An organocatalytic method for synthesizing chiral cyclobutene

Abstract

This invention provides a method for the organocatalytic synthesis of chiral cyclobutenes, belonging to the field of organic synthesis technology. Utilizing the easily cleaved carbon-carbon bonds of bicyclo[1.1.0]butane, this invention introduces an ester group at the C1 position of bicyclo[1.1.0]butane to form a hydrogen bond with the catalyst, and introduces an aryl group at the C3 position to stabilize the carbocation intermediate. Under the catalysis of a chiral Brønsted acid, efficient and highly selective isomerization is achieved to obtain chiral cyclobutene products. This method has good substrate universality, including good tolerance to halogen, alkyl, and aryl groups. The method is characterized by simple operation, mild reaction conditions, high yield, and good selectivity.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, and more specifically to an organocatalytic method for synthesizing chiral cyclobutene. Background Technology

[0002] Chiral cyclobutenes are not only the core framework for constructing active drug molecules or natural products, but can also be further derivatized and assembled into other complex molecular fragments. Their asymmetric synthesis has high academic research value and application prospects.

[0003] Currently, the synthesis of chiral cyclobutenes mainly relies on transition metal catalysis or photocatalysis for the [2+2] cycloaddition reaction between olefins and alkynes, such as the synthesis of chiral cyclobutene derivatives disclosed in US2008005159. Reports on catalysis using small organic molecule catalysts are relatively few; they primarily involve the reaction of alkynes with additional olefin sources catalyzed by chiral phosphine or chiral boron. Chiral phosphoric acid catalysts are a very important class of chiral catalysts. Acid catalysts can catalyze many asymmetric reactions and have shown high application value in fields such as pharmaceuticals and synthetic chemistry. However, the low acidity of chiral phosphoric acid limits its application to some extent. In 2006, Yamamoto's group developed chiral phosphoramides with stronger acidity, which showed higher catalytic activity in the reaction. Therefore, by improving the chirality... The acidity of acid catalysts may enable challenging asymmetric transformations of low-activity substrates. Meanwhile, catalytic modes based on chiral Brønsted acids are attracting increasing attention and research from scientists.

[0004] Furthermore, bicyclo[1.1.0]butane (BCB), as a novel small-ring compound, exhibits significant ring strain. Racemic cyclobutene products can be obtained through photocatalysis, heating, Lewis acids, or lithium reagents. However, in these reactions, it mainly exists as a byproduct or is generated in situ during the reaction, with low yields. For example, the method reported by Dhake and Kushal's group in 2022 for synthesizing azatricyclohexane and cyclobuteneamine from bicyclo[1.1.0]butane, using gallium catalysis, resulted in low yields and racemic products with poor selectivity.

[0005] Although some progress has been made in the synthesis of chiral cyclobutenes, methods for obtaining chiral cyclobutene compounds through novel and convenient asymmetric organocatalytic construction strategies still have high academic research value.

[0006] Therefore, the study of the catalytic synthesis of chiral cyclobutene compounds by small organic molecules is of great significance. Summary of the Invention

[0007] The aforementioned methods for synthesizing chiral cyclobutene suffer from technical problems such as harsh reaction conditions, low yields, expensive catalysts, numerous byproducts, low catalytic activity, and poor selectivity. This invention provides a method for the catalytic synthesis of chiral cyclobutene using small organic molecules. This method utilizes the easily cleaved carbon-carbon bonds of bicyclo[1.1.0]butane. An ester group is introduced at the C1 position of bicyclo[1.1.0]butane to form a hydrogen bond with the catalyst, and an aryl group is introduced at the C3 position to stabilize the carbocation intermediate. Under the catalysis of a chiral Brønsted acid, efficient and highly selective isomerization is achieved to obtain the chiral cyclobutene product. This method has good substrate universality, including good tolerance to halogen, alkyl, and aryl groups. The method is simple to operate, has mild reaction conditions, high yield, and good selectivity.

