Asymmetric Total Synthesis Of(-)-Galanthamine,(-)-Lycoramine,(-)-Morphine,and(-)-Codeine

Author:Zhang Qing

Supervisor:tu yong qiang


Degree Year:2019





The all-carbon quaternary carbon is widely found in bioactive natural products and drugs.Synthetically,highly efficient construction of the all-carbon quaternary stereocenter,especially in a catalytic asymmetric fashion,and its applications to the syntheses of bioactive natural products and drugs have always been an important and challenging research topic.In the past two decades,our research interest has focused on the efficient syntheses of important bioactive natural products based on the construction of quaternary carbon centers.In the continuation of this research interest and further application of our newly developed spiro-pyrrolidine(SPD)organocatalysts,we achieved the intramolecular asymmetric Michael reaction to efficiently construct cis-hydrobenzofuran framework bearing the synthetically challenging all-carbon quaternary center for the first time.Moreover,based on the above mentioned synthetic methods,we accomplished the catalytic asymmetric divergent total syntheses of(?)-galanthamine,(–)-lycoramine,(?)-morphine and(–)-codeine.The thesis consists of the following five chapters:Chapter 1: the development of spirocyclic pyrrolidine(SPD)catalysis and spirocyclic amide(SPA)catalysis and their applications to the novel reactions were briefly reviewed.Chapter 2: we introduced the background of the intramolecular asymmetric Michael reaction and the main research idea of this project.Chapter 3: according to design of synthetic route,we achieved the preparation of the key reaction precursor.Meanwhile,by using our newly developed SPD organocatalyst,an unprecedented intramolecular Michael addition was explored to afford a series of synthetically challenging cis-hydrobenzofuran derivatives bearing the benzylic quaternary stereocenters in excellent enantio-and diastereoselectivities(up to 96% ee and >20:1 dr)as well as good to high yields(up to 87% yield).Based on this efficient transformation,the one-pot enantioselective Robinson annulation was also accomplished to rapidly construct the highly functionalized cis-hydrodibenzofuran scaffold containing vicinal stereocenters with an all-carbon quaternary center.Chapter 4: based on the above mentioned synthetic methods,we achieved the catalytic asymmetric total syntheses of(?)-galanthamine and(?)-lycoramine.Chapter 5: a concise and catalytic asymmetric total synthesis of(?)-morphine was achieved in a longest linear sequence of 15 steps from commercially available 3-butyn-1-ol.The key elements included the Friedel-Crafts reaction,Wharton rearrangement,removal of benzyl group,Mitsunobu reaction,and hydroamination reaction.The current synthetic study presents the first synthetic strategy toward(?)-morphine by direct and catalytic asymmetric construction of the challenging all-carbon quaternary stereocenter.