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16-Step Scalable Chemoenzymatic Synthesis of Tetrodotoxin
Chen Peng1, Weilin Wu1, Yuxuan Ye1
1Zhejiang Key Laboratory of Precise Synthesis of Functional Molecules, Department of Chemistry, School of Science and Research Center for Industries of the Future, Westlake University, 600 Dunyu Road, Hangzhou 310030, Zhejiang Province, P. R. China.
None:
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.
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