Studies On Divergent Synthesis Of Lycopodine-type Lycopodium Alkaloids

Lycopodium genus plants are widely distributed all over the world.Up to now,more than 300 species of alkaloids have been isolated from the Lycopodium plants,and they are mainly classified as Fawcettimine type,Lycopodine type,Lycodine type,and Miscellaneous type in terms of their structural characteristics.The Lycopodine-type alkaloids,which feature by a bridgehead aza-quaternary carbon and a unique 6/6/6/6 tetracyclic core,have the largest number among them.Notably,the alkaloids with 6/6/6 tricyclic skeleton and conjugated diene moiety have also been isolated from the Lycopodium species.As they might be biogenetically from the Lycopodine-type alkaloids with 6/6/6/6 tetracyclic core,these new structural alkaloids are also classified as Lycopodine-type alkaloids.However,to our knowledge,there is no report on how to achieve the skeletal conversion between these alkaloids.In this dissertation,the divergent synthesis of Lycopodine-type alkaloids has been achieved,and the skeletal transformation between different structures of Lycopodine-type alkaloids is realized.The Pd-catalyzed tandem oxidative dehydrogenation/aza-Michael addition reaction as a key step could introduce the crucial bridgehead aza-quaternary carbon embedded in the [3.3.1] bridge ring system.On the basis of this investigation,the first synthesis of seven 6/6/6/6 tetracyclic skeletons alkaloids(Lycofoline,Gnidiodine,Acrifoline,Obscurumine F,Lycoannotine F,Lannotinidine D,Acetylacrifoline,and deacetyllycofawcine)have been achieved.Inspired by the original biogenetic hypothesis,the different skeletal transformation was realized by a new tandem fragmentation/oxidation rearrangement reaction.The first synthesis of new structural alkaloids,Lannotindine G,Annotinolide F,Lycoannotine A,Lycoannotine B,Lyconnotine and Lyconnotinol,have been accomplished.In addition,the configurations of chiral center with a methyl group in Lycoannotines A and B,and Lyconnotine have been corrected,and the configuration of chiral center with a methyl group in Lyconnotinol has been determined.This thesis mainly includes three parts as follows.Chapter ?: The structural characteristics of Lycopodium alkaloids and recent progress in the synthesis of Lycopodine-type alkaloids are described.Chapter ?: Focusing on the construction of the bridgehead aza-quaternary carbon in the [3.3.1] ring system,a key tandem Pd-catalyzed oxidative dehydrogenation/aza-Michael addition reaction was adopted to fabricate the crucial6/6/6 tricyclic structure.Based on this preliminary study,the first syntheses of seven Lycopodine-type alkaloids(Lycofoline,Gnidiodine,Lannotinidine D,Obscurumine F,Acrifoline,Acetylacrifoline,and Lycoannotine F)have been achieved.Chapter ?: Stimulated by the plausible biogenesis of Lycopodine-type alkaloids with 6/6/6 tricyclic skeleton and conjugated diene moiety,a new tandem fragmentation/oxidation rearrangement reaction was designed and developed as the key step to make a chemical connection between two types of skeletons in these alkaloids.Based on this exploration,the first synthesis of structurally new alkaloids,Lannotindine G,Annotinolide F,Lycoannotine A,Lycoannotine B,Lyconnotine and Lyconnotinol,have been accomplished.It is noteworthy that the configurations of chiral center with a methyl group in Lycoannotine A,Lycoannotine B,and Lyconnotine have been revised,and the configuration of chiral center with a chiral methyl group in Lyconnotinol has been assigned for the first time.Moreover,the synthetic study towards Annotinolide D as Lycopodine-type alkaloid was also conducted preliminarily,and the current investigation could lay down a foundation for further strategic improvement.