Study On Asymmetric Cascade Reaction Of Chiral Monosubstituted BINOL Amides

Binaphthalamide has become one of the core organic small molecule catalysts due to the axial asymmetry phenomenon caused by the hindered rotation of the rigid structure of its backbone and the strong hydrogen bond activation ability of the amide substrate,which can effectively promote the occurrence of asymmetric reactions.Chiral bifunctional binaphthalamide catalysts with BINOL ligands have achieved great success in asymmetric synthesis.One of the highlights of chiral catalytic reactions of organic small molecules is the synergistic catalysis through multiple catalyst combinations and multi-component cascade reaction.Asymmetric cascade reaction is one of the most attractive methods to construct chiral materials.It can quickly obtain bioactive scaffolds with wide structural diversity,atom economy and excellent bonding efficiency in one step,and realize the diversity and complexity of product molecular structure and the control of multiple chiral centers.This article uses economically available naphthol-3-carboxylic acid and 2-naphthol as raw materials to form various chiral monosubstituted BINOL amide hydrogen bonding catalysts with multiple active centers and low steric hindrance through cross coupling.This method has the advantages of low catalyst dosage,short reaction time,and simple reaction conditions.Firstly,a chiral monosubstituted BINOL amide catalyst was applied to the asymmetric Michael/Thorpe-Ziegler cascade reaction between pyrazolone and 2-benzylidenemalononitrile to synthesize pyranopyrazole derivatives,and the catalytic conditions for the reaction were optimized.The results showed that using 10 mol%of chiral monosubstituted BINOL amide catalyst 1a and CH₂Cl₂ as solvent,the optimal synthesis effect was obtained at room temperature for 1 hour,with a yield of 93%and 85%ee.Under the optimal reaction conditions,the reaction substrate was expanded to prepare 12 chiral dihydropyrano[2,3-c]pyrazole derivatives.This method has the advantages of low catalyst amount,short reaction time,and simple reaction conditions.Secondly,chiral monosubstituted BINOL amide catalyst were used to catalyze the asymmetric Sulfa-Michael/Aldol cascade reaction between3-benzylidene chromoman-4-one and 2,5-dihydroxy-1,4-dithiane to synthesize spirocyclic tetrahydrothiophene-4-one derivatives with three chiralities.The amount of catalyst,solvent,reaction time,and temperature were studied and optimized.The optimal synthesis effect was obtained using 10 mol%of catalyst 1b,CHCl₃ as solvents and reacting at45℃for 18 hours,with a yield of 91%,95:5 dr and 85%ee.Under the optimal reaction conditions,the reaction substrate was expanded to prepare 10 chiral spirothiophene chromone derivatives,providing a simple and efficient strategy for the synthesis of spirothiophene chromone 4-one derivatives with potential biological activity and enantiomeric enrichment.