Study On The Synthetic Application Of Natural Products Of Domino Aryne Nucleophilic-ene Reaction

Indoline and its derivatives have a wide range of pharmacological activities.They are the core frameworks of many drugs,natural products,and organic functional materials,which have attracted much attention from both synthetic organic chemists and pharmacologists.Traditional methods toward the construction of indoline frameworks include the use of transition metal catalyzed coupling reactions and intramolecular amination,etc.However,the disadvantages of these methods include the use of expensive transition metal catalysts,lengthy preparation steps,and harsh reaction conditions.Therefore,it remains to be one of the concerns by synthetic chemists to explore cost-effective methods for the construction of indoline skeleton.As a highly reactive organic intermediate,benzyne has been widely used in the synthesis of benzofused molecules and natural products.This is because the carbon-carbon triple bond of benzyne possesses high activity,which could be easily attacked by nucleophiles to form new chemical bonds.Our research group introduced an additional leaving group on the C3 position of a Kobayashi benzyne precursor and prepared a series of domino aryne precursors.Furthermore,we developed several new cascade transformations using those domino aryne precursors.By regulating the reactivity of domino arynes,multi-substituted benzoheterocyclic skeletons could be easily and efficiently constructed.Particularly,these skeletons exist in many natural products,demonstrating the potential of our strategies.In our previous work,we explored and developed a protocol via domino aryne process: a nucleophilic-ene cascade process with respect to domino aryne precursors and substrates containing a nucleophilic reaction end and an ene reaction end.This approach is simple,efficient,and transition-metal-free with a wide range of applications,which can also be used in the synthesis of anti-dwarfism drugs.Based on our previous achievements,we designed a cascade nucleophilic-ene reaction between a substrate containing an allyl side chain and domino aryne precursor TTPM to construct the core skeleton of a tricyclic indoline derivative.Furthermore,through functional group modification and transformation,two indoline alkaloid intermediates containing a tetracyclic skeleton were successfully synthesized,those of which are the core structures of(±)-Minfiensine and Strychnine alkaloids.The study in this thesis not only is a reflection of the potential of domino aryne chemistry in the preparation of natural products,but also provides a new maneuver for the synthesis of indoline natural products.