Total synthesis of biologically active fungal natural products daldiquinone and bulgarein, and intramolecular Diels-Alder reactions for fluoranthene synthesis

Date
2021-06
Advisor
Türkmen, Yunus Emre
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Bilkent University
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English
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Thesis
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Abstract

Natural products continue to play a significant role in drug discovery and be a substantial source for novel pharmaceutical drugs. Total synthesis of biologically active natural products is critical for deciphering how natural products regulate cellular and other biological processes and, structure determination. In addition, the total synthesis of natural products has also been a stimulus for the discovery of new methodologies and reactions.
The fungal natural product daldiquinone (15), which possesses a highly oxidized binaphthyl skeleton, was isolated in 2018 from Daldinia concéntrica, and was shown to have antiangiogenesis activity against HUVECs with an IC50 value of 7.5 M. Another fungal natural product bulgarein (1) was first isolated in 1976 from the fungus Bulgaria inquinans, and was shown to induce topoisomerase I-mediated DNA cleavage. However, as in the case of daldiquinone (15), total synthesis of bulgarein (1) has yet to be reported. In this work, we report the first total syntheses of daldiquinone (15) and bulgarein (1) starting from the commercially available 1,8-DHN (1,8-dihydroxynaphthalene, 1,8-naphthalenediol) via a concise route. Pd-catalyzed Suzuki coupling and C-H arylation reactions between functionalized naphthalenes and hypervalent iodine-mediated double oxidation of phenol to o-quinone were employed as key steps. Thanks to their thermal stability and electronic properties, fluoranthene derivatives have widespread medicinal chemistry and organic optoelectronics applications. A significant number of fluoranthene-based natural products are known, including bulgarein (1). Although many procedures have been developed to synthesize fluoranthenes, practical and modular strategy for synthesizing many substituted unsymmetrical fluoranthenes is still desirable. In this work, we report a novel approach to achieve modular syntheses of fluoranthene derivatives based on intramolecular Diels-Alder reaction.

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Keywords
Natural products, Total synthesis, Daldiquinone, Bulgarein, Fluoranthene, Diels-Alder reactions
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Published Version (Please cite this version)