Synthesis Of The Key Intermediate Of(-)-cephalotaxine And(+)-subersic Acid Derivatives

This thesis contains following two chapters:(1)Synthesis of the key intermediate of(-)-Cephalotaxine;(2)Synthesis of(+)-Subersic acid derivatives through Grignard coupling reaction catalyzed by Dilithium tetrachlorocuprate.Chapter ?:Homoharringtonine,isolated from Cephalotaxus in China,showed strong antineoplasic activities and approved by the FDA in 2012 for the treatment of an adult orphan-drug for the treatment of chronic myeloid leukemia(CML).(-)-Cephalotaxine is of the core skeleton of Homoharringtonine,two routes leading to key intermediate of(-)-Cephalotaxine were designed and conducted according to retro-synthetic analysis of(-)-Cephalotaxine.As the first route leading to compound 1-37 was failed to obtain starting from veratraldehyde,the second route was modified using Methyl L-prolinate hydrochloride to prepare spirocyclic compound 1-41 with an overall yield of 27.8%in 5 steps.Accordingly,The key intermediate of(-)-Cephalotaxine,compound 1-48,was obtained after several transformations.In The third route,new synthetic route was designed and spirocyclic compound 1-60 was obtained.After deprotection,it will couple with aldehyde 1-31 to give key intermediate precursor of Heck coupling 1-53.Chapter ?:Based on the previous result of the study of(+)-Subersic acid,the detailed reaction conditions was optimized to synthesize(+)-Subersic acid over 5 steps with an overall yield of 32.1%.The key step relied on the Grignard coupling of the arene halides with the diterpene catalyzed by dilithium tetrachlorocuprate.Substrate scope was further explored using different substituted arene fragments,up to twelve derivatives of(+)-Subersic acid were synthesized smoothly for the further biological activity studies.