Asymmetric Synthesis Of ABC Tricyclic Core In Daphniphyllum Alkaloid 21-deoxymacropodumine D

Daphniphyllum alkaloids,isolated from the genus Daphniphyllum,are a large group of polycyclic natural products consisting of over 320 members belonging to more than 20 different skeletal types.The significant bioactivities,in combination with intriguing architectural features and complex stereochemical properties of Daphniphyllum alkaloids,have rendered this family of natural product an alluring target for synthetic chemists.Within this family,the calyciphylline Atype alkaloids are among the most studied members.In 2016,Yue’s group reported a newcalyciphylline A type alkaloid 21-deoxymacropodumine D.This compound possesses an unprecedented 6-5-6-7-5-5 hexacyclic system,and the moiety of rings A,B,and C in particular features a unique fusion of 6-5-6 tricyclic unit,containing the especial N-C3 linkage and a hydroxyl group at C4,which is unusual in normal calyciphylline A-type alkaloids(most members have N-C4 linkage).The unique scaffold of 21-deoxymacropodumine D,and seven consecutive stereocenters including the vicinal all-carbon quaternary centers pose a challenge for chemical synthesis.Herein,we report our endeavors that led to the asymmetric synthesis of ABC tricyclic framework of 21-deoxymacropodumine D.First,the C5 quaternary carbon center was constructedwith high yield and high enantioselectivity using asymmetric conjugate addition.Then,three strategies were implemented for the synthesis of ABC tricyclic skeleton: I.Visible light photocatalyticN-radical cascade strategy: substrate 202 was employed for the construction of BC ring system via N-radical cascadewith visible light photocatalysis,but this transformation was not successful;II.Aza-Michael addition/radical cyclization strategy: azabicyclo 209 was successfully preparedby aza-Michael addition,but subsequent free radical cyclization was not achieved;III.Aza-Michael addition/Pd catalyzed α-alkenylation strategy: the azide compound 215 was prepared from 196,followed by Staudinger reaction and aza-Michael addition delivered an azabicyclicstructure 216.Finally,the Pd catalyzed α-alkenylation reaction and subsequent catalytic hydrogenation yielded the desired ABC tricyclic product 211 in 33% yield with five consecutive stereocenters,along with the epimer 212 in 59% yield(dr = 1:1.8).