Synthetic approach to tetrodotoxin

Article abstract of DOI:10.1055/s-2002-32984

A novel and stereoselective approach to tetrodotoxin is described. The tricyclic compound having several key functional groups on the cyclohexane ring was synthesized from p-anisaldehyde with control of the four chiral centers. Iodoaminocyclization, 1,3-dipolar cycloaddition, and Baeyer-Villiger oxidation are the key steps of our approach.

Full text of DOI:10.1055/s-2002-32984

LETTER
1323
Synthetic Approach to Tetrodotoxin
Synthetic
A
ppro
e
ach to Tet
t
rodotox
s
in uji Itoh, Manabu Watanabe, Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax +81(3)58028694; E-mail: fukuyama@mol.f.u-tokyo.ac.jp
Received 15 May 2002
tiguous
stereocenters.
Our
approach
features
Abstract: A novel and stereoselective approach to tetrodotoxin is
described. The tricyclic compound having several key functional
groups on the cyclohexane ring was synthesized from p-anisalde-
hyde with control of the four chiral centers. Iodoaminocyclization,
1,3-dipolar cycloaddition, and Baeyer–Villiger oxidation are the
key steps of our approach.
iodoaminocyclization reaction of imidodicarbonate, 1,3-
dipolar cycloaddition, and Baeyer–Villiger oxidation.
The imidodicarbonate 6 was prepared from p-anisalde-
hyde (3) in six steps (Scheme 1). Addition of allylmagne-
sium bromide to 3 followed by ozonolysis and subsequent
reduction of the resulting aldehyde afforded the 1,3-diol 4.
Birch reduction of 4 gave the 1,4-diene, which was con-
verted to the dimethylacetal 5 upon treatment with pyri-
dinium p-toluenesulfonate (PPTS) in methanol. After
selective protection of the primary alcohol, the imidodi-
carbonate 6 was easily synthesized by the reaction with
benzyloxycarbonyl isocyanate which in turn was prepared
in situ from benzylcarbamate, triphosgen, and pyridine.
This method was more practical than the reported one5 be-
cause it was not necessary to isolate the very reactive and
moisture sensitive alkoxycarbonyl isocyanates. With the
precursor of iodoaminocyclization reaction in hand, we
attempted to construct the bicyclic system according to
Taguchi’s protocol.6 Upon successive treatment with 1.8
equivalents of LiAl(t-BuO)4 and 5.0 equivalents of iodine,
iodoaminocyclization reaction proceeded successfully to
give the bicyclic oxazolidinone 7 with modest diastereo-
selectivity (ds = 3:1).7 To the best of our knowledge, dia-
stereoselective construction of a quaternary carbon
adjacent to nitrogen by this reaction has not been reported
to date.8
Key words: tetrodotoxin, stereoselective, iodoaminocyclization
reaction, intramolecular 1,3-dipolar cycloaddition, isoxazoline
Tetrodotoxin (1),1 found mostly in the livers and ovaries
of puffer fish, is one of the most well-known and most
toxic marine natural products having low molecular
weights (Figure). Because of its biological activities as
well as its unique and complex structure,2 tetrodotoxin has
been one of the most attractive and challenging synthetic
targets in the field of synthetic organic chemistry.3 In spite
of many efforts, only one total synthesis of tetrodotoxin
has been reported by Kishi and co-workers in 1972.4 The
complex structure of tetrodotoxin could be simplified as
shown in the Figure by removal of the ortho ester and
guanidine moieties. In this communication, we report a
new synthetic route to the tricyclic compound 2 having
several functional groups of the core skeleton of tetrodo-
toxin on the cyclohexane ring with control of the four con-
O
10
OMe
MeO OMe
OMe
O
HO
9
O
5
H
c,d
a, b
11
OH
4
4a
H2N
N
6
CH2OH
7
N
HO
8
H
OH
CHO
HO
OH
HO
OH
Tetrodotoxin (1)
3
4
5
OH
11
MeO OMe
TBSO OMe
MeO OMe
OH
6
HO
OH
5
7
O
g
N
e, f
4a
8
I
OHC
OH
O
4
NCbz
NH2
OH
NH
O
9
MeO2C
TBSO
O
HO2C
O
TBSO
O
NHCbz
10
O
core skeleton of 1
2
6
7
Figure Structures of tetrodotoxin (1), its core skeleton, and the tri-
cyclic compound 2 (described in this communication).
Scheme 1 Reagents and Conditions: (a) Allylmagnesium bromide,
ether, 0 °C; (b) O3, CH2Cl2–MeOH (1:1), –78 °C; NaBH4, 0 °C; (c)
Li, EtOH, THF, liquid NH3, reflux, 5 min; (d) cat. PPTS, MeOH, r.t.,
85% (4 steps); (e) TBSCl, imidazole, CH2Cl2, 0 °C. 89%; (f) triphos-
gene, benzyl carbamate, pyridine, CH2Cl2, 0 °C, 97%;
Synlett 2002, No. 8, Print: 30 07 2002.
Art Id.1437-2096,E;2002,0,08,1323,1325,ftx,en;Y06802ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
(g) LiAl(t-BuO)4, THF; I2, r.t.

