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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; 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: 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

8 Forward Synthesis: Azide 8

9 Forward Synthesis: 9-membered ring 10

10 Forward Synthesis: (+)-STX

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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