[0008] To achieve the above objectives, the present invention adopts the following technical solution:

[0009] One of the technical solutions of this invention provides a method for the organocatalytic synthesis of chiral cyclobutene. This method uses a dicyclobutane derivative as a starting material and achieves its efficient and highly selective isomerization under chiral Brønsted acid catalysis to obtain the chiral cyclobutene product. The reaction process is as follows:

[0010]

[0011] Wherein, R1 represents a C1-C4 alkyl group; R2 represents any one of H, halogen, C1-C4 alkyl, and aryl. In some embodiments, R1 is selected from at least one or more of methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl. In some embodiments, R2 is selected from at least one or more of H, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, phenyl, and substituted or unsubstituted phenyl groups.

[0012] In some embodiments, the chiral cyclobutene compound of formula B has a chemical structural formula selected from one of the following structures:

[0013]

[0014] In some embodiments, the chiral Brønsted acid is NTPA, and the chemical structural formula of NTPA is shown below:

[0015]

[0016] This invention provides a method for preparing the above-mentioned chiral cyclobutene, comprising the following steps:

[0017] 1) The substrate shown in Formula A is reacted in the presence of a solvent and a catalyst at the reaction temperature;

[0018] 2) After the reaction is complete, any post-treatment is performed to obtain the chiral cyclobutene product shown in formula B;

[0019] Formulas A and B are as described above.

[0020] The solvent in step 1) is selected from one or more of chloroform, dichloromethane, and dichloroethane. In some embodiments, chloroform is used as the solvent, which is beneficial for the smooth progress of the reaction.

[0021] The catalyst in step 1) is NTPA, whose chemical structural formula is shown below:

[0022]

[0023] The specific temperature in step 1) is -30℃ to -10℃. In some embodiments, the specific temperature is -30℃, -25℃, -20℃, -18℃, -15℃, or -10℃.

[0024] The post-processing in step 2) includes: purifying the crude product by column chromatography to obtain the target product, and then obtaining the chiral cyclobutene target product by chiral HPLC.

[0025] In some embodiments, the elution solvent used in the post-processing column chromatography in step 2) is petroleum ether and dichloromethane in a volume ratio of 1:1.

[0026] In step 1), the molar ratio of the catalyst to the substrate shown in Formula A is 0.01:1 to 0.1:1. In some embodiments, the molar ratio of the catalyst to the substrate shown in Formula A in step 1) is 0.05:1. In some embodiments, the molar ratio of the catalyst to the substrate shown in Formula A in step 1) is 0.01:1, 0.025:1, 0.05:1, or 0.1:1.

[0027] In step 1), the substrate concentration of formula A is 0.01 mol / L to 1 mol / L. In some embodiments, the substrate concentration of formula A in step 1) is 0.02 mol / L, 0.03 mol / L, 0.04 mol / L, 0.05 mol / L, 0.06 mol / L, 0.07 mol / L, 0.08 mol / L, 0.09 mol / L, 0.1 mol / L, 0.2 mol / L, 0.3 mol / L, 0.4 mol / L, 0.5 mol / L, 0.6 mol / L, 0.7 mol / L, 0.8 mol / L, or 0.9 mol / L.

[0028] The reaction time in step 1) is 1-6 hours. In some embodiments, the reaction time is 2 hours, 3 hours, 4 hours, 5 hours, or 6 hours.

[0029] In some embodiments, a method for preparing chiral cyclobutene of formula B includes the following steps: 1. Adding the substrate of formula A and chloroform to a Schlenk reaction tube, then placing it at -30°C with magnetic stirring, and then adding a chloroform solution containing NTPA catalyst dropwise, and continuing the reaction at -30°C; 2. After the reaction is complete, the crude product is purified by column chromatography to obtain the product, and then the chiral cyclobutene product of formula B is obtained by chiral HPLC; wherein formulas A and B are as described above.

