The Synthesis Of Amino Acid Derivatives Chiral Guanidine Salt And Their Application In Asymmetric Vinylogous Reactions

Enantioselective protonation is a common process in biosynthetic sequences.The dcarboxylase and enzymes that effect this valuable transformation are able to control both the steric environment around the proton acceptor(typically an enolate)and the proton donor(typically a thiol).Howevewr,in asymmetric chemical synthesis,enantioselective transfer of a proton presents unusual challenges:on the one hand,it is too hard to manipulate proton that is too small;on the another hand,it difficult to avoid product racemization at a particularly labile stereocenter.As a result,the condition for a successful entioselective protonation protocol may be very specific to a certain substrate class.In the past decade,a number of efficient ground-state catalyst platforms have been established,allowing the precise delivery of a proton to the prochiral carbanion intermediates in a highly enantioselective manner.The stereoselective formation of C-F bond is of critical importance in the pharmaceutical chemistry given the ability of fluorine atom as the isosteres of hydrogen atom in decreasing the rate of metabolic degradation without influencing the pharmacological effects.Meanwhile,chiral C-Cl and C-Br bonds can be used to introduce various important molecular architectures via simple and stereospecific transformations,thus extensively adopted in asymmetric synthesis of chiral complex molecules with significant biological activities.Nonetheless,enantioselective protonation of constructing the secondary ?-carbon-halogen bonds for ketones still remains underdeveloped as rare examples described with non-excellent enantioselectivity.In this context,the development of a new and generic catalytic asymmetric protonation approach to the valuable chiral tertiary ?-halogenated ketones represents a highly desirable task,which would be a complementary and more versatile method than catalytic enantioselective direct halogenation.Here,we report the development of an enantioselective dehalogenation protonation of ?,?-dihalogenated cyclic ketones under the cooperative catalysis of a Ru-centered photosensitizer and a chiral amino acid-derived squaramide-tertiary amine bifunctional catalyst with a secondary amine as the reductant.Chiral secondary C-F,C-Cl,C-Br bonds were successfully constructed at the ?-position of ketones in high yields with good to excellent enantioselectivities.The results demonstrated the robust compatibility of this catalytic platform,which efficiently conquered several significant challenges,including the less basicity of ketones than ketyls impairing the stereocontrol effect of H-bonding catalysis,the competitive racemic background reaction and the possible racemization of the stereocenter diminishing the enantioselectivity,and the approximate reductive potentials between dihalides and monohalides leading to the poor chemoselectivity thus deteriorating the chemical yield.