Introduction
Chemical Properties
Synthesis
Derivatives
How it works
Symptoms
Treatment
Research
Reference
 
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shuyi.quek@ic.ac.uk
 
 
 
 
 

- Synthesis -

       
With its complex structure and various functional groups, Tetrodotoxin (TTX) has been a
formidable target for total synthesis

- The structure was first elucidated by Woodward in 1964 and was later confirmed by Kishi in 1965

- In September 1972, Kishi and co-workers (Kishi, Y. et al. J. Am. Chem. Soc. 1972, 94, 9217-9221) successfully synthesized a racemic mixture of the Tetrodotoxin molecule

- The reaction is complicated involving a total of 29 steps, including a ketalization, a Meerwein-Ponndorf-Verley reduction, selenium oxidation, epoxidation, a Diels-Alder cycloaddition
amongst other techniques.

The diagram below summarizes the main steps.


"Kishi synthetic pathway for TTX"

- In January 2003, Isobe and his co-workers (Isobe, M. et al. J. Am. Chem. Soc. 2003, 125) from
Nagoya University, Japan, have accomplished the first asymmetric total synthesis of Tetrodotoxin.
- This complex reaction involves a series 67 steps. The highlights of the Isobe reaction are:

~ Chiral starting material of 2-acetoxy-tri-O-acetyl-D-glucal

~ Formation of hydroxylated cyclohexane core ring
- Claisen rearrangement
- Regioselective hydroxylation of acetone moiety
- Sonogashira coupling (Sonogashira, K. et al. Tetrahedron Lett. 1975, 16, 4467-4470)
synthesizes the precursor required for aldol condensation
- Intramolecular directed aldol condensation


~Introducing the nitrogen functionality
- Initial attempt using Overman rearrangement (Overman, L.E. Acc. Chem. Res. 1980, 13,
218-224) was unsuccessful
- New strategy of intramolecular carbamate-ester (unsaturated) conjugate addition was employed

The synthesis of Tetrodotoxin in an enantiomerically pure form was possible because:
1) Different protective groups were chosen for each íVOH group, this also to discriminate for
 future analog synthesis
2) All stereogenic centers were controlled with high selectivity

Finally, TTX was purified by ion exchange chromatography and found to be identical to the
natural molecule.

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