Study on the Synthesis of Spirooxindole-pyrrolidines Via Azomethine Ylides Anticipitated [3+2] Cycloaddition Reaction

Author:Huang Ying

Supervisor:yan chao guo

Database:Doctor

Degree Year:2019

Download:37

Pages:185

Size:13164K

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Spirooxindole-pyrrolidines are important research topics in organic chemistry and pharmaceutical chemistry because of their wide range of biological activities.As one of the important active intermediates in the synthesis of nitrogen-containing heterocyclic ring,azomethine ylides has unique high efficiency and wide application prospects.We carried on the design of multicomponent reactions by using azomethine ylide as key synthon and synthesis of nitrogen-containing spiroheterocyclic compounds in this dissertation.Several series of spirooxindole-pyrrolidine derivatives were successfully synthesized by[3+2]cycloaddition reaction with various azomethine ylides as the active intermediates.Some of influence rules such as the structures of substrates,electronic and steric effect of the substituent as well as catalyst of the multlcomponent reactions were Carefully investigated.Furtherly,the regio-and diastereo-selectivity of multicomponent reaction and the diversity of the products were thoroughly studied.In addition,the biological activities of these spirooxindole-pyrrolidines were preliminarily evaluated.The content of this dissertation mainly includes the following five parts.1.A practical methodology for the generation of a new kind of reactive 1,3-dipolar azomethine ylide from the base promoted reaction of ethyl glycinate hydrochloride with dialkyl but-2-ynedioate was successfully developed.The tandem 1,3-dipolar cycloaddition reactions of the in situ generated 1,3-dipolar azomethine ylide with typical dipolarophiles such as 2-arylidene-1,3-indanediones,1-Boc-3-arylideneoxindoles and 2-arylideneoxindoline-2-ones conveniently afforded functionalized spiro[indene-2,3’-pyrrolidines]and snirolindoline-3.3’-pyrrolidines]in good yields and with high diastereoselectivity.This reaction not only exploited new synthetic methodology for the 1,3-dipolar azomethine ylides,but also provided efficient synthetic protocol for the diverse spiro compounds.In addition,eight compounds with certain cytotoxicity to HepG2 cells and one compound with cytotoxicity to CT26 cells were found by detecting the biological activity of spirooxindole-pyrrolidines.2.An efficient strategy for the synthesis of complex dispiro compounds by a 1,3-dipolar cycloaddition of 3-methyleneoxindoles with 1,2,3,4-tetrahydroisoquinoline and isatin derivatives was developed.This three-component reaction afforded the anticipated spirooxindole-pyrrolidines in excellent yields with high regio-and stereoselectivity.This synthetic protocol has advantages of mild reaction condition,easily accessible starting materials and easy purification of the products,which makes it a useful and attractive method for the synthesis of the complex spiro heterocycles in synthetic and medicinal chemistry.Furthermore,the bioactivities detection of these spirooxindole-pyrrolidines has led to find three compounds with promising cytotoxicity to HepG2 cells.3.A series of heteropolycyclic compounds were successfully synthesized by[3+2]cycloaddition of the azomethine ylides which were in situ generated from reaction of aromatic aldehydes and 1,2,3,4-tetrahydroisoquinoline,with 3-phenacylideneoxindoles.The reaction afforded spiro[indoline-3,2’-pyrrolo[2,1-a]isoquinolin]-2-ones bearing four consecutive stereocenters in good yields with good diastereoselectivity.The bioactivity detection of the spirooxindole-pyrrolidine products has led to the discovery of two compounds with promising cytotoxicity to CT26 cells and HepG2 cells with an IC50 value of about 50 μg·mL-1.4.Three series of heteropolycyclic compounds were synthesized by sequential C(3)-alkenylation and[3+2]cycloaddition of the azomethine ylides,which were in situ generated from reaction of aromatic aldehydes and pyrrolidine,with 3-phenacylideneoxindoles,(or 2-arylidene-1,3-indanedione,2-arylidene-1,3-oxindoles).Because of the special[1,3]-H shift phenomenon in the azomethine ylide,a unique azomethine ylide with benzylidene substitution was formed in the presence of excessive benzaldehyde.The spiro[indoline-3,2’-pyrrolizin]-2-one derivatives were obtained.The unique(E)-7’-benzylidene-spiro[indoline-3,2’-pyrrolizin]-2-one derivatives and(E)-7’-benzylidene-spiro[indene-2,1’-pyrrolizine]-1,3-dione derivatives were obtained in moderate yields with good regioselectivity.The bioactivity detection of spirooxindole-pyrrolidines among all the products has led to the discovery of a compound with promising cytotoxicity to CT26 cells with an IC50 value of about 50 μg·mL-1.5.A library of novel spirooxindole-pyrrolidine derivatives were facilely synthesized from 1,3-dipolar cycloaddition of azomethine ylide generated from sarcosine and paraformaldehyde with various 3-methyleneoxindolines.This reaction afforded functionalized spirooxindole-pyrrolidines in satisfactory yields and with high regio-and stereoselectivity.This synthetic protocol has advantages of using readily available starting materials,simple reaction conditions,short reaction times and easy purification of the products,which makes it a useful and attractive method for the synthesis of the spiro heterocycles.Furthermore,the bioactivities detection of these spirooxindole-pyrrolidines has led to find five compounds with certain cytotoxicity to HepG2 cells and two compounds with certain acethycholinesterase inhibitory activity.According to the rich chemical properties of azomethine ylide,the complex spiroheterocyclic compounds with potential bioactivities were synthesized conveniently and by using readily available and cheap materials.These efficient synthetic protocols reached the aim of green chemical synthesis in this dissertation.In addition,the biological activitivies of the obtained spirooxindole-pyrrolidines,which have similar structural fragment to the active natural products were preliminarily evaluated,some new compounds with promising activities were found Therefore,the research in this dissertation will provide new technology for drug synthesis,and the synthesized new compounds with certain activity will provide material basis and theoretical basis for the research of new drugs,which has important scientific significance and application values.