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Total Synthesis of (+)- Saxitoxin

Total Synthesis of (+)- Saxitoxin. Ye- Geun Song CHEM 635 May 15 th , 2012 Fleming, J. J.; Du Bois, J. J. Am. Chem . Soc. 2006 , 128 , 3926. Saxitoxin. A neurotoxin naturally produced by certain species of marine dinoflagellates (plankton) and cyanobacteria (green algae).

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Total Synthesis of (+)- Saxitoxin

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  1. Total Synthesis of (+)-Saxitoxin Ye-Geun Song CHEM 635 May 15th, 2012 Fleming, J. J.; Du Bois, J. J. Am. Chem. Soc. 2006, 128, 3926

  2. Saxitoxin • A neurotoxin naturally produced by certain species of marine dinoflagellates (plankton) and cyanobacteria (green algae). • Is responsible for the paralytic shellfish poisoning (PSP) in human. No cure known. • Found in at least 12 marine puffer fish species in Asia and Brazil, but the ultimate source unknown. In the USA, the PSP is limited to New England and the West Coast. • Acts as a selective sodium channel blocker. It acts on the voltage-gated Na+ channels of nerve cells, preventing normal cellular of nerve cells, preventing normal cellular function and leading to paralysis (Medicinal interest) • Toxicity of 8µg/Kg in mice; 0.2-1.0 mg would prove fatal to humans;100x more poisonous than strychnine, 1000x (sarin gas), 2000x (NaCN) (Millitary interest)

  3. The Challenge for Chemical Synthesis • Dense arrangement of heteroatoms • 3 contiguous stereocenters • Tricyclic skeleton possessing two guanidine groups • The dicationic nature of the molecule complicates the manipulation/purification

  4. Total Syntheses of Saxtoxin • 1977 – First by Kishi; racemic saxitoxin • 1984 – Second by Jacobi; racemic saxitoxin • 2006 – Third by Du Bois; natural (+)-saxitoxin using commercially available SM, (R)-glycerol acetamide. (JACS. 2006, 128, 3926)

  5. Retrosynthesis

  6. Forward Synthesis: Oxathiazinane 6

  7. Step 3 -> 4: oxathiazinaneiminium ion equivalent Proposed TS: Nucleophilic additions to tetrahydropyridinium ions - Axial attack by the alkynyl anion on the twist-chair form of the iminium intermediate would give the cis-C4,C5 stereochemistry. Not confirmed yet. Du Bois, J. et. al, J. Am. Chem. Soc. 2003, 125, 2028

  8. Forward Synthesis: Azide 8

  9. Forward Synthesis: 9-membered ring 10

  10. Forward Synthesis: (+)-STX β-saxitoxinol

  11. Conclusion • 1.6% overall yield • First total synthesis of (+) saxitoxin • Stereocontrolled formation of the 9-membered ring and condensation to prepare the bicyclic guanidine core • 19 steps from commercially available (R)- glycerol acetamide

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