Synthetic Studiy On The Daphniphyllum Alkaloid Dapholdhamine B

In this thesis,the synthesis of the tricyclic core of Daphnezomine type Daphniphyllum alkaloids have been achieved.Daphniphyllum alkaloids are a class of alkaloids with novel backbones,and most of the members have been confirmed good biological activity.Today,this family has more than 320 members.In the past few decades,chemists in the world have finished the total syntheses of some types daphniphyllum alkaloids.As far as we know,daphnezomine type alkaloids have not been completed yet.In this thesis,the retrosynthetic analysis of dapholdhamine B was carried out.The asymmetric Robinson annulation and the aza-Michael addition reaction were proposed as two key steps to construct the ABC tricyclic system.Firstly,the AB ring system of dapholdhamine B was constructed by using aldol-reduction,Michael addition and asymmetric Robinson annulation with 1.3-cyclohexanedione as starting material.Next,the side chain and all-carbon quaternary center were constructed by a vinylogous Mannich reaction and conjugate addition.Enone was introduced by an oxidation reaction and halogenation,and the isopropenyl group was introduced by the Suzuki coupling reaction,followed by an aza-Michael addition.With the adjustment of oxidation state,the ABC tricyclic system of dapholdhamine B was successfully constructed.In this paper,a series of theoretical analysis,condition selection and synthesis strategy adjustment have been performed facing the challenges in halogenation of double bond and aza-Michael addition.This gram-scale synthesis has been achieved in 13 total steps.It lays a foundation for the subsequent total synthesis works,and provides a general method for the synthesis of other members of the daphnezomine type alkaloids.