Access To Chiral 1,3-dihydroisobenzofu Via Asymmetric Transfer Hydrogenation

α-substituted 1,3-dihydroisobenzofuran is a kind of important structural unit.This heterocyclic structure exists in a variety of pharmacologically active compounds and natural products.In the past decade,the asymmetric synthesis of optically active a-substituted 1-substituted 3-dihydroisobenzofuran has attracted the attention of many organic chemists.At present,the reported asymmetric synthesis of these compounds is mainly achieved by the addition of chiral oxonium ions and chiral nucleophiles and various asymmetric cyclization,kinetic resolution,redox racemization and so on.In these existing reports,the range of substrates of diferent reaction types also has some limitations.The realization of atomic economy and the type of reaction with high yield and high enantiomeric excess is still one of the difficult problems in the current research.Asymmetric hydrogenation of unsaturated organic molecules is one of the most important methods to produce chirality of compounds.The asymmetric construction ofα,β-unsaturated aldehydes/ketones,imines,quinolines,isoquinolines,benzochromenes and some complex natural products has been successfully realized by using the strategy of asymmetric hydrogen transfer,but the synthesis of isobenzofurans has not been reported.Here we will further use this strategy to study the asymmetric synthesis of α-substituted 1,3-dihydroisobenzofurans.Because of the compatibility problem betweenα-substituent cyclic ether substrates and asymmetric reduction system in principle,we used chiral phosphoric acid to catalyze the asymmetric hydrogenation of α-isobenzofuran ketal with the participation of Hantzsch ester.This paper mainly discusses the synthesis of α-isobenzofurans by asymmetric transfer hydrogenation.By reviewing the literature and summarizing the previous research results of our group,we first selected 1-methoxy-1-(4-methoxyphenyl)-3,3-dimethyl-1-dihydroisobenzofuran as the starting substrate and 2-dimethyl-1-line 4-dihydro-3-pyridine dicarboxylic acid diethyl ester(Hantzsch ester)as the reductant as the model reaction.We screened and optimized the reaction conditions by studying the leaving groups,catalysts,reducing agents,reaction solvents,reaction temperature and other aspects,and determined the best reaction conditions.Subsequently,we expanded different substrates,Through the experimental results,we found that this method has good reaction activity and excellent enantioselectivity for different α-substituted isobenzofuran substrates and removing other different forms of isobenzofuran substrates.When the α-substituent is the electron donor,both the position and the number of substituents have excellent results,while when the α-substituent is the electron acceptor,the enantiomeric selection needs to be slightly reduced.Generally speaking,this method basically obtains α-substituted 1,3-dihydroisobenzofurans with high efficiency and high selectivity,which shows that this method has good applicability and application prospect.Finally,the reaction mechanism was deduced by consulting the literature.And the absolute configuration of the product was determined by the existing experimental data.We successfully synthesized optically active α-substituted 1,3-dihydroisobenzofurans by asymmetric transfer hydrogenation.In this process,firstly,the ketal substrate will form an oxonium ion intermediate under the action of chiral phosphoric acid,and a chiral ion pair will be formed in situ between the oxonium ion intermediate and the chiral phosphoric acid.Then the hydrogen atom of Hantzsch ester was used as a nucleophile to attack the activated oxonium ion intermediate and finally the photoactive product was obtained.This method shows good compatibility in both the electronic effect and the substituent effect of the substrate.Therefore,this method provides a new idea for the construction of α-substituted cyclic ethers by asymmetric hydrogen transfer reaction catalyzed by chiral phosphoric acid.