Design And Synthesis Of 3-Position Oxindole Compounds Containing Quaternary Carbon Centers

The oxindole building block is widely present in many important natural products and drug molecules,and is known as the star molecule in the active structure of drugs.In view of the outstanding value of oxindole molecules in the field of clinical treatment and drug development,the efficient construction and transformation of oxindole molecules and late-stage modification have been enduring research hotspots in the field of organic synthesis.Focusing on the efficient construction of total carbon substituted quaternary carbon oxindole,a new strategy for asymmetric catalytic construction of quaternary carbon oxindole from alkenyl oxindole was developed,and the asymmetric 3-position addition reaction of alkenyl oxindole was optimized.the construction of 3-position chiral all-carbon quaternary carbon center was realized successfully.In addition,we designed and developed copper-catalyzed propargylation based on oxindole to construct oxindole with all-carbon quaternary carbon center.The specific contents of the study are as follows:1.Under the catalysis of chiral central metal complexes,3,3-disubstituted oxindole compounds with all-carbon quaternary carbon centers were synthesized by the direct Michael addition reaction ofα,α-dicyanolefin with 3-alkenyl oxindole,which has excellent enantioselectivity.In the presence of 1.0 mol%chiral Rh（III）complex,the corresponding addition product was obtained with a yield of 21-98%and an ee value of 80-97%.It is worth noting that this method shows a great advantage in enantioselectivity,because under the catalysis of chiral Rh（III）complexes with catalyst content as low as 0.05mol%,the gram-level reaction can still be achieved and the enantioselectivity remains unchanged.In addition,through the derivation of the product,the sulfur-containing heterocyclic compounds were obtained,and the practicability of the method was verified.2.Propargylation reaction ofα,α-dicyanoolefin with tert-alkyne propanol esters was carried out by chiral Cu/pyridine-bis-oxazoline catalytic system,and a series of 3-position oxindole propargyl compounds with quaternary carbon centers were synthesized.Through the optimization of a series of conditions,such as copper salt,alkali additive,solvent,ratio of reaction substrate,reaction time and temperature,the best reaction conditions were obtained,that is,the best ligand is Pybox,copper salt is Cu I,alkali additive Et₃N,reaction temperature is room temperature,solvent is methanol.The reaction has high reaction activity under mild conditions,and can effectively construct quaternary carbon center at 3-position.Then,the universality of the substrate was investigated,and the 3,3-disubstituted oxindole compounds containing quaternary carbon centers were obtained in medium to excellent yields.The gram scale magnification experiment was carried out,and the target compound could be obtained with good yield.Finally,benzyl and p-toluenesulfonyl triazole compounds were synthesized by derivatization reaction,and the effectiveness of the strategy was verified.