Catalytic Asymmetric Oxa-Diels-Alder Reaction And 1,6-Michael Addition Reaction Of 3-Methylene Isoindolinone

As the core structure,isoindolinone compounds exist widely in natural products and pharmacologically active molecules,and are a very important class of nitrogen-containing heterocyclic compounds.The active site in its structure is mainly a hydrocarbon group in the dihydropyrrole ring.When a substituent is introduced at this site,the stability of such compounds during metabolism in the body can be significantly improved,and the activity of the compound expression can also be enhanced.Therefore,it has a great significance to synthesize a series of compounds with different substituents at three positions of isoindolinone.In this article,3-methylene isoindolinone is used as a substrate,and a series of compounds with different substituted isoindolinone skeletons at 3 positions are constructed through the reaction with quinone methides.1: Br(?)nsted acid-catalyzed asymmetric inverse-electron-demand Oxa-Diels-Alder reaction of 3-methylene isoindolinone and o-quinone methides.This article reports a Br(?)nsted acid-catalyzed asymmetric Oxa-Diels-Alder reaction of 3-methyleneisoindolinone with o-hydroxybenzyl alcohol to construct a nitrogen-oxyspiro heterocyclic compound containing a quaternary carbon stereocenter.Under acidic conditions,o-hydroxybenzyl alcohol can generate o-quinone methide(o-QMs)in situ,thereby acting as the diene of the asymmetric Oxa-DielsAlder reaction.Through optimization of the reaction conditions,4-phenylspiro(chroman-2,1'-isoindoline)-3'-one was finally produced with 64% yield,3: 1 d.r.,93/92% ee.Furthermore,3-methylene isoindolinone and o-hydroxybenzyl alcohol were structurally modified to construct a series of highly enantioselective oxirane heterocyclic chiral compounds containing quaternary carbon stereocenters.The derivative experiment of nitrogen substitution of the product was carried out successfully,and the enantioselectivity did not decrease.2: 1,6-Michael addition reaction of 3-methylene isoindolinone and p-quinone methides.2,6-Di-tert-butyl-p-methylenebenzoquinone is a kind of very stable para-quinone methides(p-QMs),which can be used as michael receptor for 1,6-Michael addition reaction with nucleophiles.Therefore,we made use of the nucleophilicity of the ? position carbon of 3-methylene isoindolinone to react with p-methylene benzoquinone by 1,6-Michael addition reaction,and finally a series of diaryl compounds containing isoindolinone skeleton were obtained in 15-75% yield.At the same time,we also simply optimized the conditions of asymmetric 1,6-Michael addition reaction,and obtained 84% ee and 35% yield of the target compound.