Total synthesis of (-)-decarbamoyloxysaxitoxin

Article abstract of DOI:10.1002/anie.200703326

(Chemical Equation Presented) A facile and general synthetic strategy for saxitoxin derivatives has been developed, as exemplified by the efficient synthesis of (-)-decarbamoyloxysaxitoxin ((-)-doSTX), the putative enantiomer of the natural product, in 17

Full text of DOI:10.1002/anie.200703326

Angewandte
Chemie
DOI: 10.1002/anie.200703326
Alkaloid Synthesis
Total Synthesis of (À)-Decarbamoyloxysaxitoxin**
Osamu Iwamoto, Hiroyuki Koshino, Daisuke Hashizume, and Kazuo Nagasawa*
Dedicated to Professor Yoshito Kishi and Professor Tadashi Nakata
Saxitoxin (1, STX) is a neurotoxin that blocks voltage-gated
sodium channels, which are critical for depolarization and
conduction in most excitable cells.[1] It also binds to other
receptor proteins, such as calcium and potassium channels,[2,3]
and to saxiphilin, which is a member of the transferrin
family.[4] Many natural STX analogues have been isolated
(Scheme 1), with each having its own characteristic biological
activity.[5] For example, the most structurally complex ana-
logue, zetekitoxin AB (2), which was isolated from the
Panamanian golden frog Atelopus zeteki, shows very high
affinity for the sodium channel in rat brain, unlike STX (1).[6]
As a consequence of their biological activities, together with
their unique trialkyl tetrahydropurine (bis-bicyclic guanidine)
structure, many synthetic studies have been made on STX and
its analogues. Three elegant syntheses of STX (1) were
reported by Kishi and co-workers,[7] Jacobi et al.,[8] as well as
Fleming and Du Bois.[9]
We have recently focused on the synthesis of decarba-
moyloxysaxitoxin (3, doSTX)[10] as an entry point for the
development of isoform-selective sodium-channel blockers.
Decarbamoyloxysaxitoxin (3), which has the common STX
skeleton, was isolated from the Australian shellfish Gymno-
dinium catenatum by Oshima et al. in 1990.[11] A total
synthesis of racemic 3 was reported by Strichartz et al. in
1995.[12] The optical rotation of natural 3 is not yet known.
Herein, we describe a total synthesis of (À)-doSTX (3), the
putative antipode of the natural product.
The synthetic plan is illustrated in Scheme 2. In this
strategy, the configurations at C5 and C6 in 3 are controlled
by the stereogenic center of 9,[10,13] which corresponds to the
ketone at C12 in 3. Direct construction of the characteristic
bis-bicyclic guanidine structure 4 from monocyclic guanidine
5 is the key feature of this synthesis. For this transformation,
we planned to apply the hypervalent iodine(V) reagent o-
iodoxybenzoic acid (IBX), which is well known to be a mild
oxidant for alcohols. Recently, Nicolaou et al. reported that
IBX can oxidize alcohols, ketones, and aldehydes to the
corresponding a,b-unsaturated systems through formation of
an enol from a carbonyl group followed by an oxidation
reaction based on a single electron transfer (SET).[14] In the
case of the alcohol 5, enol II is obtained via ketone I under
IBX oxidation conditions.[14b] At this stage, we envisaged
Scheme 1. Structure of STX (1) and its analogues.
[*] O. Iwamoto, Prof. Dr. K. Nagasawa
Department of Biotechnologyand Life Science
Tokyo University of Agriculture and Technology (TUAT)
2-24-16 Nakamachi, Koganei, Tokyo 184-8588 (Japan)
Fax: (+81)42-388-7295
E-mail: knaga@cc.tuat.ac.jp
Dr. H. Koshino, Dr. D. Hashizume
RIKEN (The Institute of Physical and Chemical Research)
2-1 Hirosawa, Wako, Saitama 351–0198 (Japan)
[**] We thank Prof. Oshima (Tohoku University) for kindly providing us
with copies of the spectra of natural doSTX (3). We also thank Dr.
Kei-ichi Noguchi (TUAT) for the X-raystructure analysis of 23. This
work was supported bya Grant-in-Aid for Scientific Research on
PriorityAreas 17035025 from The Ministryof Education, Culture,
Sports, Science, and Technology(MEXT).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 2. Synthetic plan for (À)-doSTX (3). PG=protecting group,
TIPS=triisopropylsilyl.
