Figure 5 It is a diagram of the mechanism of action of the regulatory reagent.

[0033] Figure 6 The NMR of the product prepared in Example 2 is 1 H NMR spectrum.

[0034] Figure 7 The NMR of the product prepared in Example 2 is 13 C NMR spectrum.

[0035] Figure 8 This is the determination diagram of the absolute configuration of the product (S)-1 prepared in Example 2.

[0036] Figure 9 The NMR of the product prepared in Example 3 is 1 H NMR spectrum.

[0037] Figure 10 The NMR of the product prepared in Example 3 is 13 C NMR spectrum.

[0038] Figure 11 The NMR of the product prepared in Example 4 is 1 H NMR spectrum.

[0039] Figure 12 The NMR of the product prepared in Example 4 is 13 C NMR spectrum.

[0040] Figure 13 The NMR of the product prepared in Example 4 is 19 F NMR spectrum.

[0041] Figure 14 The NMR of the product prepared in Example 5 is 1 H NMR spectrum.

[0042] Figure 15 The NMR of the product prepared in Example 5 is 13 C NMR spectrum.

[0043] Figure 16 The NMR of the product prepared in Example 6 is 1 H NMR spectrum.

[0044] Figure 17 The NMR of the product prepared in Example 6 is 13 C NMR spectrum.

[0045] Figure 18 The NMR of the product prepared in Example 7 is 1 H NMR spectrum.

[0046] Figure 19 The NMR of the product prepared in Example 7 is 13 C NMR spectrum.

[0047] Figure 20 The NMR of the product prepared in Example 8 is 1 H NMR spectrum.

[0048] Figure 21 The NMR of the product prepared in Example 8 is 13 C NMR spectrum.

[0049] Figure 22 The NMR of the product prepared in Example 9 is 1 H NMR spectrum.

[0050] Figure 23 The NMR of the product prepared in Example 9 is 13 C NMR spectrum. DETAILED DESCRIPTION

[0051] The preferred embodiments of the present invention are described below with reference to the accompanying drawings. It should be understood that the preferred embodiments described herein are only used to illustrate and explain the present invention, and are not used to limit the present invention.

[0052] Example 1

[0053] The preparation method of the catalyst used in the present invention is as follows:

[0054] S1: Chiral diphenylethylenediamine A (2.12 g, 10 mmol, 1.0 equiv) and potassium carbonate (5.53 g, 40 mmol, 4.0 equiv) were added to a round-bottom flask and dissolved in acetonitrile (40 ml). 3,5-Bistrifluoromethylbenzyl bromide (7.3 g, 24 mmol, 2.4 equiv) was dissolved in acetonitrile (30 ml) and slowly added dropwise to the reaction flask over 1 h via a syringe pump. The mixture was stirred at room temperature for 12 h. After the reaction, water (20 ml) was added to quench the reaction, and then extracted with dichloromethane (30 ml × 3). The obtained organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The organic phase was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain a light yellow chiral secondary amine B.

[0055] S2: Chiral secondary amine B (3.85 g, 5.8 mmol, 1.0 equiv) and potassium carbonate (2.4 g, 17.4 mmol, 3.0 equiv) were placed in a round-bottom flask and dissolved in dichloromethane (20 ml) and water (20 ml). A solution of thiophosgene (575 μl, 7.54 mmol, 1.3 equiv) in dichloromethane (5 ml) was added dropwise to the reaction flask at 0°C and stirred at room temperature for 1 hour. After the reaction, the mixture was extracted with dichloromethane (30 ml × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 40:1) to obtain a light yellow chiral thiourea C.

[0056] S3: Chiral thiourea C (2.6 g, 3.8 mmol, 1.0 equiv) was placed in a 100 ml round-bottom flask and dissolved in dry toluene (10 ml) under nitrogen atmosphere. Oxalyl chloride (3.2 ml, 38 mmol, 10.0 equiv) was added and reacted at 90°C for 10 h. After the reaction was complete, the toluene was quickly spin-dried.

