Graduate Thesis Or Dissertation
 

Regioselective Synthesis of Substituted Phenols, Benzenes, Benzofuranones and Benzofurans and Synthesis of Homoharringtonine Analogs

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https://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/2r36v609r

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  • Substituted phenols are important substructures for pharmaceuticals, agrochemicals, natural products and biological probe molecules. The properties of phenolic molecules are substantially influenced by the substitution patterns of the phenolic ring. The chemical synthesis of phenols with various substitution patterns is an enduring challenge and multiple strategies have emerged. However, some classical methods such as rearrangement and directed C–H bond functionalization have limitations to deliver substituted phenols regioselectively. In order to overcome this gap, we developed a general cycloaddition-based method to synthesize substituted phenols with complete control of regioselectivity. Both electronically polarized diene (3-hydroxypyrone) and dienophile (nitroalkene) can undergo regiospecific Diels–Alder–elimination–retro–Diels–Alder cascade to deliver phenols. Utilizing this method, high levels of substitution are tolerated and fully substituted phenols are prepared. Yields are synthetically useful and wide range of functional groups are tolerated. Finally, conversion of the phenols to the corresponding benzenes allows synthesis of highly substituted benzenes with full control of substituent location. Based on phenol synthesis method, we further investigated other functional groups which might take advantage of this regioselective synthesis. A benzofuranone synthesis has been developed involving 3-hydroxypyrones and nitroalkenes bearing a carbomethoxymethyl group. In this reaction, phenols bearing a tethered ester would be formed and these phenols would cyclize to benzofuranones under the reaction conditions. A variety of substituted bezofuranones have been synthesized regioselectively. Functional groups are well tolerated and yields are synthetically useful. Finally, these benzofuranones can conveniently converted into the corresponding substituted benzofurans. Cephalotaxine is a natural product with no biological activity, but its ester derivative homoharringtonine (HHT) shows IC50 value of 17 nM against P-338 leukemia cells, and was approved by FDA for the treatment of chronic myeloid leukemia. The therapeutic potential difference between cephalotaxine and homoharringtonine is caused by the side chain. Even though hundreds of HHT analogs were prepared, no modification have been shown on the cephalotaxine framework. We are interested in how oxygenation on the cephalotaxine core affects cytotoxicity in molecules with simplified side chains. Five different side chains have been designed and added to cephalotaxine and its oxygenated analog cephlotaxamide. In total, 20 new derivatives have been synthesized and send out for biological testing.
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file details ZhangXiaojie2022.pdf 2022-03-25 Öffentlich Herunterladen