Modular total synthesis of Lasalocid acid A through direct C(sp3)-C(sp3) attached ring coupling

Lasalocid acid A is an agricultural antibiotic used on a massive scale globally. The compound was originally introduced for controlling intestinal parasitic infections (coccidiosis) in poultry, but broader use as a growth promoter (via modulation of the microbiome), makes lasalocid acid A, and related agricultural polyether antibiotics, controversial compounds. Still, they remain highly important antimicrobial agents for ensuring consistent meat and dairy production in many countries. Lasalocid acid A possesses broad anti-microbial activities, including against drug-resistant bacterial pathogens, such as methicillin-resistant Staphylococcus aureus, but a narrow therapeutic index precludes its use in human medicine. It remains unknown if structural optimization, through synthesis, can provide analogs with sufficiently improved properties, however the complex, polycyclic nature of lasalocid acid A mandates the development of a very short synthesis to unlock such investigations. Here, we report a highly concise and module-based synthesis of lasalocid acid A in 11 steps in the longest linear sequence. A central element in the route is a new Tsuji-Trost-type C-glycosylation reaction to construct – in a single step – the challenging attached oxacyclic rings, which include a quaternary stereocenter. We employed the route to also prepare the mirror-image isomer of lasalocid acid A and demonstrated that this compound, interestingly, fully preserves the potent activity of the natural product.