Synthetic Studies Of Daphnezomine A-type And L-type And Secodaphniphylline-type Daphniphyllum Alkaloids

Daphniphyllum alkaloids are a family of complex polycyclic cage-like natural products,which contain more than 340 molecules and can be categorized into 35 basic skeleton structures.They are isolated from plant Daphniphyllum that are widely distributed in China,which have multi-bioactivities,such as anti-tumor,anti-oxidation,and have important research and application value in natural product isolation,pharmaceutical chemistry,organic synthesis chemistry and other fields.Therefore,the total synthesis of Daphniphyllum alkaloids has been a long hotspot in the field of natural product synthesis.Besides,various impressive cyclization reactions and bonding strategies in the synthesis of polycyclic structure of Daphniphyllum alkaloids have been extensively studied.In this thesis,the applications of various cyclization reactions in the construction of skeletons have been investigated,focusing on the highly efficient and selective synthesis of their chemical skeletons.The new application of von Braun reaction for C-N bond activation to introduce the isopropyl side chain has also been studied.In order to further enrich the research on the synthesis of Daphniphyllum alkaloids and fill some gaps in related fields,this dissertation studied daphnezomine A-type alkaloids daphnezomines A and B,secodaphniphylline-type alkaloid caldaphnidine D,daphnezomine L-type alkaloids,daphnezomine L methyl ester,calyciphylline K and paxdaphnidine A.The main contents are as follows:The syntheses of daphnezomine A-type alkaloids daphnezomines A and B were first studied.A known secondary amine was used as the starting material to construct a tricyclic system through Michael addition reaction.The key tetracyclic skeleton was obtained via Suzuki coupling reaction through trifluoromethanesulfonate and amide side chain and Huang’s amide-activation-annulation reaction.Then the crucial newly bonding strategy via Hutchins-Kabalka rearrangement and a derived Kabalka rearrangement,as well as 1,4-reduction reaction was studied.Meanwhile,the free radical cyclization strategy mediated by phenyl selenate was studied after the introduction of selenate via Suzuki coupling reaction of tricyclic compound.Another strategy was based on the enyne cycloisomerization which was carried out after the propargyl group was introduced into the amine of tetracyclic framework.Then,the isopropyl side chain was obtained via a von Braun reaction through the activation of allylamine.This work might be impressive for the syntheses of daphnezomines A and B.Total synthesis of secodaphniphylline-type alkaloid caldaphnidine D was completed.Using a known diene compound as a starting material,a cage-like hexacyclic compound was constructed through a radical cyclization reaction.The C-N bond of allylamine was cleaved through optimization of a von Braun reaction to give the precursor that contained the isopropyl side chain,and then the pentacyclic framework of caldaphnidine D was constructed.Last,total synthesis of caldaphnidine D was completed through cleavage of protecting groups and hydrogenation of unsaturated carbon-carbon bond,within simple 6steps and 20% overall yield.Besides,this route could be applied into many secodaphniphylline-type alkaloids.Finally,total syntheses of daphnezomine L-type alkaloids,daphnezomine L methyl ester and calyciphylline K were achieved,and synthesis of paxdaphnidine A was also studied.Starting from a known diol compound,a pentacyclic cage-like intermediate was constructed through the free radical cyclization reaction of tetracyclic tertiary amine.The C-N bond of allylamine was cleaved through a von Braun reaction.Last,through the transformation of functional groups,the total syntheses of daphnezomine L methyl ester and calyciphylline K were completed via functional group modification within 12 steps,10% overall yield,and 13 steps,8% overall yield,respectively.On the basis above,starting also from the same diol compound,trifluoromethanesulfonic acid-promoted Prins cyclization was employed to the synthesis of paxdaphnidine A.The key reactions include an enyne cycloisomerization reaction that could build a tetrahydropyrrole ring and a von Braun reaction that could regioselectively cut off C-N bond of allylamine.Thus,the construction of an entire skeleton of paxdaphnidine A was achieved.Within different cyclization strategy and C-N bond activation strategy,our investigation has laid a solid foundation for the total syntheses of various Daphniphyllum alkaloids.