Scale Synthetic Studies On The Skeleton Of Cephalotaxus Ester Alkaloids

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.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.Nonetheless,development of a more practical and efficient synthetic approach is still urgent in view of the potential clinical needs.This thesis focused on the solution of drug resources of the Cephalotaxus ester alkaloids.Based on previous synthetic method,we designed an efficient and practical route and optimized every synthetic step to improve efficiency and lower cost.This synthesis provided partial technological basis for large scale preparation and try to make up for the insufficient natural drug resources of Cephalotaxus Alkaloids.In this thesis,we developed a new synthetic method and optimized reaction conditions for construction of the four ring skeleton of Cephalotaxine.Our initial route starting from 3,4-methylenedioxy phenyl ethylamine.Protection of the N atom using diethyl phosphite followed by alkylation and Friedel-Crafts acylation allowed construction of the third ring.Deprotection of the diethyl phosphite group,N-acylation with 3-chlorine propionyl chloride and intramolecular alkylation of the chloride provided the fourth ring in 15.17%overall yield.In the progress of optimization,we first employed 4-nitrobenzene sulfonyl as protecting group instead of diethyl phosphate,thus avoiding the difficulty of removal of the protection group and lowering environmental pollution.Using slight excess of alkylating reagent and a catalytic amount of KI could improve the yield from 62%to 91%for the N-alkylation.The yield of Friedel-Crafts acylation can also be improved to 87%from 56%by changing Lewis acid catalyst.Similarly,screening of reaction conditions involving different type of base,amount and solvent enhanced the efficiency for the next two steps(yield from 56%to 76.5%for the two steps).Consequently,the final product bearing four rings could be obtained in an overall yield of 53.96%without isolation by column chromatography,Simple recrystallization could offer pure product for every step and the solvent could be recovered for reusing.This synthetic method should have great potential for large scale preparation of the ester derivatives of Cephalotaxine.