Synthesis method for efficiently synthesizing caged ketal skeleton through Bronsted acid

Abstract

The invention develops a cascade reaction strategy for realizing efficient synthesis of a caged ketal skeleton compound by taking Bronsted acid as a catalyst and taking a 3-hexene-2, 5-diketone derivative and a cinnamyl alcohol analogue as substrates, and synthesizes a natural product (+ / -)-catunaregin and a series of novel analogues of the natural product (+ / -)-catunaregin which are not reported in literatures. Important technical support and early-stage theoretical basis are provided for the creation of new drugs of the compounds. The cinnamyl alcohol analogue disclosed by the invention is simple and easy to prepare, wide in derivation range and low in price, and can better enrich the structural diversity of caged ketal skeleton compounds. The method disclosed by the invention can be prepared by a one-pot method, is efficient and rapid, simple to operate, short in reaction step, good in substrate tolerance, mild in reaction condition and wide in application range, and overcomes the defects of complex operation, harsh reaction conditions, substrate limitation, intolerant substrate functional groups, tedious steps and the like in the traditional reaction.

Description

Technical Field

[0001] This invention relates to the field of synthetic chemistry, specifically to a method for the efficient catalytic synthesis of cage-like ketal skeletons using Brønsted acid. Background Technology

[0002] Cage-like ketals are commonly found in natural products and pharmaceutical molecules. Currently, there are several main synthetic methods for cage-like ketals. For example, they can be prepared from the mangrove plant *Punica granatum* using a combination of column chromatography and thin-layer chromatography with 95% industrial ethanol extraction. Cage-like ketals can also be synthesized by constructing a tricyclic skeleton from multi-substituted furans through a series of reactions such as addition. This method starts with readily available substrates and requires only one reaction to achieve the structure construction that would otherwise require multiple steps in traditional synthesis. It avoids the use of toxic or rare raw materials and is characterized by its simplicity and high efficiency. Summary of the Invention

[0003] A Brønsted acid-catalyzed tandem reaction has been developed, providing a one-step synthetic strategy for the efficient construction of cage-like ketal skeletons. Compared with traditional cumbersome multi-step total synthetic routes, this method can obtain the natural product (±)-catunaregin and a series of analogues in just one step, achieving a simple and efficient preparation of known compounds. This method has comprehensive advantages such as simple operation, readily available starting materials, broad functional group compatibility, high step economy, and excellent yield.

[0004] This invention is achieved through the following technical solution:

[0005] This invention provides a multifunctional cage-like ketal skeleton derivative 3, characterized in that: under an inert gas atmosphere, compound 1, compound 2, a catalyst, and a solvent are mixed to generate a product with the following structure: R 1 R 2 R represents a C1-C12 straight-chain alkyl group. 3 R represents hydroxyl, alkoxy, alkylthio, phenoxy, etc. 4 This refers to substituents such as hydroxyl, alkyl, aryl, olefin, alkyne, methoxy, ethoxy, and halogen at independent ortho, meta, and para positions on the benzene ring, including disubstituted, trisubstituted, or polysubstituted groups. The present invention describes a method for the efficient synthesis of cage-like ketal skeleton compounds via Lewis acids, characterized by the synthetic route shown in Formula I:

[0006] Formula I

[0007] The catalyst is selected from one of trifluoroacetic acid, p-toluenesulfonic acid, camphorsulfonic acid, and acetic acid.

[0008] The synthesis reaction takes 1-10 hours.

[0009] The solvent is acetonitrile.

[0010] Furthermore, the reaction temperature is 0℃-120℃, preferably 25℃.

[0011] Furthermore, the molar amount of compound 2 is 1-5 times that of compound 1, preferably 1-3 times, and more preferably 1.1 times.

[0012] This invention develops a tandem reaction of 3-hexene-2,5-dione compounds with cinnamyl alcohol analogs using Brønsted acid as a catalyst, achieving efficient synthesis of cage-like ketal skeletons and synthesizing a series of novel product structures with potential drug activity, aiming to provide important technical support and preliminary theoretical foundation for the discovery of new drugs of this type of compound.

[0013] The 3-hexene-2,5-dione and cinnamyl alcohol analogs in this invention have simple structures, are easy to prepare, have a wide range of derivatization, and are inexpensive, which can better enrich the structural diversity of cage-like ketal skeleton compounds.

[0014] The method of this invention can be prepared in a one-pot process, which is efficient, fast, simple to operate, and has a short reaction step. At the same time, it has good substrate tolerance, mild reaction conditions, and a wide range of applications. It solves the shortcomings of traditional reactions, such as difficult separation, complicated operation, harsh reaction conditions, limited substrates, intolerant substrate functional groups, and cumbersome steps.

