阅读说明：本技术 含环外z,e-双烯顺式四氢苯并呋喃类化合物及其合成方法 (Cis-tetrahydrobenzofuran compound containing Z, E-diene outside ring and synthesis method thereof ) 是由 刘丙贤 王娟娟 李鹏飞 张雅雯 戴雨倩 高紫莹 王辰喆 于 2019-12-04 设计创作，主要内容包括：本发明提供了一种含环外Z,E-双烯单元的顺式四氢苯并呋喃类化合物以及制备方法,属于有机化学领域。本发明中,所述化合物具体结构为<Image he="297" wi="522" file="DDA0002301637090000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>在铑催化剂存在下,一步即可完成对上述化合物的合成,高选择性得到含环外(Z,E)-双烯单元的顺式四氢苯并呋喃结构化合物。该方法具有反应条件温和,反应路径合理,后处理简单,反应产物立体选择性和区域选择高,该类化合物在NF-κB信号传导通路的抑制上显示出了良好的活性。(The invention provides a cis-tetrahydrobenzofuran compound containing an exocyclic Z, E-diene unit and a preparation method thereof, belonging to the field of organic chemistry. In the invention, the compound has a specific structure In the presence of rhodium catalyst, the synthesis of the compound can be completed in one step, and the cis-tetrahydrobenzofuran structure compound containing exocyclic (Z, E) -diene unit can be obtained with high selectivity. The method has the advantages of mild reaction conditions, reasonable reaction path, simple post-treatment, high stereoselectivity and regional selection of reaction products, and good activity of the compounds on the inhibition of NF-kB signal transduction pathways.)

1. The cis-tetrahydrobenzofuran compound containing exocyclic Z, E-diene is characterized by having the following structure:

wherein R is selected from alkyl, aryl or halogen, R¹,R²Each independently selected from aryl or alkyl, or R¹And R²Together forming an aromatic ring.

2. The method for synthesizing the structural compound according to claim 1, wherein the reaction equation is as follows:

the method is characterized by comprising the following steps:

the compound 1, the compound 2 and a rhodium catalyst are mixed and heated to react in an organic solvent to obtain a compound 3.

3. The method of synthesis according to claim 2, characterized in that: the rhodium catalyst is CpRh (OAc)₂.H₂O or [ Cp RhCl₂]₂NaOAc in situ produced rhodium catalyst.

4. The method of synthesis according to claim 2, characterized in that: the molar ratio of the compound 1 to the compound 2 to the rhodium catalyst is 2.0-3.0:1.0: 0.04-0.10.

5. The method of synthesis according to claim 2, characterized in that: the organic solvent is selected from chlorine-containing solvents.

6. The method of synthesis according to claim 5, characterized in that: the organic solvent is 1, 2-dichloroethane.

7. The method of synthesis according to claim 2, characterized in that: the heating reaction temperature is 60-90 ℃.

8. The method of synthesis according to claim 2, characterized in that: the reaction can be directly carried out in the air without inert gas protection.

9. Use of a structural compound according to claim 1 in an inhibitor of the NF- κ B signalling pathway.

Technical Field

The invention belongs to the field of organic synthesis, and particularly relates to a cis-tetrahydrobenzofuran structure compound containing an exocyclic (Z, E) -diene unit, and a preparation method and application thereof.

Background

Cis-tetrahydrobenzofuran compounds are a very important class of structures which are widely present in natural products as well as active compounds, such as Sorbicilactone A (Angew. chem., int. Ed.2008,47, 1935-. The framework III, which contains an exocyclic double bond structure, has also been shown to be an inhibitor of the NF-. kappa.B signaling pathway (ACS Med. chem. Lett.2012,3, 459-.

At present, the method for preparing cis-tetrahydrobenzofuran structure compounds containing exocyclic diene units is not reported yet. Therefore, the development of efficient synthesis of the compounds can obtain a skeleton structure with a special structure, and the method has an important effect on screening of drug lead compounds.

