Asymmetric Monofluoroalkylation Of Oxindoles

Asymmetric synthesis plays an important role in the discovery of medicines.The research demonstrates that the incorporation of a fluorine-containing substituent could improve metabolic stability,affect the molecular physicochemical properties,play an important role in combining the protein and ligand,and thereby improve the biological activity profile.While natural fluorinated organic compounds are rare,synthetic fluoro-organic chemistry has not evoked adequate attention from medicinal chemists until recent decades,especially the optical organofluorine compounds.3,3'-Disubstituted oxindoles having a chiral all-carbon quaternary center at the C3 position are frequently found in many natural products,pharmaceuticals,and biologically active compounds.The substitution of a hydrogen atom in biologically active oxindoles with a fluorine atom in a nonaromatic position might improve their physiological properties.An example worth noting is the monofluorinated oxindole BMS-204352,a promising agent for the treatment of stroke.However,the synthesis of enantioenriched 3-monofluoroalkyl oxindoles has been less studied.Based on the previous research and our continuous interest in the construction of enantioenriched oxindoles,we have successfully developed a new practical organocatalytic asymmetric protocol for the introduction of a monofluoroalkyl group into the oxindole framework.Excellent diastereoselectivities and enantioselectivities of the products were obtained with a wide range of 3-bromooxindoles and a-fluorinated ?-keto gem-diols.In addition,the synthetic utility of our methodology was further illustrated by the assembly of fluorinated 3,4'-piperidyl spirooxindoles and hexahydropyrrolo[2,3-b]indolines,which showed great potential in clinical efficiency in nervous system diseases.At the same time,our methodology enrichs the library of biologically active oxindoles greatly.Our methodology not only makes an important implement in the synthesis of monofluorinated oxindoles,but also plays potential significant roles in the screening of small molecular medicines,the construction of unnatural fluorinated amino acids and the modifications of peptides.