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
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)
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
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)
Retrosynthesis
Forward Synthesis: Oxathiazinane 6
Step 3 -> 4: oxathiazinane iminium 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
Forward Synthesis: Azide 8
Forward Synthesis: 9-membered ring 10
Forward Synthesis: (+)-STX
β-saxitoxinol
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