A concise synthesis of tetrodotoxin

Tetrodotoxin (TTX) is a neurotoxic natural product that is an indispensable probe in neuroscience, a biosynthetic and ecological enigma, and a celebrated target of synthetic chemistry. Here, we present a stereoselective synthesis of TTX that proceeds in 22 steps from a glucose derivative. The central cyclohexane ring of TTX and its α-tertiary amine moiety were established by the intramolecular 1,3-dipolar cycloaddition of a nitrile oxide, followed by alkynyl addition to the resultant isoxazoline. A ruthenium-catalyzed hydroxylactonization set the stage for the formation of the dioxa-adamantane core. Installation of the guanidine, oxidation of a primary alcohol, and a late-stage epimerization gave a mixture of TTX and anhydro-TTX. This synthetic approach could give ready access to biologically active derivatives. Tetrodotoxin is a potent bacterial neurotoxin widely associated with pufferfish and thoroughly studied for its sodium channel–blocking properties. Its intricate structure of oxygen-rich interconnected rings has also long intrigued synthetic chemists. Konrad et al . report a comparatively concise route to the natural product from a glucose derivative. A dipolar cycloaddition enabled the formation of the cyclohexyl core at a later stage than prior approaches. Ruthenium catalysis was then key in assembling the surrounding oxygenated rings. —JSY A dipolar cycloaddition and ruthenium-catalyzed oxidation enables comparatively efficient synthesis of a potent neurotoxin.