Total Synthesis of (?)-Tetrodotoxin and 11-norTTX-6(R)-ol

Article abstract of DOI:10.1002/anie.201611574

The enantioselective total synthesis of (?)-tetrodotoxin [(?)-TTX] and 4,9-anhydrotetrodotoxin, which are selective blockers of voltage-gated sodium channels, was accomplished from the commercially available p-benzoquinone. This synthesis was based on efficient stereocontrol of the six contiguous stereogenic centers on the core cyclohexane ring through Ogasawara's method, [3,3]-sigmatropic rearrangement of an allylic cyanate, and intramolecular 1,3-dipolar cycloaddition of a nitrile oxide. Our synthetic route was applied to the synthesis of the tetrodotoxin congeners 11-norTTX-6(R)-ol and 4,9-anhydro-11-norTTX-6(R)-ol through late-stage modification of the common intermediate. Neutral deprotection at the final step enabled easy purification of tetrodotoxin and 11-norTTX-6(R)-ol without competing dehydration to their 4,9-anhydro forms.

Full text of DOI:10.1002/anie.201611574

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201611574
German Edition: DOI: 10.1002/ange.201611574
Natural Product Synthesis Hot Paper
Total Synthesis of (À)-Tetrodotoxin and 11-norTTX-6(R)-ol
Tomoaki Maehara, Keisuke Motoyama, Tatsuya Toma, Satoshi Yokoshima, and
Tohru Fukuyama*
Abstract: The enantioselective total synthesis of (À)-tetrodo-
toxin [(À)-TTX] and 4,9-anhydrotetrodotoxin, which are
selective blockers of voltage-gated sodium channels, was
accomplished from the commercially available p-benzoqui-
none. This synthesis was based on efficient stereocontrol of the
six contiguous stereogenic centers on the core cyclohexane ring
through Ogasawaraꢀs method, [3,3]-sigmatropic rearrange-
ment of an allylic cyanate, and intramolecular 1,3-dipolar
cycloaddition of a nitrile oxide. Our synthetic route was
applied to the synthesis of the tetrodotoxin congeners 11-
norTTX-6(R)-ol
and
4,9-anhydro-11-norTTX-6(R)-ol
through late-stage modification of the common intermediate.
Neutral deprotection at the final step enabled easy purification
of tetrodotoxin and 11-norTTX-6(R)-ol without competing
dehydration to their 4,9-anhydro forms.
[
1]
T
etrodotoxin (TTX, 1), a puffer fish toxin isolated in
Figure 1. The structure of TTX and its analogues.
[
2]
1
909, is a potent inhibitor of voltage-gated sodium channels
(
Na s). The chemical structure was revealed by Tsuda,
v
Woodward, and Goto to possess a polyfunctionalized dioxaa-
damantane skeleton with nine contiguous stereogenic centers
[
3,4]
and a cyclic guanidine containing a hemiaminal moiety.
Several natural congeners of TTX have since been isolated,
including 4,9-anhydroTTX (10) and other analogues with
different oxidation states and stereochemistries at C-6 and C-
[5]
1
1 (Figure 1). Although TTX displays a high inhibitory
activity against Na 1.1, 1.2, 1.3, 1.4, 1.6, and 1.7, 4,9-
v
anhydroTTX is a highly selective inhibitor of Na 1.6, in
v
spite of minute structural differences between TTX and 4,9-
[
6]
anhydroTTX. Therefore, designing a TTX-derived inhibitor
with high specificity against a single Na isoform would make
v
a significant contribution to pharmacological research. How-
ever, the densely oxygenated chemical structure of natural
TTX hampers its modification. Herein, we disclose a practical
synthetic route that applicable to TTX and its congeners.
Our retrosynthetic analysis is outlined in Scheme 1. The
late-stage installation of the orthoester and the guanidine
moieties was envisioned owing to their high reactivities and
polarities. In this way, TTX could be simplified to densely
oxidized cyclohexane 11. The simultaneous introduction of
a formyl group at C-4a and a hydroxy group at C-5 could be
Scheme 1. Retrosynthetic analysis of TTX.
achieved through a process involving intramolecular 1,3-
dipolar cycloaddition and fragmentation of the resultant
[
7]
isoxazoline. We planned the stereoselective addition of
nitrile oxide equivalent 14 to aldehyde 15, the quaternary
[
*] T. Maehara, Dr. T. Toma, Dr. S. Yokoshima, Prof. T. Fukuyama
Graduate School of Pharmaceutical Sciences, Nagoya University
Furo-cho, Chikusa-ku, Nagoya 464-8601 (Japan)
stereogenic center of which could be constructed through
[8]
[
3,3]-sigmatropic rearrangement of an allylic cyanate.