[0030] In some embodiments, a method for preparing chiral cyclobutene of formula B includes the following steps: 1. Adding the substrate of formula A and chloroform to a Schlenk reaction tube, then placing it at -30°C with magnetic stirring, and then adding a chloroform solution containing NTPA catalyst dropwise, and continuing the reaction at -30°C for 4 hours; 2. After the reaction is complete, the crude product is purified by column chromatography to obtain the product, and then the chiral cyclobutene product of formula B is obtained by chiral HPLC; wherein formulas A and B are as described above; the eluent for the column chromatography purification is petroleum ether and dichloromethane in a volume ratio of 1:1.

[0031] The second technical solution of the present invention relates to the use of chiral cyclobutene as shown in Formula B above in the preparation of pharmaceutical active molecules or natural products. Alternatively, chiral cyclobutene as shown in Formula B above serves as a fundamental raw material for many complex molecular structures, and it has promising application prospects.

[0032] The present invention also provides a use of the above-mentioned cyclobutene compound (I), which is used to prepare proto-ilulane natural product skeleton compounds by Negishi coupling and DA cycloaddition reaction.

[0033] In the technical solution of this invention, a chiral Brønsted acid is creatively used as a chiral catalyst. Taking advantage of the easy cleavage of the carbon-carbon bond of bicyclo[1.1.0]butane, an ester group is introduced at the C1 position of bicyclo[1.1.0]butane to generate hydrogen bonding between the catalyst and the ester group. An aryl group is introduced at the C3 position to stabilize the carbocation intermediate. This allows for efficient and highly selective isomerization to obtain chiral cyclobutene products. This method investigates the effects of catalyst type, catalyst dosage, reaction temperature, solvent, and post-treatment on the yield of the main reaction and the enantioselectivity of the chiral product, determining the optimal process conditions. The optimized process yields chiral cyclobutene with high yield and good selectivity. Furthermore, the inventors prepared numerous substrates and applied this method to synthesize chiral cyclobutene, demonstrating the broad substrate applicability of the method: it exhibits good tolerance to halogen, alkyl, and aryl groups. In summary, the technical solution of this invention is highly original, has a broad substrate range, is simple to operate, and operates under mild conditions. Compared to existing technologies, the technical solution of this invention does not require stringent conditions and features simple operation, high yield, and good selectivity.

[0034] In summary, the present invention has the following beneficial technical effects:

[0035] 1. The chiral cyclobutene of formula B provided by this invention has good application prospects in the preparation of pharmaceutical active molecules or natural products.

[0036] 2. This invention provides a method for the organocatalytic synthesis of chiral cyclobutene. This method uses a chiral Brønsted acid as a catalyst to achieve efficient and highly selective isomerization to obtain chiral cyclobutene products. Compared with existing technologies, photocatalysis, heating, Lewis acids, or lithium reagents are used to obtain racemic cyclobutene products. In these reactions, the products mainly exist as byproducts or are generated in situ during the reaction process, and the yield is low. The technical solution of this invention solves the technical problems of harsh reaction conditions, expensive transition metal catalysts, narrow substrate range, and many photocatalytic byproducts. At the same time, the inventors have studied many substrates, and the method of this invention has broad substrate applicability.

[0037] 3. This invention provides a method for the organic catalytic synthesis of chiral cyclobutene. The effects of catalyst type, catalyst dosage, reaction temperature, solvent, and post-treatment on the main reaction yield and enantiomer purity were investigated. Optimal process conditions were determined, and the optimized process yields chiral cyclobutene with high yield, good selectivity, and broad substrate versatility. In summary, the technical solution of this invention is highly original, has a broad substrate range, significantly increases product value compared to raw material prices, and is characterized by simple operation and mild conditions.

[0038] In the description of this invention, it should be understood that the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of indicated technical features. Therefore, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of this invention, "a plurality of" means two or more, unless otherwise explicitly specified.

[0039] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0040] In this invention, the terms "compound A" and "compound represented by formula A" refer to the same compound.

