Studies Toward Asymmetric Total Synthesis Of Daphniphyllum Alkaloid Calyciphylline N

Notable structural features of Daphmanidin A type Daphniphyllum alkaloid is an unprecedented hexacyclic structure,which contains 6 to 9 stereogenic centers,a fused A ring dihydropyrrole,and a DEF decahydrocyclopentazulene ring system surrounding a central bicyclo[2.2.2]octane BC core.Owing to their intricate structures and prominent bioactivities,Daphmanidin A type alkaloids have attracted considerable attention from the synthetic community.To date,the asymmetric total synthesis of the architecturally complex Daphmanidin A type Daphniphyllum alkaloid(+)-Daphmanidin E and(-)-Calyciphylline N have been achieved by the Carreira's group and Smith's group respectively.Calyciphylline N,isolated in 2009 by Kobayashi and co-workers,was chosen as our initial target.This thesis consists of two parts:(1)A review of the total synthesis and skeleton synthesis of Daphniphyllum alkaloids.(2)Studies towards asymmetric total synthesis of Daphniphyllum alkaloid Calyciphylline N.Base on copper-catalyzed asymmetric conjugate addition strategy,reaction of trisubstituted enones in the presence of trimethylaluminum and biphenol-based phosphoramidite ligand generated the desired products,with high yield and excellent enantioselectivity,thus C5 all carbon quaternary center was successfully built.Then the central bicyclo[2.2.2] core was constructed by twice Aldol reaction,which possessed C2 all carbon quaternary center.The C18 chiral center was successfully constructed through a highly stereoselective catalytic hydrogenation.After established secondary amine group,the acid-mediated cyclization readily produced ABC tricyclic scaffold.Next,the C8 all carbon center was constructed through Aldol reaction and Tsuji-Trost allylation.The F ring was constructed by RCM reaction or Aldol reaction,and a series of ABCF tetracyclic skeleton intermediates were obtained.But the subsequent attempts to construct E ring and DE macrocycle were unsuccessful.In addition,the EF bicyclic ring was constructed through radical reaction and Ru-catalyzed cyclization reaction,although the products were not the desired configuration.Moreover,the EF eight-membered macrocycle can also be constructed by RCM reaction.Finally,a number of tetracyclic high-level intermediates with all the carbon atoms of the Calyciphylline N skeleton were synthesized in 23-26 steps.