| While daphniyunnine B was isolated from the stems and leaves of D.yunnanense,daphnicyclidin A was isolated from the stems of D.teijsmanni and D.humile,and dehydroxymacropodumine A was isolated from the bark of D.macropodum,they are all triterpenoid alkaloids.Due to their fused polycyclic system,unique structure and potential medicinal value,they can be used as lead compounds for the study of new anticancer drugs,which have attracted many synthetic chemists to conduct total synthesis studies.In 2017,our research group also made corresponding progress in the research on the synthesis of daphnicyclidin A,which provided a strategy for the development and extension of the work.This thesis mainly contains two parts:(1)The chiral fragment designed is directly introduced to molecular skeleton to construct the C-18 chiral center.We explore the synthetic methods of the A/D/E tricyclic rings system of daphniyunnine B and daphnicyclidin A,and complish the construction of the skeletons of them.(2)The cut-off of dehydroxymacropodumine A is a new path,and the mature synthesis scheme is optimized by RCM reaction which can shorten the experimental routes.A new cyclopentene derivative lithium salt is designed for nucleophilic addition with aldehydes and E ring is directly introduced.Seven-membered A ring and C-5 quaternary carbon center are constructed through synergistic visible light catalyzed decarboxylation free radical Michael addition by transition metal Ir or Ru.Thus,the total synthesis of dehydroxymacropodumine A is completed.The achievement of this thesis as follows:(1)We constructed the CDE tricyclic skeleton of daphniyunnine B in 3.9%yield with 30 steps,commencing with 4,5,6-tris-trisubstituted pyrrolidine compound 155a.The key transformations include aldol condensation,Johnson-Claisen orthoacetate rearrangement,Dieckmann ester condensation and SmI2-mediated free radical Michael addition.(2)We completed the A/E spiral ring of daphniyunnine B and C-8 quaternarycarbon in a yield of 22.1%commencing with compound 210 in 7 steps by the ester condensation under heating reaction and the SmI2-mediated radical Michael addition reaction.(3)We used divergent synthetic strategies to complete the ACD tricyclic skeleton of daphnicyclidin A in 22.0%yield beginning with compound 165 in 8 steps.The key transformations include:Dieckmann ester condensation and SmI2-mediated radical Michael addition.Based on this,we also completed the investigative test of the synthesis of the E ring.(4)A strategy of divergent synthesis was used to constuct the ACE tricyclic skeleton of daphnicyclidin A and dehydroxymacropodumine A(before structural correction)in 26.5%yield commencing with compound 191b in 8 steps.The key transformations include:the nucleophilic addition between lithium saltand aldehyde,transition metal Ru combined with blue-catalyzed decarboxylation free radical Michael addition.Based on this,we also explored the construction of B/D ring.(5)We recognized the RCM reaction as the key transformation to complete the synthesis of compound 235 starting with material 155a.Compared with previous route,this process has been shortened two steps.Subsequently,the coupling of B ring C-N bond was completed by SN2 reaction.And the same approach was used to construct the A/E ring.Finally,we synthesized the four-ring skeleton of daphnicyclidin A and dehydroxymacropodumine A(before structural correction)in 21 steps.(6)Based on the structural modification of the carbonyl group at the C-9 position on the E ring in the dehydroxymacropodumine A,we designed two possible cyclopentene derivatives.The construction of the BCE tricyclic skeleton of dehydroxymacropodumine A(structural modifications)was completed through the nucleophilic addition between lithium salt and aldehyde.Therefore,the construction of the molecular skeleton of natural products daphniyunnine B,daphnicyclidin A and dehydroxymacropodumine A has laid a solid foundation for their later total synthesis and the synthesis of calyciphylline A and daphnicyclidins family alkaloids. |
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