[0041] In this invention, "optional" indicates whether or not post-processing can be performed; for example, "optional post-processing" indicates whether post-processing can be performed or not. Attached Figure Description

[0042] Figure 1 HPLC spectrum of racemic product 2a in Example 1;

[0043] Figure 2 HPLC spectrum of S-configuration product 2a in Example 1;

[0044] Figure 3 HPLC spectrum of racemic product 2b in Example 2;

[0045] Figure 4 HPLC spectrum of S-configuration product 2b in Example 2;

[0046] Figure 5 HPLC spectrum of racemic product 2c in Example 3;

[0047] Figure 6 HPLC spectrum of S-configuration product 2c in Example 3;

[0048] Figure 7 HPLC spectrum of racemic product 2d in Example 4;

[0049] Figure 8 HPLC spectrum of S-configuration product 2d in Example 4;

[0050] Figure 9 HPLC spectrum of racemic product 2e in Example 5;

[0051] Figure 10 HPLC spectrum of S-configuration product 2e in Example 5. Detailed Implementation

[0052] To enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to provide a more detailed description of the present invention.

[0053] All reagents used in this invention can be purchased commercially or prepared by the methods described in this invention.

[0054] In this invention, min represents minutes; h represents hours; g represents grams; mL represents milliliters; and mg represents milligrams.

[0055] In this invention, 1 H NMR represents the hydrogen nuclear magnetic resonance spectrum; 13 C NMR stands for carbon nuclear magnetic resonance spectroscopy; HRMS (ESI) stands for high-resolution mass spectrometry, with ESI as the ion source.

[0056] Example 1

[0057] Weigh 0.5 mmol (1.0 equiv) of dicyclobutane derivative 1a into a 25 mL Schlenk tube, add 10 mL of chloroform, and stir at -30 °C for 10 min. Then, add 0.5 mL of chloroform solution containing NTPA catalyst (2 mol%) dropwise to the system and continue the reaction at -30 °C until TLC monitoring shows complete consumption of the starting material 1a. After the reaction, the crude product is purified by column chromatography to obtain product 2a, 89.3 mg, yield 95%. The enantioselectivity of product 2a is 90% ee, obtained by chiral HPLC. HPLC conditions: Chiralpak OJ-3 (hexane / i-PrOH = 99 / 01, 1.0 mL / min, t S (major) = 24.9 min, t S (minor) = 30.5 min).

[0058] 1 H NMR (400MHz, CDCl3) δ7.38-7.28 (m, 5H), 6.28 (d, J = 1.4Hz, 1H), 3.72 (s, 3H), 3 .68-3.66(m,1H),3.08(dd,J=13.0,4.7Hz,1H),3.01(dd,J=13.0,2.2Hz,1H).

[0059] 13 C NMR (100MHz, CDCl3) δ174.11,148.41,133.85,128.51,124.85,124.57,52.00,41.40,32.74.

[0060] HRMS(ESI)Calcd for C 12 H 13 O2 + [M+H] + 189.0910; Found: 189.0908.

[0061] Example 2

[0062]

[0063] Weigh 0.5 mmol (1.0 equiv) of dicyclobutane derivative 1b into a 25 mL Schlenk tube, add 10 mL of chloroform, and stir the reaction tube at -30 °C for 10 min. Then, add 0.5 mL of chloroform solution containing NTPA catalyst (2 mol%) dropwise to the system. Continue the reaction at -30 °C until TLC monitoring shows complete consumption of starting material 1b. After the reaction, the crude product was purified by column chromatography to obtain a product yield of 95%; the enantioselectivity of the product was 91% ee obtained by chiral HPLC.

[0064] HPLC condition:Chiralpak AY-3(hexane / i-PrOH=99 / 01,1.0mL / min,t S (major) = 9.9 min, t S (minor) = 8.6 min).

