UC Irvine

Chapter 1 provides an overview of lissoclimide natural products and previous synthetic efforts. The isolation of lissoclimides and their anticancer properties against various cell lines are detailed. Subsequently, the mechanism of protein translation inhibition by chlorolissoclimide is discussed. Our group's previous synthetic endeavors, including the semi-synthesis of chlorolissoclimide, analogue-oriented synthesis of lissoclimide derivatives, and Lewis acid-catalyzed bicyclization to access a related natural product, are presented. In collaboration with the Yusupov, Blanchard, Furche, and Horne groups, we explored novel halogen-π dispersive interactions of chlorolissoclimide within the tRNA E-site pocket. Additionally, the anticancer activities of synthetic lissoclimides were evaluated.Chapter 2 describes the conversion of sclareolide into fluorolissoclimide and methyllissoclimide. Selective C–H functionalization of sclareolide was achieved using an Alexanian hydroxyamide reagent to introduce fluorine and methyl groups with the desired stereochemistry at the C2 position. The mechanism underlying C–H fluorination and the structural basis for selective radical C–H modification of sclareolide were elucidated. Methylsclareolide was subsequently synthesized through methylation of the corresponding iodinated derivative. The syntheses of fluorolissoclimide and methyllissoclimide were completed in concise 9-10 step sequences. Finally, the halogen-π interactions of these compounds, along with bromolissoclimide, chlorolissoclimide, and haterumaimide Q, were investigated within the 80S ribosomal pocket. Chapter 3 commences with a description of. the isolation and structural characterization of brasilicardin A, along with its biological activities and proposed biosynthetic pathway. The complex trans/syn/trans-perhydrophenanthrene core of brasilicardin A has posed significant synthetic challenges, with previous total syntheses relying on Diels–Alder cyclization and intramolecular Michael addition strategies. Our group developed a novel cobalt-catalyzed MHAT-induced polycyclization approach to efficiently construct the tricyclic core of a brasilicardin analogue. Structure-activity relationship studies using SARS models highlighted the critical roles of the disaccharide, amino acid side chain, and diterpenoid core in the biological activity of brasilicardin A. Chapter 4 details the synthesis of brasilicardin A via a polyene cyclization strategy inspired by the biosynthetic pathway. A retrosynthetic analysis identified directed hydrogenation as a key step to construct the desired perhydrophenanthrene core. Epoxypolyene intermediates were prepared via a crucial B-alkyl Suzuki–Miyaura cross-coupling reaction. Both cationic and radical cyclization pathways were explored. Cyclization of a diene-containing epoxypolyene afforded the tricyclic core of brasilicardin A. Investigation of C2 hydroxyl protection revealed that a free alcohol facilitated the desired 6-endo-trig cyclization of an enone-terminated polyene. Future work will focus on optimizing polyene substrate synthesis.