[0015] The technical solution of the present invention is described clearly and completely below. Obviously, the embodiments described herein are only a part of the present invention and not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the protection scope of the present invention.

[0016] Compound 1 in this invention can be synthesized using existing technologies. Reference: Wang, H. Silver-Catalyzed Tandem Reaction of 2-Alkynylbenzenesulfonamides with Isocyanoacetates: Synthesis of 1,2-Dihydroisoquinoline Derivatives. Chem. Commun. 2015, 51(82), 15169-15171.

[0017] Compound 2 in this invention can be purchased directly or synthesized using existing technologies. Reference: Li, L. One-PotFour-Component Tandem Reaction: Synthesis of Polysubstituted Dihydrofuro3,4−b3,4−bpyran-5(1H)-one Derivatives. Org. Lett. 2013, 15 (4), 856–859.

[0018] Example 1.

[0019] The specific synthesis of cage-like ketal skeleton compounds is as follows:

[0020] 0.20 mmol of cinnamyl alcohol analog 1, 0.22 mmol of (3-hexen-dione) analog 2, and 0.02 mmol of p-toluenesulfonic acid were added to a 10 ml reaction tube with a stir bar, and the tube was evacuated three times with nitrogen. Under nitrogen atmosphere, 2 ml of acetonitrile was injected into the reaction tube. The reaction tube was stirred on a magnetic stirrer at room temperature. The reaction progress was monitored using a TLC plate, and the reaction was stopped when reactant 2 was completely consumed. The solvent was removed by rotary evaporation, and the product was separated by silica gel (200-300 mesh) column chromatography to obtain a pale yellow viscous liquid (yield: 74%).

[0021] The product testing data is as follows: 1 H NMR (500 MHz, CDCl3) δ 7.18 (d, J= 8.5 Hz, 2H), 6.80 (d, J= 8.6 Hz, 2H), 4.99 (s, 1H), 4.96 (d, J= 3.9 Hz, 1H), 3.76 (d, J=1.7 Hz, 2H), 2.72 (dd, J= 10.2, 3.8 Hz, 1H), 2.50-2.46 (m, 1H), 2.27 (d, J=12.5 Hz, 1H), 1.88 (dd, J= 12.5, 4.0 Hz, 1H), 1.60 (s, 3H), 1.49 (s, 3H).

[0022] Example 2:

[0023] The specific synthesis of cage-like ketal skeleton compounds is as follows:

[0024] 0.20 mmol of cinnamyl alcohol analog 1, 0.22 mmol of (3-hexen-dione) analog 2, and 0.02 mmol of p-toluenesulfonic acid were added to a 10 ml reaction tube with a stir bar, and the tube was evacuated three times with nitrogen. Under nitrogen atmosphere, 2 ml of acetonitrile was injected into the reaction tube. The reaction tube was stirred on a magnetic stirrer at room temperature. The reaction progress was monitored using a TLC plate, and the reaction was stopped when reactant 2 was completely consumed. The solvent was removed by rotary evaporation, and the product was separated by silica gel (200-300 mesh) column chromatography to obtain a pale yellow viscous liquid (yield: 44%).

[0025] The product testing data is as follows: 1 H NMR (400 MHz, CDCl3) δ 7.06–6.96 (m, 2H),6.73(d, J= 8.1Hz,1H), 5.08 (s, 1H), 4.93 (d,J= 4.0 Hz,1H),3.75 (d,J= 2.2 Hz,2H), 2.72(dd,J= 10.3,3.7Hz,1H), 2.52-2.43 (m,1H), 2.26 (d,J= 12.4 Hz,1H),2.23 (s,3H),1.88 (dd, J= 12.5,4.0 Hz,1H),1.60(s, 3H),1.49(s,3H).

[0026] Example 3:

[0027] The specific synthesis of cage-like ketal skeleton compounds is as follows:

[0028] 0.20 mmol of cinnamyl alcohol analog 1, 0.22 mmol of (3-hexen-dione) analog 2, and 0.02 mmol of p-toluenesulfonic acid were added to a 10 ml reaction tube with a stir bar, and the tube was evacuated three times with nitrogen. Under nitrogen atmosphere, 2 ml of acetonitrile was injected into the reaction tube. The reaction tube was stirred on a magnetic stirrer at room temperature. The reaction progress was monitored using a TLC plate, and the reaction was stopped when reactant 2 was completely consumed. The solvent was removed by rotary evaporation, and the product was separated by silica gel (200-300 mesh) column chromatography to obtain a pale yellow viscous liquid (yield: 62%).

