Unified Total Synthesis of Lysolipin Natural Products

Abstract

Lysolipin natural products are a family of bacterial polycyclic xanthones, renowned for their antibiotic potency and structural diversity. Yet, their complex architectures have long eluded synthetic access, and their antimicrobial prowess is offset by pronounced cytotoxicity. This thesis presents a modular total synthesis of the lysolipin family, integrating synthetic innovation, methodological development, and structure activity exploration. <br/> We began by reengineering Brassard's polar annulation sequence to accommodate halogenated, sterically congested xanthones resembling the lysolipin subunit. Detailed studies identified bromoquinones as superior coupling partners, optimized base solvent systems for yield and scalability, and fine tuned the acidity of the cyclization medium for selectivity. These improvements enabled efficient access not only to lysolipin fragments, but also to a broader class of densely functionalized polyhalogenated xanthones – substantially expanding the attainable chemical space. <br/> These halogenated scaffolds proved potent lead structures and identified the xanthone unit as source for cytotoxicity in lysolipin natural products. In detail, chemoselective cross coupling yielded a diversified set of xanthones with potent antiproliferative activity – comparable to the clinical benchmark doxorubicin – yet likely operating through a distinct mode of action. Moreover, potent xanthones resembled the lysolipin family, revealing the natural chloride as a tunable pharmacophore: cross coupling leads to anticancer scaffolds, whereas dehalogenation reduces off target toxicity in antibiotic design. To streamline bond formation in complex target synthesis, recent mechanistic insights in Suzuki Miyaura cross couplings were condensed into rational selection guides that replace trial and error optimization. Crucially, ligand geometry emerged as the key determinant of reaction outcome, leading to the definition of four universal ligand types to simplify reaction planning. <br/> This mechanistic framework enabled the total synthesis of lysolipin members CBS72, CBS87 and CBS100. Guided by ligand types, a very demanding aromatic keto arylation merged sensitive xanthone and isocoumarin fragments into a synthetically versatile desoxybenzoin. Complementary advances – including base catalyzed asymmetric Davis oxidation and late stage aminolysis – addressed substrate lability and catalyst poisoning while minimizing protective group chemistry. These innovations culminated in concise, high-yielding total syntheses, with two out of three reactions forming a lysolipinic bond – a remarkable two to threefold improvement over prior strategies. <br/> Together, this work demonstrates how mechanistically guided synthesis can unlock inaccessible chemical space, translating rational design into architectural complexity and pharmacological potency, and reaffirms total synthesis as a powerful driver of scientific discovery.