Disclosure of Invention

The invention aims to provide a cis-tetrahydrobenzofuran structure compound containing an exocyclic (Z, E) -diene unit, and a preparation method and application thereof. In the invention, the compound has a novel structure, and the specific structure is

The synthesis of the compound can be completed in one step in the presence of a rhodium catalyst, and a cis-tetrahydrobenzofuran structure compound containing an exocyclic (Z, E) -diene unit is obtained with high selectivity, and the synthesis method is not reported at present. The method has the following advantages: the invention has the advantages of universality, mild reaction conditions, low cost, high stereoselectivity and high regioactivity, and reasonable reaction pathThe compound of the type is prepared with high efficiency.

An exocyclic (Z, E) -diene cis-tetrahydrobenzofuran compound has the following specific structure:

wherein R is selected from alkyl, aryl or halogen, R¹,R²Each independently selected from aryl or alkyl, or R¹And R²Together forming an aromatic ring.

The invention also provides a synthetic method of the structural compound, and the synthetic route is as follows:

the method comprises the following steps:

the compound 1, the compound 2 and a rhodium catalyst are mixed and heated to react in an organic solvent to obtain a compound 3.

Further, the rhodium catalyst is CpRh (OAc)₂.H₂O or [ Cp RhCl₂]₂NaOAc in situ produced rhodium catalyst.

Furthermore, in the technical scheme, the mol ratio of the compound 1, the compound 2 and the rhodium catalyst is 2.0-3.0:1.0: 0.04-0.10.

Further, in the above technical solution, the organic solvent is selected from chlorine-containing solvents, such as dichloromethane, chloroform, 1, 2-dichloroethane, chlorobenzene, or the like, and preferably the solvent is 1, 2-dichloroethane.

Further, in the above technical scheme, the heating reaction temperature is 60-90 ℃.

Furthermore, in the technical scheme, the reaction can be directly carried out in the air without the protection of inert gas.

To investigate the reaction mechanism, the following comparative experiments were performed, and the results were as follows:

from the above comparative test results, the presumed possible reaction mechanism is as follows:

further, in the above technical scheme, the obtained product is further derived as follows (taking 3aa and 3ab as examples):

a third object of the invention: in addition to the compound 3, a cis-tetrahydrobenzofuran structure compound containing an exocyclic (Z, E) -diene unit was used as an inhibitor of NF- κ B signaling pathway, and IC50 ═ 26 μ M was preferably obtained.

Advantageous effects of the invention

The invention can synthesize the cis-tetrahydrobenzofuran structure compound containing the exocyclic (Z, E) -diene unit with high selectivity, and has the advantages that: the compound is synthesized for the first time, the reaction condition is mild, the efficiency is high, the reaction path is reasonable, and the post-treatment is simple. As a new structure, the compound shows good activity on the inhibition of NF-kB signal transduction pathway.

Drawings

FIG. 1 is a graph showing the inhibition rate of compound 3ab against A549 cells obtained in example 2;

FIG. 2 is a graph showing the inhibition rate of Compound 3bb on A549 cells obtained in example 8;

FIG. 3 is a graph showing the inhibition rate of compound 3mb obtained in example 10 on A549 cells.

FIG. 4 is a single crystal diagram of Compound 3eb obtained in example 12.

Detailed Description

The technical solution of the present invention is further described in detail with reference to the following specific examples, but the scope of the present invention is not limited thereto.

Optimization test of reaction conditions: (taking the example of the rhodium-catalyzed formation of 3a of 1a and 2 a) typically, compound 1a (0.2mmol), rhodium catalyst (4.0 mol%), compound 2a (0.2mmol,1.0eq), was reacted at 60-80 ℃ until complete disappearance of starting material 2a was monitored by thin layer plate (TLC) (9-12 h); the solvent was dried by spinning and separated by column chromatography (eluent: petroleum ether/ethyl acetate volume ratio 2:1) to give 3aa of yellow solid. The reaction optimization results are as follows:

it should be noted that: in reaction scheme 1, the self-coupled byproduct 3 aa' was isolated up to 26% in addition to the product 3 aa.

Through the optimization of the reaction conditions, the optimal reaction conditions are finally determined as follows: in 1, 2-dichloroethane solvent, Cp Rh (OAc) is adopted₂.H₂O or [ Cp RhCl₂]₂The reaction was carried out in the presence of sodium acetate.