Highly Efficient Asymmetric Synthesis Of Chiral Compounds Containing β,β-Difluoroethylamine Building Blocks

The introduction of fluorine atoms in amine compounds will significantly reduce the basicity of organic compounds,and then affect their bioavailability.The synthesis of chiral β-fluoroamines has attracted continued attention from medicinal chemists.Among them,the asymmetric synthesis of organic compounds containing β,β-difluoroethylamine modules becomes particularly noticeable due to the special nature of difluoromethyl as a hydrogen bond donor.In recent decades,the synthesis of chiral compounds containing β,β-difluoroethylamine modules is rare.Most of them use unstable imines as substrates to obtain products with good diastereoselectivity.There are few studies on the direct enantioselective synthesis of β,β-difluoroethylamine stereocenters.In a limited number of reports,either severe catalytic conditions and toxic reagents are used,or the scope of application of the substrate is narrow,or the subsequent applications are very limited,and it is urgent to create new synthetic methods.In order to more simply and efficiently construct compounds containing chiral centers of β,β-difluoroethylamine,we have designed a brand-new synthetic route,ingeniously synthesizing chiral precursor difluoroethyl ketoimide with thioindigo and2,2-difluoroethylamine.Under the action of traditional organic bifunctional catalyst,this prochiral compound performs addition reaction with simple nitroene compounds,with extremely high enantioselectivity(up to 99% enantiomeric excess value)and excellent conversion rate(more than 80% yield of most products)to obtain a series of corresponding chiral γ-difluoromethylimine compounds,the product is rapidly hydrolyzed by concentrated hydrochloric acid to obtain almost completely enantiomerized γ-nitro-β β-difluoroethylamine chiral center.In this study,we have unprecedentedly used thioisatin and 2,2-difluoroethylamine as raw materials for building difluoroethylketimine modules,and successfully obtained a target product with high enantioselectivity.Moreover,the other substrate used,nitroene,is not only cheap and easy to synthesize,but also because of the unique nature of nitro group that is easy to oxidize and reduce,the product can be converted into a variety of organic compounds that have a unique role in drug design.The enantioselective synthesis of chiral compounds containing β,β-difluoroethylamine provides a new way of thinking.