1,1-Difluorinated sulfonamides are known to have better anti-inflammatory activity and enzyme inhibitory potency than their nonfluorinated counterparts.Two geminal fluorine atoms cause electronic perturbation of the n...1,1-Difluorinated sulfonamides are known to have better anti-inflammatory activity and enzyme inhibitory potency than their nonfluorinated counterparts.Two geminal fluorine atoms cause electronic perturbation of the nearby polar groups enhanced the biological activity of the 1,1-difluorinated sulfonamides.However,because methods for their stereoselective synthesis are scarce,such entities remain entirely unexplored.Here,we outline an efficient method for the stereoselective introduction of the difluoro(aminosulfonyl)methyl group(CF_(2)SO_(2)NH_(2))into carbonyls,imines,and alkyl halides with a new(R)-2-pyridyl difluoromethyl sulfoximine reagent,which provides a unique solution for the synthesis of chiralα,α-difluorinated sulfonamides with a quaternary stereocenter.Its potency is illustrated by the synthesis of fluorinated analogues of bioactive compounds such as 2-OH-SA,an antagonist for the GABA_(B)receptor in guinea pig ileum,and the late-stage modification of complex molecules such as haloperidol,ebastine,cholesterol,and(+)-δ-tocopherol derivatives.Stereoselective difluoro(aminosulfinyl)methylation to yield chiral sulfinylamides is presented,showcasing other uses of this new reagent.展开更多
基金Financial support was provided by the National Key Research and Development Program of China(no.2016YFB0101200)the National Natural Science Foundation of China(no.21632009)+2 种基金the Key Programs of CAS(no.KGZD-EW-T08)the Key Research Program of Frontier Sciences of CAS(no.QYZDJ-SSW-SLH049)Shanghai Science and Technology Program(no.16QA1404600).
文摘1,1-Difluorinated sulfonamides are known to have better anti-inflammatory activity and enzyme inhibitory potency than their nonfluorinated counterparts.Two geminal fluorine atoms cause electronic perturbation of the nearby polar groups enhanced the biological activity of the 1,1-difluorinated sulfonamides.However,because methods for their stereoselective synthesis are scarce,such entities remain entirely unexplored.Here,we outline an efficient method for the stereoselective introduction of the difluoro(aminosulfonyl)methyl group(CF_(2)SO_(2)NH_(2))into carbonyls,imines,and alkyl halides with a new(R)-2-pyridyl difluoromethyl sulfoximine reagent,which provides a unique solution for the synthesis of chiralα,α-difluorinated sulfonamides with a quaternary stereocenter.Its potency is illustrated by the synthesis of fluorinated analogues of bioactive compounds such as 2-OH-SA,an antagonist for the GABA_(B)receptor in guinea pig ileum,and the late-stage modification of complex molecules such as haloperidol,ebastine,cholesterol,and(+)-δ-tocopherol derivatives.Stereoselective difluoro(aminosulfinyl)methylation to yield chiral sulfinylamides is presented,showcasing other uses of this new reagent.
