152
4, Nitrogenous Compounds
Tetrodotoxin derivative 109 differs, however, from the toxin itself in one
important structural feature. Compound 109 is a lactone possessing the
requisite ir band at 1751 cm"
1 , but tetrodotoxin (111) is devoid of lactonic
absorption. On the other hand, the infrared bands assigned to guanidine
(1658, 1605 cm
- 1 ) remain unchanged as one proceeds from tetrodotoxin
(111) to derivative 109. This indicated that the new crystalline hydrochloride
(109) cannot be a guanidinium salt of tetrodotoxin (111). As has been pointed
out, tetrodotoxin (111) is too weak a base for its basicity (pK a 8.5) to be
associated with the guanidine moiety of the molecule. Derivative 109 is an
equally weak base, having a pK a in water of 8.3. The pK a of 109, however, is
9.2 when the measurement is made in dioxane water. This is a significant
finding since enhanced pK a values are characteristic of hydroxyl group dissociation when one proceeds from solvents of high to solvents of low dielectric constant. From this series of arguments it can be concluded that
tetrodotoxin (111) itself is a zwitterion, one of whose hydroxyl groups is
deprotonated.
The answer to the next question, which of the hydroxyl groups of tetrodotoxin is acidic enough to lose a proton to be gained by nitrogen, came through
analysis of the nmr spectrum of heptaacetylanhydrotetrodotoxin. This
derivative was one of a mixture of polyacetates which was formed when
tetrodotoxin (111) was acetylated for ten days at 25° (Woodward, 1964).
HO
Q
?"
OH
OH
)
k
!
IS?H
Z _ O H K
ΗΝ^Ί^Μ.Ί"CH 2 OH
H
7
r
^
\
Ο
°
ΗΛΝ-Μ' "
A/LU/'
Cl"
I
ÔHÎ
l
H/i
\\
il
#V
OH
\LCH 2 OH
HO^ ιΐγ
%
Ο
OH
110
111
In order to arrive at a structure for heptaacetylanhydrotetrodotoxin, one needs
to examine the hypothetical precursor of derivative 109, i.e., a hydrochloride
of tetrodotoxin minus the methyl ether and isopropylidene functions, which is
represented by structure 110. If this compound 110 were to be acetylated,
I
I
III
H—C—OH + —C—O—C—
> Η
CO
CO
C
I
II
I
III
ο
OH
Alcohol
Lactone
Hemilactal
SCHEME 4.4
4, Nitrogenous Compounds
Tetrodotoxin derivative 109 differs, however, from the toxin itself in one
important structural feature. Compound 109 is a lactone possessing the
requisite ir band at 1751 cm"
1 , but tetrodotoxin (111) is devoid of lactonic
absorption. On the other hand, the infrared bands assigned to guanidine
(1658, 1605 cm
- 1 ) remain unchanged as one proceeds from tetrodotoxin
(111) to derivative 109. This indicated that the new crystalline hydrochloride
(109) cannot be a guanidinium salt of tetrodotoxin (111). As has been pointed
out, tetrodotoxin (111) is too weak a base for its basicity (pK a 8.5) to be
associated with the guanidine moiety of the molecule. Derivative 109 is an
equally weak base, having a pK a in water of 8.3. The pK a of 109, however, is
9.2 when the measurement is made in dioxane water. This is a significant
finding since enhanced pK a values are characteristic of hydroxyl group dissociation when one proceeds from solvents of high to solvents of low dielectric constant. From this series of arguments it can be concluded that
tetrodotoxin (111) itself is a zwitterion, one of whose hydroxyl groups is
deprotonated.
The answer to the next question, which of the hydroxyl groups of tetrodotoxin is acidic enough to lose a proton to be gained by nitrogen, came through
analysis of the nmr spectrum of heptaacetylanhydrotetrodotoxin. This
derivative was one of a mixture of polyacetates which was formed when
tetrodotoxin (111) was acetylated for ten days at 25° (Woodward, 1964).
HO
Q
?"
OH
OH
)
k
!
IS?H
Z _ O H K
ΗΝ^Ί^Μ.Ί"CH 2 OH
H
7
r
^
\
Ο
°
ΗΛΝ-Μ' "
A/LU/'
Cl"
I
ÔHÎ
l
H/i
\\
il
#V
OH
\LCH 2 OH
HO^ ιΐγ
%
Ο
OH
110
111
In order to arrive at a structure for heptaacetylanhydrotetrodotoxin, one needs
to examine the hypothetical precursor of derivative 109, i.e., a hydrochloride
of tetrodotoxin minus the methyl ether and isopropylidene functions, which is
represented by structure 110. If this compound 110 were to be acetylated,
I
I
III
H—C—OH + —C—O—C—
> Η
CO
CO
C
I
II
I
III
ο
OH
Alcohol
Lactone
Hemilactal
SCHEME 4.4