Highly oxygenated cyclohexene 15 was envisaged to arise
through functionalization of chiral enone 17 by means of the
E-mail: fukuyama@ps.nagoya-u.ac.jp
Dr. K. Motoyama
Graduate School of Pharmaceutical Sciences, University of Tokyo
[
9]
steric bias of the tricyclic skeleton.
7
-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
The synthesis of (À)-TTX commenced with the stereose-
lective oxygenation of a cyclohexene ring. Stereo- and
enantioselective control of a functionalized cyclohexene
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201611574.
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could be achieved by taking advantage of the structural
characteristics of the endo-tricyclo[6.2.1.0]undecene system.
Complete stereocontrol at C-6, C-7, and C-8 of TTX was
realized by using this strategy (Scheme 2). A Diels–Alder
reaction of 5-TMS-cyclopentadiene (16) and p-benzoquinone
With access to cyclohexene 24 achieved, the remaining
task was to install a nitrogen atom at C-8a, an oxygen atom at
C-5, and a carbon atom at C-4a (Scheme 3). The nitrogen
group was stereoselectively installed via [3,3]-sigmatropic
rearrangement of allylic cyanate. The rearrangement precur-
[9]
Scheme 2. Stereocontrol at C-6, C-7, and C-8. a) 5-TMS-cyclopenta-
diene (16), CH Cl , MeOH, RT; NaBH , CeCl ·7H O, 08C, 62%;
2
2
4
3
2
b) isopropenyl acetate, lipase PS IM Amano, Et N, RT, 89%, >99%
3
ee; c) TBSCl, imidazole, DMF, RT; d) K CO , MeOH, RT, quant. (2
Scheme 3. Intramolecular 1,3-dipolar cycloaddition. a) Cl CC(O)NCO,
2
3
3
steps); e) PDC, Celite, DMF, 08C; f) n-Bu SnCH OMOM, n-BuLi, THF,
CH Cl , RT; Et N, MeOH, RT, 98%; b) TFAA, i-Pr NEt, CH Cl , À788C
3
2
2
2
3
2
2
2
À988C, 73% (2 steps); g) OsO
4
, NMO, quinuclidine·HCl, acetone,
to RT; LiOt-Bu, À78 to 08C, 79%; c) OsO , NMO, acetone, RT;
4
H O, reflux, 90%; h) p-TsOH·H O, CuSO , acetone, reflux; Jones’
Pb(OAc) , RT, 75%; d) 14, EtMgBr, THF, 08C, 88%; e) H , Pd/C,
2
2
4
4
2
reagent, 08C; i) TMSCH CO Et, LDA, THF, À78 to 08C; j) o-dichlor-
quinoline, EtOH, EtOAc, RT; f) CsF, MeCN, 608C; g) TMSCl, imida-
zole, DMF, RT; h) 31, AcOH, EtOH, RT; aq. HCl, RT, 68% (4 steps).
Boc=tert-butyloxycarbonyl, Nu=nucleophile, t-Bu=tert-butyl, TFAA=
trifluoroacetic anhydride, Ts=tosyl.
2
2
obenzene, 1608C; k) DIBAL, toluene, À78 to 08C, 38% (4 steps).
Ac=acetyl, DIBAL=diisobutylaluminium hydride, DMF=N,N-dime-
thylformamide, LDA=lithium diisopropylamide, MOM=methoxy-
methyl, NMO=N-methylmorpholine N-oxide, PDC=pyridinium
dichromate, TBS=tert-butyldimethylsilyl, THF=tetrahydrofuran,
TMS=trimethylsilyl.
sor was prepared from allylic alcohol 24 through carbamoy-
lation. Upon dehydration of 25 with TFAA and Hunigꢀs
[
13]
(18), followed by a Luche reduction provided meso diol 19,
base, a facile rearrangement took place to give a sterically
hindered isocyanate, which, through treatment with t-butox-
ide, furnished carbamate 26. The resultant terminal alkene
was selectively converted into aldehyde 27 through Os-
mediated dihydroxylation and oxidative cleavage with lead
tetraacetate. The addition of alkynyl magnesium bromide to
aldehyde 27 furnished propargyl alcohol as a single diaste-
reomer. The stereochemical outcome was rationalized in
terms of the chelation model 28, as depicted in the brackets,
where the magnesium acetylide approaches from the less
which was converted into monoacetate 20 through lipase-
[10]
mediated desymmetrization
with high yield and ee. The
requisite enone 21 was formed through a 3-step sequence
involving silylation, deacetylation, and PDC oxidation. Con-
struction of the tetrasubstituted carbon at C-6 was realized
[
11]
through 1,2-addition of a hydroxymethyl equivalent from
the sterically more accessible face of the tricyclic skeleton.
