Redox Deracemization Of Isobenzofuran

α-substituted cyclic ethers are the basic structural skeleton contained in many natural product molecules,bioorganic active molecules and drug molecules,for example,chiral α-substituted 1,3-dihydroisobenzofuran is an important glycoside.In the past few decades,the asymmetric synthesis of optically active α-substituted cyclic ethers has attracted the attention of many organic chemists.At present,the reported asymmetric synthesis of this type of compound is mainly achieved by the enantioselective addition of oxonium ions and various asymmetric cyclization reactions.In these existing reports,different types of substrates are also limited asymmetric construction of α-substituted cyclic ethers with high yield and high enantiomeric excess optical activity is still a major scientific challenge.At present,studies on redox deracemization have been reported,but these existing reaction reports mainly focus on the secondary benzyl alcohol and secondary amine,which are relatively stable oxidation intermediates,and the redox deracemization of α-substituted cyclic ethers are rarely reported.Due to the instability of oxonium ions after the oxidation of α-substituted cyclic ethers,in this paper,we adopt the "acetal pool" strategy to generate stable acetal intermediates,and then form chiral ion pair intermediates with chiral catalysts,and finally asymmetric hydrogenation to obtain optically active α-substituted cyclic ether.First of all,racemic 3-(4-methoxyphenyl)First of all,-1,1-dimethyl-1,3-dihydroisobenzofuran is used as a template substrate,due to the lack of asymmetric synthesis of such compounds The reactivity and chiral centers are difficult to control,and there are few reports on enantioselective synthesis,so we use redox deracemization to achieve their asymmetric synthesis.Using Hantzsch ester as a reducing agent,after screening the oxidant and different 3-(4-methoxyphenyl)-1,1-disubstituted-1,3-dihydroisobenzofuran additives reactivity,knowing that the additive MeOH is essential for complete oxidation and high enantioselective transfer hydrogenation,then screened for influencing factors such as catalysts and solvents to determine the optimal reaction conditions.Then,based on the optimal conditions of the reaction,we expanded the scope of the substrate of the reaction,with 1,1-dimethyl-1,3-dihydroisobenzofuran and other benzofuran derivatives,the reaction system has good tolerance and compatibility of electronic effects at different substitution positions,reflecting high reaction enantioselectivity.Finally,we explored the mechanism of the reaction through a controlled experiment and verified that the acetal intermediate was formed during the reaction,and then enantiomerically selective hydrogenation reaction was performed to obtain an optically active product.In conclusion,we used the "acetal pool" strategy to achieve the redox deracemization of isobenzofuran compounds.This method has good applicability to substrates,mild reaction conditions,and asymmetric synthesis of α-substituted isobenzofurans provides new methods and ideas.