Studies Towards The Total Syntheses Of Bioactive Sesquiterpene Lactones

Sesquiterpene lactones broadly exist in nature and possess a wide array ofbiological activities, including antitumor, anti-inflammation activities. The family ofsesquiterpene lactones includes not only the conventional monomeric sesquiterpenoidcontaining a lactone ring, but also the naturally occurring oligomers which originatefrom the dimerization or trimerization of identical or different sesquiterpene lactonemonomers. The combination of diverse and complex structures, as well as thesignificant biological activities of these natural products has evoked long-term interestfrom the synthetic community. In this thesis, I devote to elaborate the efficientsyntheses of monomeric sesquiterpenoid lactones, the exploration of possiblebiogenetic pathways to their oligomers, and the biomimetic syntheses of theseintriguing oligomeric natural products. Additionally, the preliminary studies towardsthe mechanism of action and biological activities of some synthetic products aredescribed as well.In Chapter2, we described the concise and efficient total syntheses of damsinand psilostachyin C. The synthesis of racemic damsin was achieved in only12stepswith23%overall yield, which was a significant advancement comparing with theprevious synthetic works. In addition, we also supported the biomimetic conversion ofdamsin to psilostachyin C via direct Baeyer-Villiger oxidation. Preliminary biologicalstudies indicated that both damsin and psilostachyin C could enhance the antitumor ofcamptothecin (CPT).In Chapter3, we described the first biomimetic and asymmetric total synthesis ofainsliadimer A, a dimeric sesquiterpene lactone with an unprecedented sturcture. Oursynthesis was accomplished efficiently in14steps without the use of protectinggroups. Remarkably, we also developed a novel hydrogen bond-mediatedhetero-Diels-Alder reaction which was an original discovery in the field ofDiels-Alder cycloaddition.In Chapters4, we described the first biomimetic and asymmetric syntheses ofdimeric sesquiterpenoids: gochnatiolides A-C, and ainsliadimer B. In this work, wedeveloped an unprecedented one-pot cascade transformations, including Saegusaoxidation, intermolecular Diels-Alder cycloaddition, and radical-mediated allylicoxidation, which allowed for the rapid generation of (-)-gochnatiolides A-C in acollective manner. Our synthetic endeavors not only led to the structural reassignmentof (-)-gochnatiolide B, but also disclosed many new reactions, including copper-catalyzed stereochemically controlled allylic oxidation and the direct chemo-and regioselective enone hydration that ultimately enabled the biomimetic synthesisof ainsliadimer B.In Chapters5, we described the first biomimetic and asymmetric syntheses oftwo trimeric sesquiterpenoids：ainsliatrimers A and B. Our initial examination of thereported data for the structural elucidation of the natural products revealed twopossible structures. Accordingly, we designed and subsequently completed twodifferent biosynthetically inspired pathways. These synthetic endeavors ultimately ledto the unambiguous structural assignments for the stunningly complex naturalproducts. Preliminary biological studies also revealed that ainsliatrimers A and B, aswell as their analogues significantly inhibited cancer cell growth through inducingapoptosis.