Scalable, Convergent Total Synthesis of (+)-Saxitoxin and Related Natural Products

The urgent demand for innovative pain therapies is underscored by pain affecting 20% of the global population, costing the U.S. $600 billion annually, more than cancer, heart disease, and diabetes combined, with current treatments lacking in efficacy or causing severe side effects1 . Saxitoxin (STX, 1), a potent neurotoxin from shellfish, first isolated in 19572, offers immense pharmaceutical potential due to its interaction with voltage-gated sodium channels, promising long-term anesthesia for conditions like anal fissures3 and chronic headaches4. However, its deadly nature, with just 1 mg potentially lethal, and the complexity of its over 50 related toxins5, challenge its clinical use. Efforts to modify STX aim to reduce its systemic toxicity while enhancing selectivity, potentially revolutionizing pain management and detoxification strategies, while also providing insights into cellular electrical transmission6. Hundreds of synthetic studies towards this end have been disclosed thus far, yet a fully modular and scalable approach to the family remains elusive. Here we show how a tactical combination of radical retrosynthesis, biocatalysis, and C–H functionalization logic can be combined to solve this problem resulting in a scalable approach to the STX family in less than 10 steps including the first total synthesis of neosaxitoxin (neoSTX, 4), a hydroxylated naturally occurring STX analog previously under clinical investigation7