[0057] S4: Take another round-bottom flask, add chiral diphenylethylenediamine A (2.55 g, 12 mmol, 1.0 equiv) to the round-bottom flask, dissolve cyanogen bromide (1.53 g, 14.4 mmol, 1.2 equiv) in dry acetonitrile, and add it to the reaction flask at 0°C under a nitrogen atmosphere. Raise the temperature to 80°C and react for 12 h. After the reaction is completed, directly concentrate the solvent under reduced pressure and separate and purify it by silica gel column chromatography (ethyl acetate) to obtain a light yellow chiral 2-imidoimidazolium salt E.

[0058] S5: Add chiral 2-imidoimidazolium salt E (1.1 g, 3.42 mmol, 0.9 equiv) to the round-bottom flask after the reaction in step S3. Under a nitrogen atmosphere, dissolve the mixture in dry acetonitrile (16 ml). Then, add triethylamine (2.13 ml, 15.2 mmol, 4.0 equiv). Incubate the mixture at 80°C for two hours, then cool to room temperature and stir overnight. Upon completion of the reaction, the solvent can be directly concentrated under reduced pressure. Purification by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) yields the pale yellow chiral guanidine salt phase transfer catalyst cat.

[0059] The principle of the entire reaction process is as follows:

[0060]

[0061] Figure 1 The NMR of the prepared catalyst cat 1 H NMR spectrum. 1 H NMR(400MHz,CDCl3)δ7.83(br s,2H),7.71(s,2H),7.54(s,4H),7.33-7.26(m,10H),7.23-7.14(m,10H),4.98-4.92(m,6H),4.65(d,J=15.9Hz,2H).

[0062] Figure 2 The NMR of the prepared catalyst cat 13 C NMR spectrum. 13 C NMR (100MHz, CDCl3) δ163.6,158.9,138.2,133.8,132.0(q,J C-F =34.0Hz),129.8,129.2,129.1,128.7,126.7,123.0(q,J C-F =273.7Hz),121.9,72.0,67.8,49.9.

[0063] Figure 3 The NMR of the prepared catalyst cat 19 F NMR spectrum.19 F NMR (376 MHz, CDCl3) δ -63.0. Further high-resolution mass spectrometry analysis revealed a molecular weight of 910.2780 for the catalyst cat, close to the theoretical molecular weight of 910.2774. Both the NMR characterization data and mass spectrometry data confirmed the successful synthesis of the catalyst cat.

[0064] The present inventors selected and studied 17 existing cinchona alkaloid catalysts (QN1-17, molecular structural formula see Figure 4 ) was applied to chiral sulfilimine esters, but the synthesis results only yielded sulfilimine esters with low enantioselectivity and were not suitable for the synthesis of chiral sulfilimine esters. However, the catalyst cat prepared by the present invention can provide chiral sulfilimine esters with high yield and high enantioselectivity of R / S.

[0065] The following examples respectively provide specific methods for synthesizing chiral sulfilimine esters using different substrates, wherein the catalyst used is the catalyst cat prepared in Example 1.

[0066] Example 2

[0067] A method for the asymmetric synthesis of chiral sulfilimine esters, the chemical reaction principle is as follows:

[0068]

[0069] N-chlorophthalimide (NCP) and TCCA are used as regulatory agents, and their mechanism of action is as follows Figure 5 As shown: The starting material sulfenamide is deprotonated under alkaline conditions, and the resulting sulfenamide anion forms an ion pair with the chiral cationic catalyst cat (abbreviated as PN), thereby directing the enantioselective chlorination reaction of the sulfenamide anion with NCP or TCCA. The resulting (R)-sulfenimidoyl chloride intermediate (Int I) is highly reactive and, when TCCA is used as a modulating reagent, is rapidly displaced by a nucleophilic alcohol to form an (S)-sulfenimidate. When NCP is used as a modulating reagent, the formation of the chiral sulfenimidoyl chloride intermediate (Int I) is accompanied by the in situ formation of nucleophilic phthalimide anions, which immediately undergo SN2 nucleophilic substitution reactions with the sulfenimidoyl chloride to form a new (S)-sulfenimidamide intermediate (Int II). (S)-Int II is less reactive and is gradually displaced by a nucleophilic alcohol to form an (R)-sulfenimidate. The mechanism of action of NCP and TCCA in subsequent examples is the same.

