The Construction Of Drug-like Skeleton γ-lactone Via Two Synthesis Strategies Based On Benzoin Condensation

Aim:Benzoin condensation product have a stereocenter,which is used as many useful reaction intermediate.In order to synthesis drug-like skeletonγ-lactone,we design two organocatalytic cascade systems based on benzoin condensation,N-heterocyclic carbine（NHC）and secondary amine system.Methds:1.Strategy one was based on the HOMO and LUMO activation of NHC and we successfully synthesize a series ofγ-lactones.The structures are drived by ¹H-NMR,¹³C-NMR,HRMS,X-ray single crystal.2.Strategy two was carried out by NHC-secondary amine cascade.A hemiacetal derivative could gain through the benzoin condensation and Michael reaction,the hemiacetal derivative product was oxidated by PCC,then obstained the drug-like scaffold chiralγ-lactone.The structures are drived by ¹H-NMR,¹³C-NMR,HRMS,X-ray single crystal.Result:In the process of the experiments,21 compounds were synthesized through strategy one,of which 20 compounds contain drug-likeγ-lactones.48compounds contain trifluoromethyl were successfully obtained through strategy two,and we also achieved the asymmetric synthesis ofγ-lactones.The structures were all confirmed by HRMS,¹H-NMR,¹³C-NMR analysis.Conslusion:Our experiments enrich the application of NHC and secondary amine catalyst in the construction of natural drug-like skeleton.Through the design of tandem catalytic system or a combination of two catalysts,we can not only complete the synthesis methods of drug-like scaffolds,but also find some innovations of these two catalytic systems.In a word,it has positive significance to develope new drugs or lead compounds.