[
12]
Subsequent stereo- and chemoselective dihydroxylation of
the adjacent alkene proceeded in the same stereoselective
fashion without affecting the other alkene owing to steric
shielding by the TMS group. Treatment of triol 22 with p-
toluenesulfonic acid in acetone triggered removal of the
MOM and TBS groups and simultaneous protection of the
cis-diols with acetonides. The resulting material was subjected
to Jones oxidation in one pot to furnish ketone 23. Peterson
olefination, removal of the cyclopentadiene appendage by
thermolysis, and DIBAL reduction of the ester yielded highly
oxygenated cyclohexene 24.
[
4h]
hindered side.
After partial reduction of the alkyne,
desilylative elimination of p-toluenesulfinate through treat-
ment with CsF yielded the cis-a,b-unsaturated oxime without
[
14]
isomerization of the double bond. Since the presence of
a free hydroxy group at C-9 proved problematic owing to
undesired cyclization to the nitrile oxide, both hydroxy groups
were transiently protected with TMS groups. Subsequent
[
15]
treatment with chloramine 31
and acetic acid induced
selective deprotection of the oxime, nitrile oxide formation,
2
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and intramolecular 1,3-dipolar cycloaddition. The other TMS
group was removed during workup.
With the highly functionalized cyclohexane in hand, the
next task was to excise the unnecessary carbon atom
formation of the orthoester and cyclic guanidine
(Scheme 4). d-Lactone 38 was generated through hydro-
[19]
genolysis and subsequent Yamaguchi lactonization.
[
20]
Removal of the Boc group with TMSI, and guanidinyla-
[21]
(
Scheme 4). Ozonolysis of 32 caused regioselective cleavage
tion
of the resultant amine furnished the penultimate
intermediate 39. Deprotection under acidic conditions led to
a mixture of mono-Cbz-protected TTX 41 and its anhydro
form 40, which was easily separable by preparative TLC.
Finally, 4,9-anhydroTTX (10) and TTX (1), respectively, were
obtained through hydrogenolysis of the Cbz groups without
using laborious HPLC separation. The spectroscopic data for
the synthetic samples were identical to those reported for
TTX.
Having developed an efficient route to (À)-TTX, our next
challenge was the divergent synthesis of TTX congeners from
a late-stage intermediate (Scheme 5). To this end, selective
Scheme 4. Total synthesis of TTX. a) O , CH Cl , À788C; NaClO ,
3
2
2
2
NaH PO , t-BuOH, H O, RT; n-Bu P, RT; b) BnBr, K CO , DMF, RT,
2
4
2
3
2
3
6
0% (2 steps); c) NiCl , NaBH , MeOH, CH Cl , À408C; AllocCl, aq.
2
4
2
2
NaHCO , 08C; d) Pb(OAc) , MeOH, reflux; e) Pd(PPh ) , PhSiH ,
3
4
3
4
3
Scheme 5. Divergent synthesis of the TTX congeners. a) TFA, H O, RT,
2
CH Cl , RT; NaNO , aq. HCl, dioxane, RT, 40% (3 steps); f) PPTS,
2
2
2
7
4%; b) NaIO , MeOH, H O, RT; c) NaBH , MeOH, RT, 66% (2
4
2
4
MeC(OMe) , MeOH, RT, 78%; g) H , Pd/C, MeOH, RT; h) 2,4,6-
3
2
steps); d) TFA, H O, 608C, 18% (44), 43% (45); e) H , Pd/C, MeOH,
2
2
trichlorobenzoylchloride, Et N, toluene, RT; DMAP, RT, 78% (2 steps);
3
RT, 88%; f) H , Pd/C, MeOH, RT, 85%.
