Graduate Thesis Or Dissertation
 

Total Synthesis of Cephalotaxus Alkaloids and Synthetic Studies toward Bazzanin K

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https://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/j3860d083

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  • Dearomatization reactions exist broadly in biosynthesis and chemical synthesis. The highly functionalized atoms of arenes can be masked by it aromaticity, and upon dearomatization, those reactive atoms can be readily applied to bond formation and further manipulation. The total synthesis of (–)-cephalotaxine and (–)- homoharringtonine is described via an oxidative furan opening-spontaneous transannular Mannich reaction. The first generation route involved the development of coupling reaction between 3-methoxyfuran-2-carboxylate and bromide to form diarylmethane. Due to the lack of electrophilicity in the ester functionality, the formation of a macrocycle was not observed. The second generation route utilized a Friedel-Crafts alkylation to avoid this problem, enabling the preparation of the macrocycle for the key transformation. Racemic cephalotaxinone was obtained by the oxidative furan opening-spontaneous transannular Mannnich reaction of the macrocycle. A Noyori asymmetric hydrogenation converted racemic cephalotaxinone to (–)-cephalotaxine in excellent yield and enantioselectivity (krel=278), (–)- cephalotaxine was advanced to (–)-homoharringtonine via a three-step sequence. The undesired enantiomer of cephalotaxinone could be recycled through an acid-mediated racemization. Molecular chirality plays a critical role in chemistry, biology, and medicine. Identification of chirality in molecules without sp3-hybridized stereogenic carbon atoms is not straightforward. Bazzanin K is a macrocyclic bis(bibenzyls) with diastereotopic protons at its two methylene position, indicating the possibility of conformational chirality. We describe a synthetic approach toward bazzanin K by a double Suzuki coupling. Sequential Suzuki couplings were tested and the desired terphenyl was isolated as two disastereomers. Ring closing metathesis of terphenyls furnished the phenanthrene moiety of Bazzanin K. The one-pot three-component Suzuki coupling reaction is under investigation.
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