Study On Total Synthesis Of Noscapine

Noscapine（1）,a tetrahydroisoquinoline alkaloid,was obtained from opium.All over the world it was widely used as a classical peripheral antitussive,and was also considered as a new anti-tumor drug with high anti-tumor activity,unique mechanism and low toxicity.The cause of cough,the mechanism of antitussive and noscapine’s peripheral antitussive pharmacology effect were summarized in this thesis.Here also particularly introduced the mechanism of antitumor drug which functioned on the microtubulein and the research development of noscapine’s anti-tumor activity.Noscapine had four stereoisomers because of its two adjacent chiral centers.So far there was no report about the total synthesis of natural（-）-α-（3S,5’R）-noscapine.Hence the construction of isoquinoline skeleton by Pictet-Splengler reaction or Bischler-Napieralski reaction via chiral induction was attempted in this thesis.After all kinds of studies,α-noscapine was eventually prepared by Bischler-Napieralski reaction,and its structure was confirmed by MS,¹H NMR,¹³C NMR and NOESY.For the sake of the total synthesis of noscapine,the preparation of some key intermediates related was also studied in detail.Hence,compound 17 and 19 were successfully synthesized from meconine（3）,but the yield for 19 was moderate.So careful tuning on the synthetic method of compound 19 was carried out,and it was eventually found that the compound could be prepared in one-step sequence from 2,3-dimethoxybenzoic acid（9）and anhydrous glyoxylate via lactonization catalyzed by trifluoroacetic acid,and the yield was reached up to 47.9%.In addition,another intermediate,compound 11,was synthesized in 5 steps with 13.8%over yield from vanillic aldehyde（40）via successive bromonation,hydroxylation,methylenation, condensation and reduction.