Studies On The Synthesis Of Daphniphyllum Alkaloids Daphnilongeranin B,Daphniyunnine D,and Daphlongamine E

Daphniphyllum alkaloids can be divided into 14 major classes from the structural viewpoint,including calyciphylline A-type alkaloids.Calyciphylline A-type alkaloids comprise an unique aza-bridged[3,3,1]ring system and a highly congested[6-6-5-7-5]pentacyclic framework.Fascinated by the challenging molecular architecture,we start a program directing at the total synthesis of daphnilongeranin B,daphniyunnine D,and daphlongamine E.Based on the structural analysis of daphnilongeranin B and daphniyunnine D,we designed a synthetic route toward theses natural products featuring a free radical cyclization,triple-Michael addition sequence,and an intramolecular Pauson-Khand reaction as key steps.However,this strategy failed to establish the seven-membered ring,and we only obtained the ABC-tricyclic intermediate.Then,we sought to use an intramolecular Diels-Alder cycloaddition followed by dibromocyclopropanation to establish the[6/3]fused ring system and to construct the seven-membered ring through a ring-expansion process.The ACD-tricyclic core was successfully obtained;however,the remaining rings could not be constructed starting from this advanced intermediate.Although the total syntheses of these two natural products have not been realized,our phasic accomplishments have definitely laid a solid foundation for the relevant research in the future.Finally,we sought to construct the seven-membered ring via an intramolecular free radical cyclization and use an intermolecular[3+2]cycloaddition ofα,β-unsaturated ketone and tert-butyl 2-butynoate as the key steps to synthesis daphlongamine E.Disappointingly,the intermolecular[3+2]cycloaddition failed to take place;instead,the undesired formal hetero-Diels-Alder reaction occurred.Further investigations are ongoing in our laboratory.