1324
T. Itoh et al.
LETTER
In order to prepare a precursor of the ensuing intramolec-
ular 1,3-dipolar cycloaddition, 7 was converted to the ni-
troalkane 10 in 5 steps (Scheme 2). After deprotection of
the silyl group, the resulting alcohol was converted to the
iodide 8. Hydrolysis of the dimethylacetal of 8 with 80%
aqueous acetic acid at 100 °C caused concomitant dehy-
droiodination to yield the enone 9 quantitatively. After
formation of the silyl enol ether, 10 was synthesized by
substitution reaction with sodium nitrite in DMF. Upon
treatment of 10 with di-tert-butyl dicarbonate and a cata-
lytic amount of N,N-dimethylaminopyridine (DMAP) in
acetonitrile,9 smooth formation of the nitrile oxide and the
subsequent intramolecular 1,3-dipolar cycloaddition with
the olefin occurred to give the isoxazoline 11 as a single
diastereomer in good yield.
TBSO OMe
TBSO OMe
O
O
a,b
c
N
11
N
NCbz
NHCbz
O
O
12
13
TBSO OMe
TBSO OMe
O
O
d
e, f
N
AllocN
H
NH
NH
O
O
HO
HO
O
O
14
15
Scheme 3 Reagents and Conditions: (a) PhSeCl, pyridine, CH2Cl2–
MeOH, 0 °C, 79%; (b) m-CPBA, dichloroethane; NaHCO3, reflux,
quant.; (c) DBU, THF, r.t., quant.; (d) cat. OsO4, NMO, acetone–
H2O–t-BuOH, r.t.; sat. Na2SO3; (e) NaBH4, MeOH, r.t., 89% (2
steps); (f) Alloc-Cl, sat. NaHCO3–CH2Cl2, r.t., 85%.
O
MeO OMe
a, b
c
4a
8
7
I
NCbz
O
NCbz
9
The alcohol 15 was oxidized to the ketone 16 with Dess–
Martin periodinane12 (Scheme 4). The regioselective
Baeyer–Villiger oxidation occurred upon treatment of 16
with m-CPBA in the presence of solid sodium bicarbonate
to furnish the 6-membered lactone 17. This lactone was
cleaved easily by methanolysis to give the hemiaminal 18.
Palladium-mediated deprotection of the Alloc group of 18
led to further dehydration of the hemiaminal to afford the
isoxazoline 2.13
I
I
10
O
O
O
8
9
OTBS
OTBS
O
f
d, e
N
NCbz
O
NCbz
O2N
O
O
O
10
11
TBSO OMe
TBSO OMe
Scheme 2 Reagents and Conditions: (a) TBAF, THF, r.t.; (b) PPh3,
I2, imidazole, benzene, r.t., 54% (3 steps); (c) 80% aq HOAc, 100 °C,
quant.; (d) TBSOTf, Et3N, CH2Cl2, 0 °C, 89%; (e) NaNO2, DMF,
66%; (f) Boc2O, cat. DMAP, CH3CN, 90%.
O
O
AllocN
a
b
AllocN
H
15
NH
H
NH
O
O
O
O
O
O
O
Having synthesized the tetracyclic compound 11 stereose-
lectively, we then investigated the oxidation of the cyclo-
hexane and cyclopentane rings (Scheme 3). Introduction
of the double bond into the cyclohexane ring was per-
formed by usual procedures. Phenylselenylation of 11 in
CH2Cl2 and methanol did not afford the expected ketone
but instead gave the mixed acetal. After m-CPBA oxida-
tion of the selenide, heating the reaction mixture at reflux-
ing temperature caused selenoxide elimination to furnish
the cyclohexene 12 in a quantitative yield. Treatment of
12 with DBU caused elimination of carbon dioxide to give
the olefin 13. Dihydroxylation10 of 13 proceeded selec-
tively at the olefin on the cyclopentene ring from the con-
vex face of the tricyclic system to give a diol, which was
converted to the oxazolidinone 14 after reductive and mild
basic work-up with saturated Na2SO3.11 Formation of the
oxazolidinone allowed the differentiation of the two hy-
droxy groups. Reduction of the isoxazoline 14 with sodi-
um borohydride followed by selective N-protection of the
isoxazolidine with an Alloc group afforded 15.
16
17
TBSO OMe
TBSO OMe
O
O
c
d
N
AllocN
H
8
9
NH
NH
OH
MeO2C
MeO2C
O
O
O
O
18
2
Scheme 4 Reagents and Conditions: (a) Dess–Martin periodinane,
CH2Cl2, r.t.; (b) m-CPBA, NaHCO3, CH2Cl2, r.t.; (c) K2CO3, MeOH,
r.t.; (d) cat. Pd(PPh3)4, pyrrolidine, CH3CN, r.t., 42% (4 steps).
In conclusion, we have successfully synthesized the tricy-
clic compound 2 having several key functional groups of
tetrodotoxin (1) on the cyclohexane ring with control of
the four chiral centers. In addition, 2 possesses other func-
tional groups that could potentially provide access to tet-
rodotoxin. Further elaboration toward the synthesis of
tetrodotoxin is currently underway in our laboratory.
Synlett 2002, No. 8, 1323–1325 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthetic Approach to Tetrodotoxin
1325
Nishikawa, T.; Asai, M.; Ohyabu, N.; Yamamoto, N.; Isobe,
M. Angew. Chem. Int. Ed. 1999, 38, 3081. (i) Asai, M.;
Nishikawa, T.; Ohyabu, N.; Yamamoto, N.; Isobe, M.
Tetrahedron 2001, 57, 4543.
Acknowledgement
This work was partly supported by CREST, The Japan Science and
Technology Corporation, and Mitsubishi Foundation. TI acknow-
ledges the Japan Society for the Promotion of Science (JSPS).
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(7) The stereochemistry at C-9 position was confirmed by NOEs
after conversion of 7 to 9. NOEs between C-8 and C-9, C-4a
and C-10 were observed.
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Synlett 2002, No. 8, 1323–1325 ISSN 0936-5214 © Thieme Stuttgart · New York