阅读说明：本技术 一种具有螺环结构的吡咯啉衍生物的不对称合成方法 (Asymmetric synthesis method of pyrroline derivative with spiro structure ) 是由 王志鹏 向四川 邵攀霖 贺耘 于 2018-07-06 设计创作，主要内容包括：具有螺环结构的吡咯啉衍生物在抗菌、抗病毒等领域体现出重要的生理活性。本发明涉及螺环吡咯啉衍生物的不对称合成方法,是以异氰基乙酸酯类化合物与橙酮衍生物进行1,3-偶极环加成反应,该反应能够快速、高效地构建三个连续手性中心的螺环吡咯林衍生物,具有很高的原子经济性。本发明所用底物易于制备、价格低廉,且反应条件温和,操作简单,不需要进行无水无氧操作,即可高收率、高对映选择性地得到目标化合物,底物适用范围广。(The pyrroline derivative with the spiro structure shows important physiological activity in the fields of antibiosis, antivirus and the like. The invention relates to an asymmetric synthesis method of a spiro pyrroline derivative, which is characterized in that an isocyanoacetic acid ester compound and an aurone derivative are subjected to 1, 3-dipolar cycloaddition reaction, the reaction can quickly and efficiently construct the spiro pyrroline derivative with three continuous chiral centers, and the spiro pyrroline derivative has high atom economy. The substrate used in the invention is easy to prepare, low in price, mild in reaction condition, simple to operate, free of anhydrous and anaerobic operation, capable of obtaining the target compound with high yield and high enantioselectivity, and wide in application range.)

1. An asymmetric synthesis method of pyrroline derivatives with spiro structures is shown as a reaction formula (1):

characterized in that R in the formula¹Methoxy, halogen atom substituent, etc.; ar is phenyl, methyl, methoxy, halogen atom substituted phenyl, naphthyl, indolyl, pyridyl, furyl, thienyl, ferrocenyl and the like; r²Is hydrogen, C_1-4Alkyl, allyl, cyclohexyl, n-propyl, benzyl, and methoxy substituted phenyl.

2. The synthesis process according to claim 1, wherein the reaction catalyst ag (i) is: silver acetate, silver oxide, silver carbonate, silver triflate, silver trifluoroacetate.

3. The method of claim 1, wherein the ligand is of formula (2):

4. the synthesis process according to claim 1, characterized in that the reaction temperature is from-40 ℃ to 25 ℃.

5. The synthesis method according to claim 1, wherein the molar percentage of the catalyst Ag (I) to the substrate in the reaction reagent composition is: ag (I)5 mol% -20 mol%.

6. The method of synthesis of claim 1, wherein the molar percentage of ligand to substrate in the reactant composition is: 10mol percent to 40mol percent.

7. The synthesis process according to claim 1, characterized in that the reaction solvent is: dichloromethane, tetrahydrofuran, chloroform, toluene, diethyl ether, ethyl acetate.

8. The synthetic method of claim 1 wherein the substrate concentrations are: 0.05-0.2 mol/L.

Technical Field

The invention belongs to the field of organic synthesis methodology, and relates to an asymmetric synthesis method of a pyrroline derivative with a spiro structure and participation of an isocyan compound.

Background

Pyrroline and pyrrolidine skeletons with spiro structures widely exist in natural products and compounds with biological activity, show important physiological activity in the fields of antibiosis, antivirus and the like, are also important intermediates for organic synthesis, and are more and more concerned by synthetic chemists in recent years due to unique structural characteristics and important biological activity.

In 2012, Wang (chem. Commun.,2012,48,5175-5177) et al reported that under the catalysis of cinchona-derived thiourea, asymmetric 1, 3-dipolar cycloaddition reaction of 3-alkenyl-2-indolone and α -phenyl substituted isocyanoacetate successfully realizes the regulation and control of product stereoselectivity by changing the protecting group on indole nitrogen, and constructs the pyrroline indole skeleton compound with spiro structure. The reaction achieved excellent enantioselectivity (> 90%), but the yields (41-65%) and diastereoselectivity were relatively poor (<10: 1).

An example of efficient synthesis of spirocyclic pyrrolidine derivatives containing benzofuran structure using ionic liquid as catalyst was reported by Ding and Fu (chemistry select,2016,1, 4403-one 4407) at Henan university, 2016. The authors achieved a selective construction of spiro pyrrolidine strategies at different sites under the same reaction conditions by using benzofuran derivatives of different structures as substrates, but, because of the use of achiral ionic liquid catalysts, the catalytic systems did not allow asymmetric synthesis of such compounds.