[0029] The product testing data is as follows: 1H NMR (400 MHz, CDCl3) δ 6.88 (d, J= 8.7 Hz, 1H), 6.79 (d, J= 7.0 Hz, 2H), 5.64 (s, 1H), 4.93 (d, J= 3.9 Hz, 1H), 4.11 (d, J=7.0 Hz, 2H), 3.75 (d, J= 2.2 Hz, 2H), 2.70 (dd, J= 10.3, 3.9 Hz, 1H), 2.50-2.46 (m, J= 10.3, 4.2, 2.2 Hz, 1H), 2.26 (d, J= 12.5 Hz, 1H), 1.87 (dd, J=12.5, 3.9 Hz, 1H), 1.59 (s, 3H), 1.49 (s, 3H).

[0030] Example 4:

[0031] The specific synthesis of cage-like ketal skeleton compounds is as follows:

[0032] Add 0.20 mmol of cinnamyl alcohol analog 1, 0.22 mmol of (3-hexen-dione) analog 2, and 0.02 mmol of p-toluenesulfonic acid to a 10 ml reaction tube with a stir bar, and purge the tube three times with nitrogen under vacuum. Inject 2 ml of acetonitrile into the reaction tube under nitrogen atmosphere. Stir the reaction tube on a magnetic stirrer at room temperature. Monitor the reaction progress using a TLC plate; stop the reaction when reactant 2 is completely consumed. Remove the solvent using a rotary evaporator, and separate the product by silica gel (200-300 mesh) column chromatography to obtain a pale yellow viscous liquid (yield: 63%).

[0033] The product testing data is as follows: 1H NMR (500 MHz, CD3OD) δH 6.75 (dd, J= 10.2, 5.0 Hz, 2H), 6.65 (dd, J= 8.1, 1.9 Hz, 1H), 4.82 (d, J= 3.8 Hz, 1H), 3.80 (dd, J=11.4, 3.3 Hz, 1H), 3.71 (d, J= 11.4 Hz, 1H), 2.80 (dd, J= 10.2, 3.8 Hz, 1H), 2.47 (dt, J= 10.2, 3.2 Hz, 1H), 2.34 (d, J= 12.6 Hz, 1H), 1.94 (dd, J= 12.7,4.0 Hz, 1H), 1.56 (s, 3H), 1.42 (s, 3H).

[0034] Example 5:

[0035] The specific synthesis of cage-like ketal skeleton compounds is as follows:

[0036] 0.20 mmol of cinnamyl alcohol analog 1, 0.22 mmol of (3-hexen-dione) analog 2, and 0.02 mmol of p-toluenesulfonic acid were added to a 10 ml reaction tube with a stir bar, and the tube was evacuated three times with nitrogen. Under nitrogen atmosphere, 2 ml of acetonitrile was injected into the reaction tube. The reaction tube was stirred on a magnetic stirrer at room temperature. The reaction progress was monitored using a TLC plate, and the reaction was stopped when reactant 2 was completely consumed. The solvent was removed by rotary evaporation, and the product was separated by silica gel (200-300 mesh) column chromatography to obtain a pale yellow viscous liquid (yield: 64%).

[0037] The product testing data is as follows: 1 H NMR (400 MHz, CDCl3) δ 7.06–6.98 (m, 1H), 6.95 (d,J= 5.5 Hz, 1H), 5.44 (s, 1H), 4.94 (d, J= 3.9 Hz, 1H), 3.76 (d, J= 2.1 Hz,2H), 2.69 (dd, J= 10.3, 3.9 Hz, 1H), 2.47 – 2.42 (m, 1H), 2.26 (d, J= 12.5Hz, 1H), 1.88 (dd, J= 12.6, 3.9 Hz, 1H), 1.60 (s, 3H), 1.49 (s, 3H).

[0038] Example 6:

[0039] The specific synthesis of cage-like ketal skeleton compounds is as follows:

[0040] 0.20 mmol of cinnamyl alcohol analog 1, 0.22 mmol of (3-hexen-dione) analog 2, and 0.02 mmol of p-toluenesulfonic acid were added to a 10 ml reaction tube with a stir bar, and the tube was evacuated three times with nitrogen. Under nitrogen atmosphere, 2 ml of acetonitrile was injected into the reaction tube. The reaction tube was stirred on a magnetic stirrer at room temperature. The reaction progress was monitored using a TLC plate, and the reaction was stopped when reactant 2 was completely consumed. The solvent was removed by rotary evaporation, and the product was separated by silica gel (200-300 mesh) column chromatography to obtain a pale yellow viscous liquid (yield: 64%).

[0041] The product testing data is as follows: 1 H NMR (400 MHz, CDCl3) δ 7.09 (dd, = 8.2, 2.1 Hz, 1H), 6.97 (d,J= 8.3 Hz,1H), 5.69 (s,1H), 4.93 (d,J= 3.9Hz,1H), 3.75 (d,J= 2.2 Hz,2H), 2.70 (dd, J= 10.3,3.9 Hz,1H), 2.49–2.40 (m,1H), 2.26 (d, J= 12.5 Hz,1H), 1.88 (dd,J= 12.6, 3.9 Hz,1H), 1.60 (s, 3H), 1.49 (s,3H).

