Asymmetric Synthesis Of Abc Tricyclic Core In Daphniphyllum Alkaloid Calyciphylline N And 21-deoxymacropodumine D

Since the isolation of the first member in 1909,more than 320 Daphniphyllum alkaloids with a vast range of structural diversity have been isolated from the genus Daphniphyllum.Some of these alkaloids have shown interesting biological activities including anticancer,antioxidation,anti-HIV and anti-platelet activating factor effects.Structurally,these triterpenoid alkaloids with highly variable polycyclic skeletons can be categorized into more than 20 different types based on the structural characteristics of the ring systems.Calyciphylline N,a emblematic Daphmanidin A type Daphniphyllum alkaloid,was isolated by Kobayashi and co-workers in 2008,containing a fused dihydropyrrole A ring and a bicyclo[2.2.2]octane BC ring with six contiguous stereocenters,three of which are bridgehead quaternary and two are vicinal quaternary.21-deoxymacropodumine D is an unique Calyciphylline A type alkaloid,currently only two compounds have been reported,which possess an inimitable [6-5-6-7-5-5] hexacyclic system and contain a exceptional N-C3 linkage and a hydroxyl group at C4,differing from most members of this type with N-C4 linkage along with seven consecutive stereocenters including the vicinal all-carbon quaternary centers.The synthesis of the above two compounds is quite challenging,and 21-deoxymacropodumine D has not been reported in total synthesis.Here we developed two efficient synthetic routs,starting from a common chiral intermediate,to rapidly construct the ABC tricyclic systems of Daphmanidin A type and Calyciphylline A type alkaloids.First,the formation of the bicyclo[2.2.2]octane skeleton was completed by HCl-mediated intramolecular Aldol reaction,and then the ABC tricyclic system of calyciphylline N was obtained by thermal condensation and C8 hydroxymethylation reaction.In addition,based on previous studies,the synthesis pathway of ABC tricyclic system in 21-deoxymacropodumine D was improved,and the formation of C2-C18 bond was completed by Pd-mediated intramolecular oxidative cyclization.The resulting tricyclic product was obtained from Convex.The sterically hindered group is pre-positioned,forcing the subsequent catalytic hydrogenation to occur preferentially on the Concave surface,resulting in a mixture of epimers based on the target product,thereby reversing the diastereoselectivity of the critical reaction(from dr = 0.5:1 to dr = 1.5:1),this preliminary study demonstrates the feasibility of this strategy..