Tetrodotoxin (TTX) is a potent neurotoxin and a promising analgesic that selectively blocks voltage-gated sodium channels at nanomolar concentrations. Its complex structure features an octa-substituted cyclohexane core, excessive polar functionalities, and exceedingly high (1:1) heteroatom-to-carbon ratio. Prior syntheses required 22-69 steps from heavily oxygenated starting materials, with excessive protecting group and functional group manipulations. Here, we report a scalable 16-step synthesis from simple parabromobenzyl alcohol via a distinct chemoenzymatic strategy. Key to this approach is a strategic merger of engineered enzyme-catalyzed arene dihydroxylation and two sequential cycloaddition-fragmentation reactions, which rapidly culminate in the densely substituted cyclohexane core. Late-stage neighboring-group-assisted chemoselective nitrile reduction enables efficient guanidine installation to complete the total synthesis. This work provides a concise route to TTX and a blueprint for synthesizing other densely oxygenated, biologically significant molecules.
Peng et al. (Thu,) studied this question.