| Cephalotaxus alkaloids exist widely in plants of the Cephalotaxus genus.Since the first Cephalotaxus alkaloid cephalotaxine was isolated from C.drupacea and C.fortunei by Paudler group in 1963,so far,approximately 100 members have been isolated and reported successively.Among them,homoharringtonine,one of the naturally occurring esters of cephalotaxine,has been approved by the FDA for the treatment of chronic myeloid leukemia in 2012.Due to its structurally unique 1-azaspiro[4.4]nonane unit as well as significant biologic activity of its esters,Cephalotaxus alkaloids have received considerable and enduring attention in the arena of total syntheses.To date,there have been 24 reports on asymmetric syntheses of Cephalotaxus alkaloids,in which 4 reports on formal synthesis of(-)-cephalotaxine via asymmetric catalytic strategy are included,but the effectiveness and divergence of their synthesis remains to be improved.Therefore,the development of new asymmetric catalytic methodologies for effectively constructing the tetracyclic core skeleton of Cephalotaxus alkaloids as well as the enantioselective divergent total syntheses of high oxygenated Cephalotaxus alkaloids has always been an important research topic in the related field of research.In this thesis,we focused on the efficient and enantioselective construction of D ring with the densest part of functional groups and chiral stereocenters in Cephalotaxus alkaloids,and a novel rhodium-catalyzed asymmetric(2+3)annulation reaction of tertiary enamides with vinyldiazoacetates has been designed and developed.On the basis of this exploration,enantioselective divergent syntheses of Cephalotaxus alkaloids including(-)-cephalotaxine(type I),(-)-torreyafargesine A(type I),(-)-cephalotine B(type III),(-)-cephafortunine A(type IV)and(-)-fortuneicyclidin B(type V)have been accomplished.This thesis is mainly divided into the following four chapters.Chapter I: A brief introduction is given to the isolation,structure,biological activity,and biosynthetic hypothesis of Cephalotaxus alkaloids.Subsequently,three types of synthetic strategies including chiral resolution,chiral pools,and asymmetric catalysis are outlined,in which 24 reports describe the asymmetric synthesis of(-)-cephalotaxine(type I)and the only two reports present asymmetric syntheses of Cephalotaxus alkaloids(types II-IV).Chapter II: According to the strategies for the construction of its ring system,an analysis and classification of the existing synthetic routes of(-)-cephalotaxine is conducted.Based on these facts,our proposed strategy mainly concentrates on the design for a novel asymmetric catalytic(2+3)annulation of tertiary enamides and vinyldiazoacetates,which might lead to a one-step and efficient assembly of chiral multi-functionalized ring D in Cephalotaxus alkaloids.Following the regioselective oxidation,asymmetric syntheses of a series of low-oxygenated and high-oxygenated Cephalotaxus alkaloids would be achieved.Chapter III: Guided by one-step construction of the ring D having two consecutive chiral centers(including an aza-quaternary carbon stereocenter)in Cephalotaxus alkaloids,a chiral rhodium-catalyzed asymmetric(2+3)annulation of seven-membered enamides and vinyldiazoacetates has been designed and developed.Based on this key reaction,the asymmetric synthesis of(-)-cephalotaxine(type I)as well as sixteen tetracyclic analogues has been achieved.Chapter IV: Combined with the strategic introduction of regioselective oxidation,the syntheses of high-oxygenated Cephalotaxus alkaloids with types(I,III-V)framework have been explored starting from different low-oxygenated intermediates.After the regioselective introduction of C3-keto moiety via Meinwald rearrangement as a key reaction,we finally achieved the first asymmetric syntheses of(-)-cephalotine B(type III)and(-)-fortuneicyclidin B(type V).In addition,following attempts to regioselectively introduce the C3-OH via a key ring-opening reaction of the cyclic ether intermediate,studies on the syntheses of(-)-torreyafargesine A(type I)and(-)-cephafortunine A(type IV)are still actively ongoing. |
