| Alkaloids of the Cephalotaxus family were isolated from the Cephalotaxus species.The structure of these alkaloids shared a common pentacyclic ring system.Most of these ester alkaloids possess potential anti-cancer activity.The absolute configuration of the skeleton of Cephalotaxus alkaloids is 3S,4S,5R.However,the limited natural resources of the clinically useful ester derivatives prevent its further application.The unique structure and the important biological activities rendered this group of ester alkaloids attractive synthetic targets.Numerous elegant synthetic method to cephalotaxine have been reported and some asymmetric strategy were also developed to construct the chiral spirocycle.However,the relative more synthetic steps and low total yield of reported synthesis makes the development of a more practical and efficient asymmetric approach is still urgent in view of the potential clinical needs.The asymmetric construction of the quaternary stereogenic center of cephalotaxine is a challenge task.This thesis focused on the solution of drug resources of the Cephalotaxus ester alkaloids.Based on our previous synthetic work,we intend to employ the catalytic asymmetric allylation to complete the enantioselective total synthesis of cephalotaxine.The influence of the metal-catalyzed asymmetric decarboxylation allylation will be investigated in detail,including catalysts,chiral ligands,reaction medium,temperature and additives.Further optimization of the reaction conditions will provide a scalable chemical synthetic method for obtaining the naturally limited homoharringtonine resource.In this thesis,we describe a highly efficient enatioselective synthesis of Cephalotaxine using a catalytic asymmetric allylation as key step.At first,we employed pyrrole benzazepine compound as starting material.On treatment with allyl chloroforate under basic conditions,we can easily obtain the chiral allylated product in 94% yield and93% ee.The value of ee was improved upto 98% by one times recrystallization.With the chiral allylated product in hand,a sequence of functional group transformation involving Wacker oxidation,aldol condensation,hydrogenation,reduction were made to finally complete the catalytic asymmetric total synthesis of cephalotaxine. |