[0070] The specific method is as follows:

[0071] To a round-bottom flask were added N-tert-butyl acyl-protected sulfenamide (0.1 mmol, 22.3 mg), catalyst (3 mol%, 0.003 mmol, 2.8 mg), Et2O (1.5 mL), 50% aqueous Cs2CO3 solution (3.5 equiv., 0.35 mmol) and ethanol (1.5 equiv., 0.15 mmol, 6.9 mg), and the mixture was cooled to -40°C. After cooling for 5 minutes, N-chlorophthalimide (21.8 mg, 1.2 equiv.) was added, and the mixture was stirred at -40°C for 12-24 hours and then purified by flash chromatography to give the product (R)-1 (95% yield, 96% ee).

[0072] To a round-bottom flask were added N-tert-butyl acyl-protected sulfenamide (0.1 mmol, 22.3 mg), catalyst (6 mol%, 0.006 mmol, 5.6 mg), CPME (1.5 mL), 50% aqueous Cs2CO3 solution (3.5 equiv., 0.35 mmol) and ethanol (1.5 equiv., 0.15 mmol, 6.9 mg), and the mixture was cooled to -40°C. After cooling for 5 minutes, TCCA (40.6 mg, 1.75 equiv.) was added, and the mixture was stirred at -40°C for 5 minutes and then purified by flash chromatography to give the product (S)-1 (94% yield, 95% ee).

[0073] Figure 6 The NMR of the product prepared in Example 2 is 1 H NMR spectrum. 1 H NMR (400MHz, CDCl3) δ7.81(d,J=8.4Hz,2H),7.34(d,J=8.1Hz,2H),4.22(dq,J=10.2,7. 1Hz, 1H), 3.94 (dq, J = 10.0, 7.1Hz, 1H), 2.43 (s, 3H), 1.29 (s, 9H), 1.26 (t, J = 7.1Hz, 3H).

[0074] Figure 7 The NMR of the product prepared in Example 2 is 13 C NMR spectrum. 13 C NMR (100 MHz, CDCl3) δ193.0, 143.3, 134.2, 130.1, 127.8, 64.1, 41.1, 28.4, 21.6, 15.8. H NMR and C NMR data confirmed the successful preparation of the target product.

[0075] Determination of absolute configuration: Figure 8As shown, the obtained product (S)-1 was used to obtain the corresponding conversion product 9, and the absolute configuration of product 9 was determined by X-ray to be S. Since the formation of this derivative product is mainly carried out by the configuration inversion of the sulfur atom, the absolute configuration of sulfilimine ester (S)-1 is considered to be S.

[0076] Example 3

[0077] A method for the asymmetric synthesis of chiral sulfilimine esters, the chemical reaction principle is as follows:

[0078]

[0079] The specific method is as follows:

[0080] To a round-bottom flask were added N-tert-butyl acyl-protected sulfenamide (0.1 mmol, 20.9 mg), catalyst (3 mol%, 0.003 mmol, 2.8 mg), Et2O (1.5 mL), 50% aqueous Cs2CO3 solution (3.5 equiv., 0.35 mmol) and ethanol (1.5 equiv., 0.15 mmol, 6.9 mg), and the mixture was cooled to -40°C. After cooling for 5 minutes, N-chlorophthalimide (21.8 mg, 1.2 equiv.) was added. The mixture was stirred at -40°C for 12-24 hours and then purified by flash chromatography to give the product (R)-2 (97% yield, 95% ee).