2
i) TMSI, MeCN, 08C; j) CbzNC(SMe)NHCbz, HgCl , Et N, CH Cl , RT,
2
3
2
2
9
7% (2 steps); k) TFA, H O, 608C, 27% (40), 46% (41); l) H , Pd/C,
2
2
MeOH, RT, 98%; m) H , Pd/C, MeOH, RT, 96%. Alloc=allyloxycar-
2
bonyl, Bn=benzyl, Cbz=benzyloxycarbonyl, DMAP=N,N-dimethyl-4-
aminopyridine, n-Bu=normal-butyl, Ph=phenyl, PPTS=pyridinium
p-toluenesulfonate, TFA=trifleoroacetic acid.
removal of the terminal acetonide of guanidine 38 was
performed under mildly acidic conditions. Oxidative cleavage
of 1,2-diol 42, followed by reduction of the ketone, provided
secondary alcohol 43 as a single diastereomer. Alcohol 43 was
successfully converted into 4,9-anhydro-11-norTTX-6(R)-ol
(46) and 11-norTTX-6(R)-ol (7) in the same manner. The
neutral deprotection strategy at the very end was also
applicable to 11-norTTX-6(R)-ol (7).
[
16]
of the cyclohexene
and interception of the resultant
carbonyl oxide by the hydroxy group at C-9 to yield
[
17]
a peroxyacetal. Subsequent Pinnick oxidation and a reduc-
tive work-up with tri-n-butylphosphine gave carboxylic acid
3
3. After protecting the carboxylic acid as the benzyl ester,
In conclusion, an asymmetric total synthesis of (À)-TTX
and 4,9-anhydroTTX was achieved from p-benzoquinone in
31 steps. Our synthesis features efficient stereoselective oxy-
genation at C-6, C-7, and C-8 by taking advantage of the
tricyclic skeleton, diastereoselective [3,3]-sigmatropic rear-
rangement of an allylic cyanate, and intramolecular 1,3-
dipolar cycloaddition of a nitrile oxide. In addition, a unified
synthesis of 11-norTTX-6(R)-ol and its anhydro form was
accomplished from the common late-stage intermediate. Non
acidic/basic deprotection at the final step could potentially
reduction of the isoxazoline was achieved by using nickel
boride to provide an aminoalcohol, which was protected with
an Alloc group. Treatment of 34 with lead tetraacetate in
methanol provoked oxidative cleavage of the CÀC bond,
methanolysis of the resultant formate, and NÀO acetal
formation. Removal of the Alloc group, hydrolysis of the
hemiaminal assisted by sodium nitrite, and acetal formation
gave acetal 37. The synthesis of the core skeleton of TTX
[
18]
was now accomplished. The remaining issues included
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deliver other TTX congeners in pure form without laborious
HPLC purification. Accordingly, our strategy is applicable to
the synthesis of a variety of natural and unnatural TTX
congeners to study structure–activity relationships. Details of
the physiological studies will be reported in due course.
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[
Acknowledgements
This work was financially supported by JSPS KAKENHI
Grant Numbers 25221301 and 16H01141, Platform for Drug
Discovery, Informatics, and Structural Life Science from the
Ministry of Education, Culture, Sports, Science and Technol-
ogy, Japan. T.M. was supported by research fellowships from
JSPS. K.M. was supported by Yoshida Scholarship Founda-
tion.
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Conflict of interest
The authors declare no conflict of interest.
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1
Keywords: alkaloids · natural products · stereocontrol ·
tetrodotoxin · total synthesis
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Manuscript received: November 27, 2016
Nakamura, Y. Kajihara, M. Funabashi, J. Yoshimura, J. Org.
Final Article published: && &&, &&&&
4
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Angewandte
Communications
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Communications
Natural Product Synthesis
T. Maehara, K. Motoyama, T. Toma,
S. Yokoshima,
T. Fukuyama*
&&& — &&&
Total Synthesis of (À)-Tetrodotoxin and
Pick your poison: Total synthesis of the
voltage-gated sodium channel inhibitor
tures efficient stereoselective oxygenation
1
1-norTTX-6(R)-ol
at C-6, C-7, and C-8 by taking advantage
of the tricyclic skeleton, diastereoselec-
tive [3,3]-sigmatropic rearrangement of
an allylic cyanate, and intramolecular 1,3-
dipolar cycloaddition of a nitrile oxide.
(
À)-tetrodotoxin (TTX) was achieved
from p-benzoquinone in 31 steps. The
synthesis, which is also applicable to TTX
congeners like 11-norTTX-6(R)-ol, fea-
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ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!