[0042] Example 7:

[0043] The specific synthesis of cage-like ketal skeleton compounds is as follows:

[0044] Add 0.20 mmol of cinnamyl alcohol analog 1, 0.22 mmol of (3-hexen-dione) analog 2, and 0.02 mmol of p-toluenesulfonic acid to a 10 ml reaction tube with a stir bar, and purge the tube three times with nitrogen under vacuum. Inject 2 ml of acetonitrile into the reaction tube under nitrogen atmosphere. Stir the reaction tube on a magnetic stirrer at room temperature. Monitor the reaction progress using a TLC plate; stop the reaction when reactant 2 is completely consumed. Remove the solvent using a rotary evaporator, and separate the product by silica gel (200-300 mesh) column chromatography to obtain a pale yellow viscous liquid (yield: 60%).

[0045] The product testing data is as follows: 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J= 2.1 Hz, 1H), 7.14 (dd, J= 8.4, 2.1 Hz, 1H), 6.98 (d, J= 8.4 Hz, 1H), 5.58 (s, 1H), 4.93 (d, J= 3.9 Hz, 1H), 3.75 (d, J= 2.2 Hz, 2H), 2.70 (ddd, J= 10.2, 4.0, 1.0 Hz, 1H), 2.45 (m, J= 10.4, 4.2, 2.1 Hz, 1H), 2.26 (d, J= 12.5 Hz, 1H),1.88(dd, J=12.5, 4.0 Hz, 1H),1.60 (s, 3H),1.49 (s, 3H).

[0046] Example 8:

[0047] The specific synthesis of cage-like ketal skeleton compounds is as follows:

[0048] 0.20 mmol of cinnamyl alcohol analog 1, 0.22 mmol of (3-hexen-dione) analog 2, and 0.02 mmol of p-toluenesulfonic acid were added to a 10 ml reaction tube with a stir bar, and the tube was evacuated three times with nitrogen. Under nitrogen atmosphere, 2 ml of acetonitrile was injected into the reaction tube. The reaction tube was stirred on a magnetic stirrer at room temperature. The reaction progress was monitored using a TLC plate, and the reaction was stopped when reactant 2 was completely consumed. The solvent was removed by rotary evaporation, and the product was separated by silica gel (200-300 mesh) column chromatography to obtain a pale yellow viscous liquid (yield: 54%).

[0049] The product testing data is as follows: 1 H NMR (400 MHz, CDCl3) δ 6.68 (dd, J = 10.8, 1.8 Hz, 1H), 6.61 (t, J = 1.8 Hz, 1H), 4.91 (d, J = 3.9 Hz, 1H), 3.89 (s, 3H), 3.76 (d, J = 2.2 Hz, 2H), 2.68 (dd, J = 10.2, 3.9 Hz, 1H), 2.48 – 2.41 (m, 1H), 2.26 (d, J = 12.5 Hz, 1H), 1.87 (dd,J = 12.5, 4.0 Hz, 1H), 1.60 (s, 3H), 1.48 (s, 3H)。

Claims

1. A process for the preparation of a caged ketal skeleton derivative 3, characterized by Mixing compound 1, compound 2, catalyst, solvent to form product structure: R 1 , R 2 represents C1-C12 straight chain alkyl, R 3 represents alkoxy or other electron donating substituent, substituent is halogen, alkyl, trifluoromethyl independently substituted at ortho, meta, para position of benzene ring, R 4 represents alkyne, alkoxy, halogen and various substituents, substituent position can be ortho, meta, para, or multiple positions simultaneously substituted, etc. Its synthetic route is shown in formula I 2. The preparation method according to claim 1, characterized in that, The catalyst is selected from one of (+)-p-toluenesulfonic acid, trifluoroacetic acid, camphorsulfonic acid, acetic acid, preferably (+)-p-toluenesulfonic acid.

3. The preparation method according to claim 1, characterized in that, The time of the synthetic reaction is 1 min-600 min.

4. The preparation method according to claim 1, characterized in that, The solvent is one of acetonitrile, dichloromethane and other mixed solvents, preferably acetonitrile.

5. The method of claim 1, wherein the step of forming the first and second layers is performed by a method selected from the group consisting of: sputtering, evaporation, and chemical vapor deposition. The temperature is 0℃-120℃, preferably 25℃.

6. The preparation method according to claim 1, characterized in that, The molar amount of the compound 2 is 1.5 times, preferably 1-3 times, of the molar amount of the compound 1.

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