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Communications
generating the iminium cation III from this enol II instead of
forming the a,b-unsaturated ketone through an SET-based
oxidation reaction, since this enol II has an enamine moiety,
and might generate the bis-bicyclic guanidine 4 directly from
the alcohol 5 (Scheme 2).
The synthesis of 16 commenced with a 1,3-dipolar cyclo-
addition reaction using the optically active nitrone
9
(Scheme 3).[15] The 1,3-dipolar cycloaddition reaction
between methyl crotonate (8) and the chiral nitrone 9 gave
Scheme 4. IBX oxidation of 16 and the proposed reaction mechanism.
IBA=iodosobenzoic acid.
19 was obtained as the sole product in 45% yield.[19] This
unexpected formation of 19 was interpreted as follows
(Scheme 4): After oxidation of the alcohol at C12, the
resulting ketone reacted with another molecule of IBX to
form the enol intermediate IV. Electron transfer in this
intermediate would then take place to generate the iminium
cation, and the hydroxy group on IBX would attack intra-
molecularly at C4 (IV to V), instead of at the amino group of
the guanidine, to generate 19.[20] Although the desired
compound 18 was not obtained, we were pleased to find
that the hydroxy group could be installed selectively at C4,
and we decided to apply this IBX oxidation reaction to the
synthesis of 3.
Scheme 3. Synthesis of bis-monocyclic guanidine 16: a) toluene, 808C
(93%); b) LiOH, THF/H2O, 08C; c) 1. (COCl)2, DMF (cat.), toluene;
2. NaN3, acetone/H2O, 08C; 3. 1,4-dioxane, 1008C, then 10% HCl,
=
then (Boc)2, K2CO3, (86% from 7); d) H2, Pd(OH)2, MeOH; e) NCbz
C(SMe)NHCbz (12), HgCl2, Et3N, DMF; f) DEAD, PPh3, toluene (97%,
=
three steps); g) TFA, CH2Cl2; h) NBoc C(SMe)NHBoc (14), HgCl2,
Et3N, DMF (77% two steps); i) TBAF, THF (92%); j) 5% TFA/CH2Cl2,
08C (15: 13%, 16: 71%, 17: 16%). Boc=tert-butyloxycarbonyl,
DEAD=diethyl azodicarboxylate, Cbz=benzyloxycarbonyl, TBAF=
tetrabutylammonium fluoride, TFA=trifluoroacetic acid.
The IBX oxidation reaction was applied to alcohol 20,
which was obtained by removal of the TIPS ether of 13 with
TBAF. When the reaction was conducted with IBX (4 equiv)
in DMSO at 708C, the aminal 21 was obtained in 28% yield,
together with a further oxidized product, 22 (29% yield;
Scheme 5). Hence, a two-step oxidation reaction, namely,
Swern oxidation of 20 followed by IBX oxidation (1.1 equiv)
was examined, which gave the desired aminal 21 as a sole
product in 64% yield.
the isoxazolidine 7 in 93% yield. Treatment of 7 with lithium
hydroxide in aqueous THF at 08C proceeded through
isomerization of the pseudoaxially oriented ester moiety at
C5 to the equatorial position, followed by hydrolysis of the
ester to give the carboxylic acid 10. The carboxylic acid 10 was
then converted into the N-Boc-protected amine 11 in 86%
yield by a Curtius rearrangement reaction. The reductive
À
cleavage of the N O bond of 11 was achieved with hydrogen
Thus, (À)-doSTX (3) was synthesized as follows. Treat-
ment of 21 with sodium borohydride at 08C gave diastereo-
selectively the alcohol, whose Boc group was cleaved with
TFA, and then a Cbz-protected guanidine group was installed
to give 23. The structure of 23 was confirmed unequivocally
by X-ray crystallographic analysis. The synthesis of 3 from 23
was completed with the following three steps: Cleavage of the
four Cbz groups with hydrogen in the presence of Pd(OH)2,
followed by treatment with TFA at 508C, gave the decar-
bamoyloxysaxitoxinol 25 in 60% overall yield. Finally,
oxidation of the alcohol with dimethylsulfoxide and diisopro-
pylcarbodiimide afforded (À)-doSTX (3) in 63% yield.[5b,9]
All the spectroscopic data of the synthetic material were
consistent with the reported data for the natural product.[22]
The optical rotation value of 3 was À23.3 (c = 0.2, MeOH).
