Palladium-Catalyzed Allylic Alkylation Reaction And Its Applacation In Total Synthesis Of Monoterpene Indole Alkaloids

Monoterpene indole alkaloids have been the hotspot in the field of natural product total synthesis and they have attracted widespread attentions due to their special skeleton structures and biological activities,such as the strychnos alkaloid(minifiensine)and akuammiline alkaloids(aspidophylline A,vincorine,strictamine and so on).These alkaloids can be divided into several classes according to their key skeleton structures,and we focus on two different kinds of core structures:(1)a 4a,9a-heterocycle-fused tetrahydrocarbazole skeleton,which contains a tetrahydrocarbazole and a five-menbered heterocycle(minifiensine,aspidophylline A,vincorine);(2)a bridged tetracyclic tetrahydrocarbazole skeleton,which contains a tetrahydrocarbazole and a six-membered heterocycle(strictamine).These two common core structures pose great challenges for synthesis.During the past decade,these alkaloids attracted much research interest from the synthetic community.As a result,a large number of total syntheses have been reported.However,the strategies that rendered efficient asymmetric syntheses are still limited.Before we started our research work,only two asymmetric syntheses of minfiensine had been reported,and only one asymmetric synthesis of strictamine had been reported.In this thesis,we developed two new synthetic strategies utilizing the palladium-catalyzed allylic alkylation as the key step to realize the construction of these two common core structures.(1)Using palladium-catalyzed asymmetric allylic alkylation/iminium cyclization cascade,we realized the asymmetric construction of the first core structure.(2)Using chiral phosphoric acid catalyzed Pictet-Spengler reaction/palladium-catalyzed allylic alkylation,we realized the construction of the second core structure.Based on these new strategies,we have completed the asymmetric total synthesis of minifiensine and formal total syntheses of strictamine.Total synthesis of(+)-minfiensine was achieved by a cincise route consisted of an indium-mediated cross-coupling,a palladium-catalyzed asymmetric cascade cyclization,and a palladium-catalyzed intra-molecular Heck-type reaction.Starting from commercially available 2-methyltryptamine,the synthetic route consists of 15 steps(11 column separations)with an overall yield of 21%.Formal total synthesis of strictamine was achieved by a cincise route featuring a chiral phosphoric acid catalyzed Pictet-Spengler reaction and a palladium-catalyzed allylic alkylation.Starting from tryptamine derivative,the synthetic route consists of 6 steps.Our study not only achieved two new reaction modes of palladium-catalyzed allylic alkylation,but also realized highly efficient total syntheses of two monoterpene indole alkaloids with this reaction as the key steps.The present study showcases the importance of Pd-catalyzed allylic allylation reactions in natural product total synthesis.