Total Synthesis Of Hasubanan Alkaloids Based Intramolecular PEDA Reaction

This paper mainly develops the intramolecular PEDA reaction promoted by Lewis acid and applies this reaction strategy to the synthesis of hasubanan alkaloids.Asymmetric total synthesis of periglaucines A,B,C,N,O-dimethyloxostephine and oxostephabenine was achieved.Intramolecular PEDA reaction:under the excitation of ultraviolet light,the aromatic aldehyde substrate forms electron-rich and highly active dienes,which are captured by the electron-deficient diolenophiles in the molecule,and a tandem intramolecular Diels-Alder reaction occurs.TADDOL-type ligand controls enantioselectivity,Ti（Oi-Pr）₄ controls diastereoselectivity.The reaction constructs a multicyclic skeleton structure of the benzyl quaternary carbon center in one step,which can solve the problems of reactivity and stereoselectivity of large steric hindrance and multi-substituted diolephates.Hasubanan alkaloids are biologically active against viruses such as HBV and HIV.In 2008,Chen’s group of the state key laboratory of phytochemistry and plant resources in west china isolated four new members,periglaucines A-D,in the fine Pericampylus glaucus in southwest China,which has good anti-HBV activity.In the synthesis process,we use L-ribose as the source of chirality.The aldehyde compound will be synthesized by Rh-catalyzed Miyaura-Hayashi reaction.The key strategy of intramolecular PEDA reaction with substrate control is to obtain[4+2]cyclic products,which can construct the[6,6,6]phenanthrene ring skeleton structure in one step,mainly based on more thermodynamically stable endo configuration products.The[4+2]cyclic product is first constructed by intramolecular aza-Michael reaction to achieve substrate-controlled nitrogen five-membered D ring construction.Then,through the intramolecular acetalization reaction,the tetrahydrofuran E ring was successfully constructed,and the subsequent conversion could realize the synthesis of（+）-periglaucine C.Next,we used the highly oxidized（+）-periglaucine C as a precursor compound,through the reduction and oxidation,and the adjustment of stereochemistry,we subsequently realized the collective synthesis of the hasubanan alkaloids:periglaucines A-B,N,O-dimethyloxostephine and oxostephabenine.This study provides new solution for the synthesis of hydrophenanthrene alkaloids such as steroids and terpenoids.