Studies Towards The Total Syntheses Of Lycopodium Alkaloids&the Development Of Small-molecule Agonists Of DR5

Lycopodium alkaloids are a large group of complex but structurally connectednatural products. More than250this type alkaloids have been isolated so far. Owingto their intricate polycyclic structures and potential biological activities, thesecompounds have received considerable attention from the synthetic chemists. Thisdissertation describes the total syntheses of five important fawcettimine-typeLycopodium alkaloids through highly concise and efficient routes as the first part.Another part of this dissertation is the structure elucidation of small molecules A2C2which can activate the TRAIL receptor DR5in human cancer cells alongwithstructure-activity relationship (SAR) study and syntheses of A2C2analogues andbiological activity test.In this thesis, the first Chapter introduced the isolation，the category and thestructural features of Lycopodium alkaloids. The total syntheses of fawcettimine-typealkaloids were summarized in detail along with the possible biogenetic relationshipsor biomimetic transformations of fawcettimine-type alkaloids.In Chapter2, we fully described the the collective total syntheses of Lycopodiumalkaloids (+)-fawcettimine,(+)-fawcettidine,(+)-alopecuridine，(-)-8-deoxyserratinineand (-)-lycojapodine A. After examing the above alkaloids from a structural point ofview，we envisioned a retro-synthetic analysis of target molecules with a collectivesyntheses strategy based on a biomimetic transformation. All of the molecules weresynthesized from a common precursor based on a highly concise route (all wereaccomplished in either12steps or13steps). The Michael-Aldol cascade reaction, theintramolecular C-alkylation and SmI2-mediated pinacol couplings were regarded askey steps. The biosynthesis-inspired transformation from serratinine-type skeleton tofawccettimine-type skeleton was completed in high efficiency. In the course of ourinvestigation on the synthesis of lycojapodine A，many designed approaches wereattempted but failed. Finally, a one-pot4steps biomimetic oxidation procedure wasrealized to transform the precursor of alopecuridine into lycojapodine A.In Chapter3, we described the structure elucidation small molecules A2C2,structure-activity relationship (SAR) study and syntheses of the analogues. Throughsynthetic and analytic method, we proved that the originally assigned structure ofA2C2which was discovered through a high-throughput chemical screen was not exact. A2C2was a mixture of tthree compounds. Through extensive chemicalsynthesis and purification of A2C2and its derivatives, we elucidated the chemicalcomponents of A2C2. Based on this work and further structure-activity relationshipstudy, we synthesized a single and well-defined analog biomifi, which is moreeffective in activating the apoptosis of human cancer cells.The experimental procedure and spectra data of intermediates and products werealso recorded in detail.