In conclusion, an enantioselective total synthesis of (À)-
doSTX (3), the putative antipode of the natural product, has
in the presence of Pd(OH)2, and a guanidine group was
introduced into the resulting pyrrolidine by using bis(Cbz)-2-
methyl-2-thiopseudourea (12) and mercury(II) chloride.[16]
Under the Mitsunobu reaction conditions with DEAD and
triphenylphosphine, this product afforded the cyclic guani-
dine 13 in 97% yield (from 11).[17] Removal of the Boc group
of 13 with TFA, followed by reaction with bis(Boc)-2-methyl-
2-thiopseudourea (14) in the presence of mercury(II) chlo-
ride, and cleavage of the TIPS ether with TBAF, gave alcohol
15 in 71% yield from 13. One of the Boc groups of 15 could be
mostly removed with 5% TFA in dichloromethane to give 16
in 71% yield, and 17 was obtained in 16% yield.[18]
With 16 in hand, we then examined the direct trans-
formation of 16 into 18 with IBX (Scheme 4). Contrary to
expectation, the reaction of 16 with IBX (4 equiv) in DMSO
at 708C for 4 h failed to give 18, and the fused-type guanidine
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Angewandte
Chemie
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Scheme 5. Completion of the synthesis of (À)-doSTX (3): a) TBAF,
THF, 08C (94%); b) IBX (4 equiv), DMSO, 708C (21: 28%, 22: 29%);
c) 1. (COCl)2, DMSO, Et3N, CH2Cl2, À788C; 2. IBX (1.1 equiv), DMSO,
508C (21: 64%, 22: 0% two steps); d) NaBH4, MeOH, 08C (72%);
=
e) TFA, CH2Cl2; f) NCbz C(SMe)NHCbz (12), HgCl2, Et3N, DMF (82%
two steps); g) H2, Pd(OH)2, MeOH/EtOAc (2:1); h) TFA, 508C (60%
two steps); i) DMSO, diisopropylcarbodiimide, pyridinium trifluoro-
acetate (63%).
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10% overall yield. The synthesis features a diastereoselective
1,3-dipolar cycloaddition reaction of 8 and 9, and the direct
oxidation of 20 at C4 with IBX. The optical rotation of 3 was
determined. This efficient methodology provides a facile and
general synthetic strategy for STX derivatives. Further work
to synthesize natural STXs and various derivatives is in
progress with the aim of developing isoform-selective sodium-
channel inhibitors.
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[18] Oxidation of the alcohol 15 did not take place with the various
oxidants tested under various conditions. Thus, we cleaved the
Boc group on guanidine.
Received: July 24, 2007
Published online: October 10, 2007
Keywords: guanidine · natural products · oxidation ·
.
sodium channels · total synthesis
[19] The structure of 19 was determined on the basis of X-ray
analysis. Details are contained in the Supporting Information.
[20] Conversion of the fused-type bicyclic guanidine 26 into 3 was
examined under various acidic dehydration conditions (aq
H2SO4, 908C; 7.5n aq HCl, 1008C; 1808C under vacuum
conditions[21]), but no reaction occurred, and 26 was recovered
quantitatively in all cases.
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[21] J. A. McCauley, K. Nagasawa, P. A. Lander, S. A. Mischke,
J = 2.3, 10.7 Hz, 1H), 3.65 (dq, J = 1.8, 6.9 Hz, 1H), 3.55 (m, 1H),
2.36 (m, 1H), 1.24 ppm (d, J = 6.9 Hz, 3H); 13C NMR (100 MHz,
4% CD3COOD in D2O, determined by HMBC): d = 159.0,
157.5, 100,3, 84.2, 61.2, 51.9, 44.6, 34.4, 19.7 ppm; HRMS (ESI,
M+H+) calcd for C9H17N6O2 241.1413; found 241.1452.
M. A. Semones, Y. Kishi, J. Am. Chem. Soc. 1998, 120, 7647 –
7648.
[22] Spectral data for (À)-doSTX (3): [a]2D0 = À23.3 (c = 0.2, MeOH);
1H NMR (400 MHz, D2O): d = 4.46 (d, J = 1.8 Hz, 1H), 3.76 (dt,
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