In the same year, the group Albrecht (Synthesis,2016,49,880-890) reported a method for the catalytic asymmetric Synthesis of pyrrolidine derivatives with spiro structure in the presence of aurone compounds. The authors found that unmodified natural product quinine can be used as an excellent chiral catalyst to realize asymmetric cycloaddition reaction of aurone and methyleneamine ylide, and a series of spiro pyrrolidine derivatives with benzofuranone structure can be obtained with high yield and high stereoselectivity. The catalytic system used by the method is simple and efficient, and provides a new reference for asymmetric synthesis of the compounds.

On the basis, Peng (org. chem. front.,2017,4,81-85) and the like in 2017 realize the asymmetric cycloaddition reaction of non-activated 3-alkenyl-2-indolone and isocyanoacetate by using a chiral ligand-silver co-catalytic system, and expand the application range of the isocyanoacetate, and the isocyanoacetate unsubstituted or substituted by alkyl at alpha position can be well applied to the system and obtains good reaction effect.

In 2017, Wang (org. Lett.,2017,19,1862-1865) et al reported that under the catalysis of chiral phosphoric acid, 3-aminooxidation indole-derived methyleneamine ylide and asymmetric 1, 3-dipolar cycloaddition reaction of alpha, beta-unsaturated double bond, a series of spiro pyrrolidine derivatives can be obtained with high yield and high stereoselectivity, and the corresponding spiro pyrroline derivatives can be obtained under the oxidation of DDQ of the compounds, and the stereoselectivity of the products is hardly influenced.

The aurone is an important class of flavonoid compounds, has wide biological activity and pharmacological action, such as antitumor and cytotoxic activity, anti-inflammatory and antibacterial activity, and can be used as acetylcholinesterase inhibitor. Although few reactions of aurone and methyleneamine ylide for constructing the spiro pyrrolidine derivative are reported at present, no examples of the reaction of the compound with important physiological activity and an isocyanoacetic ester compound for constructing the spiro pyrroline are reported. Therefore, the development of simple and efficient catalytic asymmetric cycloaddition reaction between the aurone and the isocyanoacetic ester compound and the construction of the pyrroline derivative with the spiro structure have important significance.

Disclosure of Invention

The invention provides an asymmetric synthesis method for pyrroline derivatives with spiro structures by using an aurone derivative and an isocyanoacetic ester compound as substrates through 1, 3-dipolar cycloaddition reaction. The method has mild conditions and simple operation, can obtain the target compound with high yield and high stereoselectivity without carrying out anhydrous and anaerobic operation, and has wide substrate application range and high product application value.

The invention provides a method for asymmetrically synthesizing pyrroline derivatives with spiro structures, which has the following reaction equation:

in the formula R¹Methoxy group, halogen atom substituent, etc.; ar is phenyl, methyl, methoxy, halogen atom substituted phenyl, naphthyl, indolyl, pyridyl, furyl, thienyl, ferrocenyl and the like; r²Is hydrogen, C_1-4Alkyl, allyl, cyclohexyl, n-propyl, benzyl, and methoxy substituted phenyl.

The implementation operation of the technical scheme comprises the following steps: putting a reaction catalyst Ag (I) and a ligand into a reaction bottle, putting a magnetic stirrer with proper size, adding a certain amount of proper solvent, dropwise adding isocyanoacetic ester, stirring for 5 minutes at a certain temperature, then adding the auranone derivative into the reaction bottle, reacting at a certain temperature, and tracking and monitoring by TLC. After the reaction is finished, concentrating the reaction solution, and separating by silica gel column chromatography to obtain the product.

In the preparation method, the reaction temperature is-40 ℃ to 25 ℃; preferably 0 ℃ and-20 ℃.

In the preparation method of the invention, the catalyst Ag (I) in the reaction reagent composition is: silver acetate, silver oxide, silver carbonate, silver triflate, silver trifluoroacetate; most preferably: and (3) silver oxide.

In the preparation method of the invention, the ligand in the reaction reagent composition is preferably 1-6,

most preferably: and (2) a ligand.

In the preparation method, the mol percentage of the catalyst Ag (I) and the substrate in the reaction reagent composition is preferably 5-20 mol% of Ag (I), and most preferably: 10mol percent.

In the preparation method of the invention, the mol percentage of the ligand to the substrate in the reaction reagent composition is preferably 10 mol% to 40 mol%, and most preferably: 20mol percent.

In the preparation method of the present invention, the reaction solvent is preferably: dichloromethane, tetrahydrofuran, chloroform, toluene, diethyl ether, ethyl acetate, most preferably: tetrahydrofuran.

In the preparation method of the present invention, the substrate concentration is preferably: 0.05 to 0.2mol/L, most preferably: 0.1 mol/L.

Detailed Description

The monitoring method in any embodiment of the invention is: thin layer chromatography.

The technical means for structure confirmation are all common technical means known to the technicians in the field, such as nuclear magnetic resonance technology and high-resolution mass spectrometry.