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Studies On The Synthesis Of Morphine Alkaloid

Posted on:2014-02-20Degree:DoctorType:Dissertation
Country:ChinaCandidate:J LiFull Text:PDF
GTID:1221330398969645Subject:Organic Chemistry
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Morphine as one of medicinally significant molecules having highly potent opiate analgesic effect was originally isolated from the opium poppy(Papaver sonmiferum) in the very beginning of the nineteenth century. After more than one hundred years, the British chemist Robinson eventually established the correct chemical structure of morphine. Since then, the effective synthesis and structurally diverse modification of morphine and related alkaloids become one of the important research contents of synthetic and medicinal chemists. As one milestone during the chemical synthesis of morphine, its first total synthesis was achieved by M. Gates in1952. Despite the substantial progress in the synthetic studies of morphine alkaloids, the development of novel synthetic strategies and routes has always been one important topic in the synthesis of morphine alkaloids. This dissertation mainly aims at the design and development of some strategies in the synthetic studies of morphine. Focusing on this issue, the target-oriented methodology was investigated, providing the alternative way to the formal synthesis of morphine. The following two parts are included in this thesis:Part I:With the retrospective analysis for the previous literature reports on the synthesis of morphine alkaloids, some representative achievements are summarized on the basis of the application of key strategies, which mainly included the biomimetic synthesis, the phenanthrene core-oriented synthesis, the intramolecular cyclization-mediated synthesis, the cyclohexadienone-derived synthesis, and Diels-Alder cycloaddition-based synthesis.Part II:Focusing on the construction of the key "all-carbon six-membered ring B" and "five-membered hetero-ring E" in the molecular skeleton of morphine, we developed a novel synthetic strategy featuring "tandem alcoholysis/oxo-Michael reaction" and "SmI2-mediated reductive coupling/desulfurization reaction" successfully leading to a formal synthesis of morphine. Additionally, considering the importance of asymmetric establishment of ring E for the enantioselective synthesis of morphine, a novel "asymmetric tandem alcoholysis/oxo-Michael addition of prochiral cyclohexadienones" was also preliminarily explored on the basis of the enantioselective desymmetrization. Significantly, this stereocontrolled methodology will provide a new route to the enantioselective synthesis of morphine.
Keywords/Search Tags:Alkaloids, Morphine, Quaternary carbon, Oxidative coupling, Cvclohexadienones, Enantioselective Desymmetrization, Asymmetric catalysis, Tandem alcoholysis/oxa-Michael addition, Reductive coupling/desulfurization, SmI2
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