[0065] 1 H NMR (400MHz, CDCl3) δ7.27(s,1H),7.25(s,1H),7.14(d,J=8.2Hz,2H),6.21(d,J=1.3Hz,1H),3.72( s,3H),3.66-3.64(m,1H),3.06(dd,J=13.0,4.7Hz,1H),2.99(dd,J=13.0,2.2Hz,1H),2.35(s,3H).

[0066] 13 C NMR (100MHz, CDCl3) δ174.27,148.36,138.45,131.23,129.19,124.82,123.42,51.97,41.38,32.76,21.55.

[0067] HRMS(ESI)Calcd for C 13 H 15 O2 + [M+H] +203.1067; Found: 203.1067.

[0068] Example 3

[0069]

[0070] Weigh 0.5 mmol (1.0 equiv) of dicyclobutane derivative 1c into a 25 mL Schlenk tube, add 10 mL of chloroform, and stir the reaction tube at -30 °C for 10 min. Then, add 0.5 mL of chloroform solution containing NTPA catalyst (2 mol%) dropwise to the system. Continue the reaction at -30 °C until TLC monitoring shows complete consumption of the starting material 1c. After the reaction, the crude product was purified by column chromatography to obtain a product yield of 90%; the enantioselectivity of the product was 94% ee obtained by chiral HPLC.

[0071] HPLC condition:Chiralpak AY-3(hexane / i-PrOH=99 / 01,1.0mL / min,t S (major) = 11.5 min, t S (minor) = 8.8min).

[0072] 1 H NMR (400MHz, CDCl3) δ7.29(d,J=8.1Hz,2H),7.17(d,J=8.0Hz,2H),6.22(d,J=1.3Hz,1H),3.72(s,3H),3.67-3. 65(m,1H),3.06(dd,J=13.0,4.7Hz,1H),2.99(dd,J=13.0,2.2Hz,1H),2.67-2.62(m,2H),1.23(t,J=7.6Hz,3H). 13 C NMR (100MHz, CDCl3) δ174.24,148.37,144.84,131.47,128.01,124.89,123.48,51.95,41.39,32.75,28.91,15.67.

[0073] HRMS(ESI)Calcd for C 14 H 17 O2 + [M+H] + 217.1223; Found: 217.1221.

[0074] Example 4

[0075]

[0076] Weigh 0.5 mmol (1.0 equiv) of the dicyclobutane derivative 1d into a 25 mL Schlenk tube, add 10 mL of chloroform, and stir the reaction tube at -30 °C for 10 min. Then, add 0.5 mL of chloroform solution containing NTPA catalyst (2 mol%) dropwise to the system. Continue the reaction at -30 °C until the reactant 1d is completely consumed by TLC. After the reaction is complete, the crude product is purified by column chromatography to obtain a product yield of 85%; the enantioselectivity of the product is 93% ee obtained by chiral HPLC.

[0077] HPLC condition:Chiralpak AY-3(hexane / i-PrOH=95 / 05,1.0mL / min,t S (major) = 13.0 min, t S (minor) = 7.6 min).

[0078] 1 H NMR (400MHz, CDCl3) δ7.30(d,J=8.2Hz,2H),7.20(d,J=8.2Hz,2H),6.22(d,J=1.3Hz,1H),3.71(s,3H),3.67-3.65 (m,1H),3.06(dd,J=13.0,4.7Hz,1H),2.99(dd,J=13.0,2.2Hz,1H),2.94-2.87(m,1H),1.25(s,3H),1.24(s,3H). 13 C NMR (100MHz, CDCl3) δ174.23,149.45,148.36,131.62,126.57,124.89,123.52,51.94,41.41,34.16,32.75,24.02.

[0079] HRMS(ESI)Calcd for C 15 H 19 O2 + [M+H] + 231.1380; Found: 231.1378.

[0080] Example 5

[0081]

[0082] Weigh 0.5 mmol (1.0 equiv) of the dicyclobutane derivative 1e into a 25 mL Schlenk tube, add 10 mL of chloroform, and stir the reaction tube at -30 °C for 10 min. Then, add 0.5 mL of chloroform solution containing NTPA catalyst (2 mol%) dropwise to the system. Continue the reaction at -30 °C until TLC monitoring shows complete consumption of the starting material 1e. After the reaction is complete, the crude product is purified by column chromatography to obtain a product yield of 97%; the enantioselectivity of the product is 96% ee obtained by chiral HPLC.

