Synthetic Studies Of Aplykurodinone-1 And Carpedilactones A-G

This thesis is mainly focused on the synthetic studies of aplykurodinone-1 and carpedilactones A-G.It includes the following two parts:Part 1:Synthetic studies of aplykurodinone-1Aplykurodinone-1 is a highly degraded steroidal natural product.The intriguing molecular architecture of aplykurodinone-1 comprises a peculiar cis-fused hydrindane moiety,a strained?-lactone ring,and an unsaturated side chain.Moreover,six contiguous stereocenters including one quaternary stereocenter are concentrated in this highly-fused tricyclic framework.The highly-congested stereochemical complexity of aplykurodinone-1 poses a particular synthetic challenge,which motivates us to develop a more convergent and efficient synthetic route to this appealing molecule.The tricyclic intermediate 1-35 has been synthesized in eight steps from known compound 1-185 in 20%overall yield.As such,this constitutes a highly efficient formal synthesis of?±?-aplykurodinone-1.This represents the highest-yield route to the advanced intermediate?±?-1-35.This synthesis features a unique one-pot intramolecular oxa-Pauson-Khand/desilylation sequence to efficiently construct the tricyclic framework,a stereoselective Michael addition to simultaneously install the contiguous C7 and C8 stereocenters,and a late-stage rational establishment of the stereocenters at C3 and C4 through stereoselective hydrogenation,all of which highlight the high stereoselectivity and the atom economy of the present route.Meanwhile,our work has thus provided a significant extension of the existing oxa-Pauson-Khand reaction strategy.In addition,asymmetric synthetic studies towards aplykurodinone-1 were conducted based on our completed formal synthesis of?±?-aplykurodinone-1.However,satisfactory results have not been obtained so far.Part 2:Synthetic studies of carpedilactones A-GCarpedilactones A-G are isomeric sesquiterpene lactone dimers.They exhibite potent cytotoxicities against human leukemia cells and human cancer cells.Structurally,the complex polycyclic molecular architectures of carpedilactones A-G possess seven rings and ten or twelve stereogenic centers,which pose a significant synthetic challenge.There have been no synthetic reports of carpedilactones A-G to date.Biogenetically,carpedilactones A-G may be derived from the Diels-Alder cycloaddition between two monomers guaianolide and eudesmanolide.We wish to develop a robust synthetic route to the two monomers guaianolide and eudesmanolide and then explore the intermolecular Diels-Alder reaction for completing the synthesis of the seven architecturally complex sesquiterpene lactone dimers.We have accomplished the synthesis of guaianolide monomer 2-91,the 6/6/5tricyclic skeleton of eudesmanolide monomer 2-145 and an efficient total synthesis of natural product atractylenolide II.The guaianolide monomer 2-91 has been synthesized starting from known compound 2-105.After careful screening various reaction conditions of the photochemical rearrangement,we constructed the desired 5/7-fused ring system and then efficiently established the C7'stereocenter by utilizing a stereoselective hydrogenation.The 6/6/5 tricyclic compound 2-145 has been synthesized in seven steps from the cheap commercial starting material 1,3-cyclohexanedione in 13%overall yield.Key features of this synthesis include an intramolecular oxa-Pauson-Khand reaction to rapidly construct the tricyclic framework 2-131 and a Ni?acac?₂-catalysed Michael addition to install the C10 quaternary stereocenter.Furthermore,additional experiments were conducted to confirmed the relative configuration of compound 2-145,and we accomplished a highly efficient total synthesis of natural product atractylenolide II?8 steps,11%overall yield?.In terms of step economy and atom economy,our synthesis does not require for any protecting group chemistry and represents the shortest synthetic route to atractylenolide II,which offers an efficient protocol for the synthesis of eudesmanolides natural products.In the future studies,we wish to realize the conversion of compound 2-145 into the eudesmanolide monomers 2-4,2-6 and 2-7 through functional group modification,and then explore the Diels-Alder reaction between the two monomers to complete the total synthesis of carpedilactones A-G.