The Synthesis Of 3,4-diaryl Substituted Spirocyclopentyl Oxindole

Spirocyclopentyl oxindoles are an important class of alkaloids.Developing new spirocyclopentyl oxindole compounds with a unique pharmacological profile is greatly attractive to numerous sections of academia and pharma industry.Structure-activity relationship(SAR)studies suggested that huge difference could be existed in efficacy of spirocyclopentyl oxindoles with various substituents.Due to the applicabilities of reactions are generally limited,exploiting different range of methods to synthesize spirocyclopentyl oxindole derivatives is useful and has already achieved great success.But among them,the methods to provide 3,4-diaryl substituted spirocyclopentyl oxindoles are only a handful,and all of them have some limitations.In this thesis,a novel methodology for the synthesis of 3,4-diaryl substituted spirocyclopentyl oxindole has been established,which compensate for the shortcomings of previous methods,as a result,further enriching the molecule bank of spirocyclopentyl oxindole.Five-membered carbon ring could be constructed form spirocyclopropyl oxindoles and ynamides respectively.As can be seen from literatures,4-aryl substituted spirocyclopentyl oxindoles were able to be efficiently assembled by ring opening-cyclization reaction of spirocyclopropyl oxindoles.As another substrate of the cyclization reaction,however,the electron-withdrawing olefins could not provide4-aryl substituent at position 3 of spirocyclopentyl oxindoles.The highly polarized ynamide rendered the alkyne had both electrophilic and nucleophilic properties,as a result,can form five-membered carbon ring via cyclization with C3 synthons easily.The application of ynamides facilitated the aryl substitution.Therefore,Lewis acid-catalyzed cyclization of spirocyclopropyl oxindoles with aryl ynamides was developed to access 3,4-diaryl substituted spirocyclopentyl oxindole.By employing spirocyclopropyl oxindoles and ynamides as substrates,the optimal result was obtained via systematic condition screening of the reaction: 5mol% Cu(OTf)2 was used as Lewis acid-catalyst,CH2Cl2 as solvent,and the reaction was carried out for 4 h at room temperature(25 °C).Under this condition,the influences of aryl ynamides and spirocyclopropyl oxindoles with substituents varied from properties to positions toward the reaction results were investigated systematically.In summary,64% to 90% yield and 1.3:1 to > 40:1 dr were obtained.The regularity of reactions was gained through an analysis of the 21 products.In general,electron-rich spirocyclopropyl oxindoles processed more efficiently,and the inefficiency of electron-poor spirocyclopropyl oxindoles can be overcame by utilized para-nitro phenyl sulfonamide-based ynamide.Scaling up to gram level did not affect the reaction efficiency.The removal of p-toluenesulfonyl group yielded α,β-unsaturated carbonyl compound which was more convenience for further transformation.The relative configuration of the product was determined by single crystal X-Ray diffraction analysis.