Modular strategies for the synthesis of tetrahydrofuran and tetrahydropyran containing acetogenins
Item
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Title
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Modular strategies for the synthesis of tetrahydrofuran and tetrahydropyran containing acetogenins
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Identifier
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d_2009_2013:98889fbd61de:11136
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Creator
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Wang, Feng,
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Contributor
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David R. Mootoo
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Date
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2009
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Language
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English
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Publisher
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City University of New York.
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Subject
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Pharmacy sciences
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Abstract
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Annonaceous acetogenins, a family of naturally occurring polyketides, are well known for their cytotoxic, antitumoral, insecticidal, and immunosuppressive activities. The majority of structures contain one or more stereochemically complex tetrahydrofuran (THF) rings. A smaller subset referred to as non-classical congeners contain a highly substituted tetrahydropyran (THP). This thesis describes modular strategies for both THF and THP containing acetogenins, using as test cases the mono-THF acetogenin, 4-deoxyannoreticuin and the THF-THP congener muconin. 4-Deoxyannoreticuin, a typical member of the mono-THF acetogenin with two flanking carbinol groups at C-15 and C-20, shows cytotoxicity at the micromolar level against several human cancer cell lines, including MCF-7, HT-29, A-498, PC-3 and PACA. Muconin shows micromolar and selective cytotoxicity against PACA-2 and MCF-7.;Chapter 1 presents a review of the different structural types and bioactivity of the acetogenins.;Chapter 2 describes an olefin cross metathesis strategy for coupling of cyclic ether and butenolide segments of the acetogenins. This approach was applied to alcohol epimers of 4-deoxyannoreticuin in an attempt to assign the configuration at the C9 carbinol in the natural product. The activity of these compounds against two human tumor cell lines, PC3 and Jurkat, was also evaluated. Unfortunately, identification of one or the other epimeric structures with the natural product was not possible because of the closeness of the physical and cytotoxicity data for all three compounds.;Chapter 3 deals with a tandem, iodonium ion promoted, cyclization on acetals of dihydroxydienes diene-acetals. These precursors are assembled in a modular fashion from aldehydes and easily accessible dihydroxydienes and the reaction products are stereochemically complex THF-THP subunits as found in the non-classical acetogenins. Vicinal or 1,3-diol precursors produced adjacently or methylene linked cyclic ethers in good to moderate yield. In all cases the cascade appears to be initiated by a 5-exo trig type cyclization to give a 2,5-disubstituted THF connected to an oxocarbenium ion which undergoes attack by the second alkene to form the THP ring. The substitution pattern and connectivity of the second alkene determines the mechanism of formation and constitution of the THP, i.e. a 2,5,6-tri-alkylated or 2,6-dialkyl-4-halogenated. Altogether, three new stereogenic centers are generated in the THF-THP products. The feasibility of this tandem reaction for non-classical acetogenin synthesis was illustrated in the preparation of an advanced precursor to muconin.
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Type
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dissertation
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Source
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2009_2013.csv
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degree
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Ph.D.