[0081] To a round-bottom flask were added N-tert-butyl acyl-protected sulfenamide (0.1 mmol, 20.9 mg), catalyst (6 mol%, 0.006 mmol, 5.6 mg), CPME (1.5 mL), 50% aqueous Cs2CO3 solution (3.5 equiv., 0.35 mmol) and ethanol (1.5 equiv., 0.15 mmol, 6.9 mg), and the mixture was cooled to -40°C. After cooling for 5 minutes, TCCA (40.6 mg, 1.75 equiv.) was added. The mixture was stirred at -40°C for 5 minutes and then purified by flash chromatography to give the product (S)-2 (89% yield, 94% ee).

[0082] Figure 9 The NMR of the product prepared in Example 3 is 1 H NMR spectrum. 1 H NMR (400MHz, CDCl3) δ7.93 (d, J = 7.7Hz, 2H), 7.60-7.52 (m, 3H), 4.29-4.22 (m, 1H), 4.01-3.93 (m, 1H), 1.30-1.26 (m, 12H).

[0083] Figure 10 The NMR of the product prepared in Example 3 is 13 C NMR spectrum. 13 C NMR (100 MHz, CDCl3) δ193.2, 137.3, 132.5, 129.4, 127.9, 64.5, 41.2, 28.4, 15.8. H NMR and C NMR data confirmed the successful preparation of the target product.

[0084] Example 4

[0085] A method for the asymmetric synthesis of chiral sulfilimine esters, the chemical reaction principle is as follows:

[0086]

[0087] The specific method is as follows:

[0088] To a round-bottom flask were added N-tert-butyl acyl-protected sulfenamide (0.1 mmol, 22.7 mg), catalyst (3 mol%, 0.003 mmol, 2.8 mg), Et2O (1.5 mL), 50% aqueous Cs2CO3 solution (3.5 equiv., 0.35 mmol) and ethanol (1.5 equiv., 0.15 mmol, 6.9 mg), and the mixture was cooled to -40°C. After cooling for 5 minutes, N-chlorophthalimide (21.8 mg, 1.2 equiv.) was added, and the mixture was stirred at -40°C for 12-24 hours and then purified by flash chromatography to give the product (R)-3 (88% yield, 94% ee).

[0089] To a round-bottom flask were added N-tert-butyl acyl-protected sulfenamide (0.1 mmol, 22.7 mg), catalyst (6 mol%, 0.006 mmol, 5.6 mg), CPME (1.5 mL), 50% aqueous Cs2CO3 solution (3.5 equiv., 0.35 mmol) and ethanol (1.5 equiv., 0.15 mmol, 6.9 mg), and the mixture was cooled to -40°C. After cooling for 5 minutes, TCCA (40.6 mg, 1.75 equiv.) was added, and the mixture was stirred at -40°C for 5 minutes and then purified by flash chromatography to give the product (S)-3 (79% yield, 90% ee).

[0090] Figure 11 The NMR of the product prepared in Example 4 is 1 H NMR spectrum. 1H NMR (400 MHz, CDCl3) δ 7.97-7.92 (m, 2H), 7.27-7.22 (m, 2H, CHCl3 residual signal), 4.25 (dq, J = 10.1, 7.1 Hz, 1H), 3.97 (dq, J = 10.1, 7.1 Hz, 1H), 1.30-1.27 (m, 12H).

[0091] Figure 12 The NMR of the product prepared in Example 4 is 13 C NMR spectrum. 13 C NMR(100MHz,CDCl3)δ193.0,165.2(d,J C-F =254.3Hz),132.9(d,J C-F =3.4Hz),130.4(d,J C-F =9.2Hz),116.7(d,J C-F =22.4Hz),64.5,41.1,28.3,15.8.

[0092] Figure 13 The NMR of the product prepared in Example 4 is 19 F NMR spectrum. 19 F NMR (376MHz, CDCl3) δ-106.1.

[0093] Three NMR characterization data demonstrated the successful preparation of the target product.

