Studies On Total Synthesis Of Lycopodium Alkaloid Lyconadins A-E And Lupin Alkaloid Hosieines A-D

Alkaloids are a class of natural products containing nitrogen atom,most of them exihibit good biological activities and complex polycyclic skeletons.They have been attracting the attention of chemists and pharmacologists.However,some alkaloids can’t meet the needs of research only by extraction and separation.Chemical synthesis is an effective way to solve this problem.Moreover,the structure of natural products can be modified through chemical synthesis,and it is possible to create more active derivatives.This thesis mainly focused on the total synthetic research through divergent strategy toward two types of alkaloids with nerve-related activities,including asymmetric total syntheses of lyconadins A-E and synthetic study with hosieines A-D.Lyconadins A-E is a class of alkaloids with significant neurotrophic activities and a complex cage-like skeleton,isolated from Lycopodium complanatum by Kobayashi’s research group,which contain a common 6/6/7-azatricyclic skeleton.Our research group developed a divergent synthesis strategy to the total synthesis of these five natural products,which enables the asymmetric syntheses efficiently.Notably,total syntheses of lyconadins D-E were achieved for the first time.During the synthesis process,we constructed the key aza-6/6/7 tricyclic skeleton and rapidly prepared tricyclic intermediates 2.69 in a large scale through a novel thiocarbamates-mediated palladiumcatalyzed Heck reaction.Based on this intermediate,we formed the C6-N bond and constructed a tetracyclic cage skeleton 2.67 using the intramolecular Rabe electrophilic amination reaction;we formed two consecutive four substituted carbon centers and realized the synthesis of the tetracyclic compound 2.116 through a nitrone-mediated intramolecular Mannich reaction.Hosieines A-D is a new class of alkaloids isolated from Ormosia hosiei Hemsl.Et Wils.This type of alkaloids contains an unique aza-[3.2.1] octane skeleton and has a good affinity for nicotinic acetylcholine receptors.Our research group designed a divergent synthesis route: starting from a common tricyclic intermediate,to carry out total syntheses of these four alkaloids.At present,through copper-catalyzed [3+2]cycloaddition reaction and ring opening,dehydration,selective 1,6-aza-Michael addition domino reaction,the tricyclic intermediate 3.70 has been successfully constructed.Subsequent divergent total synthesis work is currently underway.