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Synthesis of Complex ortho-Allyliodoarenes via Reductive Iodonio-Claisen Rearrangement and Total Synthesis of Antitumor Antibiotic Derhodinosylurdamycin A

Abstract Details

2015, Doctor of Philosophy, University of Toledo, Chemistry.
The chemistry related to hypervalent iodine compounds has been extensively studied in the past few decades due to the environmentally benign character of hypervalent iodine compounds. Most of those hypervalent iodanes-mediated chemical reactions involve the use of stoichiometric reagent and generate aryl iodide as a chemical waste, which makes the transformation a less atom economic processes. In the quest for more atom economic hypervalent iodine chemistry, we developed a reductive iodonio-Claisen rearrangement (RICR) involving ¿3-iodanes and allylsilanes in presence of Lewis acid to afford ortho-allyliodoarenes. It was found that an electron-donating group at the meta-position is required in order to favor the [3,3] sigmatropic rearrangement over reductive elimination. Moreover, the experimental results involving deuterated allylsilane support the reaction mechanism involving [3,3] sigmatropic rearrangement. The application of this method in organic synthesis has been demonstrated by converting ortho-allyliodoarenes into various building blocks such as benzofuran, dihydrobenzofuran, dihydrobenzopyran and indolines as well as by the concise synthesis of an antifungal natural product, broussin. We also developed Lewis acid-free RICR in which fluoroalcohols were used as the solvent and promoter. Angucycline antibiotics, the type of natural products bearing angularly assembled tetracyclic ring frame, have become a rapidly growing field of bioactive natural products in past few decades. Besides their interesting structural features, they possess widespread biological activities including antimicrobial, antiviral, and anticancer properties. The urdamycins are the class of angucyclines produced by Streptomyces fradiae and were first detected in chemical screening by Drautz and co-workers in 1986. Derhodinosylurdamycin A, obtained by methanolysis of urdamycin A, was first reported as a bioactive natural product derivative by Henkel and co-workers in 1986. It consists of an angucycline core with three 2,6-dideoxyhexoses comprising two D-olivose and one L-rhodinose, two with O-glycosidic linkage and one with C-glycosidic linkage to the aromatic core. Derhodinosylurdamycin A shows significant in-vitro activity against L1210 leukemia cell lines with IC50 value of 0.75µg/mL. Despite the interesting activities as well as structural intrigues, no total synthesis of derhodinosylurdamycin A has been accomplished thus far. Starting from commercially available starting materials, we have successfully completed the first enantioselective total synthesis of derhodinosylurdamycin A. Key steps in the synthesis include 1) a Hauser annulation between cyanophthalide and complex cyclohexenone to construct the tricyclic aryl iodide; 2) a palladium-catalyzed coupling between functionalized tetracyclic aryl iodide and D-rhamnal derived glycal stannane followed by reduction to form the ß-C-arylglycoside and 3) a late stage glycosylation between a disaccharide-derived glycosyl acetate donor and the ß-C-arylglycoside acceptor to afford the derhodinosylurdamycin A after functional group manipulations.
Jianglong Zhu (Advisor)
Mark Mason (Committee Member)
Kana Yamamoto (Committee Member)
L. M. Viranga Tillekeratne (Committee Member)
378 p.

Recommended Citations

Citations

  • Khatri, H. R. (2015). Synthesis of Complex ortho-Allyliodoarenes via Reductive Iodonio-Claisen Rearrangement and Total Synthesis of Antitumor Antibiotic Derhodinosylurdamycin A [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1431342601

    APA Style (7th edition)

  • Khatri, Hem Raj. Synthesis of Complex ortho-Allyliodoarenes via Reductive Iodonio-Claisen Rearrangement and Total Synthesis of Antitumor Antibiotic Derhodinosylurdamycin A. 2015. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=toledo1431342601.

    MLA Style (8th edition)

  • Khatri, Hem Raj. "Synthesis of Complex ortho-Allyliodoarenes via Reductive Iodonio-Claisen Rearrangement and Total Synthesis of Antitumor Antibiotic Derhodinosylurdamycin A." Doctoral dissertation, University of Toledo, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1431342601

    Chicago Manual of Style (17th edition)