[0094] Example 5

[0095] A method for the asymmetric synthesis of chiral sulfilimine esters, the chemical reaction principle is as follows:

[0096]

[0097] The specific method is as follows:

[0098] To a round-bottom flask were added N-tert-butyl acyl-protected sulfenamide (0.1 mmol, 23.8 mg), catalyst (3 mol%, 0.003 mmol, 2.8 mg), Et2O (1.5 mL), 50% aqueous Cs2CO3 solution (3.5 equiv., 0.35 mmol) and ethanol (1.5 equiv., 0.15 mmol, 6.9 mg), and the mixture was cooled to -40°C. After cooling for 5 minutes, N-chlorophthalimide (21.8 mg, 1.2 equiv.) was added, and the mixture was stirred at -40°C for 12-24 hours and then purified by flash chromatography to give the product (R)-4 (87% yield, 93% ee).

[0099] To a round-bottom flask were added N-tert-butyl acyl-protected sulfenamide (0.1 mmol, 23.8 mg), catalyst (6 mol%, 0.006 mmol, 5.6 mg), CPME (1.5 mL), 50% aqueous Cs2CO3 solution (3.5 equiv., 0.35 mmol) and ethanol (1.5 equiv., 0.15 mmol, 6.9 mg), and the mixture was cooled to -40°C. After cooling for 5 minutes, TCCA (40.6 mg, 1.75 equiv.) was added, and the mixture was stirred at -40°C for 5 minutes and then purified by flash chromatography to give the product (S)-4 (82% yield, 94% ee).

[0100] Figure 14 The NMR of the product prepared in Example 5 is 1 H NMR spectrum. 1 H NMR (400MHz, CDCl3) δ7.52-7.51(m,2H),7.19-7.18(m,1H),4.24(dq,J=10.1 ,7.1Hz,1H),3.97(dq,J=10.1,7.1Hz,1H),2.40(s,6H),1.30-1.26(m,12H).

[0101] Figure 15 The NMR of the product prepared in Example 5 is 13 C NMR spectrum. 13 C NMR (100 MHz, CDCl3) δ193.1, 139.4, 136.9, 134.3, 125.2, 64.5, 41.1, 28.4, 21.5, 15.8. H NMR and C NMR data confirmed the successful preparation of the target product.

[0102] Example 6

[0103] A method for the asymmetric synthesis of chiral sulfilimine esters, the chemical reaction principle is as follows:

[0104]

[0105] The specific method is as follows:

[0106] To a round-bottom flask were added N-tert-butyl acyl protected sulfenamide (0.1 mmol, 25.9 mg), catalyst (3 mol%, 0.003 mmol, 2.8 mg), Et2O (1.5 mL), 50% Cs2CO3 aqueous solution (3.5 equiv., 0.35 mmol) and ethanol (1.5 equiv., 0.15 mmol, 6.9 mg) in sequence, and the mixture was then cooled to -40°C. After cooling for 5 minutes, N-chlorophthalimide (21.8 mg, 1.2 equiv.) was added. The mixture was stirred at -40°C for 12-24 hours and then purified by flash chromatography to give the product (R)-5 (98% yield, 94% ee).

[0107] To a round-bottom flask were added N-tert-butyl acyl-protected sulfenamide (0.1 mmol, 25.9 mg), catalyst (6 mol%, 0.006 mmol, 5.6 mg), CPME (1.5 mL), 50% aqueous Cs2CO3 solution (3.5 equiv., 0.35 mmol) and ethanol (1.5 equiv., 0.15 mmol, 6.9 mg), and the mixture was cooled to -40 ° C. After cooling for 5 minutes, TCCA (40.6 mg, 1.75 equiv.) was added. The mixture was stirred at -40 ° C for 5 minutes and then purified by flash chromatography to give the product (S)-5 (82% yield, 92% ee).

[0108] Figure 16 The NMR of the product prepared in Example 6 is 1 H NMR spectrum. 1 H NMR (400MHz, CDCl3) δ8.47-8.46(m,1H),8.01-7.97(m,2H),7.94-7.91(m,2H),7.66-7.59(m,2H) ,4.29(dq,J=10.1,7.1Hz,1H),3.98(dq,J=10.1,7.1Hz,1H),1.34(s,9H),1.29(t,J=7.1Hz,3H).