[0083] HPLC condition:Chiralpak OJ-3(hexane / i-PrOH=95 / 05,1.0mL / min,t S (major) = 9.8 min, t S (minor) = 12.2 min).

[0084] 1 H NMR (400MHz, CDCl3) δ7.37(d,J=8.5Hz,2H),7.31(d,J=8.4Hz,2H),6.23(d,J=1.3Hz,1H),3.71(s ,3H),3.66-3.65(m,1H),3.06(dd,J=13.0,4.7Hz,1H),2.99(dd,J=13.0,2.2Hz,1H),1.32(s,9H).

[0085] 13 C NMR (100MHz, CDCl3) δ174.24,151.68,148.29,131.21,125.42,124.64,123.67,51.96,41.45,34.85,32.75,31.38.

[0086] HRMS(ESI)Calcd for C 16 H 21 O2 + [M+H] + 245.1536; Found: 245.1534.

[0087] Investigation of reaction conditions

[0088] Example 6

[0089] Following the method described in Implementation 1, the effects of reaction temperature and solvent on the reaction were investigated, and the results are shown in the table below.

[0090]

[0091]

[0092] Comparative Examples

[0093] Weigh 0.5 mmol (1.0 equiv) of dicyclobutane derivative 1a into a 25 mL Schlenk tube, add 10 mL of chloroform, and stir the reaction tube at -30 °C for 10 min. Then, add 0.5 mL of chloroform solution containing Cat-1 catalyst (2 mol%) dropwise to the system. Continue the reaction at -30 °C until TLC monitoring shows complete consumption of reactant 1a. After the reaction is complete, the crude product is purified by column chromatography to obtain the product 2a, 90.2 mg, yield 96%. The enantioselectivity of product 2a is 84% ​​ee, obtained by chiral HPLC.

[0094] The catalyst in the comparative example was Cat-1, whose chemical structural formula is shown below:

[0095]

[0096] The method of this invention has been described through preferred embodiments. Those skilled in the art will readily be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and context of this invention to implement and apply the technology of this invention. Those skilled in the art can refer to the content herein to appropriately improve process parameters. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of this invention.

Claims

1. A method for organocatalytic synthesis of chiral cyclobutene, the reaction process is shown as follows: ； wherein R1 represents C1-C4 alkyl;R2 represents any one of H, halogen, C1-C4 alkyl, aryl; characterized in comprising the following steps: 1) reacting the substrate shown in formula A in the presence of a solvent and a catalyst at a reaction temperature; 2) after the reaction is completed, optionally post-treating to obtain the chiral cyclobutene product shown in formula B; wherein, formula A, formula B, R1, R2 are the same as described above; the catalyst is NTPA, and its chemical structural formula is shown as follows: ； the reaction temperature is-30℃ to-10℃.

2. The method of claim 1, wherein, the solvent in step 1 is selected from one or more of chloroform, dichloromethane and dichloroethane.

3. The method of claim 1, wherein, the molar ratio of the catalyst to the substrate shown in formula A in step 1 is 0.01:1 to 0.1:

1.

4. The method of claim 1, wherein, the concentration of the substrate shown in formula A in step 1 is 0.01 mol / L-1 mol / L.

5. The method of claim 1, wherein, the reaction time in step 1 is 1h-6h.

6. The method of claim 1, wherein, the post-treatment in step 2 comprises purifying the crude product by column chromatography to obtain the target product, and then obtaining the chiral cyclobutene target product by chiral HPLC.

7. The method of claim 1, wherein, the elution solvent used in the column chromatography in the post-treatment in step 2 is petroleum ether and dichloromethane, and the volume ratio of the two is 1:1.

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