154
4. Nitrogenous Compounds
newt, Taucha torosa, a potent neurotoxin which they named tarichatoxin.
It soon became evident that the two toxins from two totally unrelated sources,
tetrodotoxin from puffers and tarichatoxin from salamanders, were identical
(Buchwald et al, 1964). Mosher and co-workers (1964) brought their structural studies to a successful conclusion at the same time as did the three
groups working on tetrodotoxin.
Recently Hashimoto and Noguchi (1971) have reported the isolation of a
toxin almost certainly identical with, or closely related to tetrodotoxin from
yet another source, a goby, Gobius criniger, from the Ryukyu islands. Close
similarity or identity of the two toxins was suggested by identical doseresponse curves in the bioassay and by identical tic spots in three solvent
systems.
c. Synthetic approaches
Two research groups have so far published details of their efforts toward a
total synthesis of tetrodotoxin. One of these is that of Keana at the University of Oregon; the other is that of Goto at Nagoya University, who had
participated earlier in the structural work with Professor Hirata (Goto et al.,
1965).
Goto's ingenious approach to a total synthesis of tetrodotoxin (111) has
been outlined in two published communications (Kishi et al, 1970a,b).
Perhaps the most remarkable features of Goto's synthesis are the wellchosen starting material and the stereospecificity of each step, which achieve
an intermediate that possesses all six centers of chirality of the carbocyclic
ring of tetrodotoxin. The synthesis, which is presented in Chart 4.5, proceeds
from a Diels-Alder reaction of butadiene (117) with 5-(«-oximinoethyl)toluquinone (114) in acetonitrile in the presence of stannic chloride in yield
of 83%. Adduct 115a is converted to mesylate 115b, which in boiling water
undergoes a Beckmann rearrangement to amide 116. Sodium borohydride
in methanol reduces selectively and stereospecifically the carbonyl at C-5
(tetrodotoxin numbering) to yield alcohol 117, which with m-chloroperbenzoic acid and camphorsulfonic acid is transformed to hydroxyether 118.
Alkaline hydrogen peroxide treatment of 118 transformed the remaining
olefinic linkage into epoxide 119. This epoxide on sodium borohydride
reduction lost its remaining carbonyl group and was transformed into alcohol
120a. The corresponding epoxide acetate (120b) when treated with a 1:1
mixture of sulfuric and acetic acids at —20° was opened in desired fashion
and yielded key intermediate 121, which possesses the necessary functionality
and the correct stereochemistry toward a total synthesis of tetrodotoxin.
Correctness of intermediate structures and stereochemistry was established
by nmr analysis and by preparation and comparison with several epimeric
compounds.
4. Nitrogenous Compounds
newt, Taucha torosa, a potent neurotoxin which they named tarichatoxin.
It soon became evident that the two toxins from two totally unrelated sources,
tetrodotoxin from puffers and tarichatoxin from salamanders, were identical
(Buchwald et al, 1964). Mosher and co-workers (1964) brought their structural studies to a successful conclusion at the same time as did the three
groups working on tetrodotoxin.
Recently Hashimoto and Noguchi (1971) have reported the isolation of a
toxin almost certainly identical with, or closely related to tetrodotoxin from
yet another source, a goby, Gobius criniger, from the Ryukyu islands. Close
similarity or identity of the two toxins was suggested by identical doseresponse curves in the bioassay and by identical tic spots in three solvent
systems.
c. Synthetic approaches
Two research groups have so far published details of their efforts toward a
total synthesis of tetrodotoxin. One of these is that of Keana at the University of Oregon; the other is that of Goto at Nagoya University, who had
participated earlier in the structural work with Professor Hirata (Goto et al.,
1965).
Goto's ingenious approach to a total synthesis of tetrodotoxin (111) has
been outlined in two published communications (Kishi et al, 1970a,b).
Perhaps the most remarkable features of Goto's synthesis are the wellchosen starting material and the stereospecificity of each step, which achieve
an intermediate that possesses all six centers of chirality of the carbocyclic
ring of tetrodotoxin. The synthesis, which is presented in Chart 4.5, proceeds
from a Diels-Alder reaction of butadiene (117) with 5-(«-oximinoethyl)toluquinone (114) in acetonitrile in the presence of stannic chloride in yield
of 83%. Adduct 115a is converted to mesylate 115b, which in boiling water
undergoes a Beckmann rearrangement to amide 116. Sodium borohydride
in methanol reduces selectively and stereospecifically the carbonyl at C-5
(tetrodotoxin numbering) to yield alcohol 117, which with m-chloroperbenzoic acid and camphorsulfonic acid is transformed to hydroxyether 118.
Alkaline hydrogen peroxide treatment of 118 transformed the remaining
olefinic linkage into epoxide 119. This epoxide on sodium borohydride
reduction lost its remaining carbonyl group and was transformed into alcohol
120a. The corresponding epoxide acetate (120b) when treated with a 1:1
mixture of sulfuric and acetic acids at —20° was opened in desired fashion
and yielded key intermediate 121, which possesses the necessary functionality
and the correct stereochemistry toward a total synthesis of tetrodotoxin.
Correctness of intermediate structures and stereochemistry was established
by nmr analysis and by preparation and comparison with several epimeric
compounds.