[0109] Figure 17 The NMR of the product prepared in Example 6 is 13 C NMR spectrum. 13C NMR (100 MHz, CDCl3) δ 193.1, 135.1, 134.3, 132.7, 129.6, 129.2, 129.0, 128.7, 128.1, 127.5, 123.1, 64.4, 41.2, 28.4, 15.8. Further high-resolution mass spectrometry analysis revealed a molecular weight of 304.1366, close to the theoretical molecular weight of 304.1361. Both the NMR characterization data and the mass spectrometry data demonstrated the successful preparation of the target product.

[0110] Example 7

[0111] A method for the asymmetric synthesis of chiral sulfilimine esters, the chemical reaction principle is as follows:

[0112]

[0113] The specific method is as follows:

[0114] To a round-bottom flask were added N-tert-butyl acyl protected sulfenamide (0.1 mmol, 22.3 mg), catalyst (3 mol%, 0.003 mmol, 2.8 mg), Et2O (1.5 mL), 50% Cs2CO3 aqueous solution (3.5 equiv., 0.35 mmol) and 1-adamantanemethanol (1.5 equiv., 0.15 mmol, 24.9 mg), and the mixture was cooled to -40°C. After cooling for 5 minutes, N-chlorophthalimide (21.8 mg, 1.2 equiv.) was added, and the mixture was stirred at -40°C for 12-24 hours and then purified by flash chromatography to give the product (R)-6 (85% yield, 93% ee).

[0115] To a round-bottom flask were added N-tert-butyl acyl-protected sulfenamide (0.1 mmol, 22.3 mg), catalyst (6 mol%, 0.006 mmol, 5.6 mg), CPME (1.5 mL), 50% aqueous Cs2CO3 solution (3.5 equiv., 0.35 mmol) and 1-adamantane methanol (1.5 equiv., 0.15 mmol, 24.9 mg), and the mixture was cooled to -40°C. After cooling for 5 minutes, TCCA (40.6 mg, 1.75 equiv.) was added, and the mixture was stirred at -40°C for 5 minutes and then purified by flash chromatography to give the product (S)-6 (95% yield, 92% ee).

[0116] Figure 18 The NMR of the product prepared in Example 7 is 1 H NMR spectrum. 1H NMR (400MHz, CDCl3) δ7.79(d,J=7.6Hz,2H),7.34(d,J=8.1Hz,2H),3.71(d,J=9.6Hz,1H),3. 26(d,J=9.6Hz,1H),2.43(s,3H),1.93(s,3H),1.69-1.58(m,6H),1.45(s,6H),1.29(s,9H).

[0117] Figure 19 The NMR of the product prepared in Example 7 is 13 C NMR spectrum. 13 C NMR (100 MHz, CDCl3) δ 192.8, 143.1, 134.0, 130.0, 127.9, 76.2, 41.1, 39.1, 37.0, 34.0, 28.4, 28.1, 21.6. H NMR and C NMR data confirmed the successful preparation of the target product.

[0118] Example 8

[0119] A method for the asymmetric synthesis of chiral sulfilimine esters, the chemical reaction principle is as follows:

[0120]

[0121] The specific method is as follows:

[0122] To a round-bottom flask were added N-tert-butyl acyl protected sulfenamide (0.1 mmol, 22.3 mg), catalyst (3 mol%, 0.003 mmol, 2.8 mg), Et2O (1.5 mL), 50% Cs2CO3 aqueous solution (3.5 equiv., 0.35 mmol) and neopentyl alcohol (1.5 equiv., 0.15 mmol, 13.2 mg), and the mixture was cooled to -40°C. After cooling for 5 minutes, N-chlorophthalimide (21.8 mg, 1.2 equiv.) was added, and the mixture was stirred at -40°C for 12-24 hours and then purified by flash chromatography to give the product (R)-7 (86% yield, 96% ee).

[0123] To a round-bottom flask were added N-tert-butyl acyl-protected sulfenamide (0.1 mmol, 22.3 mg), catalyst (6 mol%, 0.006 mmol, 5.6 mg), CPME (1.5 mL), 50% aqueous Cs2CO3 solution (3.5 equiv., 0.35 mmol) and neopentyl alcohol (1.5 equiv., 0.15 mmol, 13.2 mg), and the mixture was cooled to -40°C. After cooling for 5 minutes, TCCA (40.6 mg, 1.75 equiv.) was added, and the mixture was stirred at -40°C for 5 minutes and then purified by flash chromatography to give the product (S)-7 (97% yield, 95% ee).

[0124] Figure 20 The NMR of the product prepared in Example 8 is 1 H NMR spectrum. 1 H NMR (400MHz, CDCl3) δ7.81 (d, J = 9.2 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 3.81 (d, J = 9.9 Hz, 1H), 3.37 (d, J = 9.4 Hz, 1H), 2.43 (s, 3H), 1.28 (s, 9H), 0.86 (s, 9H).

[0125] Figure 21 The NMR of the product prepared in Example 8 is 13 C NMR spectrum. 13 C NMR (100 MHz, CDCl3) δ 192.8, 143.2, 134.0, 130.0, 127.9, 76.2, 41.2, 32.2, 28.4, 26.5, 21.7. Further high-resolution mass spectrometry analysis revealed a molecular weight of 310.1835, close to the theoretical molecular weight of 310.1831. Both the NMR characterization data and mass spectrometry data demonstrated the successful preparation of the target product.

[0126] Example 9

[0127] A method for the asymmetric synthesis of chiral sulfilimine esters, the chemical reaction principle is as follows:

[0128]

[0129] The specific method is as follows:

[0130] To a round-bottom flask were added N-tert-butyl acyl protected sulfenamide (0.1 mmol, 22.3 mg), catalyst (3 mol%, 0.003 mmol, 2.8 mg), Et2O (1.5 mL), 50% Cs2CO3 aqueous solution (3.5 equiv., 0.35 mmol) and N-Boc-4-piperidinemethanol (1.5 equiv., 0.15 mmol, 32.2 mg), and the mixture was cooled to -40°C. After cooling for 5 minutes, N-chlorophthalimide (21.8 mg, 1.2 equiv.) was added, and the mixture was stirred at -40°C for 12-24 hours and then purified by flash chromatography to give the product (R)-8 (95% yield, 96% ee).

[0131] To a round-bottom flask were added N-tert-butyl acyl-protected sulfenamide (0.1 mmol, 22.3 mg), catalyst (6 mol%, 0.006 mmol, 5.6 mg), CPME (1.5 mL), 50% aqueous Cs2CO3 solution (3.5 equiv., 0.35 mmol) and N-Boc-4-piperidinemethanol (1.5 equiv., 0.15 mmol, 32.2 mg), and the mixture was cooled to -40°C. After cooling for 5 minutes, TCCA (40.6 mg, 1.75 equiv.) was added, and the mixture was stirred at -40°C for 5 minutes and then purified by flash chromatography to give the product (S)-8 (95% yield, 91% ee).

[0132] Figure 22 The NMR of the product prepared in Example 9 is 1 H NMR spectrum. 1 H NMR (400MHz, CDCl3) δ7.80(d,J=7.9Hz,2H),7.35(d,J=8.1Hz,2H),4.07-4.04(m,2H),3.96(dd,J=9.6,6.7Hz,1H),3.59(dd,J=9. 5,6.8Hz,1H),2.66-2.60(m,2H),2.44(s,3H),1.80-1.69(m,1H),1.64-1.60(m,2H),1.43(s,9H),1.28(s,9H),1.12-1.00(m,2H).

[0133] Figure 23 The NMR of the product prepared in Example 9 is 13 C NMR spectrum. 13C NMR (100 MHz, CDCl3) δ 193.0, 154.8, 143.5, 133.6, 130.1, 127.8, 79.5, 70.7, 43.8, 43.0, 41.1, 36.5, 28.5, 28.3, 21.7. Further high-resolution mass spectrometry analysis revealed a molecular weight of 437.2469, close to the theoretical molecular weight of 437.2460. Both the NMR characterization data and the mass spectrometry data demonstrated the successful preparation of the target product.

[0134] The above description is merely a preferred embodiment of the present invention and does not constitute any form of limitation to the present invention. Although the present invention has been disclosed as a preferred embodiment as above, it is not intended to limit the present invention. Any technician familiar with this profession can make some changes or modifications to equivalent embodiments of the technical contents disclosed above without departing from the scope of the technical solution of the present invention. However, any simple modifications, equivalent changes and modifications made to the above embodiments based on the technical essence of the present invention without departing from the content of the technical solution of the present invention are still within the scope of the technical solution of the present invention.

Claims

1. A method for the asymmetric synthesis of chiral sulfilimine esters by organocatalysis, characterized in that: A sulfenamide compound, an alcohol compound, a catalyst, and an alkaline regulator are added to an organic solvent, the mixed solution is cooled to -40°C, a regulating reagent is added after cooling for 5 minutes, and the mixture is stirred at -40°C for reaction. After the reaction, the mixture is purified by flash chromatography to obtain a chiral (R)-sulfilimine ester or a chiral (S)-sulfilimine ester. The structural formula of the sulfenamide compound is as follows: Where R 1 is alkyl, aryl, or heteroaryl; R 2 is an acyl group; The structural formula of the alcohol compound is R 3- OH, R 3 is an alkyl group or a benzyl group; The regulating reagent is reagent A or reagent B, reagent A is selected from any one of N-chlorosuccinimide, N-bromosuccinimide, N-chlorophthalimide, N-bromophthalimide, 1,3-dichloro-5,5-dimethylhydantoin, 1,3-dibromo-5,5-dimethylhydantoin, and bromochlorodimethylhydantoin; reagent B is trichloroisocyanuric acid; By selecting different types of regulating reagents, chiral (R)-sulfurimidate or chiral (S)-sulfurimidate can be selectively synthesized; when the regulating reagent is selected as reagent A, the synthesized product is a chiral (R)-sulfurimidate; when the regulating reagent is selected as reagent B, the synthesized product is a chiral (S)-sulfurimidate.

2. The method for asymmetric synthesis of organocatalytic chiral sulfilimine esters according to claim 1, wherein: The catalyst has the following molecular structural formula: Wherein, R is 3,5-(CF3)2PhCH2-.

3. The method for asymmetric synthesis of organocatalytic chiral sulfilimine esters according to claim 1, wherein: The alkaline compound is one of cesium carbonate, potassium carbonate, cesium hydroxide, sodium hydroxide, potassium hydroxide, potassium phosphate, and sodium phosphate.

4. The method for asymmetric synthesis of organocatalytic chiral sulfilimine esters according to claim 1, wherein: The organic solvent is one of ethyl acetate, dichloromethane, tetrahydrofuran, benzene reagents and ethers.

5. The method for asymmetric synthesis of chiral sulfilimine esters according to claim 4, wherein: The organic solvent is diethyl ether or cyclopentyl methyl ether.

6. The method for asymmetric synthesis of organocatalytic chiral sulfilimine esters according to claim 1, wherein: When reagent A is selected as the regulating reagent, the reaction conditions are: stirring the reaction at -40°C for 12-24 hours, and the synthesized product is a chiral (R)-sulfilimine ester.

7. The method for asymmetric synthesis of organocatalytic chiral sulfilimine esters according to claim 6, characterized in that: The amount of reagent A used is 1.2 times the molar amount of the sulfenamide compound.

8. The method for asymmetric synthesis of organocatalytic chiral sulfilimine esters according to claim 1, wherein: When reagent B is selected as the regulating reagent, the reaction conditions are: stirring the reaction at -40°C for several minutes, and the synthesized product is chiral (S)-sulfilimine ester.

9. The method for asymmetric synthesis of organocatalytic chiral sulfilimine esters according to claim 8, characterized in that: The amount of reagent B used is 1.75 times the molar amount of the sulfenamide compound.

10. The method for asymmetric synthesis of organocatalytic chiral sulfilimine esters according to claim 9, wherein: The molar ratio of the sulfonamide compound to the alcohol compound is 1:1.5.

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